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WO2003062186A1 - Sels metalliques d'acide (3s)-3-methoxycarbonyl-4-phenylbutyrique et utilisation de ceux-ci - Google Patents

Sels metalliques d'acide (3s)-3-methoxycarbonyl-4-phenylbutyrique et utilisation de ceux-ci Download PDF

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Publication number
WO2003062186A1
WO2003062186A1 PCT/JP2003/000341 JP0300341W WO03062186A1 WO 2003062186 A1 WO2003062186 A1 WO 2003062186A1 JP 0300341 W JP0300341 W JP 0300341W WO 03062186 A1 WO03062186 A1 WO 03062186A1
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WO
WIPO (PCT)
Prior art keywords
formula
methoxycarbonyl
represented
salt
calcium
Prior art date
Application number
PCT/JP2003/000341
Other languages
English (en)
Japanese (ja)
Inventor
Takashi Yanagi
Ken Kikuchi
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 JP2003562070A priority Critical patent/JP4000113B2/ja
Publication of WO2003062186A1 publication Critical patent/WO2003062186A1/fr

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Classifications

    • 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
    • A61K31/40—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • A61K31/403—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil condensed with carbocyclic rings, e.g. carbazole
    • A61K31/4035—Isoindoles, e.g. phthalimide
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
    • C07C69/612—Esters of carboxylic acids having a carboxyl group bound to an acyclic carbon atom and having a six-membered aromatic ring in the acid moiety
    • 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
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the present invention provides a compound represented by the general formula:
  • the present invention relates to a metal salt of (3S) -3-methoxycarboxy-4_phenylbutyric acid and a method for using the same.
  • the present invention provides, for example, a compound having an insulin secretion promoting effect and a blood glucose lowering effect, which is useful as a therapeutic agent for diabetes.
  • 3-Alkoxycarbonyl-4-phenylbutyric acid derivatives or reactive functional derivatives thereof are used as intermediates in the manufacture of various pharmaceuticals having a benzylsuccinic acid partial structure, and have, for example, an insulin secretion promoting action and a hypoglycemic action. It is described that it is useful for producing a benzylsuccinic acid derivative represented by the above formula (A) and a pharmacologically acceptable salt thereof, which is useful as a therapeutic agent for diabetes (see Reference 1 below). ).
  • Patent Application Laid-Open No. 2000-01-26 1645 3-Methoxycarbonyl 4-phenylbutyric acid represented by the formula (B) is unstable to heat, and gradually decomposes during storage at room temperature to reduce its purity. have. Therefore, in order to use 3-methoxycarbonyl 4-phenylbutyric acid of reduced formula represented by the formula (B) as an intermediate for the production of pharmaceuticals, it is necessary to carry out purification to remove impurities. Since 3-methoxycarbonyl-4-phenylbutyric acid represented by the formula (B) is a viscous oily substance, it is difficult to remove impurities by purification and reuse it as a pharmaceutical intermediate.
  • the benzylsuccinic acid derivative represented by the formula (A) or a derivative thereof It is difficult to remove impurities in the middle or final step of producing a pharmacologically acceptable salt.
  • a heat-labile compound such as 3-methoxycarboxy 4-phenylbutyric acid, represented by the formula (B), which has been reported so far, is used as a production intermediate to obtain the compound represented by the formula (A).
  • the method for producing the benzyl succinic acid derivative represented by the formula requires special equipment such as cooling and storage to prevent impurities from being included due to purity reduction, and extra time such as temperature control during storage. However, it is not a satisfactory manufacturing method in terms of manufacturing on an industrial scale and cost. Therefore, there has been a demand for a method that can more efficiently and stably serve as a pharmaceutical intermediate. Disclosure of the invention
  • the inventors of the present invention have conducted intensive studies to solve the above-mentioned problems, and as a result, a novel sodium salt of (3S) -3-methoxycarbodilu-41-phenylbutyric acid represented by the above general formula (I) of the present invention.
  • the calcium salt is extremely stable to heat, and the compound (A) or a pharmaceutically acceptable salt thereof can be easily produced by using the compound as a production intermediate. I found what I could do.
  • the present invention relates to a novel drug having excellent storage stability, which is suitable for producing various pharmaceuticals having a benzylsuccinic acid partial structure, for example, a benzylsuccinic acid derivative represented by the formula (A) useful as a therapeutic agent for diabetes. It provides a production intermediate and a method for using the same.
  • the sodium salt and calcium salt of (3S) —3-methoxycarbonyl-4-phenylbutyric acid of the present invention represented by the general formula (I) are extremely susceptible to heat. It was found that it was stable and did not decompose when stored under heating.
  • the metal salt of (3S) -3-methoxycarpine-l-41-phenylbutyrate represented by the general formula (I) of the present invention can be produced by the above-mentioned formula (B (3S) — Compared with 3-methoxycarboxy 4-phenylbutyric acid, it has excellent properties that it is extremely stable to heat.
  • the metal salt of (3S) —3-methoxycarbovinyl-4-phenylbutyrate represented by the general formula (I) of the present invention is represented by the formula (B): After derivation of the reactive functional derivative without conversion to 4-methoxycarbonyl 4-phenylbutyric acid, reaction with cis-hexahydroisoindrin represented by the formula (C) or an acid addition salt thereof is performed. Possible and thermally unstable Since it is not necessary to pass through a production intermediate again, the benzylsuccinic acid derivative represented by the formula (A) can be easily produced without performing any extra steps or purification.
  • the present invention is useful as an intermediate for the production of various drugs having a benzylsuccinic acid partial structure, including the benzylsuccinic acid derivative represented by the formula (A).
  • a drug such as a benzylsuccinic acid derivative represented by the above formula (A) useful as a therapeutic agent for diabetes can be efficiently and stably produced, which is suitable for production on an industrial scale.
  • the metal (3S) -3-methoxycarbonyl 4-phenylbutyrate represented by the general formula (I) of the present invention can be produced by the following method.
  • the (3S) -3-methoxycarbonyl-4-phenylbutyric acid represented by the formula (B) is converted into a solvent such as water, acetone, methanol, isopropanol, or ethyl acetate, or a mixed solvent thereof.
  • a solvent such as water, acetone, methanol, isopropanol, or ethyl acetate, or a mixed solvent thereof.
  • the metal salt of (3S) -3-methoxycarbonyl-4-phenylbutyrate represented by the general formula (I) can be easily produced.
  • the reaction temperature is usually from 110 to 60 ° C, and the reaction time is usually from 1 to 24 hours, depending on the starting materials used, the solvent and the reaction temperature.
  • the metal salt of (3S) -3-methoxycarbonyl-2-phenylbutyrate represented by the above general formula (I) of the present invention has a hypoglycemic effect by, for example, the method of Scheme 1, and is used as a drug for treating diabetes.
  • the useful benzyl succinic acid derivative represented by the above formula (A) can be produced, and is extremely useful as an intermediate for producing pharmaceuticals.
  • M in the formula is a sodium ion or calcium ion, and n indicates 1 when M is sodium ion and 2 when M is calcium ion
  • the metal salt of (3S) -3 -methoxycarbonyl-4 -phenylbutyrate represented by the general formula (I) is added to an inert solvent in the presence of a trace amount of iV, iV-dimethylformamide, if necessary.
  • the compound (II) can be obtained by distilling off the solvent under reduced pressure after reacting with 5 to 5 equivalents of salted thiol, and if necessary, isolating the compound (II) without isolating the compound (II)
  • the solution can be used as it is for the next step. Wear.
  • the inert solvent used in the reaction include toluene, methylene chloride, chloroform, ethyl acetate and the like.
  • the reaction temperature is usually from 110 to 80 ° C, and the reaction time is usually from 15 minutes to 5 hours, depending on the used starting materials, solvent and reaction temperature.
  • Compound (II) is converted to a compound of the formula (C) in an amount of 1-3 equivalents in a solvent in the presence of a base such as triethylamine, diisopropylethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide.
  • a base such as triethylamine, diisopropylethylamine, sodium hydrogen carbonate, sodium carbonate, potassium carbonate, sodium hydroxide, or potassium hydroxide.
  • the compound (III) can be obtained by reacting the compound with the cis-hexahydroisoindoline or an acid addition salt thereof.
  • Solvents used for the reaction include, for example, water, toluene, methylene chloride, chloroform, ethyl acetate, tetrahydrofuran,
  • Examples thereof include 1,2-dimethoxyethane and a mixed solvent thereof.
  • the reaction temperature is usually from 110 to 50 ° C, and the reaction time is usually from 10 minutes to 12 hours, depending on the used starting materials, solvent and reaction temperature.
  • Examples of the acid addition salts of cis-hexahydroisoindoline include salts of hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid and the like.
  • Compound (III) is dissolved in an alcohol such as methanol, ethanol, or isopropanol, and hydrolyzed by adding an aqueous solution of sodium hydroxide, potassium hydroxide, or the like at 0 to 70 ° C.
  • Compound (A) can be obtained by neutralizing with an acid such as hydrochloric acid as necessary.
  • the compound (A) produced as described above can be converted into a pharmacologically acceptable salt thereof according to a known method.
  • examples of such compounds include salts with inorganic bases such as sodium salt, potassium salt, calcium salt, etc .; organic amines such as morpholine, piperidine, phenylalaninol, and amino acids. Can be.
  • the calcium salt represented by can also be produced by directly adding calcium chloride to the reaction solution after the completion of the above-mentioned hydrolysis reaction, followed by salt conversion.
  • (3S) — 3-Methoxycarbonyl_4 Dissolve monophenylbutyric acid (3.00 g) in acetone (30 mL) and add sodium hydroxide (0.57 g) in water (0. .60 mL) solution and stirred at room temperature. The precipitated crystals were collected by filtration and washed with acetone (1 mL) to obtain sodium salt of (3S) _3-methoxycarbonyl 4-phenylbutyrate (2.93 g).
  • (3S) 13-Methoxycarbonyl-4'-phenylbutyric acid (0.25 g) was dissolved in methanol (3 mL), and calcium hydroxide (0.042 g) was added thereto while stirring at room temperature, and the same temperature was added. After stirring at for 2 hours, methanol (0.6 mL) was added, and the mixture was further stirred at room temperature overnight. The crystals were collected by filtration and washed with methanol (1 mL) to obtain calcium salt of (3S) -13-methoxycarbonyl 4-phenylbutyrate (0.22 g).
  • (3 S) 3-Methoxycarbonyl-4-phenylbutyric acid (0.98 g) was dissolved in acetone (20 mL), and potassium hydroxide (0.20 g) in water (0.5 mL) was stirred under ice-cooling and stirring. ) The solution was added, and the solvent was distilled off under reduced pressure. Getyl ether (50 mL) was added to the residue, and the mixture was stirred at room temperature for 10 minutes. The precipitated crystals were collected by filtration and washed with getyl ether to obtain potassium salt of (3S) -3-methoxycarbonyl 4-phenylbutyrate (0.60 g).
  • a sodium aqueous solution (5 mol / L, 5.4 mL) was added, and the mixture was stirred at room temperature for 1 hour and then at 50 ° C for 4 hours.
  • isopropanol (5 mL) and water (4 OmL) were added to the reaction solution
  • an aqueous solution of calcium chloride (1.7 g) dissolved in water (10 mL) was added dropwise with stirring at 50 ° C.
  • the mixture was stirred for 3 hours while allowing to cool, and the precipitated crystals were collected by filtration, and the obtained crystals were washed with water (5 OmL) to remove the crystals (7.38 g). Obtained.
  • the gradient was performed as shown in Table 1. The linear gradient from 15 minutes to 40 minutes.
  • Degradation rate was calculated based on the following formula from the purity before storage under heating and the purity after storage under heating.
  • Decomposition rate (%) 100- (Purity after storage under heating Z Purity before storage under heating) X 100 Table 2 shows the results.
  • the metal salt of (3S) -3-methoxycarbonyl 4-phenylbutyrate represented by the general formula (I) of the present invention includes a benzyl succinic acid derivative represented by the formula (A): It is useful as an intermediate for the production of various drugs having a benzylsuccinic acid partial structure, and via this, for example, a benzylsuccinic acid derivative represented by the above formula (A) useful as a therapeutic agent for diabetes, etc. Can be efficiently and stably produced, and is suitable for production on an industrial scale.

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  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Diabetes (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Animal Behavior & Ethology (AREA)
  • General Health & Medical Sciences (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Endocrinology (AREA)
  • Emergency Medicine (AREA)
  • Epidemiology (AREA)
  • Engineering & Computer Science (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Indole Compounds (AREA)

Abstract

L'invention concerne de nouveaux sels métalliques d'acide (3S)-3-méthoxycarbonyl-4-phénylbutyrique représentés par la formule générale (I), utiles en tant qu'intermédiaires pour la production de divers médicaments : (I). [M représente un ion sodium ou un ion calcium ; lorsque M est un ion sodium, n représente le nombre 1, tandis que lorsque M est un ion calcium, n représente le nombre 2]. L'invention concerne en outre un procédé permettant de préparer le dérivé (A) d'acide benzylsuccinique, et des sels pharmacologiquement acceptables de ceux-ci, en utilisant le sel décrit ci-dessus en tant qu'intermédiaire. Les composés ainsi préparés produisent une stimulation de la sécrétion d'insuline et une réduction du glucose sanguin. Ils sont utiles en tant que médicaments anti-diabétiques.
PCT/JP2003/000341 2002-01-22 2003-01-17 Sels metalliques d'acide (3s)-3-methoxycarbonyl-4-phenylbutyrique et utilisation de ceux-ci WO2003062186A1 (fr)

Priority Applications (1)

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JP2003562070A JP4000113B2 (ja) 2002-01-22 2003-01-17 （３ｓ）−３−メトキシカルボニル−４−フェニル酪酸金属塩およびその使用方法

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JP2002-012245 2002-01-22
JP2002012245 2002-01-22

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WO2003062186A1 true WO2003062186A1 (fr) 2003-07-31

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1324010C (zh) * 2005-01-12 2007-07-04 江苏省药物研究所 一种米格列奈的制备方法
US7847107B2 (en) 2005-12-27 2010-12-07 Kissei Pharmaceutical Co., Ltd. Asymmetric reduction method
JP2014034521A (ja) * 2012-08-07 2014-02-24 Tokuyama Corp ミチグリニドカルシウム水和物の結晶を製造する方法
CN102911107B (zh) * 2012-09-28 2015-11-25 迪沙药业集团有限公司 米格列奈钙的制备方法

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001261644A (ja) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd ヘキサヒドロイソインドリン・酸付加塩およびその使用方法
JP2001261645A (ja) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd （３ｓ）−３−メトキシカルボニル−４−フェニル酪酸クロリドおよびその使用方法

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP2001261644A (ja) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd ヘキサヒドロイソインドリン・酸付加塩およびその使用方法
JP2001261645A (ja) * 2000-03-22 2001-09-26 Kissei Pharmaceut Co Ltd （３ｓ）−３−メトキシカルボニル−４−フェニル酪酸クロリドおよびその使用方法

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN1324010C (zh) * 2005-01-12 2007-07-04 江苏省药物研究所 一种米格列奈的制备方法
US7847107B2 (en) 2005-12-27 2010-12-07 Kissei Pharmaceutical Co., Ltd. Asymmetric reduction method
JP2014034521A (ja) * 2012-08-07 2014-02-24 Tokuyama Corp ミチグリニドカルシウム水和物の結晶を製造する方法
CN102911107B (zh) * 2012-09-28 2015-11-25 迪沙药业集团有限公司 米格列奈钙的制备方法

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JPWO2003062186A1 (ja) 2005-05-19

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