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WO2019176732A1 - Procédé de production d'un composé contenant un cycle tétrahydroisoquinoléine - Google Patents

Procédé de production d'un composé contenant un cycle tétrahydroisoquinoléine Download PDF

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WO2019176732A1
WO2019176732A1 PCT/JP2019/009128 JP2019009128W WO2019176732A1 WO 2019176732 A1 WO2019176732 A1 WO 2019176732A1 JP 2019009128 W JP2019009128 W JP 2019009128W WO 2019176732 A1 WO2019176732 A1 WO 2019176732A1
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formula
group
compound represented
alkyl group
optionally substituted
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博毅 大栗
涼 谷藤
及川　英秋
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Hokkaido University NUC
Tokyo University of Agriculture and Technology NUC
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Hokkaido University NUC
Tokyo University of Agriculture and Technology NUC
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C271/00—Derivatives of carbamic acids, i.e. compounds containing any of the groups, the nitrogen atom not being part of nitro or nitroso groups
    • C07C271/06—Esters of carbamic acids
    • C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
    • C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C271/22—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by carboxyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/18—Bridged systems
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12P—FERMENTATION OR ENZYME-USING PROCESSES TO SYNTHESISE A DESIRED CHEMICAL COMPOUND OR COMPOSITION OR TO SEPARATE OPTICAL ISOMERS FROM A RACEMIC MIXTURE
    • C12P17/00—Preparation of heterocyclic carbon compounds with only O, N, S, Se or Te as ring hetero atoms
    • C12P17/10—Nitrogen as only ring hetero atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/4995—Pyrazines or piperazines forming part of bridged ring systems
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B53/00—Asymmetric syntheses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B61/00—Other general methods
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for producing a compound having a structure in which a plurality of tetrahydroisoquinoline rings are linked, and particularly to a method for producing saframycins and analogs thereof.
  • the present invention also relates to an intermediate compound for synthesizing the compound.
  • the antitumor alkaloid group represented by saframycins is a compound having a complex pentacyclic skeleton in which a plurality of tetrahydroisoquinoline (THIQ) rings are linked.
  • THIQ tetrahydroisoquinoline
  • saframycin A compound 1
  • saframycin Y3 compound 2
  • Jornamycin A, Renieramycin M, Extenasaidin 743 Compounds 3 to 5 have been reported as a group of natural products sharing a similar pentacyclic mother skeleton.
  • Compounds 1 to 4 are composed of two THIQ rings and have a function of alkylating a guanine base of DNA with an iminium cation generated from an aminonitrile. Further, Compound 5 having both a nucleic acid alkylation site and a protein interaction site has been clinically applied as an anticancer drug ("Trabectedin", "Yonderis”).
  • Non-patent Documents 1 and 2 For the tetrahydroisoquinoline alkaloid compound group having such a unique structure and exhibiting excellent anticancer activity, various total synthesis studies have been actively developed (Non-patent Documents 1 and 2).
  • the above-mentioned ectenasaidin 743 (compound 5), which is an anticancer drug with a very complex polycyclic structure, is supplied in a multi-stage semi-synthetic cocoon (21 steps) cocoon obtained from cyanosafracin (compound 6) obtained by culture.
  • Non-Patent Document 3 Non-Patent Document 3
  • these conventionally reported synthesis processes involve complicated starting materials, and it is necessary to separate and purify the product every time the reaction is performed, so that there is a problem of production efficiency that requires a multi-step synthesis step. was there.
  • Non-patent Document 4 An enzyme with unique properties that forms a pentacyclic skeleton containing a THIQ ring by catalyzing imine formation between long-chain fatty acid aldehydes and amino acids and subsequent Pictet-Spengler (PS) -type cyclization This is reported (Non-patent Document 4).
  • an object of the present invention is to provide a production method capable of easily synthesizing a compound having a structure in which a plurality of tetrahydroisoquinoline rings are linked with fewer steps. It is another object of the present invention to provide a chemically modifiable intermediate that enables the synthesis of novel derivatives other than natural tetrahydroisoquinoline ring-containing alkaloids.
  • the present inventors have used a non-natural aldehyde substrate and a tyrosine derivative having a specific structure that do not exist in the biosynthetic pathway using a non-ribosome-dependent peptide synthase. It was found that a non-natural intermediate compound having a pentacyclic skeleton linked with a tetrahydroisoquinoline ring can be rapidly synthesized in one pot.
  • a non-natural aldehyde substrate having a specific structure chemical conversion after skeleton formation of an intermediate can be freely performed while ensuring adaptability to an enzyme reaction, and it is simple and highly efficient. It has been found that a class and its analogs are obtained. Based on these findings, the present invention has been completed.
  • ⁇ 1> A method for producing a compound represented by the following formula (I): Wherein X is —C (R 3 ) NH— or —C (R 3 ) O—; Y is —C ( ⁇ O) R 4 —NH—, —C ( ⁇ O) R 4 —O—, —S ( ⁇ O) 2 R 4 —NH—, —S ( ⁇ O) 2 R 4 —O—, —P ( ⁇ O) (OR 5 ) R 4 —NH—, or —P ( ⁇ O) (OR 5 ) R 4 —O—; Z is —C ( ⁇ O) R 6 , —C ( ⁇ O) OR 6 , —S ( ⁇ O) 2 R 6 , or —P ( ⁇ O) (OR 5 ) R 6 ; R 1 and R 2 are each independently a C 1 -C 10 alkyl group, which may be the same or different; R 3 is a hydrogen atom or a substituent An optional
  • Step A a compound represented by the following formula (a): (Wherein R 1 and R 2 have the same meaning as in formula (I).) A compound represented by the following formula (b): (In the formula, X, Y and Z have the same meaning as in formula (I).) A step of obtaining a compound represented by the following formula (II) by reacting in the presence of a non-ribosome-dependent peptide synthase (Wherein X, Y, Z, R 1 and R 2 have the same meaning as in formula (I)); [Step B] A step of adding a cyanide ion to the compound represented by the formula (II) to obtain a compound represented by the following formula (III) (Wherein X, Y, Z, R 1 and R 2 have the same meaning as in formula (I)); and [Step C] an aldehyde and a reducing agent for the compound represented by formula (III) N-alkylation of a secondary amine moiety by adding a compound to obtain a compound to obtain
  • the present invention provides ⁇ 6> From an intermediate compound represented by the following formula (I) Wherein X is —C (R 3 ) NH—; Y is —C ( ⁇ O) R 4 —NH—; Z is —C ( ⁇ O) OR 6 ; R 1 and R 2 are each independently a C 1 -C 10 alkyl group, which may be the same or different; R 3 is a hydrogen atom or an optionally substituted C 1 -C 5 alkyl group R 4 is an optionally substituted alkylene group; R 6 is a saturated or unsaturated hydrocarbon chain; R a is an optionally substituted alkyl group.)
  • Step E The production comprising the step of obtaining the compound represented by the formula (IV) by oxidizing the compound represented by the formula (V) in the presence of a transition metal catalyst and converting phenol to quinone.
  • the present invention provides: ⁇ 10> From the intermediate compound represented by the following formula (I) Wherein X is —C (R 3 ) NH—; Y is —C ( ⁇ O) R 4 —O—; Z is —C ( ⁇ O) R 6 ; R 1 and R 2 are each independently a C 1 -C 10 alkyl group, which may be the same or different; R 3 is a hydrogen atom or an optionally substituted C 1 -C 5 alkyl group R 4 is a 1-methylmethylene group; R 6 is a saturated or unsaturated hydrocarbon chain; R a is an optionally substituted alkyl group.)
  • a compound represented by the following formula (VII) is obtained by hydrolyzing the compound represented by the above formula (I) under basic conditions and converting the end of the Y site into
  • Step G A step of obtaining a compound represented by the following formula (VIII) by oxidizing the compound represented by the formula (VII) in the presence of a transition metal catalyst and converting phenol to quinone. (Wherein X, R 1 , R 2 and R a have the same meaning as in formula (I)); and [Step H] The compound represented by (VIII) is subjected to DMSO oxidation or hypervalence.
  • the production method comprising a step of obtaining a compound represented by the formula (VI) by converting a terminal OH group into a carbonyl group by oxidation with an iodine reagent; ⁇ 11>
  • the transition metal catalyst in is a cobalt complex, The manufacturing method as described in said ⁇ 10> or ⁇ 11> is provided.
  • the present invention also relates to the following intermediate compounds:
  • ⁇ 13> A compound represented by the following formula (I); Wherein X is —C (R 3 ) NH— or —C (R 3 ) O—; Y is —C ( ⁇ O) R 4 —NH—, —C ( ⁇ O) R 4 —O—, —S ( ⁇ O) 2 R 4 —NH—, —S ( ⁇ O) 2 R 4 —O—, —P ( ⁇ O) (OR 5 ) R 4 —NH—, or —P ( ⁇ O) (OR 5 ) R 4 —O—; Z is —C ( ⁇ O) R 6 , —C ( ⁇ O) OR 6 , —S ( ⁇ O) 2 R 6 , or —P ( ⁇ O) (OR 5 ) R 6 ; R 1 and R 2 are each independently a C 1 -C 10 alkyl group, which may be the same or different; R 3 is a hydrogen atom or a
  • ⁇ 14> The compound according to ⁇ 13>, selected from the group consisting of the following compounds; (Wherein, Z a is a C 6 -C 20 alkyl group, Me represents a methyl group.) ⁇ 15> a compound represented by the following formula (II); Wherein X is —C (R 3 ) NH— or —C (R 3 ) O—; Y is —C ( ⁇ O) R 4 —NH—, —C ( ⁇ O) R 4 —O—, —S ( ⁇ O) 2 R 4 —NH—, —S ( ⁇ O) 2 R 4 —O—, —P ( ⁇ O) (OR 5 ) R 4 —NH—, or —P ( ⁇ O) (OR 5 ) R 4 —O—; Z is —C ( ⁇ O) R 6 , —C ( ⁇ O) OR 6 , —S ( ⁇ O) 2 R 6 , or —P ( ⁇ O) (OR 5 ) R 6 ; R 1 and
  • a non-natural intermediate compound having a pentacyclic skeleton linked by a tetrahydroisoquinoline ring can be rapidly synthesized in one pot.
  • the terminal long-chain fatty acid moiety can be selectively removed even after the formation of the pentacyclic skeleton even in the presence of many other functional groups, compared with conventional synthesis methods.
  • an excellent effect is obtained that saframycins and analogs thereof can be efficiently obtained in a short process.
  • the intermediate compound of the present invention can not only selectively remove the long-chain fatty acid moiety, which has been difficult in the conventional enzyme-catalyzed reaction as described above, but also can be substituted with any substituent after the intermediate skeleton is formed. Since it can be introduced and subjected to chemical conversion freely, it can be applied to the synthesis of novel derivatives other than natural tetrahydroisoquinoline ring-containing alkaloids. Furthermore, there is an advantage that benzene rings / quinone rings at both ends of the pentacyclic skeleton involved in the activity expression of the final target product can be separately produced.
  • the “alkyl or alkyl group” may be any of an aliphatic hydrocarbon group composed of a straight chain, a branched chain, a ring, or a combination thereof.
  • the number of carbon atoms of the alkyl group is not particularly limited. For example, the number of carbon atoms is 1 to 20 (C 1-20 ), the number of carbons is 1 to 15 (C 1 to 15 ), and the number of carbon atoms is 1 to 10 (C 1 to 10).
  • the alkyl group may have one or more arbitrary substituents.
  • C 1-8 alkyl includes methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neo-pentyl, n-hexyl, isohexyl, n-heptyl, n-octyl and the like are included.
  • substituents examples include an alkoxy group, a halogen atom (which may be a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom), an amino group, a mono- or di-substituted amino group, a substituted silyl group, or Although acyl etc. can be mentioned, it is not limited to these.
  • the alkyl group has two or more substituents, they may be the same or different. The same applies to the alkyl part of other substituents containing an alkyl part (for example, an alkoxy group, an arylalkyl group, etc.).
  • alkylene is a divalent group consisting of a linear or branched saturated hydrocarbon, such as methylene, 1-methylmethylene, 1,1-dimethylmethylene, ethylene, 1-methylethylene, 1-ethylethylene, 1,1-dimethylethylene, 1,2-dimethylethylene, 1,1-diethylethylene, 1,2-diethylethylene, 1-ethyl-2-methylethylene, trimethylene, 1 -Methyltrimethylene, 2-methyltrimethylene, 1,1-dimethyltrimethylene, 1,2-dimethyltrimethylene, 2,2-dimethyltrimethylene, 1-ethyltrimethylene, 2-ethyltrimethylene, 1,1 -Diethyltrimethylene, 1,2-diethyltrimethylene, 2,2-diethyltrimethylene, 2-ethyl-2-methyltrime Len, tetramethylene, 1-methyltetramethylene, 2-methyltetramethylene, 1,1-dimethyltetramethylene, 1,2-d
  • a functional group when a functional group is defined as “may be substituted”, the type of substituent, the position of substitution, and the number of substituents are not particularly limited, and two or more When they have a substituent, they may be the same or different.
  • the substituent group include, but are not limited to, an alkyl group, an alkoxy group, a hydroxyl group, a carboxyl group, a halogen atom, a sulfo group, an amino group, an alkoxycarbonyl group, and an oxo group. These substituents may further have a substituent. Examples of such include, but are not limited to, a halogenated alkyl group.
  • acyl or acyl group may be either an aliphatic acyl group or an aromatic acyl group, or an aliphatic acyl group having an aromatic group as a substituent.
  • Acyl groups may contain one or more heteroatoms.
  • an alkylcarbonyl group such as an acetyl group
  • an alkyloxycarbonyl group such as an acetoxycarbonyl group
  • an arylcarbonyl group such as a benzoyl group
  • an aryloxycarbonyl group such as a phenyloxycarbonyl group
  • an aralkylcarbonyl group Benzylcarbonyl group
  • alkylthiocarbonyl group such as methylthiocarbonyl group
  • alkylaminocarbonyl group such as methylaminocarbonyl group
  • arylthiocarbonyl group such as phenylthiocarbonyl group
  • arylaminocarbonyl group phenylaminocarbonyl group
  • acyl groups may have one or more arbitrary substituents.
  • substituents include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and an acyl group.
  • the acyl group has two or more substituents, they may be the same or different.
  • the “aryl or aryl group” may be either a monocyclic or condensed polycyclic aromatic hydrocarbon group, and a hetero atom (for example, an oxygen atom, a nitrogen atom, Or a sulfur atom or the like). In this case, it may be referred to as “heteroaryl” or “heteroaromatic”. Whether aryl is a single ring or a fused ring, it can be attached at all possible positions. In the present specification, an aryl group may have one or more arbitrary substituents on the ring.
  • substituents examples include, but are not limited to, an alkoxy group, a halogen atom, an amino group, a mono- or di-substituted amino group, a substituted silyl group, and acyl.
  • the aryl group has two or more substituents, they may be the same or different. The same applies to the aryl moiety of other substituents containing the aryl moiety (for example, an aryloxy group and an arylalkyl group).
  • the “alkoxy group” is a structure in which the alkyl group is bonded to an oxygen atom, and examples thereof include a saturated alkoxy group that is linear, branched, cyclic, or a combination thereof.
  • methoxy group, ethoxy group, n-propoxy group, isopropoxy group, cyclopropoxy group, n-butoxy group, isobutoxy group, s-butoxy group, t-butoxy group, cyclobutoxy group, cyclopropylmethoxy group, n- Pentyloxy group, cyclopentyloxy group, cyclopropylethyloxy group, cyclobutylmethyloxy group, n-hexyloxy group, cyclohexyloxy group, cyclopropylpropyloxy group, cyclobutylethyloxy group, cyclopentylmethyloxy group, etc. are preferable Take as an example.
  • ring structure when formed by a combination of two substituents, means a heterocyclic or carbocyclic ring, such ring being saturated, unsaturated, or aromatic. be able to. Accordingly, it includes cycloalkyl, cycloalkenyl, aryl, and heteroaryl as defined above.
  • phenolic OH group or phenolic hydroxyl group means an OH group bonded to an arbitrary position on the benzene ring.
  • a specific substituent can form a ring structure with another substituent, and when such substituents are bonded to each other, those skilled in the art will recognize a specific substituent, for example, hydrogen. It can be understood that the bonds are formed. Therefore, when it is described that specific substituents together form a ring structure, those skilled in the art can understand that the ring structure can be formed by an ordinary chemical reaction and can be easily generated. Both such ring structures and their process of formation are within the purview of those skilled in the art. Moreover, the said heterocyclic structure may have arbitrary substituents on the ring.
  • the intermediate compound represented by the formula (I) has a pentacyclic skeleton in which two tetrahydroisoquinoline (THIQ) rings are connected.
  • the XYZ moiety in the molecule is a side chain containing a long-chain alkyl necessary for proceeding with the enzyme reaction in Step A described later. Since saframycins such as saframycin Y3 and saframycin A have the pentacyclic skeleton as a common skeleton, the long chain alkyl moiety in XYZ is finally cleaved and removed. Saframycins are obtained. Therefore, a desired target product can be obtained by selecting the linker portions of X and Y together with the structure of the target product.
  • R 4 is an optionally substituted alkylene group.
  • X and Y can be selected according to the desired structure of the target object.
  • X is —C (R 3 ) NH—
  • Y is —C ( ⁇ O) R 4 —NH—.
  • —NHC ( ⁇ O) O— in the connecting portion of X and Y has a structure called carbamate or urethane.
  • X is preferably —C (R 3 ) NH—
  • Y is preferably —C ( ⁇ O) R 4 —O—.
  • R 3 in X is a hydrogen atom or an optionally substituted C 1 -C 5 alkyl group, preferably a hydrogen atom or a methyl group.
  • R 4 which is a linking group in Y is an optionally substituted alkylene group.
  • a C 2 -alkylene group is preferred, and 1-methylmethylene (—CH (CH 3 ) —) is more preferred.
  • R 4 -NH- or -P ( O) (OR 5 )
  • R 4 -O- 5 Is an optionally substituted C 1 -C 5 alkyl group, preferably methyl.
  • Z is —C ( ⁇ O) R 6 , —C ( ⁇ O) OR 6 , —S ( ⁇ O) 2 R 6 , or —P ( ⁇ O) (OR 5 ) R 6 .
  • R 6 is a saturated or unsaturated hydrocarbon chain.
  • the number of carbon atoms of R 6 is not particularly limited, but is preferably a C 5 -C 30 alkyl group, and more preferably a C 10 -C 20 alkyl group.
  • R 1 and R 2 are each independently a C 1 -C 10 alkyl group which may be the same or different, preferably a methyl group. More preferably, each of R 1 and R 2 is preferably a methyl group. However, any substituent other than an alkyl group can be used depending on the final product of interest.
  • R a is a substituent on the tertiary amine in the pentacyclic skeleton.
  • R a is preferably an optionally substituted alkyl group, and more preferably a methyl group.
  • substituents other than alkyl groups can be used depending on the final product of interest.
  • the method for producing an intermediate compound represented by the formula (I) of the invention includes the following steps A to C. That is, in Step A, a precursor compound (II) having a pentacyclic skeleton in which two THIQ rings are linked by an enzymatic reaction is synthesized, and in Steps B and C, this is subjected to cyanation and reductive N-methylation. Thus, an intermediate compound represented by the formula (I) is obtained.
  • Step A Enzyme-catalyzed reaction
  • Step A comprises a compound represented by the following formula (a):
  • Step A comprises the steps of THIQ ring formation and pentacyclic skeleton formation from a compound represented by formula (a) which is a tyrosine derivative and a compound represented by formula (b) which is a non-natural aldehyde substrate.
  • Reaction is performed to produce precursor compound (II).
  • the reaction is a biosynthetic reaction using an enzyme as a catalyst.
  • the enzyme used in Step A is a module constituting at least a part of a peptide synthase called non-ribosomal peptide synthetase (NRPS).
  • NRPS non-ribosomal peptide synthetase
  • NRPS is a huge multi-module enzyme complex with a molecular weight of several thousand kDa, and is known to synthesize short-chain physiologically active peptides without going through ribosomes.
  • a module which is a repeating unit constituting NRPS, captures an activated amino acid as a thioester by recognizing and activating an amino acid serving as a substrate (A domain: adenylation domain), and forms a covalent bond.
  • Basic composition of peptidyl carrier protein site (PCP site) also referred to as T domain (thiolation domain)
  • condensation domain C domain condensation domain
  • SfmC which is a module of saframycin A biosynthetic enzyme is preferably used.
  • This SfmC enzyme does not promote peptide formation, which is the original function, but imine formation between a long-chain fatty acid aldehyde and an amino acid (L-tyrosine derivative), followed by Pictet-Spenger (PS) -type cyclization
  • PS Pictet-Spenger
  • the SfmC enzyme is a PS domain that catalyzes the Pictet-Spengler reaction; an A domain that recognizes and activates L-tyrosine as a substrate; PCP that converts activated amino acids into thioesters and loads them onto the enzyme (Peptidyl carrier protein site); and a Red domain that reduces the thioester.
  • the PS domain originally corresponds to the C domain (condensation domain) that catalyzes peptide bonds, but here it is referred to as a “PS domain” because it catalyzes a position- and stereoselective Pictet-Spangler reaction. ing.
  • Non-Patent Document 4 The details of the reaction mechanism of pentacyclic skeleton formation by the SfmC enzyme are described in Non-Patent Document 4, and a method for producing the SfmC enzyme is also described. Therefore, those skilled in the art can understand that the SfmC enzyme is obtained and used by referring to the literature.
  • Step A of the present invention it is preferable to add ATP, NADPH, Mg 2+ and Mn 2+ .
  • non-natural aldehyde substrate represented by the formula (b) include the following compounds. However, it is not limited to this.
  • Z a is a C 6 -C 20 alkyl group
  • Me represents a methyl group
  • Step B Cyanation Reaction Step B is a step of adding a cyanide compound to the compound represented by the formula (II) obtained in Step A to convert an OH group on the pentacyclic skeleton to a cyano group (CN Group) to obtain a compound represented by the following formula (III).
  • cyan compound used in Step B a compound containing cyanide ions can be used.
  • an alkali metal cyanide such as potassium cyanide (KCN).
  • KCN potassium cyanide
  • a cyanating agent known in the art can be used.
  • Step C N-alkylation reaction
  • the compound represented by the formula (III) obtained in the above Step A is N-alkylated at the secondary amine moiety by adding an aldehyde and a reducing agent, In this step, a compound represented by (I) is obtained.
  • the aldehyde used in Step C is selected according to the type of alkyl group added by N-alkylation. For example, when adding a methyl group, formaldehyde is used.
  • a reducing agent the compound well-known in the said technical field used in a reductive amination reaction can be used.
  • a borohydride compound such as sodium triacetoxyborohydride or sodium cyanoborohydride can be used.
  • the present invention also relates to a method for producing saframycins using an intermediate compound represented by the following formula (I).
  • a method for producing saframycin Y3 and a derivative thereof (“saframycin Y3 compound”) and a method for producing saframycin A and a derivative thereof (“saframycin A compound”) will be described below.
  • the compound of the formula (IV) has a structure corresponding to saframycin Y3, and the Z-site of the side chain is converted to A in the pentacyclic skeleton, and the end of Y is the amino group end or the hydrogen of the amino group A compound having an atom as a protecting group.
  • a protecting group known in the art such as a carbamate group such as Fmoc, Boc or Alloc (allyloxycarbonyl), an ester group, a sulfonate group or a silyl group can be used.
  • A is a protecting group, the terminal can be changed to an amino group in the same manner as saframycin Y3 by subsequent deprotection.
  • X is —C (R 3 ) NH—
  • Y is —C ( ⁇ O) R 4 —NH—
  • Z is It is preferred to use a compound that is —C ( ⁇ O) OR 6 .
  • R 1 , R 2 , and R a may be the same as those described above for formula (I).
  • the method for producing the saframycin Y3 compound includes the following steps D and E.
  • Step D the acyl chain is removed from the Z site of the side chain and converted to an amino group or a protected amino group.
  • Step E the phenol in the pentacyclic skeleton is converted to quinone.
  • Step D Conversion reaction of side chain to amino group (removal of acyl chain)
  • step D the intermediate compound represented by formula (I) is converted to A which is an amino group or a protected amino group by removing the acyl chain from the Z site in the presence of a transition metal catalyst.
  • step D a compound represented by formula (V) is obtained.
  • X, Y, A, R 1 , R 2 and R a have the same meaning as in formula (IV).
  • the conversion from the Z site to A can be performed in one step by including “—NHC ( ⁇ O) O—” in X and Y, that is, a carbamate structure or a urethane structure. It has been done. Conventionally, in the situation where there are many other functional groups, selective removal and amination of the terminal acyl chain has been difficult, and thus such a conversion reaction can be achieved for the first time by the present invention.
  • the transition metal catalyst used in Step D is preferably a palladium complex.
  • Specific examples of the palladium complex include tetrakis (triphenylphosphine) palladium.
  • Step E Oxidation reaction to quinone Step E oxidizes the compound represented by the formula (V) obtained in Step D in the presence of a transition metal catalyst to convert the phenol moiety in the pentacyclic skeleton to quinone. This is a step of obtaining a saframycin Y3 compound represented by the above formula (IV).
  • the transition metal catalyst used is preferably a cobalt complex.
  • the cobalt complex include sarcomin (N, N'-ethylenebis (salicylideneaminato) cobalt (II)), Fremy salt (potassium nitrosodisulfonate), and the like.
  • R 1 , R 2 and R a are all methyl groups; R 4 is —CH (CH 3 ) — and A is a hydrogen atom.
  • the compound of formula (IV) is saframycin Y3.
  • the compound of the formula (VI) has a structure corresponding to saframycin A, and is a compound having a carbonyl group terminal by converting the YZ site of the side chain into a pentacyclic skeleton.
  • X is —C (R 3 ) NH—
  • Y is —C ( ⁇ O) R 4 —O—
  • Z is It is preferred to use a compound that is —C ( ⁇ O) R 6 .
  • R 1 , R 2 , and R a may be the same as those described above for formula (I).
  • the method for producing the saframycin A compound includes the following steps F to H.
  • Step F the acyl chain is removed from the YZ site of the side chain and converted to an OH group.
  • Step G the phenol in the pentacyclic skeleton is converted to quinone.
  • Step H the OH group at the end of the side chain is converted. Converted to a carbonyl group.
  • Step F Conversion reaction of side chain to OH group (removal of acyl chain)
  • Step F is a compound represented by the following formula (VII) by hydrolyzing the compound represented by the formula (I) under basic conditions and converting it to the OH group terminal from which the YZ site acyl chain has been removed.
  • the conversion from the YZ site to the OH group end can be performed in one step by using “—OC ( ⁇ O) —”, ie, an ester structure, as the linking part of Y and Z. It was discovered for the first time.
  • hydroxide ions OH ⁇
  • an alkali metal hydroxide such as lithium hydroxide can be used.
  • Step G Oxidation reaction to quinone Step G involves oxidation of the compound of formula (VII) obtained in Step F in the presence of a transition metal catalyst to convert the phenol moiety in the pentacyclic skeleton to quinone. And a step of obtaining a compound represented by the following formula (VIII). This process is the same reaction as in Step E above. (In the formula, X, R 1 , R 2 and R a have the same meaning as in formula (I).)
  • the transition metal catalyst used is preferably a cobalt complex.
  • the cobalt complex include sarcomin (N, N′-ethylenebis (salicylideneiminato) cobalt (II)), Fremy salt (potassium nitrosodisulfonate), and the like.
  • Step H Carbonylation of terminal OH group
  • Step H is a step of oxidizing the compound of formula (VIII) obtained in Step G using DMSO oxidation or a hypervalent iodine reagent to convert the terminal OH group to a carbonyl group.
  • This is a step of obtaining a saframycin A-based compound represented by the formula (VI).
  • Hypervalent iodine reagent used in Step H preferably a compound containing pentavalent iodine, typically 1,1,1-triacetoxy-1,1-dihydro-1, called Dess-Martin reagent Mention may be made of 2-benziodoxol-3 (1H) -one.
  • DMSO oxidation can be performed using a known activator, and examples of the activator include oxalyl chloride. In addition to these, oxidation can be carried out using compounds and reagents well known in the art.
  • R 1 , R 2 and Ra are all methyl groups; R 3 is a hydrogen atom.
  • the final product, the compound of formula (VI), is saframycin A.
  • the manufacturing method of the OH group-terminated compound includes the following steps D2 and E2.
  • Step D2 the acyl chain is removed from the XYZ site of the side chain to convert it to an OH group
  • Step E2 the phenol site in the pentacyclic skeleton is converted to quinone.
  • Step D2 Side chain OH reaction (acyl chain removal)
  • the intermediate compound represented by formula (I) is hydrolyzed under basic conditions to remove the acyl chain from the XYZ site of the side chain, and the XYZ site is This is a step of converting to a C (R 3 ) OH group.
  • step D2 hydroxide ions (OH ⁇ ) are preferably added in order to achieve basic conditions.
  • an alkali metal hydroxide such as lithium hydroxide can be used.
  • the conversion from the XYZ moiety to the primary hydroxyl group is carried out in one step by using “—O—C ( ⁇ O) R 3 ”, that is, an ester structure, as the linking part of X and Y. It has been found for the first time in the present invention. Conventionally, it has been difficult for the present invention to achieve such a conversion reaction for the first time because selective removal of an acyl chain and OH formation have been difficult in the presence of many other functional groups.
  • Step E2 Oxidation reaction to quinone Step E2 is a step of oxidizing the compound obtained in Step D2 in the presence of a transition metal catalyst to convert the phenol moiety in the pentacyclic skeleton to quinone. This process is the same reaction as in Step E above.
  • the transition metal catalyst used is preferably a cobalt complex.
  • the cobalt complex include sarcomin (N, N′-ethylenebis (salicylideneiminato) cobalt (II)), Fremy salt (potassium nitrosodisulfonate), and the like.
  • reaction conditions such as the solvent and reaction temperature in each step of the production method of the present invention described above are described in detail as typical examples in the examples described later, but are not necessarily limited thereto. Those skilled in the art can appropriately select each based on general knowledge in organic synthesis.
  • the intermediate compound represented by formula (I) has the following structure. (Wherein, Z a is a C 6 -C 20 alkyl group, Me represents a methyl group.)
  • the precursor compound represented by formula (II) has the following structure. (Wherein, Z a is a C 6 -C 20 alkyl group, Me represents a methyl group.)
  • the non-natural aldehyde substrate represented by the formula (b) is selected from the following compounds:
  • the intermediate compound represented by formula (I) has the following structure. (Wherein, Z a is a C 6 -C 20 alkyl group, Me represents a methyl group.)
  • the precursor compound represented by formula (II) has the following structure. (Wherein, Z a is a C 6 -C 20 alkyl group, Me represents a methyl group.)
  • Various intermediate compounds or products in the present invention have a plurality of asymmetric carbons, and there exist stereoisomers such as optical isomers or diastereoisomers, but pure forms of stereoisomers and stereoisomers are present. Any mixtures, racemates and the like are included within the scope of the present invention.
  • various intermediate compounds or products in the present invention may exist as hydrates or solvates, and any of these substances is included in the scope of the present invention.
  • solvents such as ethanol, acetone, isopropanol, can be illustrated.
  • Multiplicity is described as s (singlet), d (doublet), t (triplet), q (quartet), quin (quintet), m (multiplet), br (broad) .
  • Bruker Daltonics micrOTOF-QII was used.
  • Medium pressure liquid chromatography (MPLC) purification was performed with YAMAZEN YFLC-AI-580 and Biotage Isolera.
  • Dess-Martin periodinane and sarcomin were obtained from Tokyo Chemical Industry Co., Ltd.
  • ATP sodium salt trihydrate
  • EDC / HCl, HATU and HBTU were purchased from Watanabe Chemical Co., Ltd.
  • Grubbs catalyst first generation and Pd (PPh 3 ) 4 were obtained from Sigma-Aldrich. NADPH and NADH were purchased from Oriental Yeast Co. Ltd. All reagents and commercially available solvents were used as received. The reaction was monitored by thin layer chromatography using Merck Millipore TLC silica gel F254 plates (0.25 mm). Flash column chromatography was performed using Kanto Silica Gel 60N.
  • tyrosine derivative (Compound 1) was synthesized by using a non-patent document 5 (Tanifuji, R .; Oguri, H .; Koketsu, K .; Yoshinaga, Y .; Minami, A .; Oikawa, H. Tetrahedron Lett. 2016 , 57, 623.).
  • Aldehyde substrate 1 (Compound 11) was synthesized from Compound 6 according to the following reaction scheme.
  • Aldehyde substrate 11 (Compound 4) was synthesized from Compound 8 according to the following reaction scheme.
  • Ozone was bubbled through a solution of 10 (209 mg, 0.616 mmol) in CHCl 3 (140 mL, 4.4 mM) at ⁇ 30 ° C. until the solution turned blue-violet. Excess ozone was removed from the solution by bubbling oxygen and nitrogen. After repeating this process once more, Me 2 S (1.37 mL, 18.5 mmol, 30 eq) was added and stirred at ⁇ 30 ° C. for 10 minutes and at room temperature for 40 minutes. After concentration under reduced pressure, the crude residue was purified by silica gel column chromatography (CHCl 3 / AcOEt) to obtain 11 (168 mg, 0.493 mmol, 80%) as a white solid.
  • the residue was purified by HPLC using Inertsilsustain C18 (GL Sciences, ⁇ 10 ⁇ 250 mm, 5 ⁇ m) under the following conditions: increasing the ratio of MeCN to water from 30% to 75% with a linear gradient for 35 minutes It was. At this time, the flow rate was 5.0 mL / min, the column temperature was room temperature, and the wavelength of the UV detector was 280 nm. Fractions containing the desired product were concentrated under reduced pressure to give compound 13 (1.37 mg, 1.84 ⁇ mol, 23% yield over 3 steps). The resulting compound 13 was analyzed by a series of NMR measurements including 1 H-NMR, 13 C-NMR, H-COSY, HSQC, HMBC and ROESY.
  • the residue was purified by HPLC using Inertsustain C18 (GL Sciences, ⁇ 10 ⁇ 250 mm, 5 ⁇ m) under the following conditions: Increase the ratio of MeCN to water from 30% to 75% with a linear gradient for 30 minutes. It was. At this time, the flow rate was 5.0 mL / min, the column temperature was room temperature, and the wavelength of the UV detector was 280 nm. Fractions containing the desired product were concentrated under reduced pressure to give compound 15 (10.4 mg, 13.7 ⁇ mol, 80% yield over 2 steps). The resulting compound 15 was analyzed by a series of NMR measurements including 1 H-NMR, 13 C-NMR, H-COSY, HSQC, HMBC and ROESY.
  • the organic extract was washed with saturated brine and dried over Na 2 SO 4 . After filtration and concentration in vacuo, the crude product was passed through Sep-Pak® C18 and eluted with MeCN. After concentration, the residue was purified by HPLC using Inertsustain C18 (GL Sciences, ⁇ 10 ⁇ 250 mm, 5 ⁇ m) under the following conditions: Increase the ratio of MeCN to water from 30% to 75% with a linear gradient for 30 minutes. It was. At this time, the flow rate was 5.0 mL / min, the column temperature was room temperature, and the wavelength of the UV detector was 280 nm.
  • Triethylamine (56.4 ⁇ L, 40.9 mg, 404 ⁇ mol, 30 equivalents) was added to the obtained mixture at ⁇ 78 ° C., and the mixture was stirred for 10 minutes.
  • the reaction solution was heated to 0 ° C. over 50 minutes, then passed through Sep-Pak (registered trademark) Florisil and eluted with AcOEt. After concentration, the residue was purified by HPLC using Inertsil Diol (GL Sciences, ⁇ 10 ⁇ 250 mm, 5 ⁇ m) under the following conditions: The ratio of AcOEt acetate to hexane was 30% to 60% in a straight line for 30 minutes. Increased with gradient.

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Abstract

L'invention aborde le problème consistant à fournir un procédé de production susceptible de synthétiser aisément un composé ayant une structure dans laquelle une pluralité de cycles tétrahydroisoquinoléine sont liés les uns aux autres, par utilisation d'un nombre réduit d'étapes. À cet effet, il a été constaté qu'un composé intermédiaire non-naturel ayant un squelette pentacyclique dans lequel des cycles tétrahydroisoquinoléine sont liés les uns aux autres peut être rapidement synthétisés par une synthèse monotope par réaction d'un dérivé de tyrosine avec un substrat aldéhyde non naturel ayant une structure particulière, par utilisation d'une peptide synthétase non ribosomale. On a également constaté que les saframycines et les analogues de ces dernières peuvent être obtenus aisément et avec une grande efficacité par utilisation d'un substrat aldéhyde non naturel ayant une structure particulière, la capacité d'adaptation à une réaction enzymatique étant assurée, et une transformation chimique de l'intermédiaire après formation du squelette peut être librement mise en œuvre.
PCT/JP2019/009128 2018-03-16 2019-03-07 Procédé de production d'un composé contenant un cycle tétrahydroisoquinoléine Ceased WO2019176732A1 (fr)

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JPH02268145A (ja) * 1989-04-10 1990-11-01 Suntory Ltd タンパク質分解酵素阻害剤
WO2005118584A2 (fr) * 2004-05-26 2005-12-15 Axys Pharmaceuticals, Inc. Nouveaux analogues de saframycine utilises en tant qu'agents therapeutiques
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JP2013526599A (ja) * 2010-05-25 2013-06-24 ファルマ、マール、ソシエダード、アノニマ エクチナサイジン化合物の製造のための合成方法

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JPS6479113A (en) * 1987-05-21 1989-03-24 Shozo Shoji Virus multiplication inhibitor comprising myristyl compound
JPH02268145A (ja) * 1989-04-10 1990-11-01 Suntory Ltd タンパク質分解酵素阻害剤
WO2005118584A2 (fr) * 2004-05-26 2005-12-15 Axys Pharmaceuticals, Inc. Nouveaux analogues de saframycine utilises en tant qu'agents therapeutiques
CN1795861A (zh) * 2004-12-24 2006-07-05 博瑞生物医药技术(苏州)有限公司 含有1,3－氧硫杂戊烷类核苷的药物组合物及其制备方法
JP2013526599A (ja) * 2010-05-25 2013-06-24 ファルマ、マール、ソシエダード、アノニマ エクチナサイジン化合物の製造のための合成方法

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KANKANAMALAGE, A. C. G. ET AL.: "Structure-based exploration and exploitation of the S4 subsite of norovirus 3CL protease in the design of potent and permeable inhibitors", EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, vol. 126, 2017, pages 502 - 516, XP029885682, DOI: 10.1016/j.ejmech.2016.11.027 *
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