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WO2011008005A2 - Procédé de préparation de dérivés d'histidyl-prolinamide à l'aide d'un support en phase solide polymère - Google Patents

Procédé de préparation de dérivés d'histidyl-prolinamide à l'aide d'un support en phase solide polymère Download PDF

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Publication number
WO2011008005A2
WO2011008005A2 PCT/KR2010/004542 KR2010004542W WO2011008005A2 WO 2011008005 A2 WO2011008005 A2 WO 2011008005A2 KR 2010004542 W KR2010004542 W KR 2010004542W WO 2011008005 A2 WO2011008005 A2 WO 2011008005A2
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WO
WIPO (PCT)
Prior art keywords
group
formula
compound
phase support
protecting group
Prior art date
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Ceased
Application number
PCT/KR2010/004542
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English (en)
Korean (ko)
Other versions
WO2011008005A3 (fr
Inventor
임청우
박용묵
정훈휘
추두호
황려윤
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WELL E&C CO Ltd
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WELL E&C CO Ltd
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Publication date
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Priority to JP2012520538A priority Critical patent/JP5982720B2/ja
Publication of WO2011008005A2 publication Critical patent/WO2011008005A2/fr
Publication of WO2011008005A3 publication Critical patent/WO2011008005A3/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/08—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing alicyclic rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/14—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to a method for preparing a histidyl-prolineamide derivative using a polymer solid phase support. More specifically, the present invention relates to a method for economically and efficiently preparing various histidyl-prolineamide derivatives using a polymer solid-phase support.
  • histidyl-prolineamide derivatives or pharmaceutically acceptable salts thereof as shown in Formula 1 below have excellent effects in treating central nervous system disorders such as consciousness disorders and memory disorders. Specifically, they are used as drugs for stimulating thyroid stimulating hormone releasing hormone to induce the release action of thyroid stimulating hormone in the anterior pituitary gland to treat central nervous disorders.
  • R is the same as defined in Formula 1,
  • P 1 represents hydrogen or a protecting group
  • R 1 represents hydrogen, an alkyl group or an aryl group.
  • the preparation technique is to obtain a compound of formula 4 through a coupling reaction between a compound comprising a carboxylic acid represented by the formula (2) and a histidine ester derivative represented by the formula (3), and the obtained compound and the prolineamide of the formula (5).
  • the compound of formula 4 is prepared through a coupling reaction with a histidine ester, and the compound of formula 6 is prepared by hydrolysis after coupling with a prolineamide of formula 5.
  • the obtained compound is subjected to simultaneous deprotection reaction and cyclization reaction under acidic conditions to prepare the desired histidyl-prolineamide derivative of formula (1).
  • preparation route 2 is prepared by obtaining a compound of formula 1 through coupling reaction between a compound comprising a carboxylic acid represented by formula 2 and a histidine-prolineamide derivative represented by formula 7. It features technology.
  • the manufacturing route has a high manufacturing cost and mass production due to the complexity of the manufacturing process for the intermediate 7, the difficulty of the purification process and low yield.
  • the inventors have studied and developed a novel preparation method to overcome the technical problems caused by the commercial mass production of various histidyl-prolineamide derivatives as mentioned above, and the polymer solid phase support from commercially available amino acid derivatives It has been found and completed the present invention that it is possible to produce a variety of high purity histidyl-prolineamide derivatives through a simple preparation and purification process.
  • the present invention relates to a method for preparing a histidyl-prolineamide derivative of formula 1,
  • P 3 is a protecting group protecting nitrogen of proline, preferably a protecting group which is deprotected under basic conditions,
  • P 4 is a protecting group protecting nitrogen in the imidazole group of histidine, preferably a protecting group that is stable under basic conditions and deprotected under acidic conditions, and examples thereof include triphenylmethyl group (Tr), benzyloxymethyl group (Bom), t-butyloxycarbonyl group (t-Boc), adamantyl-1-oxycarbonyl group (Adoc), diphenylmethyl group (Dpm), 4-toluenesulfonyl group (Tos), 4-methoxybenzenesulfonyl group (Mbs), t-butoxymethyl group (Bum) and the like,
  • P 5 is a protecting group protecting the amine group of histidine, preferably a protecting group which is deprotected under basic conditions,
  • the method for preparing the histidyl-prolineamide derivative of the formula (1) characterized in that both the deprotection of the fourth step and the separation of the polymer solid phase support are performed simultaneously in the presence of an acid.
  • a polymer solid-phase support is used as an auxiliary starting material.
  • the polymer solid support is a resin having an amine group containing an amine group or a protecting group on its surface, as shown in the following formula (8).
  • the polymer solid-phase support is reacted with a proline compound of Formula 9 or a carboxylic acid activated compound thereof through a deprotection process.
  • P 2 is a protecting group protecting the nitrogen of hydrogen or an amine group, preferably a protecting group which is deprotected under basic conditions.
  • Preferred examples of P 2 include a fluorenyl-9-methoxy carbonyl group (Fmoc), 2-cyano-t-butoxy carbonyl group (Cyoc), 2- (4-toluenesulfonyl) ethoxy carbonyl group (Tsoc), 2- (4-nitrophenylsulfonyl) ethoxy carbonyl group (Noc), methanesulfonyl ethoxy carbonyl group (Msc), etc. are mentioned.
  • Fmoc fluorenyl-9-methoxy carbonyl group
  • Cyoc 2-cyano-t-butoxy carbonyl group
  • Tsoc 2- (4-toluenesulfonyl) ethoxy carbonyl group
  • Noc 2- (4-nitrophenylsulfonyl) ethoxy carbonyl group
  • Msc methanesulfonyl ethoxy carbonyl group
  • Bases used for the deprotection reaction include alkyl or aryl amines such as piperidine, triethylamine and pyridine, imidazole, 8-diazabicyclo [5.4.0] unde-7-ene (DBU) as a common organic base. ), Aminoethanol, morpholine, liquefied ammonia, and the like, and organic solvents used may include aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ethers, N, N-dimethylformamide, alcohols, and the like. .
  • the resin a resin used in a conventional solid phase peptide synthesis method may be used, and polystyrene having a bead size of 100-200 or 200-400 mesh is preferable.
  • the compound of formula 10 ' is obtained by a coupling reaction between a polymer solid-phase support having an amine group on the surface of formula 8 and a compound in which proline of formula 9 or a carboxylic acid thereof is activated. If a polymer solid-phase support in which an amine group is protected as a polymer solid-phase support is used, deprotection of the protecting group proceeds first, followed by coupling with a compound having a proline or a carboxylic acid activated therein.
  • Scheme 10 below shows a coupling reaction between a polymer solid-phase support protected by a protecting group deprotected by a base and a proline of formula 9 protected by a nitrogen group.
  • P 3 is a protecting group for protecting nitrogen of proline, preferably a protecting group which is deprotected under basic conditions,
  • P 2 is as defined above.
  • an organic solvent preferably N, preferably piperidine
  • an organic base preferably piperidine
  • N-dimethylformamide was added and stirred at 20 o C to 50 o C (preferably 20 o C to 25 o C) and filtered. After repeating the above procedure once or twice, washing and filtration with the organic solvent used to obtain a solid material.
  • HOBT 1-hydroxybenzotriazole
  • a mixed composition of -hydroxybenzotriazole, N-norbomen-2,3-dicarboximide or ethyl-1-hydroxy-1H-1,2,3-triazole-4-carboxylate is mentioned.
  • Preferred examples include DCC (N, N-dicyclohexylcarbodiimide) or a mixture of DIC (N, N-diisopropylcarbodiimide) and HOBT.
  • R '' and R ''' represents a C 1 ⁇ C 10 alkyl group.
  • the form in which the carboxylic acid is activated in the proline of formula (9) may be used equivalent to the proline of formula (9).
  • Examples thereof include a compound of Formula 15.
  • Another example of the form in which the carboxylic acid is activated in the proline of Formula 9 may include a compound of Formula 16 below.
  • P 3 is as defined above.
  • Compound 10 'obtained in the first step is subjected to a coupling reaction with a compound in which the nitrogen group of Formula 11 protected by histidine or its carboxylic acid is activated after deprotection of P 3 to provide a compound of Formula 12'.
  • the process is shown in Scheme 11 below.
  • P 4 is a protecting group protecting nitrogen in the imidazole group of histidine, preferably a protecting group that is stable under basic conditions and deprotected under acidic conditions, and examples thereof include triphenylmethyl group (Tr), benzyloxymethyl group (Bom), t-butyloxycarbonyl group (t-Boc), adamantyl-1-oxycarbonyl group (Adoc), diphenylmethyl group (Dpm), 4-toluenesulfonyl group (Tos), 4-methoxybenzenesulfonyl group (Mbs), t-butoxymethyl group (Bum) and the like,
  • P 5 is a protecting group protecting the amine group of histidine, preferably a protecting group which is deprotected under basic conditions,
  • P 3 is as defined above.
  • the deprotection reaction of the protecting group P 3 present in the compound of formula 10 ' is carried out in the same manner as the deprotection of the protecting group P 2 of the polymer solid-phase support.
  • the solid material obtained is subjected to coupling with a histidine of formula (11) or a carboxylic acid-activated compound thereof.
  • Coupling agents of carboxylic acids and amines are well known, and various coupling agents can be employed in the present invention.
  • the coupling agent used in the coupling reaction of the polymer solid-phase support with the proline of formula 9 may be used in the same manner.
  • the coupling reaction is easily achieved within a reaction time of 1 to 20 hours (preferably 3 to 5 hours) at a reaction temperature of 15 o C to 60 o C (preferably 20 o C to 25 o C).
  • Examples of the compound in which the carboxylic acid is activated in the histidine of the formula (11) include the compound of the formula (17).
  • the deprotection reaction of P 5 is performed on the compound of Formula 12 'in the same manner as the deprotection process of P 3 .
  • the solid material obtained is coupled with a compound of formula (2) or a carboxylic acid activated thereof to give the desired compound of formula (13 ').
  • Coupling agents of carboxylic acids and amines are well known and various coupling agents can be employed in the present invention.
  • the coupling agent used in the coupling reaction of the polymer solid-phase support with the proline of formula 9 may be used in the same manner.
  • the coupling reaction is easily achieved within a reaction time of 1 to 20 hours (preferably 3 to 5 hours) at a reaction temperature of 15 o C to 60 o C (preferably 20 o C to 25 o C).
  • Examples of the compound in which the carboxylic acid is activated in the compound of Formula 2 include a compound of Formula 18.
  • R and A are as defined above.
  • the deprotection of protecting group P 4 from the compound of formula 13 'obtained in the third step and the step of separating the polymer solid-phase support are carried out sequentially or simultaneously under the same conditions, thereby obtaining the desired compound of formula 1'.
  • the step of deprotecting protecting group P 4 from the compound of formula 13 ′ and separating the polymeric solid phase support is carried out simultaneously under acid conditions.
  • acids usable in the reaction include trifluoroacetic acid, hydrochloric acid, sulfuric acid, nitric acid, acetic acid, C One ⁇ C 10 Of alkyl sulfonic acids, R 3 Benzene sulfonic acids comprising a group, wherein R 3 Is a hydrogen atom, C One ⁇ C 6 Alkyl group, C 2 ⁇ C 6 Alkengi, C 2 ⁇ C 6 Alkingi, C One ⁇ C 6 Alkoxy group, Halogen atom, hydroxy group, amino group, thiol group, nitro group, amine group, amide group, carbonyl group, carboxyl group and the like). Most preferred is trifluoroacetic acid.
  • Examples of the silane compound usable for the reaction include compounds having a structure of R 3 SiH, wherein R is a C 1 to C 6 alkyl group, a C 2 to C 6 alkene group, a C 2 to C 6 alkyne group or a C 1 to C 6 Alkoxy group).
  • organic solvent usable for the reaction examples include aliphatic or aromatic hydrocarbons, halogenated hydrocarbons, ethers such as tetrahydrofuran, N, N-dimethylformamide, and the like.
  • the production method according to the present invention can be carried out under mild conditions using commercially available polymer solid-phase support and amino acid derivatives containing various protecting groups, and the whole manufacturing process such as coupling reaction and deprotection reaction is very simple and one. Can be carried out in a reactor.
  • the deprotection reaction and the coupling reaction for the protecting group of each amino acid are performed quantitatively in a very short time, and there is an advantage that the by-products generated in each manufacturing step are removed through a simple filtration washing process.
  • the target product is obtained in high purity after the removal reaction of the polymer solid-phase support, it is very useful for commercial mass production of various histidyl-prolineamide derivatives.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Peptides Or Proteins (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention porte sur un procédé de préparation d'une diversité de dérivés d'histidyl-prolinamide à l'échelle industrielle d'une manière économique et efficace à l'aide d'un support en phase solide polymère. Le procédé de la présente invention permet de préparer une diversité de dérivés d'histidyl-prolinamide de pureté élevée dans des conditions douces à l'aide d'un support en phase solide polymère et de dérivés d'acides aminés contenant une diversité de groupes protecteurs par des procédés simples de préparation et de raffinage.
PCT/KR2010/004542 2009-07-14 2010-07-13 Procédé de préparation de dérivés d'histidyl-prolinamide à l'aide d'un support en phase solide polymère Ceased WO2011008005A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP2012520538A JP5982720B2 (ja) 2009-07-14 2010-07-13 高分子固体状支持体を用いたヒスチジル−プロリンアミド誘導体の製造方法

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
KR1020090063770A KR101137503B1 (ko) 2009-07-14 2009-07-14 고분자 고체 지지체를 이용한 히스티딜-프롤린아미드 유도체의 제조 방법
KR10-2009-0063770 2009-07-14

Publications (2)

Publication Number Publication Date
WO2011008005A2 true WO2011008005A2 (fr) 2011-01-20
WO2011008005A3 WO2011008005A3 (fr) 2011-06-23

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JP (1) JP5982720B2 (fr)
KR (1) KR101137503B1 (fr)
WO (1) WO2011008005A2 (fr)

Family Cites Families (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
NL183764C (nl) * 1974-10-16 1989-01-16 Gruenenthal Gmbh Werkwijze voor de bereiding van een geneesmiddel met psychotrope of neurotrope werking en werkwijze voor de bereiding van een histidylprolineamide-derivaat.
CA1256650A (fr) * 1983-03-25 1989-06-27 Toshinari Tamura Procede de production de composes de 2-azetidinone-4- substitue et medicaments les contenant
IL75641A (en) * 1984-07-10 1990-11-05 Tanabe Seiyaku Co 1-methyl-4,5-dihydro-orotyl-histidyl-prolinamide,its preparation and pharmaceutical compositions comprising it
JP2503382B2 (ja) * 1991-02-26 1996-06-05 田辺製薬株式会社 ヒスチジルプロリンアミド誘導体の製法
US7202279B1 (en) * 1998-02-11 2007-04-10 Georgetown University Cyclic dipeptides and azetidinone compounds and their use in treating CNS injury and neurodegenerative disorders

Also Published As

Publication number Publication date
JP5982720B2 (ja) 2016-08-31
WO2011008005A3 (fr) 2011-06-23
KR101137503B1 (ko) 2012-04-20
JP2012533536A (ja) 2012-12-27
KR20110006231A (ko) 2011-01-20

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