JP7500119B2 - Method for producing silane-containing condensed ring dipeptide compound - Google Patents

Description

The present invention relates to a method for producing a novel silane-containing fused ring dipeptide compound.

Traditionally, amide compounds, such as peptides, have been used in a wide range of fields, including pharmaceuticals, cosmetics, and functional foods, and the development of methods for synthesizing them has been vigorously pursued as an important research topic in synthetic chemistry (Non-Patent Documents 1-3). However, for amidation, which is the most important step in peptide synthesis, there are almost no truly effective catalysts or reactants other than carboxylic acid activators. For this reason, a reaction mode that produces a large amount of by-products must be used, and peptide synthesis, which involves repeated multi-step reactions, is extremely inefficient from the standpoint of atom economy (atomic yield), and the by-products are produced in huge quantities, and there are few effective purification methods. As a result, the cost of disposing of and purifying the by-products accounts for most of the necessary expenses for peptide synthesis, and is one of the biggest obstacles to the development of this field.

In peptide synthesis using amino acids or their derivatives as raw materials, highly stereoselective amidation is required. An example of highly stereoselective amidation is enzymatic reactions that occur in vivo. For example, peptides are synthesized in vivo with extremely high stereoselectivity by making clever use of enzymes and hydrogen bonds. However, enzymatic reactions are not suitable for mass production, and applying them to synthetic chemistry requires huge financial and time costs.

In synthetic chemistry, amidation using a catalyst has also been considered; however, in conventional methods, amide bonds are formed mainly by activating carboxylic acids, which leads to rapid racemization and makes it difficult to synthesize amide compounds efficiently and with high stereoselectivity.

In addition, in conventional methods, it is extremely difficult to ligate a peptide formed by linking multiple amino acids or their derivatives with an amide bond (chemical ligation) of further amino acids or their derivatives, or to ligate two or more peptides with an amide bond. As amidation methods for ligating such peptides, a method in which an amino acid having a sulfur atom is used and ligation is performed utilizing the high reactivity of the sulfur atom (Non-Patent Document 4) and a method in which hydroxylamine of an amino acid is synthesized and ligation is performed utilizing the high reactivity of the hydroxylamine (Non-Patent Document 5) are known. However, the former method requires the synthesis of an amino acid having a sulfur atom with difficulty, and the latter method requires the synthesis of hydroxylamine over several separate steps, so both methods are time-consuming, costly, and inefficient.

The present inventors have developed techniques for synthesizing amide compounds with high chemical selectivity, such as a method of amidating a carboxylic acid/ester compound having a hydroxy group at the β-position in the presence of a specific metal catalyst (Patent Document 1), a method of using a hydroxyamino/imino compound as an amino acid precursor, amidating this in the presence of a specific metal catalyst, and then reducing it in the presence of a specific metal catalyst (Patent Document 2), and a method of amidating a carboxylic acid/ester compound in the presence of a specific metal catalyst (Patent Document 3). Furthermore, the present inventors have also developed a technique for synthesizing peptides consisting of various amino acid residues with high efficiency and high selectivity by performing an amide reaction between the carboxyl group of an N-terminal protected amino acid/peptide and the amino group of a C-terminal protected amino acid/peptide in the presence of a specific silylating agent (and a Lewis acid catalyst optionally used in combination) followed by deprotection (Patent Document 4); a technique for synthesizing peptides consisting of various amino acid residues with high efficiency and high selectivity by performing an amide reaction between the carboxyl group of an N-terminal protected or unprotected amino acid/peptide and the amino group of a C-terminal protected or unprotected amino acid/peptide in the presence of a specific silylating agent followed by deprotection (Patent Documents 5 and 6); and a technique for performing an amidation reaction using a Bronsted acid as a catalyst (Patent Document 7).

In recent years, attempts have been made to synthesize peptides using unprotected amino acids (Non-Patent Documents 6-8), but none of these have been satisfactory in terms of the types of amino acids that can be used or the reaction efficiency.

The present inventors have found that a silane-containing condensed ring dipeptide compound with a novel structure can be obtained by reacting an unprotected amino acid and then an amino acid ester in the presence of a specific silyl dihalide compound and a specific nitrogen-containing heterocyclic group-substituted silane compound. They have also found that by reacting this condensed ring dipeptide compound with an N-protected amino acid or peptide and then with a C-protected amino acid or peptide, the N-terminal elongation and C-terminal elongation of the cyclized dipeptide proceed consecutively, making it possible to efficiently synthesize polypeptides such as tetrapeptides. The present inventors have already published these findings (Non-Patent Document 9) and filed a patent application (Patent Document 8).

International Publication No. 2017/204144 International Publication No. 2018/199146 International Publication No. 2018/199147 International Publication No. 2019/208731 International Publication No. 2021/085635 International Publication No. 2021/085636 International Publication No. 2021/149814 International Publication No. 2022/190486

Chem. Rev., 2011, 111, 6557-6602 Org. Process Res. Dev., 2016, 20(2), 140-177 Chem. Rev., 2016, 116, 12029-12122 Science, 1992, 256, 221-225 Angew. Chem. Int. Ed., 2006, 45, 1248-1252 Chem. Eur. J. 2019, 25, 15091 Org. Lett. 2020, 22,8039 Chem. Eur. J. 2018, 24, 7033 J. Am. Chem. Soc. 2022, 144, 1758-1765

In most conventional peptide synthesis techniques, the C-terminus of an electrophilic amino acid with a protected N-terminus and the N-terminus of a nucleophilic amino acid with a protected (esterified) C-terminus are amide-bonded using a condensing agent. The use of a protecting group is considered essential for selectively bonding amino acids having both a nucleophilic functional group and an electrophilic functional group at a desired position, and is a concept that is inseparable from the long history of peptide synthesis. However, peptide synthesis techniques using a protecting group require the introduction of a protecting group before the reaction and the deprotection process after the reaction, which is a major disadvantage in terms of total yield and purification costs, especially when considering long-chain peptide elongation reactions. In addition, it is not easy to selectively add a protecting group to a raw amino acid that exists in large quantities in nature, and the raw material cost of such protected amino acids is high. Therefore, there is a strong demand for the development of a peptide synthesis technique using unprotected amino acids.

The method for producing the silane-containing condensed ring dipeptide compound disclosed by the present inventors in the above Patent Document 8 is a method consisting of a condensation reaction between an unprotected amino acid, which is an electrophilic species, and an amino acid ester, which is a nucleophilic species, ester deprotection, and a cyclization reaction. This method has the advantage that it is not necessary to protect the N-terminus of the electrophilic amino acid, and the nucleophilic amino acid ester can also be automatically deprotected in the system, and further peptide elongation reactions can be performed on both ends of the generated peptide. However, it is necessary to use an amino acid ester (C-terminal protected amino acid) as the nucleophilic species, and there is still room for improvement from the viewpoint of raw material costs.

On the other hand, when unprotected amino acids are used not only for the electrophilic species but also for the nucleophilic species in the above-mentioned production method, in addition to the silane-containing condensed ring dipeptide compound in which the electrophilic amino acid and the nucleophilic amino acid are incorporated at the desired positions, there is a problem that homo-coupling products between amino acids of the same species and dipeptide compounds in which the electrophilic amino acid and the nucleophilic amino acid are swapped at positions opposite to those desired are indistinguishably produced as by-products.

As a result of intensive research, the present inventors have found that by reacting a specific first silane compound (silane compound of formula (S1)) having two nitrogen-containing heterocyclic groups with an electrophilic amino acid (first amino acid), and separately reacting a specific second silane compound (silane compound of formula (S2)) having a nitrogen-containing substituent or nitrogen-containing linking group with a nucleophilic amino acid (second amino acid), and then mixing and reacting these reactants, it is possible to specifically synthesize a silane-containing condensed ring dipeptide compound of a desired structure, even when unprotected amino acids are used as both the electrophilic species and the nucleophilic species. It has also been found that it is possible to synthesize a novel silane-containing condensed ring tripeptide compound using such a silane-containing condensed ring dipeptide compound. Furthermore, it has been found that a new method for synthesizing polypeptide compounds such as tetrapeptides, hexapeptides, and heptapeptides is also provided using these silane-containing condensed ring dipeptide compounds and silane-containing condensed ring tripeptide compounds, and thus the present invention has been completed.

That is, the gist of the present invention relates to, for example, the following.
[Item 1] A method for producing a silane-containing fused ring dipeptide compound represented by the following formula (A), comprising the following steps (i) to (iii):
(i) a step of reacting a first amino acid represented by the following formula (R1) with a first silane compound represented by the following formula (S1):
(ii) A step of reacting a second amino acid represented by the following formula (R2) with a second silane compound represented by the following formula (S2):
(iii) A step of mixing the reactant from the step (i) and the reactant from the step (ii) and further reacting them to obtain the silane-containing fused ring dipeptide compound of the formula (A).
However, in formula (A),
R ¹¹ , R ¹² , R ¹³ , R ²¹ , and R ²² each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents;
R ^a1 and R ^a2 each independently represent a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group which may have one or more substituents.
However, in formula (R1),
R ¹¹ , R ¹² and R ¹³ each independently represent a group having the same definition as the group having the same symbol in formula (A).
However, in formula (S1),
R ^a1 and R ^a2 each represent a group having the same definition as the group represented by the same symbol in formula (A).
Z ^a1 and Z ^a2 each independently represent a 5-10 membered heterocyclic group containing one or more nitrogen atoms as ring constituent atoms which may have one or more substituents.
However, in formula (R2),
R ²¹ and R ²² each independently represent a group having the same definition as the group of the same symbol in formula (A).
However, in formula (S2),
R ^b1 , R ^b2 , and R ^b3 each independently represent a hydrogen atom, a halogen atom, or a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group which may have one or more substituents;
^nb represents an integer of 1 or 2;
When ^nb is 1, Z ^b represents an amino group, a carbonylamino group, an acetamide group, or a 5- to 10-membered monovalent heterocyclic group containing one or more nitrogen atoms as ring-constituting atoms, which may have one or more substituents;
When ^nb is 2, Z ^b represents a divalent linking group containing nitrogen. When ^nb is 2, R ^b1 , R ^b2 , and R ^b3 , which are present in pairs, may be the same or different.
[Item 2] The method according to Item 1, wherein in the step (i), a third silane compound is allowed to coexist in the reaction system.
[Item 3] The method according to Item 1, wherein in the step (iii), a fourth silane compound is allowed to coexist in the reaction system.
[Item 4] A method for producing a silane-containing fused ring tripeptide compound represented by the following formula (B), comprising the following steps (iv) and (v):
(iv) A step of producing a silane-containing fused ring dipeptide compound represented by the formula (A) by the method according to any one of items 1 to 3.
(v) A step of reacting the silane-containing fused ring dipeptide compound represented by the formula (A) with an amino acid ester represented by the following formula (Rx):
However, in formula (B),
R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , and R ^a2 each independently represent a group having the same definition as the group having the same symbol in formula (A);
R ^x1 and R ^x2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents;
PG ^x represents a monovalent protecting group.
However, in formula (R1),
R ^x1 , R ^x2 and PG ^x each independently represent a group having the same definition as the group having the same symbol in formula (B).
[Item 5] The method according to Item 4, wherein in the step (v), a fifth silane compound is allowed to coexist in the reaction system.
[Item 6] A silane-containing condensed ring tripeptide compound represented by the following formula (B):
However, in formula (B),
R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , and R ^a2 each independently represent a group having the same definition as the group having the same symbol in formula (A);
R ^x1 and R ^x2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents;
PG ^x represents a monovalent protecting group for a carboxyl group.
[Item 7] A method for producing a tetrapeptide or higher polypeptide compound using the silane-containing fused ring tripeptide compound according to Item 6, the method comprising the following step (vi):
(vi) A step of reacting the silane-containing fused ring tripeptide compound represented by the formula (B) with a protected amino acid or a protected peptide compound represented by the following formula (Ra) to obtain a polypeptide compound represented by the following formula (P3):
However, in formula (Ra),
PG ^a represents an amino-protecting group;
R ^a1 and R ^a2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or an amino group, which may have one or more substituents, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group;
R ^a3 represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents, and in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to a nitrogen atom via a linking group,
or R ^a1 and R ^a3 may be bonded to each other to form a heterocycle optionally having one or more substituents, together with the carbon atom to which R ^a1 is bonded and the nitrogen atom to which R ^a3 is bonded;
A ^a1 and A ^a2 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents;
p ^a1 and p ^a2 each independently represent 0 or 1;
m ^a is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when m is 2 or more, the multiple structural units represented by the structure in [ ] may be the same or different.
(P3)
However, in formula (P3),
PG ^a , R ^a1 , R ^a2 , R ^a3 , A ^a1 , A ^a2 , p ^a1 , p ^a2 , and m ^a each represent a group having the same definition as the group having the same symbol in formula (Ra);
^R11 , ^R12 , ^R13 , ^R21 , ^R22 , ^Rx1 , ^Rx2 , and ^PGx represent groups having the same definitions as the groups having the same symbols in formula (B).
[Item 8] The method according to Item 7, wherein in the step (iv), a base is allowed to coexist in the reaction system.
[Item 9] A method for producing a hexapeptide compound using two molecules of the silane-containing fused ring tripeptide compound according to item 6, comprising the following step (vii):
(vii) A step of mixing a silane-containing fused ring tripeptide compound represented by the following formula (B1) with a base:
(viii) A step of reacting the mixture of step (vii) with a silane-containing fused ring tripeptide compound represented by the following formula (B2) to obtain a polypeptide compound represented by the following formula (P4):
In formula (B1), R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^a11 , R ^a12 , R ^x11 , R ^x12 , and PG ^x1 each represent a group having the same definition as R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , R ^a2 , R ^x1 , R ^x2 , and PG ^x in formula (B).
In the formula (B2), R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^a21 , R ^a22 , R ^x21 , and R ^x22 each represent a group having the same definition as R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , R ^a2 , R ^x1 , and R ^x2 in the formula (B),
R ^x23 represents -O-PG ^x , -NH-PG ^x or -S-PG ^x , where PG ^x represents a monovalent protecting group having the same definition as PG ^x in formula (B).
(P4)
However, in formula (P4),
R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^x11 , R ^x12 and PG ^x1 represent groups having the same definitions as the groups of the same symbols in formula (B1);
R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^x21 and R ^x22 each represent a group having the same definition as the group having the same symbol in formula (B2).
[Item 10] A method for producing a heptapeptide or greater polypeptide compound, comprising the following steps (viii) and (ix):
(viii) A step of producing a hexapeptide compound represented by the formula (P4) by the method according to item 9.
(ix) A step of reacting the hexapeptide compound with a protected amino acid or a protected peptide compound represented by the following formula (Ra) to produce a polypeptide compound represented by the following formula (P5):
However, in formula (Ra),
PG ^a represents an amino-protecting group;
R ^a1 and R ^a2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or an amino group, which may have one or more substituents, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group;
R ^a3 represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents, and in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to a nitrogen atom via a linking group,
or R ^a1 and R ^a3 may be bonded to each other to form a heterocycle optionally having one or more substituents, together with the carbon atom to which R ^a1 is bonded and the nitrogen atom to which R ^a3 is bonded;
A ^a1 and A ^a2 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents;
p ^a1 and p ^a2 each independently represent 0 or 1;
m ^a is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when m is 2 or more, the multiple structural units represented by the structure in [ ] may be the same or different.
(P5)
However, in formula (P5),
PG ^a , R ^a1 , R ^a2 , R ^a3 , A ^a1 , A ^a2 , p ^a1 , p ^a2 , and m ^a each represent a group having the same definition as the group having the same symbol in formula (Ra);
R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^x11 , R ^x12 , PG ^x1 , R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^x21 , and R ^x22 represent groups having the same definitions as the groups of the same symbols in formula (P4).
Furthermore, the circled symbol A at the right end of the upper structure and at the left end of the lower structure in formula (P5) means that the upper structure and the lower structure are continuous at this position.
[Item 11] The method according to Item 10, wherein steps (viii) and (ix) are carried out in one pot.

According to the present invention, it is possible to specifically synthesize a silane-containing fused ring dipeptide compound of the desired structure using unprotected amino acids as both the electrophilic and nucleophilic species.

The present invention will be described in detail below with reference to specific embodiments. However, the present invention is not limited to the following embodiments, and can be implemented in any form without departing from the spirit of the present invention.

I. Overview
As mentioned above, the present inventors have developed a silane-containing fused ring dipeptide compound having a novel structure, which has already been published (Non-Patent Document 9) and filed a patent application (Patent Document 8). This fused ring dipeptide compound is an extremely useful compound, since both the N-terminus and C-terminus of the dipeptide are protected by silicon, which is easily deprotected, and can be easily deprotected and used as both a nucleophilic species and an electrophilic species. In addition, by reacting such a fused ring dipeptide compound with an N-protected amino acid and then with a C-protected amino acid, the N-terminus elongation and the C-terminus elongation of the cyclized dipeptide proceed successively, making it possible to efficiently synthesize polypeptides such as tetrapeptides and pentapeptides in one pot. Furthermore, multiple fused ring dipeptide compounds can be used in such a synthesis reaction, making it possible to synthesize even larger polypeptides such as hexapeptides with high efficiency.

However, the method for producing the silane-containing fused ring dipeptide compound disclosed by the present inventors in the above-mentioned Patent Document 8 can use an unprotected amino acid as the electrophilic species, but requires the use of an amino acid ester as the nucleophilic species. If an unprotected amino acid were used as the nucleophilic species as well, there would be a problem that in addition to the silane-containing fused ring dipeptide compound in which the electrophilic species amino acid and the nucleophilic species amino acid are incorporated at the desired positions, homo-coupling products of the same species of amino acids and dipeptides in which the electrophilic species amino acid and the nucleophilic species amino acid are swapped at the opposite positions to the desired positions would be produced indistinguishably as by-products.

On the other hand, according to the manufacturing method of the present invention, by reacting an electrophilic amino acid (amino acid of formula (R1)) with a specific first silane compound having two nitrogen-containing heterocyclic groups (silane compound of formula (S1)), and then adding a nucleophilic amino acid (amino acid of formula (R2)) and a specific second silane compound having one nitrogen-containing heterocyclic group (silane compound of formula (S2)) for further reaction, it becomes possible to specifically synthesize a silane-containing fused ring dipeptide compound of the desired structure even when unprotected amino acids are used as both the electrophilic species and the nucleophilic species. Without being bound by theory, it is presumed that in the present invention, the formation of a five-membered ring compound between an electrophilic amino acid (amino acid of formula (R1)) and a first silane compound of formula (S1), and the formation of a silyl ester between a nucleophilic amino acid (amino acid of formula (R2)) and a second silane compound of formula (S2) allow the reaction to proceed while distinguishing between the electrophilic amino acid (amino acid of formula (R1)) and the nucleophilic amino acid (amino acid of formula (R2)), thereby specifically synthesizing a silane-containing fused ring dipeptide compound of a desired structure.

In the following description, first, the main terms used in this disclosure are defined ([II. Definition of Terms]), and then, although it overlaps with the disclosure of Patent Document 8, the silane-containing fused ring dipeptide compound to be produced by the present invention (hereinafter, may be abbreviated as "fused ring dipeptide compound of the present invention" as appropriate) is described ([III. Fused ring dipeptide compound of the present invention]). Next, one of the gist of the present invention, a method for producing the fused ring dipeptide compound using a specific silane compound (a first silane compound of formula (S1) and a second silane compound of formula (S2)) (hereinafter, may be abbreviated as "fused ring dipeptide compound of the present invention" as appropriate) is described ([IV. Method for producing the fused ring dipeptide compound of the present invention]). Next, although it overlaps with the disclosure of Patent Document 8, a novel method for producing a polypeptide using the fused ring dipeptide compound of the present invention is described ([V. Method for producing a polypeptide using the fused ring dipeptide compound of the present invention]).

It is also possible to produce novel silane-containing fused ring tripeptide compounds (hereinafter, may be abbreviated as "fused ring tripeptide compounds of the present invention" as appropriate) using the fused ring dipeptide compounds of the present invention. Hereinafter, such novel silane-containing fused ring tripeptide compounds and their production methods, which are one of the gist of the present invention, will be described ([VI. Fused ring tripeptide compounds of the present invention and their production methods]). Finally, a novel method for producing a polypeptide using such a fused ring tripeptide compound of the present invention will be described ([VII. Production method of a polypeptide using a fused ring tripeptide compound of the present invention]).

II. Definitions of Terms
In the present disclosure, "amino acid" refers to a compound having a carboxyl group and an amino group. Unless otherwise specified, the type of amino acid is not particularly limited. For example, from the viewpoint of optical isomerism, it may be D-form, L-form, or racemic. In addition, from the viewpoint of the relative position of the carboxyl group and the amino group, it may be any of α-amino acid, β-amino acid, γ-amino acid, δ-amino acid, ω-amino acid, etc. Examples of amino acids include, but are not limited to, natural amino acids that constitute proteins, and specific examples include valine, leucine, isoleucine, alanine, arginine, glutamine, lysine, aspartic acid, glutamic acid, proline, cysteine, threonine, methionine, histidine, phenylalanine, tyrosine, tryptophan, asparagine, glycine, serine, etc.

In this disclosure, "peptide" refers to a compound in which multiple amino acids are linked via peptide bonds. Unless otherwise specified, the multiple amino acid units constituting a peptide may be the same type of amino acid unit, or may be two or more different types of amino acid units. The number of amino acids constituting a peptide is not particularly limited as long as it is two or more. Examples include 2 (also called "dipeptide"), 3 (also called "tripeptide"), 4 (also called "tetrapeptide"), 5 (also called "pentapeptide"), 6, 7, 8, 9, 10, 15, 20, 30, 40, 50, 100, or more. In addition, a peptide that is tripeptide or more may be referred to as a "polypeptide".

In the present disclosure, an "amino group" refers to a functional group represented by the formula -NH ₂ , -NRH, or -NRR' (wherein R and R' each represent a substituent) obtained by removing hydrogen from ammonia, a primary amine, or a secondary amine, respectively.

In this disclosure, unless otherwise specified, the hydrocarbon group may be aliphatic or aromatic. The aliphatic hydrocarbon group may be linear or cyclic. The linear hydrocarbon group may be linear or branched. The cyclic hydrocarbon group may be monocyclic, bridged, or spirocyclic. The hydrocarbon group may be saturated or unsaturated, in other words, may contain one or more carbon-carbon double bonds and/or triple bonds. That is, the hydrocarbon group is a concept that includes alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, cycloalkenyl groups, cycloalkynyl groups, aryl groups, etc. In addition, unless otherwise specified, one or more hydrogen atoms of the hydrocarbon group may be substituted with any substituent, and one or more carbon atoms of the hydrocarbon group may be substituted with any heteroatom depending on the valence.

In this disclosure, the term "hydrocarbon oxy group" refers to a group in which a hydrocarbon group as defined above is linked to one of the bonds of an oxy group (-O-).

In this disclosure, the term "hydrocarbonyl group" refers to a group in which a hydrocarbon group as defined above is linked to one of the bonds of a carbonyl group (-C(=O)-).

In the present disclosure, the term "hydrocarbonsulfonyl group" refers to a group in which a hydrocarbon group as defined above is linked to one bond of a sulfonyl group (-S(=O) ₂ -).

In the present disclosure, a heterocyclic group may be saturated or unsaturated, in other words, may contain one or more carbon-carbon double bonds and/or triple bonds. A heterocyclic group may be monocyclic, bridged, or spirocyclic. The heteroatoms contained in the heterocyclic rings of a heterocyclic group are not limited, but examples include nitrogen, oxygen, sulfur, phosphorus, silicon, and the like.

In this disclosure, the term "heterocyclic oxy group" refers to a group in which a heterocyclic group as defined above is linked to one bond of an oxy group (-O-).

In this disclosure, the term "heterocyclic carbonyl group" refers to a group in which a heterocyclic group as defined above is linked to one bond of a carbonyl group (-C(=O)-).

In the present disclosure, the term "heterocyclic sulfonyl group" refers to a group in which a heterocyclic group as defined above is linked to one bond of a sulfonyl group (-S(=O) ₂ -).

In the present disclosure, the term "substituent" refers to any substituent that is not particularly limited as long as the amidation step in the production method of the present invention proceeds, unless otherwise specified. Examples of the alkyl group include, but are not limited to, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, a sulfonic acid group, an amino group, an amido group, an imino group, an imido group, a hydrocarbon group, a heterocyclic group, a hydrocarbonoxy group, a hydrocarboncarbonyl group (acyl group), a hydrocarbonoxycarbonyl group, a hydrocarboncarbonyloxy group, a hydrocarbon-substituted amino group, a hydrocarbon-substituted aminocarbonyl group, a hydrocarboncarbonyl-substituted amino group, a hydrocarbon-substituted thiol group, a hydrocarbonsulfonyl group, a hydrocarbonoxysulfonyl group, a hydrocarbonsulfonyloxy group, a heterocyclicoxy group, a heterocycliccarbonyl group, a heterocyclicoxycarbonyl group, a heterocycliccarbonyloxy group, a heterocyclicamino group, a heterocyclicaminocarbonyl group, a heterocycliccarbonyl-substituted amino group, a heterocyclic-substituted thiol group, a heterocyclicsulfonyl group, a heterocyclicoxysulfonyl group, a heterocyclicsulfonyloxy group, and the like. In addition, as long as the valence and physicochemical properties of these functional groups allow, functional groups further substituted with these functional groups are also included in the "substituent" in the present disclosure. When a functional group has a substituent, the number of the substituents is not particularly limited as long as the valence and physicochemical properties allow. In addition, when multiple substituents are present, these substituents may be the same or different from each other.
Major abbreviations used in this disclosure are shown in Tables 1-1 and 1-2 below.

In this disclosure, amino acids and their residues may be represented by three-letter abbreviations well known to those skilled in the art. The three-letter abbreviations of the main amino acids used in this disclosure are shown in the following table.

In this disclosure, β-homo amino acids and their residues may be represented by adding "Ho" before the three-letter abbreviation of the corresponding α-amino acid.

[III. Fused ring dipeptide compound of the present invention]
One aspect of the present invention relates to a novel silane-containing fused ring dipeptide compound represented by the following formula (A) (hereinafter, may be appropriately abbreviated as "the fused ring dipeptide compound of the present invention").

In formula (A), ^R11 , ^R12 , ^R13 , ^R21 and ^R22 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or a monovalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, which may have one or more substituents.When these groups have a substituent, the type of the substituent is arbitrarily selected from those detailed above.The number of the substituent is not limited, and may be, for example, 5, 4, 3, 2, 1, or 0.

In formula (A), when R ¹¹ , R ¹² , R ¹³ , R ²¹ , and/or R ²² are monovalent aliphatic hydrocarbon groups, aromatic hydrocarbon groups, or heterocyclic groups, which may have one or more substituents, a linking group may be present between the aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group and the carbon atom to which it is bonded. Such linking groups are not limited, but are each independently selected from the structures shown below (note that in the following chemical formula, A each independently represents a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, which may have one or more substituents. When there are two A in the same group, they may be the same or different).

In formula (A), when R ¹¹ , R ¹² , R ¹³ , R ²¹ , and/or R ²² are aliphatic hydrocarbon groups (which may have one or more substituents), the number of carbon atoms of such aliphatic hydrocarbon groups (including the substituents when they have them) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more for alkyl groups, 2 or more for alkenyl groups or alkynyl groups, and 3 or more for cycloalkyl groups, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc.

In formula (A), when R ¹¹ , R ¹² , R ¹³ , R ²¹ and/or R ²² are aromatic hydrocarbon groups (which may have one or more substituents), the number of carbon atoms of such aromatic hydrocarbon groups (including the substituents when they have them) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example, 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In formula (A), when R ¹¹ , R ¹² , R ¹³ , R ²¹ and/or R ²² are heterocyclic groups (which may have one or more substituents), the total number of carbon atoms and heteroatoms (including the substituents when they have them) of such heterocyclic groups is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Among these, it is preferable that R ¹¹ , R ¹² , R ²¹ , and R ²² in formula (A) are each independently a hydrogen atom, a hydroxyl group, a thiol group, a carboxyl group, a nitro group, a cyano group, or a halogen atom, or an amino group, an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an alkoxy group, an aryl group, an aryloxy group, an acyl group, a heterocyclic group, or a heterocyclic oxy group, which may have one or more substituents.

Specific examples of R ¹¹ , R ¹² , R ¹³ , R ²¹ and R ²² in formula (A) include, but are not limited to, the following.

Hydrogen atom, hydroxyl group, thiol group, carboxyl group, nitro group, cyano group;
- halogen atoms such as fluorine, chlorine, bromine, and iodine atoms;
- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
- alkoxy groups such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a sec-butoxy group, or a tert-butoxy group;
- aryl groups such as a phenyl group, a benzyl group, a tolyl group, a naphthyl group, an anthracenyl group, etc.;
- aryloxy groups such as a phenyloxy group, a benzyloxy group, or a naphthyloxy group;
- acyl groups such as an acetyl group, a propionyl group, a benzoyl group, a paramethoxybenzoyl group, and a cinnamoyl group;
- unsubstituted amino groups and substituted amino groups such as a dimethylamino group, a benzylamino group, and a triphenylmethylamino group;
Furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group, 1,2,4,6-tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, heterocyclic groups such as an alkyl group, a 2,3-dihydro-1H-imidazolyl group, a pyrazolyl group, a 4,5-dihydro-1H-pyrazolyl group, a 2,3-dihydro-1H-pyrazolyl group, an oxazolyl group, a 4,5-dihydro-1,3-oxazolyl group, a 2,3-dihydro-1,3-oxazolyl group, a 2,5-dihydro-1,3-oxazolyl group, a thiazolyl group, a 4,5-dihydro-1,3-thiazolyl group, a 2,3-dihydro-1,3-thiazolyl group, a 2,5-dihydro-1,3-thiazolyl group, and a carbazolyl group;
heterocyclic oxy groups such as a furanyloxy group, a pyrrolyloxy group, an indolyloxy group, and a quinolyloxy group;
The above groups are substituted with one or more substituents (for example, halogen groups); and the like.

Among the above groups, the group having a carboxyl group may or may not have a protecting group. The protecting group for the carboxyl group will be described later.

In formula (A), R ^a1 and R ^a2 each independently represent a monovalent aliphatic or aromatic hydrocarbon group which may have one or more substituents. When these groups have a substituent, the type of the substituent is arbitrarily selected from those detailed above. The number of the substituents is not limited, and may be, for example, 5, 4, 3, 2, 1, or 0.

When R ^a1 and/or R ^a2 are aliphatic hydrocarbon groups (which may have one or more substituents), the number of carbon atoms in the aliphatic hydrocarbon group (including the substituents when they have them) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more in the case of an alkyl group, 2 or more in the case of an alkenyl group or an alkynyl group, and 3 or more in the case of a cycloalkyl group, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

When R ^a1 and/or R ^a2 is an aromatic hydrocarbon group (which may have one or more substituents), the number of carbon atoms in the aromatic hydrocarbon group (including the substituents when the aromatic hydrocarbon group has a substituent) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Among these, it is preferable that R ^a1 and R ^a2 each independently represent an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group, or the like, which may have one or more substituents.

Specific examples of R ^a1 and R ^a2 include, but are not limited to, the following.

- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
- aryl groups such as a phenyl group, a benzyl group, a tolyl group, a naphthyl group, an anthracenyl group, etc.;
The above groups are substituted with one or more substituents (for example, halogen groups); and the like.

The fused ring dipeptide compound of the present invention has a highly characteristic structure in which a dipeptide consisting of two α-amino acid residues is cyclized, and two five-membered rings share a silicon atom and a nitrogen atom to form a fused ring. In addition, since both the N-terminus and C-terminus of the dipeptide of this compound are protected by silicon atoms that are easily deprotected, they are easily deprotected in the presence of an acid or base, as shown in Reference Examples 1 and 2 below, and can be used as both a nucleophilic species and an electrophilic species. In addition, the fused ring dipeptide compound of the present invention is stable in air and easy to handle. Therefore, in addition to being usable as a substrate for the peptide production reaction described below, various other uses are expected.

[IV. Method for producing the fused ring dipeptide compound of the present invention]
One aspect of the present invention relates to a method for producing the above-mentioned fused ring dipeptide compound of the present invention using a specific silyl dihalide compound and a specific nitrogen-containing heterocyclic group-substituted silane compound (method for producing the fused ring dipeptide compound of the present invention).

The method for producing a fused ring dipeptide compound of the present invention includes at least the following steps (i) and (ii).
(i) a step of reacting a first amino acid represented by the following formula (R1) with a first silane compound represented by the following formula (S1):
(ii) A step of reacting a second amino acid represented by the following formula (R2) with a second silane compound represented by the following formula (S2):
(iii) A step of mixing the reactant from the step (i) and the reactant from the step (ii) and further reacting them to obtain the fused ring dipeptide compound of the formula (A).

・Amino acids (substrate compounds):
The amino acids used as the electrophilic species and the nucleophilic species in the method for producing a fused ring dipeptide compound of the present invention are represented by the following formulae (R1) and (R2), respectively.

R ¹¹ , R ¹² , and R ¹³ in formula (R1), and R ²¹ and R ²² in formula (R2) each independently represent the same group as defined in formula (A) above, i.e., a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, which may have one or more substituents, as described above in detail.

Examples of the first amino acid of formula (R1) and the second amino acid of formula (R2) include any α-amino acid. Specific examples include, but are not limited to, the 20 α-amino acids that constitute biological proteins, namely alanine, arginine, asparagine, aspartic acid, cysteine, glutamine, glutamic acid, glycine, histidine, isoleucine, leucine, lysine, methionine, phenylalanine, proline, serine, threonine, tryptophan, tyrosine, and valine, as well as ornithine, 2-aminoisobutyric acid, methylalanine, phenylglycine, and cyclohexylalanine. Further examples include amino acids in which the side chain of these α-amino acids is substituted with one or more of the above-mentioned substituents (e.g., halogen, etc.) and/or one or more of the below-mentioned protecting groups (protecting groups for a carboxyl group and/or protecting groups for an amino group), such as t-butyl-substituted asparagine, t-butyl-substituted glutamine, t-butyl-substituted serine, t-butyl-substituted threonine, t-butyl-substituted tryptophan, t-butyl-substituted lysine, Boc-substituted asparagine, Boc-substituted glutamine, Boc-substituted serine, Boc-substituted threonine, Boc-substituted tryptophan, Boc-substituted lysine, t-butyl-substituted aspartic acid, t-butyl-substituted glutamic acid, trityl-substituted asparagine, trityl-substituted glutamine, trityl-substituted histidine, t-butyl-substituted tyrosine, methyl-substituted tyrosine, methyl-substituted threonine, methyl-substituted serine, Cbz-substituted lysine, Fmoc-substituted lysine, and the like. The optical isomerism of these α-amino acids is not particularly limited, and they may be L- or D-isomers or racemic mixtures.

The N-terminal amino group (HNR ¹³ -) of the first amino acid of formula (R1) and the C-terminal carboxyl group (-COOH) of the second amino acid of formula (R2) are both unprotected. The method for producing a fused ring dipeptide compound of the present invention has a great advantage in that it is possible to specifically synthesize a silane-containing fused ring dipeptide compound of a desired structure even when unprotected amino acids are used as both the first amino acid, which is an electrophilic species, and the second amino acid, which is a nucleophilic species. However, this does not exclude an embodiment in which the N-terminal amino group of the first amino acid and/or the C-terminal carboxyl group of the second amino acid are each protected, and they may be protected by an amino-protecting group and/or a carboxyl-protecting group described below, so long as the reaction is not hindered.

First and second silane compounds:
One of the features of the method for producing a fused ring dipeptide compound of the present invention is the use of a combination of two types of silane compounds, namely, a first silane compound represented by the following formula (S1) and a second silane compound represented by the following formula (S2).

The first silane compound is represented by the following formula (S1).

In formula (S1), R ^a1 and R ^a2 represent the same groups as defined in formula (A).

In formula (S1), Z ^a1 and Z ^a2 each independently represent a 5-10 membered (preferably 5, 6, or 10 membered) heterocyclic group containing one or more (preferably 2 to 4, more preferably 2 or 3) nitrogen atoms as ring constituent atoms, which may have one or more substituents. In addition, when it has a substituent, the type is as described above, among which alkyl groups (for example, linear or branched alkyl groups having 1 to 10 carbon atoms. Hereinafter, they may be referred to as -R.), alkoxy groups (-O-R), amino groups (-NH ₂ ), alkylamino groups (-NHR), dialkylamino groups (-NR ₂ : two alkyl groups R may be the same or different.), thioalkyl groups (-SR), and groups in which these groups are substituted with one or more halogen atoms (for example, bromine or chlorine atoms), are preferred. Specific examples of the number of substituents are, for example, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0. When the number of the substituents is two or more, they may be the same or different.

Specific examples of the nitrogen-containing heterocyclic group of Z ^a1 and Z ^a2 include, but are not limited to, a pyrrole group, an imidazole group, a pyrazole group, a triazole group (1,2,3-triazole group, 1,2,4-triazole group), a piperidyl group, a pyridinyl group, a piperazinyl group, a tetrazole group, an indole group, a benzimidazole group, and further groups obtained by substituting these groups with the above-mentioned substituents, for example, a (2-/3-/4-/5-)methylimidazole group, a (2,3-/2,4-/2,5-)dimethylimidazole group, etc. Among these, an imidazole group, a pyrazole group, a triazole group, a 2-methylimidazole group, etc. are preferred.

Specific examples of the first silane compound of formula (S1) include, but are not limited to, dimethyldiimidazole silane, diethyldiimidazole silane, methylethyldiimidazole silane, dipropyldiimidazole silane, methylpropyldiimidazole silane, dibutyldiimidazole silane, methylbutyldiimidazole silane, dimethoxydiimidazole silane, diethoxydiimidazole silane, dimethyldipyrazole silane, diethyldipyrazole silane, dimethoxydipyrazole silane, dimethylditriazole silane, diethylditriazole silane, dimethoxyditriazole silane, etc. Among these, dimethyldiimidazole silane, dimethoxydiimidazole silane, etc. are preferred.

The second silane compound is represented by the following formula (S2).

In formula (S2), R ^b1 , R ^b2 , and R ^b3 each independently represent a hydrogen atom, a halogen atom, or an aliphatic or aromatic hydrocarbon group which may have one or more substituents. When these groups have a substituent, the type of the substituent is arbitrarily selected from those detailed above. The number of the substituents is not limited, and may be, for example, 5, 4, 3, 2, 1, or 0.

The number of carbon atoms in the aliphatic hydrocarbon group (including the substituent if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more for alkyl groups, 2 or more for alkenyl groups and alkynyl groups, and 3 or more for cycloalkyl groups, for example, 4 or more or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

The number of carbon atoms in the aromatic hydrocarbon group (including the substituents if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Among them, it is preferable that R ^b1 , R ^b2 and R ^b3 each independently represent an alkyl group, an alkenyl group, an alkynyl group, a cycloalkyl group, an aryl group or the like which may have one or more substituents.

Specific examples of R ^b1 , R ^b2 , and R ^b3 include, but are not limited to, the following.

- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
- aryl groups such as a phenyl group, a benzyl group, a tolyl group, a naphthyl group, an anthracenyl group, etc.;
The above groups are substituted with one or more substituents (for example, halogen groups); and the like.

In formula (S2), ^nb represents an integer of 1 or 2.

In formula (S2), when ^nb is 1, ^Zb represents an amino group (NR ₂ -), a carbonylamino group (R-C(=O)-NR-), an acetamide group (R-NR-C(=O)-) (wherein in the above chemical formulae, each R independently represents a hydrogen atom or a substituent), which may have one or more substituents, or a 5-10-membered (preferably 5-, 6-, or 10-membered) monovalent heterocyclic group containing one or more (preferably 2 to 4, more preferably 2 or 3) nitrogen atoms as ring-constituting atoms. Specific examples of the nitrogen-containing heterocyclic group include, but are not limited to, a pyrrole group, an imidazole group, a pyrazole group, a triazole group (1,2,3-triazole group, 1,2,4-triazole group), a piperidyl group, a pyridinyl group, a piperazinyl group, a tetrazole group, an indole group, a benzimidazole group, and further groups obtained by substituting these groups with the above-mentioned substituents, for example, a (2-/3-/4-/5-)methylimidazole group, a (2,3-/2,4-/2,5-)dimethylimidazole group, etc. Among these, an imidazole group, a pyrazole group, a triazole group, a 2-methylimidazole group, etc. are preferred.

In formula (S2), when n ^b is 2, Z ^b represents a divalent linking group containing nitrogen. Examples of the divalent linking group containing nitrogen include, but are not limited to, a divalent group obtained by removing a hydrogen atom or a substituent from the options of Z ^b when n ^b is 1, i.e., a -NR- group, a -C(=O)-NR- group, a -NR-C(=O)- group (wherein in the above chemical formula, R represents a hydrogen atom or a substituent), or a 5-10-membered (preferably 5-membered, 6-membered, or 10-membered) divalent heterocyclic group containing one or more (preferably 2 to 4, more preferably 2 or 3) nitrogen atoms as ring-constituting atoms.

In formula (S2), when each of the above-mentioned groups of Z ^b has a substituent, the type thereof is as described above, and among them, an alkyl group (for example, a straight or branched alkyl group having 1 to 10 carbon atoms, hereinafter sometimes referred to as -R), an alkoxy group (-O-R), an amino group (-NH ₂ ), an alkylamino group (-NHR), a dialkylamino group (-NR ₂ : the two alkyl groups R may be the same or different), a thioalkyl group (-SR), and groups in which these groups are substituted with one or more halogen atoms (for example, bromine or chlorine atoms) are preferred. Specific examples of the number of substituents are, for example, 10, 9, 8, 7, 6, 5, 4, 3, 2, 1, or 0. When the number of substituents is 2 or more, they may be the same or different from each other.

Needless to say, in formula (S2), when ^nb is 2, the two R ^b1 , R ^b2 and R ^b3 present may be the same or different.

Specific examples of the second silane compound of formula (S2) include, but are not limited to, the following compounds:
Specific examples when ^nb is 1: trimethylsilylimidazole, methylsilylimidazole, triethylsilylimidazole, triisopropylsilylimidazole, tritert-butyldimethylsilylimidazole, N-methyl-N-trimethylsilyltrifluoroacetamide (MSTFA), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA), and the like.
Specific examples when ^nb is 2: N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N,O-bis(trimethylsilyl)acetamide (BSA), hexamethyldisilazane (HMDS), etc.

In the method for producing a fused ring dipeptide compound of the present invention, the reason why the use of the first silane compound of formula (S1) and the second silane compound of formula (S2) enables specific synthesis of a desired silane-containing fused ring dipeptide compound using an unprotected electrophilic amino acid and an unprotected nucleophilic amino acid is speculated to be as follows, without being bound by theory. That is, in step (i), the first silane compound of formula (S1) forms a five-membered ring with the first unprotected amino acid, which is an electrophilic species, to protect the terminal amino group of the first amino acid, while in step (ii), the second silane compound of formula (S2) forms a silyl ester with the second unprotected amino acid, which is a nucleophilic species, to protect the terminal carboxyl group of the second amino acid. Thereafter, by mixing both reactants in step (iii), it is speculated to be possible to specifically react the terminal carboxyl group of the first amino acid with the terminal amino group of the second amino acid while distinguishing between the first amino acid, which is an electrophilic species, and the second amino acid, which is an electrophilic species.

Third and fourth silane compounds:
In the method for producing a fused ring dipeptide compound of the present invention, a third silane compound may be present in the reaction system in step (i). Although the third silane compound is not essential, various advantages such as improved reaction efficiency and improved reaction specificity may be obtained by carrying out step (i) in the presence of the third silane compound in the reaction system. Without being bound by theory, it is presumed that the terminal amino group of the first amino acid can be sufficiently protected by the presence of the third silane compound even if the formation of a five-membered ring between the first silane compound and the first amino acid is insufficient or has a short life and is decomposed.

When a third silane compound is used, the type is not particularly limited, but examples thereof include trimethylbromosilane (TMBS), trimethylchlorosilane (TMCS), tris(haloalkyl)silane, N-(trimethylsilyl)dimethylamine (TMSDMA), trimethylsilyl trifluoromethanesulfonate (TMS-OTf), dimethylsilylimidazole, dimethylsilyl(2-methyl)imidazole, 1-(trimethylsilyl)imidazole (TMSIM), dimethylethylsilylimidazole (DMESI), dimethylisopropylsilylimidazole (DMIPSI), It is preferable that the third silane compound is a compound selected from 1-(tert-butyldimethylsilyl)imidazole (TBSIM), 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N,O-bis(trimethylsilyl)acetamide (BSA), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA), and hexamethyldisilazane (HMDS). Note that, as the third silane compound, two or more silane compounds may be used in any combination and ratio.

In addition, in the method for producing a fused ring dipeptide compound of the present invention, step (iii) may include a step of mixing a fourth silane compound with the reaction system. Although the fourth silane compound is not essential, various advantages such as improved reaction efficiency and improved reaction specificity may be obtained by carrying out step (iii) in the presence of the fourth silane compound in the reaction system. Without being bound by theory, it is presumed that even if Si-OH is generated from the first silane compound and/or the second silane compound after the peptide bond is formed in step (iii), the coexistence of the fourth silane compound can block Si-OH as Si-O-Si.

When a fourth silane compound is used, the type is not particularly limited, but examples thereof include trimethylbromosilane (TMBS), trimethylchlorosilane (TMCS), tris(haloalkyl)silane, N-(trimethylsilyl)dimethylamine (TMSDMA), trimethylsilyl trifluoromethanesulfonate (TMS-OTf), dimethylsilylimidazole, dimethylsilyl(2-methyl)imidazole, 1-(trimethylsilyl)imidazole (TMSIM), dimethylethylsilylimidazole (DMESI), dimethylisopropylsilylimidazole (DMIPSI), It is preferable that the fourth silane compound is a compound selected from 1-(tert-butyldimethylsilyl)imidazole (TBSIM), 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N,O-bis(trimethylsilyl)acetamide (BSA), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA), and hexamethyldisilazane (HMDS). Note that, as the fourth silane compound, two or more kinds of silane compounds may be used in any combination and ratio.

Lewis acid catalyst:
In the method for producing a fused ring dipeptide compound of the present invention, a Lewis acid catalyst may be present in the reaction system. By carrying out the reaction in the presence of a Lewis acid catalyst in the reaction system, various advantages such as improved reaction yield and improved stereoselectivity may be obtained. However, when a Lewis acid catalyst is used, it may be necessary to separate and remove the Lewis acid catalyst from the reaction product. Therefore, it is preferable to appropriately determine whether or not to use a Lewis acid catalyst, taking into consideration the purpose of using the production method of the present invention, etc.

When a Lewis acid catalyst is used in the method for producing a condensed ring dipeptide compound of the present invention, the type of the catalyst is not limited, but it is preferable that the catalyst is a metal compound that functions as a Lewis acid. Metal elements constituting the metal compound include various metals belonging to Groups 2 to 15 of the Periodic Table of Elements. Specific examples of metal elements include boron, magnesium, aluminum, gallium, indium, silicon, calcium, lead, bismuth, mercury, transition metals, lanthanoid elements, etc. Specific examples of transition metals include scandium, titanium, vanadium, chromium, manganese, iron, cobalt, nickel, copper, zinc, yttrium, zirconium, niobium, molybdenum, technetium, ruthenium, rhodium, palladium, tin, silver, cadmium, hafnium, tantalum, tungsten, rhenium, osmium, iridium, platinum, gold, thallium, etc. Specific examples of lanthanoid elements include lanthanum, cerium, neodymium, samarium, europium, gadolinium, holmium, erbium, thulium, ytterbium, etc. Among these, from the viewpoint of exerting an excellent reaction promotion effect and producing an amide compound with high stereoselectivity, one or more selected from titanium, zirconium, hafnium, tantalum, niobium, boron, vanadium, tungsten, neodymium, iron, lead, cobalt, copper, silver, palladium, tin, thallium, etc. are preferred, and one or more selected from titanium, zirconium, hafnium, tantalum, niobium, etc. are preferred. The metal compound may contain one or more metal elements. When the metal compound contains two or more metal elements, these may be the same type of element, or two or more different metal elements.

The ligands constituting the metal compound are selected appropriately depending on the type of metal. Specific examples of the ligand include substituted or unsubstituted straight or branched chain alkoxy groups having 1 to 10 carbon atoms, such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a trifluoroethoxy group, a trichloroethoxy group, etc.; halogen atoms, such as a fluorine atom, a chlorine atom, a bromine atom, an iodine atom, etc.; an aryloxy group having 1 to 10 carbon atoms; an acetylacetonate group (acac), an acetoxy group (AcO), a trifluoromethanesulfonate group (TfO); a substituted or unsubstituted straight or branched chain alkyl group having 1 to 10 carbon atoms; a phenyl group, an oxygen atom, a sulfur atom, a -SR group (wherein R is a substituent, and examples of the substituent include substituted or unsubstituted hydrocarbon groups having about 1 to 20 carbon atoms), a -NRR' group (wherein R and R' are each independently a hydrogen atom or a substituent, and examples of the substituent include substituted or unsubstituted hydrocarbon groups having about 1 to 20 carbon atoms), a cyclopentadienyl (Cp) group, and the like.

Among these, titanium compounds, zirconium compounds, hafnium compounds, tantalum compounds, and niobium compounds are preferred as metal compounds. Specific examples of each are given below. These may be used alone or in any combination and ratio of two or more.

Specific examples of titanium compounds include titanium compounds represented by TiX ¹ ₄ (wherein each of the four X ¹ is independently a ligand exemplified above. The four X ¹ may be the same ligand or may be different from each other). When X ¹ is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 4 carbon atoms. When X ¹ is an aryloxy group, it is preferably an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, and further an aryloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent. When X ¹ is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like. Among these, for example, Ti(OMe) ₄ , Ti(OEt) ₄ , Ti(OPr) ₄ , Ti(Oi-Pr) ₄ , Ti(OBu) ₄ , Ti(Ot-Bu) ₄ , Ti(OCH ₂ CH(Et)Bu) ₄ , CpTiCl ₃ , Cp ₂ TiCl ₂ , Cp ₂ Ti(OTf) ₂ , (i-PrO) ₂ TiCl ₂ , (i-PrO) ₃ TiCl, and the like are preferred.

Specific examples of the zirconium compound include zirconium compounds represented by ZrX ² ₄ (wherein each of the four X ² is independently a ligand exemplified above. The four X ² may be the same ligand or may be different from each other). When X ² is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 4 carbon atoms. When X ² is an allyloxy group, it is preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and further an allyloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent. When X ² is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like. Among these, for example, Zr(OMe) ₄ , Zr(OEt) ₄ , Zr(OPr) ₄ , Zr(Oi-Pr) ₄ , Zr(OBu _{) 4} , Zr(Ot-Bu) ₄ , Zr( _OCH2CH (Et)Bu) ₄ , _CpZrCl3 , _Cp2ZrCl2 , Cp2Zr ₍ OTf) ₂ , (i-PrO) _{2ZrCl2 ,} (i-PrO) _3ZrCl , and the like are preferred.

Specific examples of hafnium compounds include hafnium compounds represented by HfX ³ ₄ (wherein each of the four X ³ is independently a ligand exemplified above. The four X ³ may be the same ligand or may be different from each other). When X ³ is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 4 carbon atoms. When X ³ is an allyloxy group, it is preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and further an allyloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent. When X ³ is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like. Among these, for example, HfCp ₂ Cl ₂ , HfCpCl ₃ , HfCl ₄ , and the like are preferable.

Specific examples of tantalum compounds include tantalum compounds represented by TaX ⁴ ₅ (wherein each of the five X ⁴ is independently a ligand exemplified above. The five X ⁴ may be the same ligand or may be different from each other). When X ⁴ is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 3 carbon atoms. When X ⁴ is an aryloxy group, it is preferably an aryloxy group having 1 to 20 carbon atoms, particularly an aryloxy group having 1 to 15 carbon atoms, and further an aryloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent. When X ⁴ is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like. Among these, tantalum alkoxide compounds (e.g., compounds in which ^X4 is an alkoxy group) are preferred, such as Ta(OMe) ₅ , Ta(OEt) ₅ , Ta(OBu) ₅ , Ta( _NMe2 ) ₅ , Ta(acac)(OEt) ₄ , _TaCl5 , _TaCl4 (THF), and _TaBr5 . Also usable is a compound in which ^X4 is oxygen, i.e. _{, Ta2O5} .

Specific examples of niobium compounds include niobium compounds represented by NbX ⁵ ₅ (wherein each of the five X ⁵ is independently a ligand exemplified above. The five X ⁵ may be the same ligand or may be different from each other). When X ⁵ is an alkoxy group, it is preferably a linear or branched alkoxy group having 1 to 10 carbon atoms, particularly a linear or branched alkoxy group having 1 to 5 carbon atoms, and further a linear or branched alkoxy group having 1 to 3 carbon atoms. When X ⁵ is an allyloxy group, it is preferably an allyloxy group having 1 to 20 carbon atoms, particularly an allyloxy group having 1 to 15 carbon atoms, and further an allyloxy group having 1 to 10 carbon atoms. These ligands may further have a substituent. When X ⁵ is a halogen atom, it is preferably a chlorine atom, a bromine atom, and the like. Among these, niobium alkoxide compounds (e.g., compounds in which ^X5 is an alkoxy group) are preferred, such as _NbCl4 (THF), _NbCl5 , Nb(OMe) ₅ , and Nb(OEt) ₅ . Compounds in which ^X5 is oxygen, i.e., _{Nb2O5 ,} can also be used.

The Lewis acid catalyst may be supported on a carrier. There are no particular limitations on the carrier that supports the Lewis acid catalyst, and any known carrier can be used. In addition, any known method can be used to support the Lewis acid catalyst on a carrier.

·base:
In the method for producing a fused ring dipeptide compound of the present invention, a base may be present in the reaction system from the viewpoint of increasing the reaction efficiency. The type of base is not limited, and any known base that is known to improve the reaction efficiency may be used. Examples of such bases include amines having 1 to 4 linear or branched alkyl groups having 1 to 10 carbon atoms, such as tetrabutylammonium fluoride (TBAF), triethylamine (Et ₃ N), diisopropylamine (i-Pr ₂ NH), and diisopropylethylamine (i-Pr ₂ EtN). Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

・Other ingredients:
In the method for producing a fused ring dipeptide compound of the present invention, other components may be present in the reaction system. Examples of such other components include, but are not limited to, iodine, trimethylsilyl chloride, trimethylsilyl bromide, trimethylsilyl iodide, etc. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

From the viewpoint of increasing the reaction efficiency, the reaction may be carried out in a solvent. The solvent is not particularly limited, but examples thereof include aqueous solvents and organic solvents. The organic solvent is not limited, but examples thereof include aromatic hydrocarbons such as toluene and xylene, ethers such as pentane, petroleum ether, tetrahydrofuran (THF), 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr ₂ O), diethyl ether (Et ₂ O), and cyclopentyl methyl ether (CPME), nitrogen-based organic solvents such as acetonitrile (MeCN), chlorine-based organic solvents such as dichloromethane (DCM), esters such as ethyl acetate (AcOEt), and organic acids such as acetic acid. These solvents may be used alone or in combination of two or more.

Reaction procedure:
In the method for producing the fused ring dipeptide compound of the present invention, in step (i), the first amino acid of the substrate compound of formula (R1) is contacted with the first silane compound of formula (S1) to react with it, while in step (ii), the other substrate compound of formula (R2) is contacted with the second silane compound of formula (S2) to react with it. Then, in step (iii), the reactant of step (i) and the reactant of step (ii) are mixed and further reacted to obtain the fused ring dipeptide compound of formula (A). Through such a reaction procedure, the fused ring dipeptide compound of the present invention is formed by the first amino acid of formula (R1) which is an electrophilic species and the second amino acid of formula (R2) which is a nucleophilic species. Although not bound by theory, the present inventors speculate that the reaction mechanism is as follows. That is, in step (i), the first silane compound of formula (S1) forms a five-membered ring with the first unprotected amino acid, which is an electrophilic species, to protect the terminal amino group of the first amino acid, while in step (ii), the second silane compound of formula (S2) forms a silyl ester with the second unprotected amino acid, which is a nucleophilic species, to protect the terminal carboxyl group of the second amino acid. It is then presumed that by mixing the two reactants in step (iii), it becomes possible to specifically react the terminal carboxyl group of the first amino acid with the terminal amino group of the second amino acid while distinguishing between the first amino acid, which is an electrophilic species, and the second amino acid, which is an electrophilic species.

The timing of adding the optional third and/or fourth silane compound, Lewis acid catalyst, base, and other components to the reaction system is not particularly limited, and each may be added at any timing. However, when the third silane compound is used, it is preferable to add it to the system at the start of step (i). When the fourth silane compound is used, it is preferable to add it to the system at the start of step (iii). When the Lewis acid catalyst is used, it is preferable to add it to the system at the start of step (ii). When the base is used, it is preferable to add it to the system at the start of step (i). When the reaction is carried out using a solvent, the components may be mixed in the solvent and brought into contact with each other.

・Ratio of each ingredient used:
In the method for producing a fused ring dipeptide compound of the present invention, the amount of each component used is not limited, but is preferably as follows.

The ratio of the amount of the amino acid of formula (R1) to the amount of the amino acid of formula (R2) is not particularly limited, but the amount of the amino acid of formula (R2) can be, for example, 0.05 moles or more, or 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or, for example, 10 moles or less, 5 moles or less, 4 moles or less, 3 moles or less, or 2 moles or less, per mole of the amino acid of formula (R1). It is preferable to use more amino acids of formula (R1) than those of formula (R2) in terms of increasing the efficiency of the reaction. Specifically, the amount of the amino acid of formula (R2) can be about 0.5 moles per mole of the amino acid of formula (R1). Of course, it is necessary to use at least 1 mole of the amino acid of formula (R1) and the amino acid of formula (R2) as substrates for the target production amount of the condensed ring dipeptide compound of formula (A) of the present invention to be produced.

The amount of the first silane compound of formula (S1) used is not particularly limited as long as it does not interfere with the reaction, but for example, the first silane compound of formula (S1) can be used in a range of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, or, for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per mole of the amino acid of formula (R1). In addition, when two or more types of first silane compounds of formula (S1) are used in combination, the total amount of the two or more types of first silane compounds of formula (S1) may be set to satisfy the above range.

The amount of the second silane compound of formula (S2) used is not particularly limited as long as it does not interfere with the reaction, but for example, the second silane compound of formula (S2) can be used in a range of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the amino acid of formula (R2). When two or more second silane compounds of formula (S2) are used in combination, the total amount of the two or more second silane compounds of formula (S2) should be such that the range is satisfied.

When a third silane compound is used, the amount used is not particularly limited as long as it does not interfere with the reaction, but for example, the third silane compound can be used in a range of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, or, for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per mole of the amino acid of formula (R1). When two or more types of third silane compounds are used in combination, the total amount of the two or more types of third silane compounds may be set to satisfy the above range.

When a fourth silane compound is used, the amount of the fourth silane compound is not particularly limited as long as it does not interfere with the reaction, but for example, the fourth silane compound can be used in a range of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, or, for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the amino acid of formula (R2). When two or more types of fourth silane compounds are used in combination, the total amount of the two or more types of fourth silane compounds may be set to satisfy the above range.

When a base is used, the amount used is not particularly limited, but may be, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and, for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the amino acid of formula (R1).

When a Lewis acid catalyst is used, its amount is not particularly limited, but when the amount of the amino acid of formula (R1) used is 100 mol%, the Lewis acid catalyst can be typically at least 0.1 mol%, for example at least 0.2 mol%, or at least 0.3 mol%, and typically at most 30 mol%, for example at most 20 mol%, or at most 15 mol%.

Reaction conditions:
The reaction conditions in the method for producing a fused ring dipeptide compound of the present invention are not limited as long as the reaction proceeds, but examples of the reaction conditions for each reaction procedure are as follows.

In step (i), the reaction conditions for contacting and reacting the amino acid of formula (R1) with the first silane compound of formula (S1) are not limited as long as the reaction proceeds, but are, for example, as follows:

The reaction temperature in step (i) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (i) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (i) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (i) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

In step (ii), the reaction conditions for contacting and reacting the amino acid of formula (R2) with the second silane compound of formula (S2) are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (ii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (ii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (ii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (ii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

The reaction conditions for step (iii), in which the reactant from step (i) and the reactant from step (ii) are brought into contact with each other and reacted, are not limited as long as the reaction proceeds, and are, for example, as follows:

The reaction temperature in step (iii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (iii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (iii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (iii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Each of steps (i), (ii), and (iii) may be carried out in a sequential (batch) or continuous (flow) manner. Specific details of the sequential (batch) and continuous (flow) procedures are known in the art. Steps (i) and (iii) may be carried out continuously in one pod by adding the reactant of step (ii) to the reaction system of step (i).

As described above, when a fourth silane compound is used, it is preferable to mix it with the second amino acid of formula (R2), which is a nucleophilic species, before the start of step (ii), and then mix it with the reactant of step (i). The conditions of temperature, pressure, atmosphere, time, etc. during such mixing are not limited as long as the reaction proceeds, but may be appropriately set in accordance with the conditions of temperature, pressure, atmosphere, time, etc. of steps (i) and (ii).

・Post-processing (refining, recovery, etc.):
The fused ring dipeptide compound of the present invention obtained by the above-mentioned production method may be subjected to various post-treatments. For example, the produced fused ring dipeptide compound of the present invention may be isolated and purified by a conventional method such as column chromatography or recrystallization. In addition, the produced fused ring dipeptide compound of the present invention may be used for producing a polypeptide by subjecting it directly or after isolation and purification to the production method of the polypeptide of the present invention described below.

[V. Method for producing a polypeptide using the fused ring dipeptide compound of the present invention]
The fused ring dipeptide compound of the present invention can be used in various reactions, and is preferably used in the production of polypeptides. There are two types of methods for producing polypeptides using the fused ring dipeptide compound of the present invention (hereinafter, these methods are appropriately abbreviated as "the first method for producing the polypeptide of the present invention" and "the second method for producing the polypeptide of the present invention"). However, the method for producing a polypeptide using the fused ring dipeptide compound of the present invention is not limited to these two methods.

(1) Method for producing a first polypeptide:
The first polypeptide production method of the present invention is a method using one molecule of the fused ring dipeptide compound of the present invention in the production of one molecule of a polypeptide compound, and comprises reacting the fused ring dipeptide compound of formula (A) with a protected amino acid or protected peptide compound represented by formula (R3) below, and an amino acid ester or peptide ester compound represented by formula (R4) below, to obtain a polypeptide compound represented by formula (P1) below.

Silane-containing condensed ring dipeptide compound (substrate compound):
The amino acid used as the substrate compound in the first method for producing a polypeptide of the present invention is the silane-containing fused ring dipeptide compound represented by the above formula (A) (the fused ring dipeptide compound of the present invention), the details of which are as described above.

Protected amino acids/peptides and amino acid/peptide esters (substrate compounds):
The protected amino acid or protected peptide, and the amino acid ester or peptide ester used as the substrate compound in the first method for producing the polypeptide of the present invention are compounds represented by the following formula (R3) and formula (R4), respectively.

In formula (R3) and formula (R4), R ³¹ , R ³² , R ⁴¹ and R ⁴² each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or an amino group, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group, which may have one or more substituents. If these groups have a substituent, the type of the substituent is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.

In formula (R3) and formula (R4), when R ³¹ , R ³² , R ⁴¹ , and/or R ⁴² are monovalent aliphatic hydrocarbon groups, aromatic hydrocarbon groups, or heterocyclic groups which may have one or more substituents, a linking group may be interposed between the aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group and the carbon atom to which it is bonded. Such linking groups are not limited, but are each independently selected from the structures shown below (note that in the following chemical formula, A each independently represents a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents. When there are two A in the same group, they may be the same or different).

In formula (R3) and formula (R4), when R ³¹ , R ³² , R ⁴¹ , and/or R ⁴² are aliphatic hydrocarbon groups, the number of carbon atoms of such aliphatic hydrocarbon groups (including the substituents if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more for alkyl groups, 2 or more for alkenyl groups or alkynyl groups, and 3 or more for cycloalkyl groups, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In formula (R3) and formula (R4), when R ³¹ , R ³² , R ⁴¹ , and/or R ⁴² are aromatic hydrocarbon groups, the number of carbon atoms of such aromatic hydrocarbon groups (including the substituents if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example, 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In formula (R3) and formula (R4), when R ³¹ , R ³² , R ⁴¹ , and/or R ⁴² are heterocyclic groups, the total number of carbon atoms and heteroatoms (including the substituents if any) of such heterocyclic groups is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

It is preferable that R ³¹ , R ³² , R ⁴¹ , and R ⁴² in formula (R3) and formula (R4) are each independently a hydrogen atom, a hydroxyl group, a thiol group, a carboxyl group, a nitro group, a cyano group, or a halogen atom, or an amino group, an alkyl group, an alkenyl group, a cycloalkyl group, an alkoxy group, an aryl group, an aryloxy group, an acyl group, a heterocyclic group, or a heterocyclic oxy group, which may have one or more substituents.

Specific examples of R ³¹ , R ³² , R ⁴¹ and R ⁴² in formula (R3) and formula (R4) include, but are not limited to, the following.

Hydrogen atom, hydroxyl group, thiol group, carboxyl group, nitro group, cyano group;
- halogen atoms such as fluorine, chlorine, bromine, and iodine atoms;
- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
- alkoxy groups such as a methoxy group, an ethoxy group, a propoxy group, a butoxy group, a sec-butoxy group, or a tert-butoxy group;
- aryl groups such as a phenyl group, a benzyl group, a tolyl group, a naphthyl group, an anthracenyl group, etc.;
- aryloxy groups such as a phenyloxy group, a benzyloxy group, or a naphthyloxy group;
- acyl groups such as an acetyl group, a propionyl group, a benzoyl group, a paramethoxybenzoyl group, and a cinnamoyl group;
- unsubstituted amino groups and substituted amino groups such as dimethylamino group, benzylamino group, and triphenylmethylamino group;
Furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group, 1,2,4,6-tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, heterocyclic groups such as an alkyl group, a 2,3-dihydro-1H-imidazolyl group, a pyrazolyl group, a 4,5-dihydro-1H-pyrazolyl group, a 2,3-dihydro-1H-pyrazolyl group, an oxazolyl group, a 4,5-dihydro-1,3-oxazolyl group, a 2,3-dihydro-1,3-oxazolyl group, a 2,5-dihydro-1,3-oxazolyl group, a thiazolyl group, a 4,5-dihydro-1,3-thiazolyl group, a 2,3-dihydro-1,3-thiazolyl group, a 2,5-dihydro-1,3-thiazolyl group, and a carbazolyl group;
Heterocyclic oxy groups such as a furanyloxy group, a pyrrolyloxy group, an indolyloxy group, a quinolyloxy group, etc.

In formula (R3) and formula (R4), R ³³ and R ⁴³ each independently represent a hydrogen atom, a carboxyl group, or a hydroxyl group, or a monovalent hydrocarbon group or heterocyclic group which may have one or more substituents. If the group has a substituent, the type of the substituent is as described above. Specific examples of the number of the substituents are, for example, 5, 4, 3, 2, 1, or 0.

In formula (R3) and formula (R4), when R ³³ and/or R ⁴³ are a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents, a linking group may be interposed between the aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group and the nitrogen atom to which it is bonded. Such linking groups are not limited, but are each independently selected from the structures shown below (note that in the following chemical formula, A each independently represents a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents. When there are two A in the same group, they may be the same or different).

In formula (R3) and formula (R4), when R ³³ and/or R ⁴³ are aliphatic hydrocarbon groups, the number of carbon atoms of such aliphatic hydrocarbon groups (including the substituents if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more in the case of an alkyl group, 2 or more in the case of an alkenyl group or an alkynyl group, and 3 or more in the case of a cycloalkyl group, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc.

In formula (R3) and formula (R4), when R ³³ and/or R ⁴³ are aromatic hydrocarbon groups, the number of carbon atoms of such aromatic hydrocarbon groups (including the substituents if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example, 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

In formula (R3) and formula (R4), when R ³³ and/or R ⁴³ are heterocyclic groups, the total number of carbon atoms and heteroatoms (including the substituents if any) of such heterocyclic groups is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

It is preferable that R ³³ and/or R ⁴³ in formula (R3) and formula (R4) are each independently a hydrogen atom, a hydroxyl group, or a carboxyl group, or an alkyl group, an alkenyl group, a cycloalkyl group, an alkoxy group, an aryl group, an aryloxy group, an acyl group, a heterocyclic group, or a heterocyclic oxy group, which may have one or more substituents.

Specific examples of R ³³ and/or R ⁴³ in formula (R3) and formula (R4) include, but are not limited to, the following.

Hydrogen atom, hydroxyl group, carboxyl group;
- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
- aryl groups such as a phenyl group, a benzyl group, a tolyl group, a naphthyl group, an anthracenyl group, etc.;
Furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group, 1,2,4,6-tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl heterocyclic groups such as a 2,3-dihydro-1H-imidazolyl group, a pyrazolyl group, a 4,5-dihydro-1H-pyrazolyl group, a 2,3-dihydro-1H-pyrazolyl group, an oxazolyl group, a 4,5-dihydro-1,3-oxazolyl group, a 2,3-dihydro-1,3-oxazolyl group, a 2,5-dihydro-1,3-oxazolyl group, a thiazolyl group, a 4,5-dihydro-1,3-thiazolyl group, a 2,3-dihydro-1,3-thiazolyl group, a 2,5-dihydro-1,3-thiazolyl group, a carbazolyl group, and the like.

Alternatively, in formula (R3), R ³¹ and R ³³ may be bonded to each other to form a heterocycle that may have one or more substituents together with the carbon atom to which R ³¹ is bonded and the nitrogen atom to which R ³³ is bonded. Similarly, in formula (R4), R ⁴¹ and R ⁴³ may be bonded to each other to form a heterocycle that may have one or more substituents together with the carbon atom to which R ⁴¹ is bonded and the nitrogen atom to which R ⁴³ is bonded. In addition, when a substituent is present, the type of the substituent is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.

The upper limit of the total number of carbon atoms and heteroatoms (including substituents, if any) in such a heterocyclic group is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of heterocyclic structure, but is usually 3 or more, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Specific examples of such heterocycles include, but are not limited to, a pyrrolinyl group, a pyrrolyl group, a 2,3-dihydro-1H-pyrrolyl group, a piperidinyl group, a piperazinyl group, a homopiperazinyl group, a morpholino group, a thiomorpholino group, a 1,2,4,6-tetrahydropyridyl group, a hexahydropyrimidyl group, a hexahydropyridazyl group, a 1,2,4,6-tetrahydropyridyl group, a 1,2,4,6-tetrahydropyridazyl group, a 3,4-dihydropyridyl group, an imidazolyl group, a 4,5-dihydro Examples of such groups include a 1H-imidazolyl group, a 2,3-dihydro-1H-imidazolyl group, a pyrazolyl group, a 4,5-dihydro-1H-pyrazolyl group, a 2,3-dihydro-1H-pyrazolyl group, an oxazolyl group, a 4,5-dihydro-1,3-oxazolyl group, a 2,3-dihydro-1,3-oxazolyl group, a 2,5-dihydro-1,3-oxazolyl group, a thiazolyl group, a 4,5-dihydro-1,3-thiazolyl group, a 2,3-dihydro-1,3-thiazolyl group, and a 2,5-dihydro-1,3-thiazolyl group.

In formula (R3) and formula (R4), A ³¹ , A ³² , A ⁴¹ , and A ⁴² each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents. Specific examples include, but are not limited to, a methylene group, an ethylene group, a propylene group, an isopropylene group, and the like, as well as groups in which these groups are substituted with one or more of the above-mentioned substituents. Specific examples of the number of substituents are, for example, 3, 2, 1, or 0.

In formula (R3) and formula (R4), p31, p32, p41, and p42 each independently represent 0 or 1.

In formula (R3) and formula (R4), m and n are each independently an integer of 1 or more, representing the number of constitutional units represented by the structure in [ ]. That is, m represents the number of amino acid units in [ ] of formula (R3). When m is 1, the compound of formula (R3) is a protected amino acid, and when m is 2 or more, the compound of formula (R3) is a protected peptide. Similarly, n represents the number of amino acid units in [ ] of formula (R4). When n is 1, the compound of formula (R4) is an amino acid ester, and when n is 2 or more, the compound of formula (R4) is a peptide ester. The upper limits of m and n are not particularly limited as long as the reaction proceeds, but are, for example, 100 or less, 80 or less, 60 or less, 50 or less, 40 or less, 30 or less, 20 or less, 15 or less, 12 or less, or 10 or less. Specific examples of m and n are each independently 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 60, 70, 80, 90, 100, etc.

In formula (R3), PG ^a represents a protecting group for an amino group. The protecting group for an amino group PG ^a is not particularly limited as long as it can protect the amino group so that it does not react during a given reaction and can be deprotected to convert it to an amino group after the reaction. Details of such protecting groups for an amino group will be described later.

In formula (R4), PG ^b represents a protecting group for a carboxyl group. The protecting group for a carboxyl group PG ^b is not particularly limited as long as it can protect the carboxyl group so that it does not react during a given reaction and can be deprotected to convert it to a carboxyl group after the reaction. Details of such a protecting group for a carboxyl group are as described above.

・Amino group protecting group:
A wide variety of amino-protecting groups PG ^a are known for use in the production methods of the present invention (the production method for the fused ring dipeptide compound of the present invention and the production method for the first and second polypeptides of the present invention). Examples include monovalent aliphatic or aromatic hydrocarbon groups which may have one or more substituents, or monovalent heterocyclic groups which may have one or more substituents. Among these, monovalent aliphatic or aromatic hydrocarbon groups which may have one or more substituents are preferred. However, a linking group may be present between such an aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group and the nitrogen atom of the amino group it protects (the nitrogen atom to which PG ^a is bonded in formula (R3)). Such linking groups are not limited, and may be each independently selected from, for example, the linking groups shown below (note that in the chemical formulas below, each A independently represents a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents. When there are two As in the same group, they may be the same or different).

The amino-protecting group PG ^a typically has 1 or more, or 3 or more, and typically has 20 or less, or 15 or less, carbon atoms.

Among these, the amino-protecting group PG ^a is preferably one or more groups selected from the group consisting of a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group, an acyl group, a hydrocarbonoxycarbonyl group, a hydrocarbylsulfonyl group, and an amide group, each of which may have one or more substituents.

Specific examples of the amino-protecting group PG ^a are listed below. Note that the names of the amino-protecting groups include not only the names of the functional groups bonded to the nitrogen atom of the amino group, but also names including the nitrogen atom, and both are included in the names below.

Specific examples of unsubstituted or substituted hydrocarbon groups include alkyl groups such as methyl, ethyl, and propyl; alkenyl groups such as ethenyl, propenyl, and allyl; alkynyl groups such as propargyl; cycloalkyl groups such as cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl; aryl groups such as phenyl, benzyl, paramethoxybenzyl, tolyl, and triphenylmethyl (Trocl) groups; and substituted hydrocarbon groups such as cyanomethyl. The number of carbon atoms is usually 1 or more, or 3 or more, and usually 20 or less, or 15 or less.

Specific examples of unsubstituted or substituted acyl groups include benzoyl (Bz), ortho-methoxybenzoyl, 2,6-dimethoxybenzoyl, para-methoxybenzoyl (PMPCO), cinnamoyl, and phthaloyl (Phth) groups.

Specific examples of unsubstituted or substituted hydrocarbon oxycarbonyl groups include tert-butoxycarbonyl group (Boc), benzyloxycarbonyl group (Cbz or Z), methoxycarbonyl group, ethoxycarbonyl group, 2-trimethylsilylethoxycarbonyl group, 2-phenylethoxycarbonyl group, 1-(1-adamantyl)-1-methylethoxycarbonyl group, 1-(3,5-di-t- butylphenyl)-1-methylethoxycarbonyl group, vinyloxycarbonyl group, allyloxycarbonyl group (Alloc), N-hydroxypiperidinyloxycarbonyl group, p-methoxybenzyloxycarbonyl group, p-nitrobenzyloxycarbonyl group, 2-(1,3-dithianyl)methoxycarbonyl, m-nitrophenoxycarbonyl group, 3,5-dimethoxybenzyloxycarbonyl group, o-nitrobenzyloxycarbonyl group, 2,2,2-trichloroethoxycarbonyl group (Troc), and 9-fluorenylmethyloxycarbonyl group (Fmoc).

Specific examples of unsubstituted or substituted hydrocarbon sulfonyl groups include methanesulfonyl groups (Ms), toluenesulfonyl groups (Ts), 2- or 4-nitrobenzenesulfonyl groups (Ns), etc.

Specific examples of unsubstituted or substituted amide groups include acetamide, o-(benzoyloxymethyl)benzamide, 2-[(t-butyldiphenylsiloxy)methyl]benzamide, 2-toluenesulfonamide, 4-toluenesulfonamide, 2-nitrobenzenesulfonamide, 4-nitrobenzenesulfonamide, tert-butylsulfinylamide, 4-toluenesulfonamide, 2-(trimethylsilyl)ethanesulfonamide, benzylsulfonamide, and the like.

In addition, from the viewpoint of the deprotection technique, examples of the protecting group PG a for the amino group also include a protecting group that can be deprotected by at least one technique selected from the group consisting of deprotection by hydrogenation, deprotection by a weak acid, deprotection by a fluoride ion, deprotection by a one-electron oxidizing agent, deprotection by hydrazine, and deprotection by ^oxygen .

Preferred specific examples of the amino-protecting group PG ^a include a mesyl group (Ms), a tert-butoxycarbonyl group (Boc), a benzyl group (Bn or Bzl), a benzyloxycarbonyl group (Cbz), a benzoyl group (Bz), a paramethoxybenzyl group (PMB), a 2,2,2-trichloroethoxycarbonyl group (Troc), an allyloxycarbonyl group (Alloc), a 2,4-dinitrophenyl group (2,4-DNP), a phthaloyl group (Phth), a paramethoxybenzoyl group (PMPCO), a cinnamoyl group, a toluenesulfonyl group (Ts), a 2- or 4-nitrobenzenesulfonyl group (Ns), a cyanomethyl group, a 9-fluorenylmethyloxycarbonyl group (Fmoc), etc. This is because, as described above, these protecting groups can easily protect an amino group and can be removed under relatively mild conditions.

More preferred specific examples of the amino-protecting group PG ^a include a mesyl group (Ms), a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a benzyl group (Bn), a paramethoxybenzyl group (PMB), a 2,2,2-trichloroethoxycarbonyl group (Troc), an allyloxycarbonyl group (Alloc), a paramethoxybenzoyl group (PMPCO), a benzoyl group (Bz), a cyanomethyl group, a cinnamoyl group, a 2- or 4-nitrobenzenesulfonyl group (Ns), a toluenesulfonyl group (Ts), a phthaloyl group (Phth), a 2,4-dinitrophenyl group (2,4-DNP), a 9-fluorenylmethyloxycarbonyl group (Fmoc), and the like.

More preferred specific examples of the amino-protecting group PG ^a include a mesyl group (Ms), a tert-butoxycarbonyl group (Boc), a benzyloxycarbonyl group (Cbz), a benzyl group (Bn), a paramethoxybenzyl group (PMB), a 2,2,2-trichloroethoxycarbonyl group (Troc), an allyloxycarbonyl group (Alloc), a paramethoxybenzoyl group (PMPCO), a benzoyl group (Bz), a cyanomethyl group, and a cinnamoyl group.

In steps (i) and/or (ii), a condensation agent and/or a racemization inhibitor may be present in the reaction system.

The method may further comprise a step of deprotecting the amino-protecting group PG ^a and/or the carboxyl-protecting group PG ^b of the polypeptide compound of formula (P1).

Carboxyl protecting group:
Examples of the carboxyl-protecting group ^PGb used in each production method of the present invention (the production method of the fused ring dipeptide compound of the present invention and the production method of the first and second polypeptides of the present invention described below) include monovalent aliphatic hydrocarbon groups, aromatic hydrocarbon groups, and heterocyclic groups, which may have one or more substituents. When the group has a substituent, the type of the substituent is as described above. Specific examples of the number of substituents are, for example, 5, 4, 3, 2, 1, or 0.

When the carboxyl group-protecting group PG ^b is an aliphatic hydrocarbon group, the number of carbon atoms in the aliphatic hydrocarbon group (including the substituent if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more in the case of an alkyl group, 2 or more in the case of an alkenyl group or an alkynyl group, and 3 or more in the case of a cycloalkyl group, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

When the carboxyl group-protecting group PG ^b is an aromatic hydrocarbon group, the number of carbon atoms in the aromatic hydrocarbon group (including the substituent if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

Specific examples of the carboxyl-protecting group ^PGb include, but are not limited to, the following:

- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
Aryl groups and arylalkyl groups such as a phenyl group, a benzyl group, a tolyl group, a cumyl group, a 1,1-diphenylethyl group, a triphenylmethyl group, a fluorenyl group, a naphthyl group, and an anthracenyl group;
Furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group, 1,2,4,6-tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, heterocyclic groups such as an alkyl group, a 2,3-dihydro-1H-imidazolyl group, a pyrazolyl group, a 4,5-dihydro-1H-pyrazolyl group, a 2,3-dihydro-1H-pyrazolyl group, an oxazolyl group, a 4,5-dihydro-1,3-oxazolyl group, a 2,3-dihydro-1,3-oxazolyl group, a 2,5-dihydro-1,3-oxazolyl group, a thiazolyl group, a 4,5-dihydro-1,3-thiazolyl group, a 2,3-dihydro-1,3-thiazolyl group, a 2,5-dihydro-1,3-thiazolyl group, and a carbazolyl group;
Silicon-based protecting groups such as a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl (TIPS) group, a tritert-butylsilyl (TBS) group, a tert-butyldiphenylsilyl (TBDPS) group, a tris(trialkylsilyl)silyl group, and the like.

Condensation agents and racemization inhibitors:
In the first peptide production method of the present invention, a condensing agent may be present in the system in order to increase the efficiency of the peptide formation reaction. The type of condensing agent is not limited, and any known condensing agent that is known to improve the efficiency of the condensation reaction may be used. Examples of such condensing agents include the following. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

- Carbodiimide condensing agents: 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide (wsc, edc), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (wscHCl, edcHCl), N,N'-dicyclohexylcarbodiimide (DCC), N,N'-diisopropylcarbodiimide (DIC), etc.

- Phosphonium-based condensing agents: 1H-benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), 1H-benzotriazol-1-yloxytripyrrolidinophosphonium hexafluorophosphate (PyBOP), (7-azabenzotriazol-1-yloxy)tripyrrolidinophosphonium hexafluorophosphate (PyAOP), chlorotripyrrolidinophosphonium hexafluorophosphate (PyCloP), bromotris(dimethylamino)phosphonium hexafluorophosphate (Brop), 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT), etc.

- Imidazole-based condensing agents: N,N'-carbonyldiimidazole (CDI), 1,1'-carbonyldi(1,2,4-triazole) (CDT), etc.

- Uronium-based condensing agents: O-(benzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HBTU), O-(7-azabenzotriazol-1-yl)-N,N,N',N'-tetramethyluronium hexafluorophosphate (HATU), O-(N-succinimidyl)-N,N,N',N'-tetramethyluronium tetrafluoroborate (TSTU), etc.

- Triazine-based condensing agents: 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n-hydrate (DMT-MM), etc.

When a condensation agent is used, a racemization inhibitor may be used in combination to prevent racemization during the peptide formation reaction. There are no limitations on the type of racemization inhibitor, and any known racemization inhibitor that is known to prevent racemization during the condensation reaction may be used. Examples of such racemization inhibitors include 1-hydroxybenzotriazole (HOBt), 1-hydroxy-7-azabenzotriazole (HOAt), N-hydroxysuccinimide (HOSu), and N,N'-disuccinimidyl carbonate (DSC). Any one of these may be used alone, or two or more may be used in any combination and ratio.

·base:
In the first peptide production method of the present invention, a base may be allowed to coexist in the system in order to increase the reaction efficiency. The type of base is not limited, and any known base that is known to improve the reaction efficiency may be used. Examples of such bases include amines having 1 to 4 linear or branched alkyl groups having 1 to 10 carbon atoms, such as tetrabutylammonium fluoride (TBAF), triethylamine (Et ₃ N), diisopropylamine (i-Pr ₂ NH), and diisopropylethylamine (i-Pr ₂ EtN), and inorganic bases such as cesium fluoride. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

・Other ingredients:
In the first peptide production method of the present invention, in addition to the substrate compounds, ie, the fused ring dipeptide compound of formula (A), the protected amino acid or protected peptide of formula (R3), the amino acid ester or peptide ester of formula (R4), and the base, condensing agent, and racemization inhibitor that are optionally used, other components may be present. Examples of such other components include, but are not limited to, conventional catalysts that can be used in amidation reactions, silane compounds, phosphorus compounds, etc. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

Examples of catalysts include the various Lewis acid catalysts detailed in the section on the method for producing the fused ring dipeptide compound of the present invention described above, such as titanium compounds, zirconium compounds, hafnium compounds, tantalum compounds, niobium compounds, etc., as well as methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide) (MABR), trimethylsilyl trifluoromethanesulfonate (TMS-OTf), methylaluminum bis(2,6-di-tert-butylphenoxide) (MAD), etc. Any one of these may be used alone, or two or more may be used in any combination and ratio.

Examples of the silane compound include _various tris{ _halo ( _preferably fluorine)-substituted _alkyl }silanes such as HSi(OCH( _CF3 ) ₂ ) ₃ , HSi _{( OCH2CF3 ) 3} , HSi _{(OCH2CF2CF2CF2H ) 3} , and HSi( _{OCH2CF2CF2CF2CF2CF2H} ) ₃ , as well as trimethylsilyl trifluoromethanesulfonate (TMS-OTf), 1-(trimethylsilyl)imidazole (TMSIM), dimethylethylsilylimidazole (DMESI), dimethylisopropylsilylimidazole (DMIPSI), 1-(tert-butyldimethylsilyl)imidazole (TBSIM), 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, dimethylsilylimidazole, dimethylsilyl ( 2-methyl)imidazole, trimethylbromosilane (TMBS), trimethylchlorosilane (TMCS), N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N,O-bis(trimethylsilyl)acetamide (BSA), N-(trimethylsilyl)dimethylamine (TMSDMA), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA), hexamethyldisilazane (HMDS), etc. Any one of these may be used alone, or two or more may be used in any combination and ratio.

Examples of phosphorus compounds include phosphine compounds (e.g., trimethylphosphine, triethylphosphine, tripropylphosphine, trimethyloxyphosphine, triethyloxyphosphine, tripropyloxyphosphine, triphenylphosphine, trinaphthylphosphine, triphenyloxyphosphine, tris(4-methylphenyl)phosphine, tris(4-methoxyphenyl)phosphine, tris(4-fluorophenyl)phosphine, tris(4-methylphenyloxy)phosphine, tris(4-methoxyphenyloxy)phosphine, tris(4-fluorophenyloxy)phosphine, etc.), phosphate compounds (e.g., trimethyl phosphate, triethyl phosphate, tripropyl phosphate, trimethyloxy phosphate, , triethyloxy phosphate, tripropyloxy phosphate, triphenyl phosphate, trinaphthyl phosphate, triphenyloxy phosphate, tris(4-methylphenyl)phosphate, tris(4-methoxyphenyl)phosphate, tris(4-fluorophenyl)phosphate, tris(4-methylphenyloxy)phosphate, tris(4-methoxyphenyloxy)phosphate, tris(4-fluorophenyloxy)phosphate, etc.), polyvalent phosphine compounds or polyvalent phosphate compounds (e.g., 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl (BINAP), 5,5'-bis(diphenylphosphino)-4,4'-bi-1,3-benzodioxole (SEGPHOS), etc.), etc. Any one of these may be used alone, or two or more may be used in any combination and ratio.

In addition, from the viewpoint of increasing the reaction efficiency, a solvent may be used during the reaction. The solvent is not particularly limited, but examples thereof include aqueous solvents and organic solvents. The organic solvent is not limited, but examples thereof include aromatic hydrocarbons such as toluene and xylene, ethers such as pentane, petroleum ether, tetrahydrofuran (THF), 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr ₂ O), diethyl ether (Et ₂ O), and cyclopentyl methyl ether (CPME), nitrogen-based organic solvents such as acetonitrile (MeCN), chlorine-based organic solvents such as dichloromethane (DCM), esters such as ethyl acetate (AcOEt), and organic acids such as acetic acid. These solvents may be used alone or in combination of two or more.

Reaction procedure:
In the first peptide production method of the present invention, a fused ring dipeptide compound of formula (A), a protected amino acid or protected peptide compound of formula (R3), and an amino acid ester or peptide ester compound of formula (R4) are reacted. Through this reaction, the ring of the amino acid residue on the left side of the fused ring dipeptide compound of formula (A) opens, and the protected amino acid or protected peptide of formula (R3) is linked to its N-terminus, and the ring of the amino acid residue on the right side of the fused ring dipeptide compound of formula (A) opens, and the protected amino acid or protected peptide of formula (R4) is linked to its C-terminus, resulting in the formation of a polypeptide compound of formula (P1).

In the first peptide production method of the present invention, the order in which the substrate compounds are mixed is not limited as long as the above reaction occurs. Examples include the following two embodiments, but the order in which the substrate compounds are mixed is not limited to these.

The first embodiment is a step (i) in which a protected amino acid or peptide of formula (R3) is added to a fused ring dipeptide compound of formula (A) and reacted, and then an amino acid ester or peptide ester of formula (R4) is added to the reaction system and reacted in step (ii). In this embodiment, in step (i), the ring of the amino acid residue on the left side of the fused ring dipeptide compound of formula (A) is opened, and the protected amino acid or peptide of formula (R3) is linked to its N-terminus, and in step (ii), the ring of the amino acid residue on the right side of the fused ring dipeptide compound of formula (A) is opened, and the protected amino acid or peptide of formula (R4) is linked to its C-terminus, resulting in the formation of a polypeptide compound of formula (P1).

In the second embodiment, in step (i), an amino acid ester or peptide ester of formula (R4) is added to the fused ring dipeptide compound of formula (A) to react, and then in step (ii), a protected amino acid or protected peptide of formula (R3) is added to the reaction system to react. In this embodiment, in step (i), the ring of the amino acid residue on the right side of the fused ring dipeptide compound of formula (A) is opened, and the protected amino acid or protected peptide of formula (R4) is linked to its C-terminus, and in step (ii), the ring of the amino acid residue on the left side of the fused ring dipeptide compound of formula (A) is opened, and the protected amino acid or protected peptide of formula (R3) is linked to its N-terminus, resulting in the formation of a polypeptide compound of formula (P1).

There is no particular restriction on the timing of adding other components, such as the optional condensing agent and base, to the reaction system, and they may all be added at any time. However, when a condensing agent and/or a base are used, it is preferable to add them to the system at the start of step (i) and/or step (ii) in both the first and second embodiments. When a racemization inhibitor is used in addition to a condensing agent, it is preferable to add it to the system together with the condensing agent. When the reaction is carried out using a solvent, the components may be mixed in the solvent and brought into contact with each other.

・Ratio of each ingredient used:
In the first method for producing a peptide of the present invention, the amount of each component used is not limited, but is preferably as follows.

The quantitative ratio of the fused ring dipeptide compound of formula (A) to the protected amino acid or protected peptide of formula (R3) is not particularly limited, but the amount of the protected amino acid or protected peptide of formula (R3) per 1 mole of the fused ring dipeptide compound of formula (A) can be, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less.

The quantitative ratio of the fused ring dipeptide compound of formula (A) to the amino acid ester or peptide ester of formula (R4) is not particularly limited, but the amino acid ester or peptide ester of formula (R4) can be used in an amount of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per mole of the fused ring dipeptide compound of formula (A).

Of course, for the target production amount of the polypeptide compound of formula (P1) of the present invention to be produced, it is necessary to use at least 1 mole each of the substrates, the fused ring dipeptide compound of formula (A), the protected amino acid or protected peptide of formula (R3), and the amino acid ester or peptide ester of formula (R4).

When a base is used, the amount used is not particularly limited, but may be, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and, for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensed ring dipeptide compound of formula (A). When a base is added in multiple steps, it is preferable to add an amount of base within the above range in each step.

When a condensing agent is used, the amount used is not particularly limited, but the condensing agent can be used in an amount of, for example, 0.2 mol or more, or 0.4 mol or more, or 0.6 mol or more, or 0.8 mol or more, or 1.0 mol or more, and for example, 40 mol or less, or 30 mol or less, or 20 mol or less, or 15 mol or less, or 10 mol or less, or 6 mol or less, or 4 mol or less, per 1 mol of the condensed ring dipeptide compound of formula (A). When the condensing agent is added in multiple steps, it is preferable to add the condensing agent in an amount within the above range in each step.

When a racemization inhibitor is used in addition to a condensing agent, the amount used is not particularly limited, but the racemization inhibitor can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensed ring dipeptide compound of formula (A). When a racemization inhibitor is added in multiple steps, it is preferable to add the racemization inhibitor in an amount within the above range in each step.

Reaction conditions:
The reaction conditions in the first peptide production method of the present invention are not limited as long as the reaction proceeds. For example, the reaction conditions for each of the first and second aspects are as follows:

First, in the case of the first aspect, the reaction conditions in step (i) for reacting the fused ring dipeptide compound of formula (A) with the protected amino acid or protected peptide of formula (R3) are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (i) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (i) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (i) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (i) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

On the other hand, in step (ii), the reaction conditions when the amino acid ester or peptide ester of formula (R4) is added to the reaction system and reacted are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (ii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (ii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (ii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (ii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Next, in the case of the second embodiment, in step (i), the reaction conditions for adding the amino acid ester or peptide ester of formula (R4) to the fused ring dipeptide compound of formula (A) and reacting them are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (i) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (i) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (i) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (i) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

On the other hand, in step (ii), the reaction conditions when the protected amino acid or protected peptide of formula (R3) is added to the reaction system and reacted are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (ii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (ii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (ii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (ii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

In both the first and second aspects, step (i) and step (ii) may each be carried out by a sequential method (batch method) or a continuous method (flow method). Specific details of the procedures for carrying out the sequential method (batch method) and the continuous method (flow method) are known in the art. Step (i) and step (ii) may also be carried out continuously in one pod.

Polypeptide (target compound):
The target polypeptide compound finally produced in the first polypeptide production method of the present invention is a compound represented by the following formula (P1).

In formula (P1), R ¹¹ , R ¹² , R ¹³ , R ²¹ , and R ²² represent the same groups as defined in formula (A), PG ^a , R ³¹ , R ³² , R ³³ , A ³¹ , A ³² , p31 , p32 , and m represent the same groups as defined in formula (R3), and PG ^b , R ⁴¹ , R ⁴² , R ⁴³ , A ⁴¹ , A ⁴² , p41 , p42 , and n represent the same groups as defined in formula (R4).

Here, the compound of formula (P1) is a polypeptide compound with the number of amino acid residues being m+n+2. That is, for example, when the compound of formula (R3) is a protected amino acid and the compound of formula (R4) is an amino acid ester (i.e., when m and n are both 1), the compound of formula (P1) produced is a polypeptide compound with the number of amino acid residues m+n+2=4, i.e., a tetrapeptide compound. Also, for example, when the compound of formula (R3) is a protected dipeptide and the compound of formula (R4) is an amino acid ester (i.e., when m is 2 and n is 1), or when the compound of formula (R3) is a protected amino acid and the compound of formula (R4) is a dipeptide ester (i.e., when m is 1 and n is 2), the compound of formula (P1) produced is a polypeptide compound with the number of amino acid residues m+n+2=5, i.e., a pentapeptide compound. Furthermore, for example, when the compound of formula (R3) is a protected dipeptide and the compound of formula (R4) is a dipeptide ester (i.e., when m is 2 and n is 2), the compound of formula (P1) produced is a polypeptide compound having m+n+2=6 amino acid residues, i.e., a hexapeptide compound. That is, it is possible to adjust the obtained polypeptide compound (m+n+2) of formula (P1) depending on the numbers of amino acid residues (m and n) of the substrate compounds of formula (R3) and formula (R4) used.

The polypeptide compound of formula (P1) obtained by the above-mentioned production method may be subjected to various post-treatments. Such post-treatments include isolation and purification of the polypeptide compound of formula (P1) obtained, deprotection of the amino-protecting group PG ^a and/or the carboxyl-protecting group PG ^b , etc. Such post-treatments will be described below.

(2) Method for producing a second polypeptide:
The second method for producing a polypeptide of the present invention is a method using two molecules of the fused ring dipeptide compound of the present invention to produce one molecule of a polypeptide, and comprises at least the following steps (i) to (iii):
(i) A step of adding a protected amino acid or a protected peptide represented by the following formula (R3) to a silane-containing fused ring dipeptide compound represented by the following formula (A1) and reacting them.
(ii) A step of adding a silane-containing fused ring dipeptide compound represented by the following formula (A2) to the reaction product of the step (i) and further reacting the product:
(iii) A step of adding an amino acid ester or peptide ester represented by the following formula (R4) to the reaction product of the step (ii) and further reacting the mixture to obtain a polypeptide compound represented by the following formula (P1):

Silane-containing condensed ring dipeptide compound (substrate compound):
The silane-containing fused ring dipeptide compound used as a substrate compound in the second method for producing a polypeptide of the present invention is the same compound as the silane-containing fused ring dipeptide compound represented by the above formula (A) (the fused ring dipeptide compound of the present invention), but differs from the first method for producing a polypeptide of the present invention described above in that two molecules of the silane-containing fused ring dipeptide compound are used to synthesize one molecule of the polypeptide. In order to distinguish between these two molecules of the silane-containing fused ring dipeptide compound, they are represented by the following formulae (A1) and (A2), respectively.

R ¹¹¹ , R ¹¹² , R ¹¹³ , R ¹²¹ and R ¹²² in formula (A1), and R ²¹¹ , R ²¹² , R ²¹³ , R ²²¹ and R ²²² in formula (A2) each independently represent the same definition as R ¹¹ , R ¹² , R ²¹ and R ²² in formula (A). In addition, R ^a11 and R ^a12 in formula (A1), and R ^a21 and R ^a22 in formula (A2) each independently represent the same definition as R ^a1 and R ^a2 in formula (A). The details are all as described above.

Protected amino acids/peptides and amino acid/peptide esters (substrate compounds):
The protected amino acid or protected peptide, and the amino acid ester or peptide ester used as the substrate compound in the method for producing the second polypeptide of the present invention are the compounds represented by the above-mentioned formula (R3) and formula (R4), as in the method for producing the second polypeptide of the present invention. The details are as described above.

Condensation agent:
In the second peptide production method of the present invention, a condensation agent may be present in the system in order to increase the efficiency of the peptide formation reaction. When a condensation agent is used, a racemization inhibitor may be used in combination. Details of the condensation agent and the racemization inhibitor are as described above in detail in the first peptide production method of the present invention.

·base:
In the second peptide production method of the present invention, a base may be present in the system in order to improve the reaction efficiency. The details of the base are as described above in detail in the first peptide production method of the present invention.

・Other ingredients:
In the second peptide production method of the present invention, other components may also be present in addition to the substrate compounds, condensed ring dipeptide compounds of formula (A1) and formula (A2), protected amino acid or protected peptide of formula (R3), amino acid ester or peptide ester of formula (R4), and optionally used base, condensing agent, and racemization inhibitor. Examples of such other components include catalysts, silane compounds, phosphorus compounds, etc. Details of such other components are as described in detail in the above description of the first peptide production method of the present invention.

In order to increase the reaction efficiency, the reaction may be carried out in a solvent. Details of the solvent are as described above in the description of the first peptide production method of the present invention.

Reaction procedure:
In the second peptide production method of the present invention, the fused ring dipeptide compounds of formula (A1) and formula (A2), the protected amino acid or protected peptide compound of formula (R3), and the amino acid ester or peptide ester compound of formula (R4) are reacted. Through this reaction, the ring of the amino acid residue on the right side of the fused ring dipeptide compound of formula (A1) and the ring of the amino acid residue on the left side of the fused ring dipeptide compound of formula (A2) are both opened, and the N-terminus of the latter amino acid residue is linked to the C-terminus of the former amino acid residue, and the ring of the amino acid residue on the left side of the fused ring dipeptide compound of formula (A1) is opened, and the protected amino acid or protected peptide of formula (R3) is linked to its N-terminus, and further, the ring of the amino acid residue on the right side of the fused ring dipeptide compound of formula (A2) is opened, and the protected amino acid or protected peptide of formula (R4) is linked, resulting in the formation of a polypeptide compound of formula (P2).

In the first peptide production method of the present invention, the order in which the substrate compounds are mixed is not limited as long as the above reaction occurs. Examples include the following two embodiments, but the order in which the substrate compounds are mixed is not limited to these.

An example of a first embodiment is a method in which, in step (i), a protected amino acid or protected peptide of formula (R3) is added to a fused ring dipeptide compound of formula (A1) and reacted, then, in step (ii), a fused ring dipeptide compound of formula (A2) is added to the reaction system and reacted, and further, in step (iii), an amino acid ester or peptide ester of formula (R4) is added to the reaction system and reacted. In this embodiment, in step (i), the ring of the amino acid residue on the left side of the formula of the fused ring dipeptide compound of formula (A1) is opened and a protected amino acid or protected peptide of formula (R3) is linked to the N-terminus thereof; in step (ii), the ring of the amino acid residue on the right side of the formula of the fused ring dipeptide compound of formula (A1) and the ring of the amino acid residue on the left side of the formula of the fused ring dipeptide compound of formula (A2) are both opened and the N-terminus of the latter amino acid residue is linked to the C-terminus of the former amino acid residue; and in step (iii), the ring of the amino acid residue on the right side of the formula of the fused ring dipeptide compound of formula (A2) is opened and a protected amino acid or protected peptide of formula (R4) is linked, resulting in the formation of a polypeptide compound of formula (P2).

In a second embodiment, in step (i), an amino acid ester or peptide ester of formula (R4) is added to a fused ring dipeptide compound of formula (A2) and reacted, then in step (ii), a fused ring dipeptide compound of formula (A1) is added to the reaction system and reacted, and further in step (iii), a protected amino acid or protected peptide of formula (R3) is added to the reaction system and reacted. In this embodiment, in step (i), the ring of the amino acid residue on the right side of the formula of the fused ring dipeptide compound of formula (A2) is opened and a protected amino acid or protected peptide of formula (R4) is linked; in step (ii), the ring of the amino acid residue on the right side of the formula of the fused ring dipeptide compound of formula (A1) and the ring of the amino acid residue on the left side of the formula of the fused ring dipeptide compound of formula (A2) are both opened and the N-terminus of the latter amino acid residue is linked to the C-terminus of the former amino acid residue; and in step (iii), the ring of the amino acid residue on the left side of the formula of the fused ring dipeptide compound of formula (A1) is opened and a protected amino acid or protected peptide of formula (R3) is linked to the N-terminus thereof, resulting in the formation of a polypeptide compound of formula (P1).

There is no particular restriction on the timing of adding other components, such as the optional condensing agent and base, to the reaction system, and they may all be added at any time. However, when a condensing agent and/or a base are used, it is preferable to add them to the system at the start of step (i) and/or step (ii) and/or step (iii) in both the first and second embodiments. When a racemization inhibitor is used in addition to a condensing agent, it is preferable to add them to the system together with the condensing agent. When the reaction is carried out using a solvent, the components may be mixed in the solvent and brought into contact with each other.

・Ratio of each ingredient used:
In the second method for producing a peptide of the present invention, the amount of each component used is not limited, but is preferably as follows.

The quantitative ratio of the fused ring dipeptide compound of formula (A1) to the fused ring dipeptide compound of formula (A2) is not particularly limited, but the fused ring dipeptide compound of formula (A2) can be used in an amount of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per 1 mole of the fused ring dipeptide compound of formula (A1).

The quantitative ratio of the fused ring dipeptide compound of formula (A1) to the protected amino acid or protected peptide of formula (R3) is not particularly limited, but the amount of the protected amino acid or protected peptide of formula (R3) that can be used per mole of the fused ring dipeptide compound of formula (A1) can be, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less.

The quantitative ratio of the fused ring dipeptide compound of formula (A1) to the amino acid ester or peptide ester of formula (R4) is not particularly limited, but the amino acid ester or peptide ester of formula (R4) can be used in an amount of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per mole of the fused ring dipeptide compound of formula (A1).

Of course, for the target production amount of the polypeptide compound of formula (P2) of the present invention to be produced, it is necessary to use at least 1 mole each of the substrates, the fused ring dipeptide compound of formula (A), the protected amino acid or protected peptide of formula (R3), and the amino acid ester or peptide ester of formula (R4).

When a base is used, the amount used is not particularly limited, but may be, for example, 0.2 moles or more, 0.4 moles or more, 0.6 moles or more, 0.8 moles or more, or 1.0 moles or more, and, for example, 40 moles or less, 30 moles or less, 20 moles or less, 15 moles or less, 10 moles or less, 6 moles or less, or 4 moles or less, per mole of the condensed ring dipeptide compound of formula (A1). When a base is added in multiple steps, it is preferable to add an amount of base within the above range in each step.

When a condensing agent is used, the amount used is not particularly limited, but the condensing agent can be used in an amount of, for example, 0.2 mol or more, or 0.4 mol or more, or 0.6 mol or more, or 0.8 mol or more, or 1.0 mol or more, and for example, 40 mol or less, or 30 mol or less, or 20 mol or less, or 15 mol or less, or 10 mol or less, or 6 mol or less, or 4 mol or less, per mol of the condensed ring dipeptide compound of formula (A1). When the condensing agent is added in multiple steps, it is preferable to add the condensing agent in an amount within the above range in each step.

When a racemization inhibitor is used in addition to a condensing agent, the amount used is not particularly limited, but the racemization inhibitor can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensed ring dipeptide compound of formula (A1). When a racemization inhibitor is added in multiple steps, it is preferable to add the racemization inhibitor in an amount within the above range in each step.

Reaction conditions:
The reaction conditions in the second peptide production method of the present invention are not limited as long as the reaction proceeds. For example, the reaction conditions for each of the first and second aspects are as follows:

First, in the case of the first aspect, the reaction conditions in step (i) for reacting the fused ring dipeptide compound of formula (A1) with the protected amino acid or protected peptide of formula (R3) are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (i) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (i) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (i) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (i) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Next, in step (ii), the reaction conditions for adding the fused ring dipeptide compound of formula (A2) to the reaction system and reacting are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (ii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (ii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (ii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (ii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Furthermore, in step (iii), the reaction conditions for adding the amino acid ester or peptide ester of formula (R4) to the reaction system and reacting are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (iii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (iii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (iii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (iii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Next, in the case of the second embodiment, in step (i), the reaction conditions for adding the amino acid ester or peptide ester of formula (R4) to the fused ring dipeptide compound of formula (A2) and reacting them are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (i) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (i) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (i) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (i) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Next, in step (ii), the reaction conditions for adding the fused ring dipeptide compound of formula (A1) to the reaction system and reacting are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (ii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (ii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (ii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (ii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Furthermore, in step (iii), the reaction conditions when the protected amino acid or protected peptide of formula (R3) is added to the reaction system and reacted are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (iii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (iii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (iii) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (iii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

In both the first and second aspects, step (i), step (ii), and step (ii) may each be carried out in a sequential (batch) method or a continuous (flow) method. Specific details of the sequential (batch) method and the continuous (flow) method are known in the art. In addition, step (i) and step (ii), and/or step (ii) and step (ii) may each be carried out continuously in one pod.

Polypeptide (target compound):
The target polypeptide finally produced in the second method for producing a polypeptide of the present invention is a compound represented by the following formula (P2).

In formula (P2), R ¹¹¹ , R ¹¹² , R ¹¹³ , R ¹²¹ , and R ¹²² represent the same groups as defined in formula (A1), R ²¹¹ , R ²¹² , R ²¹³ , R ²²¹ , and R ²²² represent the same groups as defined in formula (A2), PG ^a , R ³¹ , R ³² , R ³³ , A ³¹ , A ³² , p31 , p32 , and m represent the same groups as defined in formula (R3), and PG ^b , R ⁴¹ , R ⁴² , R ⁴³ , A ⁴¹ , A ⁴² , p41 , p42 , and n represent the same groups as defined in formula (R4).

Here, the compound of formula (P2) is a polypeptide compound with the number of amino acid residues being m+n+4. That is, for example, when the compound of formula (R3) is a protected amino acid and the compound of formula (R4) is an amino acid ester (i.e., when m and n are both 1), the compound of formula (P2) produced is a polypeptide compound with the number of amino acid residues being m+n+4=6, i.e., a hexapeptide compound. Also, for example, when the compound of formula (R3) is a protected dipeptide and the compound of formula (R4) is an amino acid ester (i.e., when m is 2 and n is 1), or when the compound of formula (R3) is a protected amino acid and the compound of formula (R4) is a dipeptide ester (i.e., when m is 1 and n is 2), the compound of formula (P2) produced is a polypeptide compound with the number of amino acid residues being m+n+4=7, i.e., a heptapeptide compound. That is, depending on the number of amino acid residues (m and n) of the substrate compounds of formula (R3) and formula (R4) used, it is possible to adjust the obtained polypeptide compound (m+n+4) of formula (P2).

The polypeptide compound of formula (P2) obtained by the above-mentioned production method may be subjected to various post-treatments. Such post-treatments include isolation and purification of the polypeptide compound of formula (P2) obtained, deprotection of the amino-protecting group PG ^a and/or the carboxyl-protecting group PG ^b , etc. Such post-treatments will be summarized later.

[VI. Fused-ring tripeptide compound of the present invention and its production method]
·overview:
In addition, it is also possible to produce a novel silane-containing fused-ring tripeptide compound in which a tripeptide forms a fused ring by using the fused-ring dipeptide compound of the present invention. Such a novel silane-containing fused-ring tripeptide compound (hereinafter, appropriately referred to as the "fused-ring tripeptide compound of the present invention") and its production method are also subject to the present invention.

Silane-containing condensed ring tripeptide compounds:
The fused ring tripeptide compound of the present invention is a silane-containing fused ring tripeptide compound having a structure represented by the following formula (B).

In formula (B), R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 and R ^a2 each independently represent a group having the same definition as the group having the same symbol in formula (A), the details of which are as described above.

In formula (B), R ^x1 and R ^x2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or a monovalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, which may have one or more substituents. The details are the same as those described above for R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , etc.

In formula (B), PG ^x represents a monovalent protecting group. Examples thereof include, but are not limited to, monovalent aliphatic hydrocarbon groups, aromatic hydrocarbon groups, or heterocyclic groups, which may have one or more substituents. In addition, when having a substituent, the type thereof is as described above. Specific examples of the number of the substituents are, for example, 5, 4, 3, 2, 1, or 0.

When the protecting group PG ^x in formula (B) is an aliphatic hydrocarbon group, the number of carbon atoms in the aliphatic hydrocarbon group (including the substituent if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aliphatic hydrocarbon group, but is 1 or more in the case of an alkyl group, 2 or more in the case of an alkenyl group or an alkynyl group, and 3 or more in the case of a cycloalkyl group, for example, 4 or more, or 5 or more. Specific examples of the number of atoms are, for example, 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20, etc.

When the protecting group PG ^x in formula (B) is an aromatic hydrocarbon group, the number of carbon atoms in the aromatic hydrocarbon group (including the substituent if any) is not particularly limited, but the upper limit is, for example, 20 or less, 15 or less, 10 or less, 8 or less, or 6 or less. The lower limit varies depending on the type of aromatic hydrocarbon group, but is usually 4 or more, for example 5 or more, or 6 or more. Specific examples of the number of atoms are, for example, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, or 20.

The specific type of the protecting group PG ^x in formula (B) is not limited, but examples include the following.

- alkyl groups such as methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, tert-butyl, sec-butyl, pentyl, isopentyl, neopentyl, hexyl, heptyl, octyl, decyl, and nonyl groups;
alkenyl groups such as ethenyl, propenyl, allyl, butenyl, pentenyl, hexenyl, heptenyl, and octenyl;
- alkynyl groups such as propargyl groups;
- cycloalkyl groups such as a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, a cyclohexyl group, a cycloheptyl group, a bicyclooctyl group, and a spirooctyl group;
Aryl groups and arylalkyl groups such as a phenyl group, a benzyl group, a tolyl group, a cumyl group, a 1,1-diphenylethyl group, a triphenylmethyl group, a fluorenyl group, a naphthyl group, and an anthracenyl group;
- the above alkyl groups, alkenyl groups, alkynyl groups, cycloalkyl groups, aryl groups and arylalkyl groups each substituted with one or more halogens;
Furanyl group, thiophenyl group, pyranyl group, pyrrolinyl group, pyrrolyl group, 2,3-dihydro-1H-pyrrolyl group, piperidinyl group, piperazinyl group, homopiperazinyl group, morpholino group, thiomorpholino group, 1,2,4,6-tetrahydropyridyl group, hexahydropyrimidyl group, hexahydropyridazyl group, 1,2,4,6-tetrahydropyridyl group, 1,2,4,6-tetrahydropyridazyl group, 3,4-dihydropyridyl group, imidazolyl group, 4,5-dihydro-1H-imidazolyl group, heterocyclic groups such as an alkyl group, a 2,3-dihydro-1H-imidazolyl group, a pyrazolyl group, a 4,5-dihydro-1H-pyrazolyl group, a 2,3-dihydro-1H-pyrazolyl group, an oxazolyl group, a 4,5-dihydro-1,3-oxazolyl group, a 2,3-dihydro-1,3-oxazolyl group, a 2,5-dihydro-1,3-oxazolyl group, a thiazolyl group, a 4,5-dihydro-1,3-thiazolyl group, a 2,3-dihydro-1,3-thiazolyl group, a 2,5-dihydro-1,3-thiazolyl group, and a carbazolyl group;
Silicon-based protecting groups such as a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl (TIPS) group, a tritert-butylsilyl (TBS) group, a tert-butyldiphenylsilyl (TBDPS) group, a tris(trialkylsilyl)silyl group, and the like;

Summary of the method for producing silane-containing fused ring tripeptide compounds:
The fused ring tripeptide compound of the present invention can be produced by a method including the following steps (hereinafter appropriately referred to as "the fused ring tripeptide compound of the present invention").
(iv) providing a fused ring dipeptide compound of formula (A).
(v) reacting the fused ring dipeptide compound of formula (A) with an amino acid ester represented by the following formula (Rx):

A condensed ring dipeptide compound of formula (A) (substrate compound):
In step (iv), a fused ring dipeptide compound of formula (A) is prepared. The method for preparing the fused ring dipeptide compound is not particularly limited, but it is preferable to prepare the compound by the above-mentioned method for preparing the fused ring dipeptide compound of the present invention.

Amino acid ester of formula (Rx) (substrate compound):
In the step (v), the fused ring dipeptide compound of formula (A) prepared in the step (iv) is reacted with an amino acid ester represented by the following formula (Rx):

In formula (R1), R ^x1 , R ^x2 and PG ^x each independently represent a group having the same definition as the group having the same symbol in formula (B), the details of which are as described above.

Fifth silane compound:
In the step (v), when the fused ring dipeptide compound of formula (A) is reacted with the amino acid ester of formula (Rx), it is preferable to optionally allow a fifth silane compound to coexist in the reaction system.

When the fifth silane compound is used, the type is not particularly limited, and examples thereof include 1-(trimethylsilyl)imidazole (TMSIM), trimethylbromosilane (TMBS), trimethylchlorosilane (TMCS), tris(haloalkyl)silane, N-(trimethylsilyl)dimethylamine (TMSDMA), trimethylsilyl trifluoromethanesulfonate (TMS-OTf), dimethylsilylimidazole, dimethylsilyl(2-methyl)imidazole, dimethylethylsilylimidazole (DMESI), dimethylisopropylsilylimidazole (DMIPSI), It is preferable that the fifth silane compound is a compound selected from 1-(tert-butyldimethylsilyl)imidazole (TBSIM), 1-(trimethylsilyl)triazole, 1-(tert-butyldimethylsilyl)triazole, N-methyl-N-trimethylsilyl trifluoroacetamide (MSTFA), N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA), N,O-bis(trimethylsilyl)acetamide (BSA), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA), and hexamethyldisilazane (HMDS). Note that, as the fifth silane compound, two or more silane compounds may be used in any combination and ratio.

・Other ingredients:
In step (v), other components may be present in the reaction system. Examples of such other components include, but are not limited to, Lewis acid catalysts, bases, phosphoric acid, etc. Details of these are as described above. These may be used alone or in any combination and ratio of two or more.

From the viewpoint of increasing the reaction efficiency, the reaction may be carried out in a solvent. The solvent is not particularly limited, but examples thereof include aqueous solvents and organic solvents. The organic solvent is not limited, but examples thereof include aromatic hydrocarbons such as toluene and xylene, ethers such as pentane, petroleum ether, tetrahydrofuran (THF), 1-methyltetrahydrofuran (1-MeTHF), diisopropyl ether (i-Pr ₂ O), diethyl ether (Et ₂ O), and cyclopentyl methyl ether (CPME), nitrogen-based organic solvents such as acetonitrile (MeCN), chlorine-based organic solvents such as dichloromethane (DCM), esters such as ethyl acetate (AcOEt), and organic acids such as acetic acid. These solvents may be used alone or in combination of two or more.

・Ratio of each ingredient used:
In step (v), the ratio of the amount of the fused ring dipeptide compound of formula (A) and the amino acid ester of formula (Rx) used is not particularly limited as long as the reaction is not inhibited.For example, the amino acid ester of formula (Rx) can be used in a range of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, relative to 1 mole of the fused ring dipeptide compound of formula (A).In addition, when two or more kinds of fused ring dipeptide compounds of formula (A) and/or two or more kinds of amino acid esters of formula (Rx) are used in combination, the total amount of each component should be set to satisfy the above range.

When the fifth silane compound is used in step (v), the amount of the fifth silane compound is not particularly limited as long as it does not interfere with the reaction. For example, the fifth silane compound can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, or 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensed ring dipeptide compound of formula (A). When two or more fifth silane compounds are used in combination, the total amount of the two or more fourth silane compounds should be within the above range.

Reaction conditions:
The reaction conditions in the step (v) are not limited as long as the reaction proceeds, but examples thereof are as follows.

The reaction temperature in step (v) is not limited as long as the reaction proceeds, but it is preferable to carry out the reaction under heating conditions. Specifically, the reaction temperature can be, for example, 10°C or higher, 20°C or higher, 30°C or higher, 40°C or higher, or 50°C or higher. The upper limit is not particularly limited, but can be, for example, 120°C or lower, 110°C or lower, or 100°C or lower.

The reaction pressure in step (v) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (v) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (v) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

・Post-processing (refining, recovery, etc.):
The fused ring tripeptide compound of the present invention obtained by the reaction of step (v) may be further subjected to various post-treatments. For example, the produced fused ring tripeptide compound of the present invention may be isolated and purified by a conventional method such as column chromatography or recrystallization. In addition, the produced fused ring dipeptide compound of the present invention may be used for producing a polypeptide by subjecting it directly or after isolation and purification to the method for producing a polypeptide of the present invention described below.

[VII. Method for producing a polypeptide using the fused ring tripeptide compound of the present invention]
The fused ring tripeptide compound of the present invention can be used in various reactions, but is preferably used in the production of polypeptides. There are two types of methods for producing polypeptides using the fused ring tripeptide compound of the present invention (hereinafter, these methods are appropriately abbreviated as "the third method for producing the polypeptide of the present invention" and "the fourth method for producing the polypeptide of the present invention"). However, the method for producing a polypeptide using the fused ring tripeptide compound of the present invention is not limited to these two methods.

(1) Method for producing a third polypeptide:
·overview:
The third method for producing a polypeptide of the present invention is a method for producing one molecule of a polypeptide compound which is a tetrapeptide or greater using one molecule of a fused ring tripeptide compound of the present invention, and comprises the following step (vi):
(vi) A step of reacting the silane-containing fused ring tripeptide compound represented by the formula (B) with a protected amino acid or a protected peptide compound represented by the following formula (Ra) to obtain a polypeptide compound represented by the following formula (P3):

Silane-containing condensed ring tripeptide compound (substrate compound):
In the third method for producing a polypeptide of the present invention, a silane-containing fused-ring tripeptide compound represented by the above formula (B) (the fused-ring tripeptide compound of the present invention) is used as a substrate compound, the details of which are as described above.

・Protected amino acids/peptides (substrate compounds):
The protected amino acid or protected peptide compound used as a substrate compound in the third method of producing a polypeptide of the present invention is a compound represented by the following formula (Ra).

In formula (Ra), PG ^a represents a protecting group for an amino group. Details of PG ^a in formula (Ra) are as described above for PG ^a in formula (R3) and formula (R4) in the first and second methods for producing peptides of the present invention.

In formula (Ra), R ^a1 and R ^a2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or an amino group, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group, which may have one or more substituents. Details of R ^a1 and R ^a2 in formula (Ra) are as described above for R ³¹ , R ³² , R ⁴¹ , and R ⁴² in formula (R3) and formula (R4).

In formula (Ra), R ^a3 represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group which may have one or more substituents. In this case, in the case of a monovalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group, it may be bonded to a nitrogen atom via a linking group. Alternatively, R ^a1 and R ^a3 may be bonded to each other to form a heterocycle which may have one or more substituents together with the carbon atom to which R ^a1 is bonded and the nitrogen atom to which R ^a3 is bonded. Details of R ^a3 in formula (Ra) are as described above for R ³³ and R ⁴³ in formula (R3) and formula (R4).

In formula (Ra), A ^a1 and A ^a2 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents. Details of A ^a1 and A ^a2 in formula (Ra) are as described above for A ³¹ , A ³² , A ⁴¹ , and A ⁴² in formula (R3) and formula (R4).

In formula (Ra), p ^a1 and p ^a2 each independently represent 0 or 1.

In formula (Ra), m ^a is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when m is 2 or more, the multiple structural units represented by the structure in [ ] may be the same or different. Details of m ^a and the structural units in [ ] in formula (Ra) are as described above for m and n in formula (R3) and formula (R4) and the structural units in [ ].

·base:
In the third peptide production method of the present invention, a base may be present in the system from the viewpoint of increasing the reaction efficiency. The type of base is not limited, and any known base that is known to improve the reaction efficiency may be used. Examples of such bases include amines having 1 to 4 linear or branched alkyl groups having 1 to 10 carbon atoms, such as tetrabutylammonium fluoride (TBAF), triethylamine (Et ₃ N), diisopropylamine (i-Pr ₂ NH), and diisopropylethylamine (i-Pr ₂ EtN), and inorganic bases such as cesium fluoride. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

Condensation agent:
In the third peptide production method of the present invention, a condensation agent may be present in the system in order to increase the efficiency of the peptide formation reaction. When a condensation agent is used, a racemization inhibitor may be used in combination. Details of the condensation agent and the racemization inhibitor are as described above in the first and second peptide production methods of the present invention.

・Other ingredients:
In the third peptide production method of the present invention, other components may also be present in addition to the substrate compounds, the fused ring tripeptide compound of formula (B), the protected amino acid or protected peptide of formula (Ra), and the base, condensing agent, and racemization inhibitor that are optionally used. Examples of such other components include catalysts, silane compounds, and phosphorus compounds. Details of such other components are as described in detail in the first and second peptide production methods of the present invention.

In order to increase the reaction efficiency, the reaction may be carried out in a solvent. Details of such a solvent are as described above in the explanation of the first and second peptide production methods of the present invention.

・Ratio of each ingredient used:
In the third method for producing a peptide of the present invention, the amount of each component used is not limited, but is preferably as follows.

The quantitative ratio of the fused ring tripeptide compound of formula (B) to the protected amino acid or protected peptide of formula (Ra) is not particularly limited, but the protected amino acid or protected peptide of formula (Ra) can be used in a range of, for example, 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per 1 mole of the fused ring tripeptide compound of formula (B).

Of course, for the target production amount of the polypeptide compound of formula (P3) of the present invention to be produced, it is necessary to use at least 1 mole each of the fused ring tripeptide compound of formula (B) and the protected amino acid or protected peptide of formula (Ra) as substrates.

When a base is used, the amount used is not particularly limited, but may be, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and, for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the fused ring tripeptide compound of formula (B). When a base is added in multiple steps, it is preferable to add an amount of base within the above range in each step.

When a condensing agent is used, the amount used is not particularly limited, but the condensing agent can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensing ring tripeptide compound of formula (B). When the condensing agent is added in multiple steps, it is preferable to add the condensing agent in an amount within the above range in each step.

When a racemization inhibitor is used in addition to a condensing agent, the amount used is not particularly limited, but the racemization inhibitor can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensed ring tripeptide compound of formula (B). When a racemization inhibitor is added in multiple steps, it is preferable to add the racemization inhibitor in an amount within the above range in each step.

Reaction conditions:
In the third method for producing a peptide of the present invention, in step (vi), a fused ring tripeptide compound of formula (B) is reacted with a protected amino acid or protected peptide compound of formula (Ra). The reaction conditions are not limited as long as the reaction proceeds, and examples are as follows.

The reaction temperature in step (vi) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (vi) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (vi) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (vi) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Polypeptide (target compound):
The target polypeptide compound finally produced in the third method for producing a polypeptide of the present invention is a compound represented by the following formula (P3).
(P3)

In formula (P3), PG ^a , R ^a1 , R ^a2 , R ^a3 , A ^a1 , A ^a2 , p ^a1 , p ^a2 , and m ^a represent groups having the same definitions as the groups having the same symbols in formula (Ra), and R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^x1 , R ^x2 , and PG ^x represent groups having the same definitions as the groups having the same symbols in formula (B).

Here, the compound of formula (P3) is a polypeptide compound having the number of amino acid residues m ^a +3. That is, for example, when the compound of formula (Ra) is a protected amino acid (i.e., when m ^a is 1), the compound of formula (P3) produced is a polypeptide compound having 1+3=4 amino acid residues, i.e., a tetrapeptide compound. Also, for example, when the compound of formula (Ra) is a protected dipeptide (i.e., when m ^a is 2), the compound of formula (P3) produced is a polypeptide compound having 2+3=5 amino acid residues, i.e., a pentapeptide compound. Also, for example, when the compound of formula (Ra) is a protected polypeptide of tripeptide or more (i.e., when m ^a is 3 or more), the compound of formula (P3) produced is a polypeptide compound having 3+3=6 or more amino acid residues, i.e., a hexapeptide or more polypeptide compound. That is, it is possible to adjust the obtained polypeptide compound of formula (P3) (m ^a +3) depending on the number of amino acid residues (m ^a ) of the substrate compound of formula (Ra) used.

The polypeptide compound of formula (P3) obtained by the above-mentioned production method may be subjected to various post-treatments. Such post-treatments include isolation and purification of the polypeptide compound of formula (P3) obtained, deprotection of the amino-protecting group PG ^a and/or the carboxyl-protecting group PG ^x , etc. Such post-treatments will be summarized below.

(2) Method for producing the fourth polypeptide:
·overview:
The fourth method for producing a polypeptide of the present invention is a method for producing one molecule of a hexapeptide compound using two molecules of the fused ring tripeptide compound of the present invention. Optionally, the resulting hexapeptide compound can be further reacted with a protected amino acid or a protected peptide compound to produce a polypeptide compound having a length of heptapeptide or more.

That is, the fourth method for producing a polypeptide of the present invention is a method comprising at least the following steps (vii) and (viii), and may further comprise, optionally, the following step (ix):
(vii) mixing a silane-containing fused ring tripeptide compound represented by the following formula (B1) with a base:
(viii) A step of reacting the mixture of step (vii) with a silane-containing fused ring tripeptide compound represented by the following formula (B2) to obtain a hexapeptide compound represented by the following formula (P4):
(ix) A step of producing a heptapeptide or longer polypeptide compound represented by the following formula (P5) by reacting the hexapeptide compound of step (viii) with a protected amino acid or protected peptide compound represented by the following formula (Ra):

Below, we will first explain the procedure for synthesizing a hexapeptide compound of formula (P4) using steps (vii) and (viii), and then explain the procedure for synthesizing a heptapeptide or higher polypeptide compound of formula (P5) using the optional step (ix).

Silane-containing condensed ring tripeptide compound (substrate compound):
The silane-containing fused ring tripeptide compound used as a substrate compound in the fourth method for producing a polypeptide of the present invention is the same compound as the silane-containing fused ring tripeptide compound represented by the above formula (B) (the fused ring tripeptide compound of the present invention), but differs from the above-mentioned third method for producing a polypeptide of the present invention in that two molecules of the silane-containing fused ring tripeptide compound are used to synthesize one molecule of the polypeptide. Here, in order to distinguish between these two molecules of the silane-containing fused ring tripeptide compound, the compound on the nucleophilic species side is represented by the following formula (B1), and the compound on the electrophilic species side is represented by the following formula (B2).

In formula (B1), R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^a11 , R ^a12 , R ^x11 , and R ^x12 each represent a group having the same definition as R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , R ^a2 , R ^x1 , and R ^x2 in formula (B).

In formula (B1), PG ^x1 represents a protecting group for a carboxyl group, as with PG ^x in formula (B). The details are as described above. However, examples of the carboxyl protecting group PG ^x in formula (B1), which is a compound on the nucleophilic species side, include, but are not limited to, alkyl groups such as a methyl group, an ethyl group, a propyl group, an isopropyl group, an n-butyl group, an isobutyl group, a tert-butyl group, a sec-butyl group, a pentyl group, an isopentyl group, a neopentyl group, a hexyl group, a heptyl group, an octyl group, a decyl group, and a nonyl group; and haloaryl groups and haloarylalkyl groups in which the alkyl group is substituted with one or more halogens.

In formula (B2), R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^a21 , R ^a22 , R ^x21 , and R ^x22 each represent a group having the same definition as R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , R ^a2 , R ^x1 , and R ^x2 in formula (B).

In formula (B2), R ^x23 represents -O-PG ^x , -NH-PG ^x , or -S-PG ^x , where PG ^x represents a monovalent protecting group having the same definition as PG ^x in formula (B). PG ^x is as described above. Among these, the protecting group PG ^x of formula (B2), which is an electrophilic species, is preferably an alkynyl group such as a propargyl group; an aryl group and an arylalkyl group such as a phenyl group, a benzyl group, a tolyl group, a cumyl group, a 1,1-diphenylethyl group, a triphenylmethyl group, a fluorenyl group, a naphthyl group, an anthracenyl group, etc.; a haloaryl group and a haloarylalkyl group such as a pentafluorophenyl group in which the aryl group and the arylalkyl group are substituted with one or more halogen groups; a silicon-based protecting group such as a trimethylsilyl (TMS) group, a triethylsilyl (TES) group, a triisopropylsilyl (TIPS) group, a tritert-butylsilyl (TBS) group, a tert-butyldiphenylsilyl (TBDPS) group, a tris(trialkylsilyl)silyl group, etc.

·base:
In the fourth peptide production method of the present invention, a base is used in step (vii). The type of base is not limited, and any known base that is known to improve reaction efficiency can be used. Examples of such bases include amines having 1 to 4 linear or branched alkyl groups having 1 to 10 carbon atoms, such as tetrabutylammonium fluoride (TBAF), triethylamine (Et ₃ N), diisopropylamine (i-Pr ₂ NH), and diisopropylethylamine (i-Pr ₂ EtN), and inorganic bases such as cesium fluoride. Any one of these may be used alone, or two or more of them may be used in any combination and ratio.

Condensation agent:
In the fourth peptide production method of the present invention, a condensation agent may be present in the system in order to increase the efficiency of the peptide formation reaction. When a condensation agent is used, a racemization inhibitor may be used in combination. Details of the condensation agent and the racemization inhibitor are as described in detail in the first to third peptide production methods of the present invention.

・Other ingredients:
In the fourth peptide production method of the present invention, in addition to the substrate compounds, the fused ring tripeptide compounds of the above-mentioned formulae (B1) and (B2), the base, and the optional condensing agent and racemization inhibitor, other components may be present. Examples of such other components include catalysts, silane compounds, and phosphorus compounds. Details of such other components are as described in detail in the first to third peptide production methods of the present invention.

In order to increase the reaction efficiency, the reaction may be carried out in a solvent. Details of such a solvent are as described in detail in the above description of the first to third peptide production methods of the present invention.

Reaction procedure:
In the fourth peptide production method of the present invention, in step (vii), a fused ring tripeptide compound of formula (B1), which is a substrate compound on the nucleophilic species side, is mixed with a base. Then, in step (viii), the mixture of step (vii) is mixed with a fused ring tripeptide compound of formula (B2), which is a substrate compound on the electrophilic species side. As a result, the fused ring tripeptide compound of formula (B1) is ring-opened to function as a nucleophilic species, while the fused ring tripeptide compound of formula (B2) is ring-opened to function as an electrophilic species, forming an amide bond, thereby obtaining a hexapeptide compound of formula (P4).

There is no particular restriction on the timing of adding other components, such as an optional condensing agent, to the reaction system, and each may be added at any time. However, when a condensing agent and/or a base are used, it is preferable to add them to the system at the start of step (vii) and/or step (viii). When a racemization inhibitor is used in addition to a condensing agent, it is preferable to add it to the system together with the condensing agent. When the reaction is carried out using a solvent, each component may be mixed in the solvent and brought into contact with each other.

・Ratio of each ingredient used:
In the fourth method for producing a peptide of the present invention, the amount of each component used is not limited, but is preferably as follows.

The quantitative ratio of the fused ring tripeptide compound of formula (B1) to the fused ring tripeptide compound of formula (B2) is not particularly limited, but the fused ring tripeptide compound of formula (B2) can be used in an amount of, for example, 0.05 moles or more, or 0.1 moles or more, or 0.2 moles or more, or 0.3 moles or more, or 0.4 moles or more, or 0.5 moles or more, and for example, 20 moles or less, or 15 moles or less, or 10 moles or less, or 8 moles or less, or 6 moles or less, or 4 moles or less, or 2 moles or less, per 1 mole of the fused ring tripeptide compound of formula (B1).

The amount of base used is not particularly limited, but may be, for example, 0.2 moles or more, 0.4 moles or more, 0.6 moles or more, 0.8 moles or more, or 1.0 moles or more, and, for example, 40 moles or less, 30 moles or less, 20 moles or less, 15 moles or less, 10 moles or less, 6 moles or less, or 4 moles or less, per mole of the fused ring tripeptide compound of formula (B1). When base is added in multiple steps, it is preferable to add an amount of base within the above range in each step.

When a condensing agent is used, the amount used is not particularly limited, but the condensing agent can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensing ring tripeptide compound of formula (B1). When the condensing agent is added in multiple steps, it is preferable to add the condensing agent in an amount within the above range in each step.

When a racemization inhibitor is used in addition to a condensing agent, the amount used is not particularly limited, but the racemization inhibitor can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, and for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the condensed ring tripeptide compound of formula (B1). When a racemization inhibitor is added in multiple steps, it is preferable to add the racemization inhibitor in an amount within the above range in each step.

Reaction conditions:
The reaction conditions in the fourth method for producing a peptide of the present invention are not limited as long as the reaction proceeds, and examples of the reaction conditions for each reaction step are as follows.

First, in step (vii), the reaction conditions for mixing the fused ring tripeptide compound of formula (B1) with a base are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (vii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (vii) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (vii) is not limited as long as the reaction proceeds, but may be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (vii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Next, in step (viii), the reaction conditions for adding the fused ring tripeptide compound of formula (B2) to the mixture of step (vii) and reacting are not limited as long as the reaction proceeds, but are, for example, as follows.

The reaction temperature in step (viii) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (viii) is not limited as long as the reaction proceeds, and may be under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (viii) is not limited as long as the reaction proceeds, but may be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (viii) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

Note that steps (vii) and (viii) may each be carried out in a sequential (batch) process or a continuous (flow) process. Specific details of the sequential (batch) and continuous (flow) process procedures are known in the art. Steps (vii) and (viii) may each be carried out continuously in one pod.

・Hexapeptide (target compound):
In the fourth method for producing a polypeptide of the present invention, the target compound, that is, a hexapeptide compound produced after carrying out step (viii), is a compound represented by the following formula (P4).

(P4)

In formula (P4), R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^x11 , R ^x12 , and PG ^x1 represent groups having the same definition as the groups having the same symbols in formula (B1), and R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^x21 , and R ^x22 represent groups having the same definition as the groups having the same symbols in formula (B2).

The hexapeptide compound of formula (P4) obtained by the above-mentioned production method may be subjected to various post-treatments. Examples of such post-treatments include isolation and purification of the hexapeptide compound of formula (P4) obtained, deprotection of the carboxyl-protecting group PG ^x1 , etc. Such post-treatments will be described below.

(3) Modified method for producing the fourth polypeptide:
·overview:
In the fourth method for producing a polypeptide of the present invention, the hexapeptide compound produced by steps (vii) and (viii) may be further reacted with a protected amino acid or a protected peptide compound in step (ix) (hereinafter, this embodiment is appropriately referred to as a "modified example of the fourth method for producing a polypeptide of the present invention"). This makes it possible to produce a polypeptide compound having a length of heptapeptide or more.

・Protected amino acids/peptides (substrate compounds):
In a modified example of the fourth method for producing a polypeptide of the present invention, in step (ix), a protected amino acid or protected peptide compound represented by the following formula (Ra) is mixed with the hexapeptide compound of formula (P4) obtained in step (viii).

Details of the protected amino acid or protected peptide compound of formula (Ra) are as described above in relation to the third peptide production method of the present invention.

The amount of the protected amino acid or peptide compound of formula (Ra) used is not particularly limited, but the base can be used in an amount of, for example, 0.2 moles or more, or 0.4 moles or more, or 0.6 moles or more, or 0.8 moles or more, or 1.0 moles or more, or, for example, 40 moles or less, or 30 moles or less, or 20 moles or less, or 15 moles or less, or 10 moles or less, or 6 moles or less, or 4 moles or less, per mole of the fused ring tripeptide compound of formula (B1). When the base is added in multiple steps, it is preferable to add the amount of the base in the above range in each step.

Reaction conditions:
In a modified example of the fourth peptide production method of the present invention, when step (ix) is carried out to synthesize a polypeptide compound having a length of heptapeptide or longer, the reaction conditions in step (ix) are not limited as long as the reaction proceeds, and examples are as follows.

The reaction temperature in step (ix) is not limited as long as the reaction proceeds, but can be, for example, 0°C or higher, or 10°C or higher, or 20°C or higher, and can be, for example, 100°C or lower, or 80°C or lower, or 60°C or lower.

The reaction pressure in step (ix) is not limited as long as the reaction proceeds, and may be carried out under reduced pressure, normal pressure, or elevated pressure, but is usually carried out at normal pressure.

The reaction atmosphere in step (ix) is not limited as long as the reaction proceeds, but can be carried out under an atmosphere of an inert gas such as argon or nitrogen.

The reaction time in step (ix) is also not limited as long as the reaction proceeds, but from the viewpoint of allowing the reaction to proceed sufficiently and efficiently, it can be, for example, 10 minutes or more, or 20 minutes or more, or 30 minutes or more, and can be, for example, 80 hours or less, 60 hours or less, or 50 hours or less.

In addition, when step (ix) is carried out after steps (vii) and (viii), steps (vii) and (viii) and step (ix) may each be carried out in a sequential (batch) process or a continuous (flow) process. Specific details of the sequential (batch) process and the continuous (flow) process are known in the art. In addition, steps (vii) and (viii) and step (ix) may each be carried out continuously in one pod.

Polypeptide (target compound):
In a modified example of the fourth method for producing a polypeptide of the present invention, the target compound, that is, a heptapeptide or higher polypeptide compound produced after carrying out step (ix), is a compound represented by the following formula (P5).

(P5)

In formula (P5),
PG ^a , R ^a1 , R ^a2 , R ^a3 , A ^a1 , A ^a2 , p ^a1 , p ^a2 and m ^a represent the same definition as the group of the same symbol in the formula (Ra), and R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^x11 , R ^x12 , PG ^x1 , R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^x21 and R ^x22 represent the same definition as the group of the same symbol in the formula (P4). In addition, the circled symbol A at the right end of the upper structure and the left end of the lower structure in the formula (P5) means that the upper structure and the lower structure are continuous at this position.

Here, the compound of formula (P5) is a polypeptide compound having the number of amino acid residues m ^a +6. That is, for example, when the compound of formula (Ra) is a protected amino acid (i.e., when m ^a is 1), the compound of formula (P5) produced is a polypeptide compound having 1+6=7 amino acid residues, i.e., a heptapeptide compound. Also, for example, when the compound of formula (Ra) is a protected dipeptide (i.e., when m ^a is 2), the compound of formula (P5) produced is a polypeptide compound having 2+6=8 amino acid residues, i.e., an octapeptide compound. Also, for example, when the compound of formula (Ra) is a protected polypeptide of tripeptide or more (i.e., when m ^a is 3 or more), the compound of formula (P5) produced is a polypeptide compound having 3+6=9 or more amino acid residues, i.e., a nonapeptide or more polypeptide compound. That is, it is possible to adjust the number of amino acid residues (m ^a ) of the substrate compound of formula (Ra) used to obtain a polypeptide compound of formula (P5) (m ^a +6).

The polypeptide compound of formula (P5) obtained by the above-mentioned production method may be subjected to various post-treatments. Such post-treatments include isolation and purification of the obtained polypeptide compound of formula (P5), deprotection of the amino-protecting group PG ^a and/or the carboxyl-protecting group PG ^b , etc. Such post-treatments will be described below.

(3) Other:
The polypeptide compounds of formulae (P1) to (P5) obtained by the above-mentioned production methods may be further subjected to various post-treatments.

For example, the polypeptide compounds of formulas (P1) to (P5) obtained by the above-mentioned production method can be isolated and purified according to conventional methods such as column chromatography and recrystallization.

In addition, in the polypeptide compounds of formulae (P1) to (P5) obtained by the above-mentioned production method, the amino group protected by the protecting group PG ^a can also be deprotected. The method for deprotecting the protected amino group is not particularly limited, and various methods can be used depending on the type of the protecting group PG ^a . Examples include deprotection by hydrogenation, deprotection by weak acid, deprotection by fluoride ion, deprotection by one-electron oxidizing agent, deprotection by hydrazine, and deprotection by oxygen. In the case of deprotection by hydrogenation, examples include (a) a method of deprotection by reduction using a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc. as a reduction catalyst in the presence of hydrogen gas, and (b) a method of deprotection by reduction using a hydrogenation reducing agent such as sodium borohydride, lithium aluminum hydride, lithium borohydride, and diborane in the presence of a metal catalyst such as palladium, palladium-carbon, palladium hydroxide, palladium hydroxide-carbon, etc.

In addition, in the polypeptide compounds of formulae (P1) to (P5) obtained by the above-mentioned production method, the carboxyl group protected by the protecting group PG ^b can also be deprotected. The method for deprotecting the protected carboxyl group is not particularly limited, and various methods can be used depending on the type of the protecting group PG ^b . Examples include deprotection by hydrogenation, deprotection by a base, and deprotection by a weak acid. In the case of deprotection by a base, examples include a method of deprotection using a strong base such as lithium hydroxide, sodium hydroxide, or potassium hydroxide as the base.

The polypeptide compounds of formulae (P1) to (P5) obtained by the above-mentioned production method may be used (after deprotection as necessary) as the above-mentioned protected peptide of formula (R3) or formula (Ra) and/or peptide ester of formula (R4) and may be subjected again to the first to fourth peptide production methods of the present invention. Alternatively, the polypeptide compounds of formulae (P1) to (P5) obtained by the above-mentioned production method may be subjected (after deprotection as necessary) to other conventionally known amidation methods or peptide production methods. In this way, other amino acids or peptides can be linked to the polypeptide compounds of formulae (P1) to (P5) by amide bonds to extend the amino acid residues and synthesize larger polypeptides. By sequentially repeating these procedures, it is possible in principle to synthesize polypeptides with any number of amino acid residues and amino acid sequence.

The present inventors have filed the following prior patent applications relating to amidation reactions for linking amino acids or peptides and methods for producing polypeptides using the same, and the methods for producing various polypeptides of the present invention can be carried out in appropriate combination with the amidation reactions and methods for producing polypeptides described in these prior patent applications, and/or can be modified as appropriate in consideration of the conditions for the amidation reactions and methods for producing polypeptides described in these prior patent applications. The descriptions of these prior patent applications are incorporated herein in their entirety by reference.
(1) International Publication No. 2017/204144 (Patent Document 1)
(2) International Publication No. 2018/199146 (Patent Document 2)
(3) International Publication No. 2018/199147 (Patent Document 3)
(4) International Publication No. 2019/208731 (Patent Document 4)
(5) International Publication No. 2021/085635 (Patent Document 5)
(6) International Publication No. 2021/085636 (Patent Document 6)
(7) International Publication No. 2021/149814 (Patent Document 7)
(8) International Publication No. 2022/190486 (Patent Document 8)

The present invention will be described in more detail below with reference to examples. However, these examples are merely illustrative and are not intended to limit the present invention in any way. Among the amino acids described below, those having optical isomerism refer to the L-form unless otherwise specified.

[Example 1: Synthesis of silane-containing condensed ring dipeptide compound]
General Synthetic Procedure

In a 5 mL vial, unprotected first amino acid (0.25 mmol), dimethylsilyldiimidazole (first silane compound; 2 equivalents; 96 mg), N-(tert-butyldimethylsilyl)-N-methyltrifluoroacetamide (MTBSTFA) (third silane compound; 1 equivalent; 58 μL), and dichloromethane (0.1 mL) were placed and stirred at room temperature for one hour. Meanwhile, in a 20 mL test tube, unprotected second amino acid (0.5 mmol) and N,O-bis(trimethylsilyl)trifluoroacetamide (BSTFA) (second silane compound; 3 equivalents; 200 μL) were placed and stirred at room temperature for one hour. After each reaction, the reactants in the vial were added to the test tube, and the inner surface of the vial was washed with dichloromethane (0.2 mL) and transferred to the test tube. Thereafter, trimethylsilylimidazole (fourth silane compound; 2 equivalents; 73.2 μL) was added to the test tube, and the mixture was stirred at 50° C. for 24 hours to obtain the desired silane-containing fused ring dipeptide compound.

(result)
The results are shown in the table below.

[Example 2: Synthesis of silane-containing fused ring tripeptide compound]
General Synthetic Procedure

A silane-containing fused ring dipeptide compound of formula (A) shown in the table below, synthesized by the method described in Example 1 (1 equivalent; 0.25 mmol), an amino acid ester of formula (Rx) (3 equivalents), and trimethylsilylimidazole (TMS-IM) (fifth silane compound; 1 equivalent) were placed in a 20 mL test tube and stirred and heated at 90°C for 24 hours to obtain a silane-containing fused ring tripeptide compound of formula (B) shown in the table below.

(result)
The results are shown in the table below.

[Example 3: Synthesis of tetrapeptide compound]
General Synthetic Procedure

A silane-containing condensed ring dipeptide compound (1 equivalent; 0.25 mmol) of formula (B) shown in the table below, synthesized by the method described in Example 2, a protected amino acid (2 equivalents) of formula (Ra) shown in the table below, a 1 M tetrabutylammonium fluoride (TBAF; base; 1.5 equivalents) solution in tetrahydrofuran (THF), and dichloromethane (DCM; 1.5 mL) were placed in a 20 mL test tube and stirred at room temperature for 12 hours to obtain the desired tetrapeptide compound of formula (P3) shown in the table below.

(result)
The results are shown in the table below.

[Example 4: Synthesis of hexapeptide compound]

In a 20 mL test tube, the silane-containing fused ring dipeptide compound shown in the above reaction formula (compound in formula (B1) where PG ^x1 is Me: 1 equivalent) synthesized by the method described in Example 2, a tetrahydrofuran (THF) solution of 1 M tetrabutylammonium fluoride (TBAF; base; 1 equivalent), and dichloromethane (DCM; 1.5 mL) were placed, and stirred at 50° C. for 24 hours. Thereafter, the silane-containing fused ring dipeptide compound shown in the above reaction formula (compound in formula (B2) where PG ^x2 is Bn: 1 equivalent) synthesized by the method described in Example 2 was placed, and stirred at 50° C. for 24 hours to obtain the hexapeptide compound shown in the above reaction formula (yield 21%).

[Example 5: Synthesis of heptapeptide compound]

In a 20 mL test tube, the silane-containing condensed ring dipeptide compound shown in the above reaction formula (compound in formula (B1) where PG ^x1 is Me: 1 equivalent) synthesized by the method described in Example 2, a tetrahydrofuran (THF) solution of 1 M tetrabutylammonium fluoride (TBAF; base; 1 equivalent), and dichloromethane (DCM; 1.5 mL) were placed, and the mixture was stirred at 50° C. for 24 hours. Thereafter, the silane-containing condensed ring dipeptide compound shown in the above reaction formula (compound in formula (B2) where PG ^x2 is Bn: 1 equivalent) synthesized by the method described in Example 2 was placed, and the mixture was stirred at 50° C. for 24 hours, thereby obtaining the hexapeptide compound shown in the above reaction formula. Furthermore, Fmoc-Ala-Cl (N-terminal Fmoc-protected alanine chloride; 2 equivalents) was added, and the mixture was stirred at room temperature for 24 hours, thereby obtaining the heptapeptide compound shown in the above reaction formula (yield 11%).

Claims (11)

A method for producing a silane-containing fused ring dipeptide compound represented by the following formula (A), comprising the following steps (i) to (iii):
(i) a step of reacting a first amino acid represented by the following formula (R1) with a first silane compound represented by the following formula (S1):
(ii) A step of reacting a second amino acid represented by the following formula (R2) with a second silane compound represented by the following formula (S2):
(iii) A step of mixing the reactant from the step (i) and the reactant from the step (ii) and further reacting them to obtain the silane-containing fused ring dipeptide compound of the formula (A).
However, in formula (A),
R ¹¹ , R ¹² , R ¹³ , R ²¹ , and R ²² each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents;
R ^a1 and R ^a2 each independently represent a monovalent aliphatic or aromatic hydrocarbon group which may have one or more substituents.
However, in formula (R1),
R ¹¹ , R ¹² and R ¹³ each independently represent a group having the same definition as the group having the same symbol in formula (A).
However, in formula (S1),
R ^a1 and R ^a2 each represent a group having the same definition as the group having the same symbol in formula (A).
Z ^a1 and Z ^a2 each independently represent a 5- to 10-membered heterocyclic group containing one or more nitrogen atoms as ring-constituting atoms which may have one or more substituents.
However, in formula (R2),
R ²¹ and R ²² each independently represent a group having the same definition as the group having the same symbol in formula (A).
However, in formula (S2),
R ^b1 , R ^b2 , and R ^b3 each independently represent a hydrogen atom, a halogen atom, or a monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group which may have one or more substituents;
^nb represents an integer of 1 or 2;
When ^nb is 1, ^Zb represents an amino group, a carbonylamino group, an acetamide group, or a 5- to 10-membered monovalent heterocyclic group containing one or more nitrogen atoms as ring-constituting atoms, which may have one or more substituents;
When ^nb is 2, ^Zb represents a divalent linking group containing nitrogen. When ^nb is 2, ^Rb1 , ^Rb2 , and ^Rb3 , each of which exists in two, may be the same or different. The method according to claim 1, wherein in step (i), a third silane compound is present in the reaction system. The method according to claim 1, wherein in step (iii), a fourth silane compound is present in the reaction system. A method for producing a silane-containing fused ring tripeptide compound represented by the following formula (B), comprising the following steps (iv) and (v):
(iv) A step of producing a silane-containing fused ring dipeptide compound represented by the formula (A) by the method according to any one of claims 1 to 3.
(v) A step of reacting the silane-containing fused ring dipeptide compound represented by the formula (A) with an amino acid ester represented by the following formula (Rx):
However, in formula (B),
R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , and R ^a2 each independently represent a group having the same definition as the group having the same symbol in formula (A);
R and ^R each independently represent a hydrogen ^atom , a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents;
PG ^x represents a monovalent protecting group.
However, in formula (R1),
R ^x1 , R ^x2 and PG ^x each independently represent a group having the same definition as the group having the same symbol in formula (B). The method according to claim 4, wherein in step (v), a fifth silane compound is present in the reaction system. A silane-containing fused ring tripeptide compound represented by the following formula (B):
However, in formula (B),
R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , and R ^a2 each independently represent a group having the same definition as the group having the same symbol in formula (A);
R ^x1 and R ^x2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, or a thiol group, or a monovalent aliphatic hydrocarbon group, an aromatic hydrocarbon group, or a heterocyclic group which may have one or more substituents, and in this case, when the monovalent aliphatic hydrocarbon group, the aromatic hydrocarbon group, or the heterocyclic group has one or more substituents, the substituents are each a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, a sulfonic acid group, an amino group, an amido group, an imino group, an imido group, a hydrocarbon group, a heterocyclic group, a hydrocarbonoxy group, a hydrocarboncarbonyl group (acyl group), a hydrocarbonoxycarbonyl group, a hydrocarboncarbonyloxy group, a hydrocarbon-substituted amino group, a carbon and wherein the number of carbon atoms of the monovalent aliphatic hydrocarbon group or aromatic hydrocarbon group, or the total number of carbon atoms and heteroatoms of the heterocyclic group, in the case where the heterocyclic group has one or more substituents, is 20 or less in total, including the substituents, and
PG ^x represents a monovalent protecting group for a carboxyl group. A method for producing a tetrapeptide or higher polypeptide compound using the silane-containing fused ring tripeptide compound according to claim 6, comprising the following step (vi):
(vi) A step of reacting the silane-containing fused ring tripeptide compound represented by the formula (B) with a protected amino acid or a protected peptide compound represented by the following formula (Ra) to obtain a polypeptide compound represented by the following formula (P3):
However, in formula (Ra),
PG ^a represents an amino-protecting group;
R ^a1 and R ^a2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or an amino group, which may have one or more substituents, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group;
^R represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents, and in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to a nitrogen atom via a linking group,
Alternatively, R ^a1 and R ^a3 may be bonded to each other to form a heterocycle optionally having one or more substituents, together with the carbon atom to which R ^a1 is bonded and the nitrogen atom to which R ^a3 is bonded.
A ^a1 and A ^a2 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents,
p ^a1 and p ^a2 each independently represent 0 or 1;
m ^a is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when m is 2 or more, the multiple structural units represented by the structure in [ ] may be the same or different.
(P3)
However, in formula (P3),
PG ^a , R ^a1 , R ^a2 , R ^a3 , A ^a1 , A ^a2 , p ^a1 , p ^a2 , and m ^a each represent a group having the same definition as the group having the same symbol in formula (Ra);
^R11 , ^R12 , ^R13 , ^R21 , ^R22 , ^Rx1 , ^Rx2 , and ^PGx each represent a group having the same definition as the group having the same symbol in formula (B). The method according to claim 7, wherein in step (iv), a base is present in the reaction system. A method for producing a hexapeptide compound using two molecules of the silane-containing fused ring tripeptide compound according to claim 6, comprising the following step (vii):
(vii) mixing a silane-containing fused ring tripeptide compound represented by the following formula (B1) with a base:
(viii) A step of reacting the mixture of step (vii) with a silane-containing fused ring tripeptide compound represented by the following formula (B2) to obtain a polypeptide compound represented by the following formula (P4):
In formula (B1), R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^a11 , R ^a12 , R ^x11 , R ^x12 , and PG ^x1 each represent a group having the same definition as R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , R ^a2 , R ^x1 , R ^x2 , and PG ^x in formula (B).
In the formula (B2), R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^a21 , R ^a22 , R ^x21 , and R ^x22 each represent a group having the same definition as R ¹¹ , R ¹² , R ¹³ , R ²¹ , R ²² , R ^a1 , R ^a2 , R ^x1 , and R ^x2 in the formula (B),
R ^x23 represents -O-PG ^x , -NH-PG ^x , or -S-PG ^x , where PG ^x represents a monovalent protecting group having the same definition as PG ^x in formula (B) above.
(P4)
However, in formula (P4),
R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^x11 , R ^x12 and PG ^x1 represent groups having the same definitions as the groups of the same symbols in formula (B1),
R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^x21 and R ^x22 each represent a group having the same definition as the group having the same symbol in formula (B2). A method for producing a heptapeptide or greater polypeptide compound, comprising the following steps (viii) and (ix):
(viii) A step of producing a hexapeptide compound represented by the formula (P4) by the method according to claim 9.
(ix) A step of reacting the hexapeptide compound with a protected amino acid or a protected peptide compound represented by the following formula (Ra) to produce a polypeptide compound represented by the following formula (P5):
However, in formula (Ra),
PG ^a represents an amino-protecting group;
R ^a1 and R ^a2 each independently represent a hydrogen atom, a halogen atom, a hydroxyl group, a carboxyl group, a nitro group, a cyano group, a thiol group, or an amino group, which may have one or more substituents, a monovalent aliphatic hydrocarbon group, a monovalent aromatic hydrocarbon group, or a monovalent heterocyclic group;
^R represents a hydrogen atom, a carboxyl group, a hydroxyl group, or a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group which may have one or more substituents, and in the case of a monovalent aliphatic hydrocarbon group, aromatic hydrocarbon group, or heterocyclic group, it may be bonded to a nitrogen atom via a linking group,
Alternatively, R ^a1 and R ^a3 may be bonded to each other to form a heterocycle optionally having one or more substituents, together with the carbon atom to which R ^a1 is bonded and the nitrogen atom to which R ^a3 is bonded.
A ^a1 and A ^a2 each independently represent a divalent aliphatic hydrocarbon group having 1 to 3 carbon atoms which may have one or more substituents,
p ^a1 and p ^a2 each independently represent 0 or 1;
m ^a is an integer of 1 or more and represents the number of structural units represented by the structure in [ ]. However, when m is 2 or more, the multiple structural units represented by the structure in [ ] may be the same or different.
(P5)
However, in formula (P5),
PG ^a , R ^a1 , R ^a2 , R ^a3 , A ^a1 , A ^a2 , p ^a1 , p ^a2 , and m ^a each represent a group having the same definition as the group having the same symbol in formula (Ra);
R ¹¹¹ , R ¹¹² , R ¹¹³ , R ²¹¹ , R ²¹² , R ^x11 , R ^x12 , PG ^x1 , R ¹²¹ , R ¹²² , R ¹²³ , R ²²¹ , R ²²² , R ^x21 , and R ^x22 represent groups having the same definitions as the groups of the same symbols in formula (P4).
Furthermore, the circled symbol A at the right end of the upper structure and at the left end of the lower structure in formula (P5) means that the upper structure and the lower structure are continuous at this position. The method of claim 10, wherein steps (viii) and (ix) are carried out in one pot.