WO1998032727A1 - Procede de production d'un acide benzylsuccinique optiquement actif et de substances intermediaires dudit acide - Google Patents

Procede de production d'un acide benzylsuccinique optiquement actif et de substances intermediaires dudit acide Download PDF

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Publication number
WO1998032727A1
WO1998032727A1 PCT/JP1998/000230 JP9800230W WO9832727A1 WO 1998032727 A1 WO1998032727 A1 WO 1998032727A1 JP 9800230 W JP9800230 W JP 9800230W WO 9832727 A1 WO9832727 A1 WO 9832727A1
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WIPO (PCT)
Prior art keywords
ethylamine
formula
carbon atom
optically active
naphthyl
Prior art date
Application number
PCT/JP1998/000230
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English (en)
Japanese (ja)
Inventor
Tetsuhide Kamijo
Toshiaki Yamaguchi
Takashi Yanagi
Original Assignee
Kissei Pharmaceutical Co., Ltd.
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Kissei Pharmaceutical Co., Ltd. filed Critical Kissei Pharmaceutical Co., Ltd.
Priority to AU55758/98A priority Critical patent/AU5575898A/en
Publication of WO1998032727A1 publication Critical patent/WO1998032727A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/44—Iso-indoles; Hydrogenated iso-indoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/42—Separation; Purification; Stabilisation; Use of additives
    • C07C51/487—Separation; Purification; Stabilisation; Use of additives by treatment giving rise to chemical modification

Definitions

  • the invention relates to the formula
  • the carbon atom with (S) in the formula represents a carbon atom in the S configuration
  • a method for producing an optically active benzylsuccinic acid, and an intermediate for the production thereof More specifically, the present invention provides (R) -1- (1-naphthyl) ethylamine, (R) -methylbenzylamine, (S) _l-phenyl-2- (p) as an optical resolving agent.
  • Tolyl Using an organic amine selected from ethylamine and quinine, the formula
  • Benzyl succinic acid which is a mixture of (R) -isomer and (S) -isomer represented by the formula, has an excellent hypoglycemic effect and is useful as a therapeutic agent for diabetes.
  • optically active benzyl succinic acid monoamide derivative represented by the formula (III) which is useful as a therapeutic agent for diabetes, comprises the optically active benzyl succinic acid represented by the formula (I) or a reactive functional derivative thereof.
  • An optically active benzyl ester represented by the formula (III) useful as a therapeutic agent for diabetes n Hakusan Monoami de derivatives are difficult, low-melting crystalline material is crystallized, for purification on not handle force easily, as a raw material to provide a high optical purity and high chemical purity of the drug substance are required as a medicament It is necessary to produce and use very high quality optically active benzyl succinic acid represented by the above formula (I).
  • the obtained optically active substance is still unsatisfactory in optical purity in order to provide an optically active benzylsuccinic acid monoamide derivative represented by the above formula (III) as a pharmaceutical.
  • it is necessary to perform another purification operation after the completion of the catalytic reduction.
  • the process is complicated, such as the need for treatment under pressure or for a long time using an expensive asymmetric catalyst, and the use of the asymmetric catalyst may cause inactivation or decrease in selectivity.
  • problems remain in terms of industrial recovery and reuse.
  • the carbon atom with (S) in the formula represents a carbon atom in the S configuration.
  • the present invention relates to a method for producing an optically active benzylsuccinic acid represented by the formula:
  • the present invention relates to an optically active benzyl succinic acid of the formula (I) and (R) -1- (1-naphthyl), which is useful as an intermediate for producing the optically active benzyl succinic acid of the formula (I).
  • Ethylamine is a salt with an organic amine selected from quinine.
  • the present invention relates to an optically resolving agent for producing the optically active benzylsuccinic acid represented by the formula (I), wherein (R)-(1-methylbenzyl) amine, (S) -1-phenyl-2- (p-) Tolyl) It relates to the use of organic amines selected from ethylamine and quinine.
  • the present invention provides an optically active benzyl succinic acid monoamide derivative represented by the above formula (III), which is useful as a therapeutic agent for diabetes.
  • the present invention provides a novel production method by optical resolution which is different from the production method by catalytic reduction using a conventional asymmetric catalyst.
  • the optical resolution method of the present invention uses benzyl succinic acid which is a mixture of the (R) -isomer and the (S) -isomer represented by the formula (II), and uses (R) as an optical resolution agent — 1— (1-naphthyl) ethylamine, (R) — 1-methylbenzylamine, (S) — 1-phenyl-2- (p-tolyl) using an organic amine selected from ethylamine or quinine And dissolving the benzyl succinic acid of the formula (II) in a predetermined solvent to obtain (R) -1- (1-naphthyl) ethylamine, (R) -methylbenzylamine, (S)- After adding an appropriate amount of an organic amine selected from 1-phenyl-1- (p-tolyl) ethylamine or quinine, crystallization is performed by inoculating a diastereomer salt as needed, and
  • the formula (II) used as a raw material in the optical resolution method of the present invention is represented by the following formula:
  • the benzyl succinic acid to be used is preferably, in consideration of the recovery rate, the content of the (S) -isomer equal to or more than the content of the (R) isomer, If the amount is small, it can be racemized by subjecting it to heat treatment and used as a racemic mixture.
  • the amount of the optical resolving agent used in the optical resolving method of the present invention is usually an equimolar amount to the benzylsuccinic acid represented by the formula (II), but the starting material and the optical resolving agent are in a 1: 2 diastereomer. When a monosalt is formed, the amount is twice as much as the benzyl succinic acid represented by the formula (II).
  • the solvent used in the optical resolution method of the present invention generally benzyl succinate force represented by raw material der Ru Formula (II)? Long as it dissolves, eg if Etano Ichiru, isopropanol Alcohol solvents such as 1 liter can be mentioned.
  • the deamidation treatment in the optical resolution method of the present invention includes an acid treatment using a mineral acid such as hydrochloric acid and sulfuric acid and an alkali treatment using an inorganic base such as sodium hydroxide and potassium hydroxide in a conventional manner. It can be implemented by appropriately combining them.
  • the benzyl succinic acid represented by the formula (II) used as a starting material in the optical resolution method can be produced by a method described in a literature or a method similar thereto (J. Am. Chem. So c., Vol. 74, pp 5147-5151 (1952); J. Org. Chem., Vol. 8, pp. 285-289 (1943)).
  • a racemic mixture obtained by subjecting (E) or (NO) and (Z) -itaconic acid derivatives represented by HOOcJL COOH to an ordinary hydrogenation operation that is widely used in industry using an ordinary catalyst such as palladium carbon Can be carried out as a raw material. Also, the general formula
  • the optical resolution method of the present invention when producing benzyl succinic acid as a raw material, is not subject to any restrictions on the geometrical isomerism of the itaconic acid derivative, which is the source of the production, and is widely used industrially. It can be manufactured by a normal hydrogenation operation, and can be easily manufactured by a separate manufacturing method. Further, the optical resolution method of the present invention is characterized in that the optically active benzyl succinic acid represented by the above formula (I), (R) -1- (1-naphthyl) ethylamine, and (R) -hydroxymethylbenzylamine , (S) —
  • the organic amine is added to the solution of the benzyl succinic acid represented by the formula (II) to cause crystallization, and recrystallization is repeated as required. After that, a deamination treatment can be carried out to make the production very simple.
  • the optically active benzylsuccinic acid represented by the formula (I) obtained by performing the optical resolution method of the present invention has high quality.
  • the filtrate obtained by carrying out the optical resolution method is appropriately deaminated, and then the obtained benzylsuccinic acid is melted at a high temperature for several hours and subjected to a racemization operation.
  • it can be reused as benzyl succinic acid represented by the formula (II) as a raw material.
  • the benzyl succinic acid of the above formula (II) as a raw material can be effectively used, which is a very useful method.
  • the precipitated crystals were collected by filtration to obtain 1.82 g of a diastereomer salt (optical purity: 80.6% e e). Similarly, recrystallization was performed three times using 30 ml, 20 ml and 30 ml of ethanol as a solvent to obtain 0.66 g of diastereomer salt (recovery rate 24.8%, optical purity 99.4% e e).
  • the Jiasutereoma salt 1.57 g was heated and dissolved in ethanol 20 ml, collected by filtration was left unattended and (precipitated crystals following inoculation with Jiasutereoma salt of interest which is separately prepared to obtain Jiasutereoma salt 0.98 g (ee optical purity 75.6%). Similarly, recrystallization was performed three times using 15 ml, 10 ml and 8 ml of ethanol as a solvent to obtain 0.18 g of diastereomer monosalt (recovery rate 10.2%, optical purity 99.2% ee).
  • the filtrates of Examples 1 to 4 were distilled off under reduced pressure, and 20 ml of 1N aqueous sodium hydroxide solution and 20 ml of methylene chloride were added to the obtained diastereomer mixture 3.2, followed by stirring.
  • the aqueous layer was separated, neutralized with concentrated hydrochloric acid, and the precipitated benzylsuccinic acid (1.50 g) was melted at 180 ° C for 1 hour.
  • 4 ml of a 5N aqueous sodium hydroxide solution was added, and the mixture was heated and returned for 2 hours. Shed. After cooling, the mixture was acidified with concentrated hydrochloric acid, and the precipitated crystals were collected by filtration and washed with water to obtain 1.36 g of a racemic mixture.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé de production d'un acide benzylsuccinique optiquement actif de la formule (III) (dans laquelle l'atome de carbone représenté par (S) présente la configuration en S), qui convient comme matière de départ du dérivé d'acide benzylsuccinique de la formule (I) et de ses sels utiles comme médicament contre le diabète. Ledit acide benzylsuccinique optiquement actif est obtenu à partir d'un mélange d'isomères optiques appropriés, par résolution optique mettant en oeuvre comme agent de résolution optique une amine organique sélectionnée dans le groupe constitué par (R)-1-(1-naphtyl)éthylamine, (R)-alpha-méthylbenzylamine, (S)-1-phényl-2-(p-tolyl)éthylamine et quinine. Des sels dudit acide benzylsuccinique optiquement actif pouvant être utilisés par la méthode de résolution optique sont obtenus à l'aide d'une amine organique sélectionnée dans le groupe constitué par (R)-1-(1-naphtyl)éthylamine, (R)-alpha-méthylbenzylamine, (S)-1-phényl-2-(p-tolyl)éthylamine et quinine. L'acide benzylsuccinique optiquement actif présente une grande pureté optique et chimique et peut être obtenu efficacement par ladite méthode de résolution optique.
PCT/JP1998/000230 1997-01-24 1998-01-22 Procede de production d'un acide benzylsuccinique optiquement actif et de substances intermediaires dudit acide WO1998032727A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU55758/98A AU5575898A (en) 1997-01-24 1998-01-22 Process for producing optically active benzylsuccinic acid and intermediate therefor

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP4687297 1997-01-24
JP9/46872 1997-01-24

Publications (1)

Publication Number Publication Date
WO1998032727A1 true WO1998032727A1 (fr) 1998-07-30

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AU (1) AU5575898A (fr)
WO (1) WO1998032727A1 (fr)

Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085833A1 (fr) * 2001-04-18 2002-10-31 Kuraray Co., Ltd. Procede de preparation d'acide 2-benzyl-succinique a activite optique et de monamides de l'acide 2-benzyl-succinique a activite optique
WO2003055831A1 (fr) * 2001-12-24 2003-07-10 Basell Poliolefine Italia S.P.A. Separation de diastereoisomeres
CN100441570C (zh) * 2006-05-24 2008-12-10 严洁 一种米格列奈钙的制备及质量控制方法

Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55118456A (en) * 1979-03-02 1980-09-11 Sumitomo Chem Co Ltd Method of collecting optically active d-alpha-methyl-beta- benzoyl-thiopropionic acid
JPS5663940A (en) * 1979-10-29 1981-05-30 Sumitomo Chem Co Ltd Preparation of optically active alpha-methyl-phenylacetic acid
JPS5890573A (ja) * 1981-11-24 1983-05-30 Nippon Chemiphar Co Ltd 光学活性トランス−オキシラン−２，３−ジカルボン酸の製造方法
JPS59170036A (ja) * 1983-03-17 1984-09-26 Hiroyuki Nohira ２−（４−ブロモフエニル）−３−メチルブタン酸の光学分割方法
JPS61293949A (ja) * 1985-06-20 1986-12-24 Sumitomo Chem Co Ltd ａ−イソプロピル−ｐ−クロルフエニル酢酸の光学分割法
JPH0276838A (ja) * 1988-09-12 1990-03-16 Tosoh Corp （ａＳ）−及び（ａＲ）−１，１’−ビナフチル−２，２′−ジカルボン酸の製造方法
US4983765A (en) * 1988-07-19 1991-01-08 Paz Arzneimittel-Entwicklungsgesellschaft Mbh Process to separate mixtures of enantiomeric arylpropionic acids
JPH0578276A (ja) * 1991-09-20 1993-03-30 Kankyo Kagaku Center:Kk ２，３‐ジフエニルコハク酸の光学分割法
JPH07149688A (ja) * 1993-11-26 1995-06-13 Teikoku Chem Ind Corp Ltd ２−アリールプロピオン酸化合物の光学分割方法

Patent Citations (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS55118456A (en) * 1979-03-02 1980-09-11 Sumitomo Chem Co Ltd Method of collecting optically active d-alpha-methyl-beta- benzoyl-thiopropionic acid
JPS5663940A (en) * 1979-10-29 1981-05-30 Sumitomo Chem Co Ltd Preparation of optically active alpha-methyl-phenylacetic acid
JPS5890573A (ja) * 1981-11-24 1983-05-30 Nippon Chemiphar Co Ltd 光学活性トランス−オキシラン−２，３−ジカルボン酸の製造方法
JPS59170036A (ja) * 1983-03-17 1984-09-26 Hiroyuki Nohira ２−（４−ブロモフエニル）−３−メチルブタン酸の光学分割方法
JPS61293949A (ja) * 1985-06-20 1986-12-24 Sumitomo Chem Co Ltd ａ−イソプロピル−ｐ−クロルフエニル酢酸の光学分割法
US4983765A (en) * 1988-07-19 1991-01-08 Paz Arzneimittel-Entwicklungsgesellschaft Mbh Process to separate mixtures of enantiomeric arylpropionic acids
JPH0276838A (ja) * 1988-09-12 1990-03-16 Tosoh Corp （ａＳ）−及び（ａＲ）−１，１’−ビナフチル−２，２′−ジカルボン酸の製造方法
JPH0578276A (ja) * 1991-09-20 1993-03-30 Kankyo Kagaku Center:Kk ２，３‐ジフエニルコハク酸の光学分割法
JPH07149688A (ja) * 1993-11-26 1995-06-13 Teikoku Chem Ind Corp Ltd ２−アリールプロピオン酸化合物の光学分割方法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2002085833A1 (fr) * 2001-04-18 2002-10-31 Kuraray Co., Ltd. Procede de preparation d'acide 2-benzyl-succinique a activite optique et de monamides de l'acide 2-benzyl-succinique a activite optique
WO2003055831A1 (fr) * 2001-12-24 2003-07-10 Basell Poliolefine Italia S.P.A. Separation de diastereoisomeres
US7067690B2 (en) 2001-12-24 2006-06-27 Basell Poliolefine Italia S.P.A. Separation of diastereoisomers
CN100390111C (zh) * 2001-12-24 2008-05-28 巴塞尔聚烯烃意大利有限公司 非对映异构体的分离
CN100441570C (zh) * 2006-05-24 2008-12-10 严洁 一种米格列奈钙的制备及质量控制方法

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