WO1994004701A1 - Procede de production d'un compose de 1,4-dihydropyridine optiquement actif - Google Patents

Procede de production d'un compose de 1,4-dihydropyridine optiquement actif Download PDF

Info

Publication number
WO1994004701A1
WO1994004701A1 PCT/JP1992/001074 JP9201074W WO9404701A1 WO 1994004701 A1 WO1994004701 A1 WO 1994004701A1 JP 9201074 W JP9201074 W JP 9201074W WO 9404701 A1 WO9404701 A1 WO 9404701A1
Authority
WO
WIPO (PCT)
Prior art keywords
enzyme
dimethyl
ester
nicotinoylaminoethyl
dihydropyridine
Prior art date
Legal status (The legal status 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 status listed.)
Ceased
Application number
PCT/JP1992/001074
Other languages
English (en)
Japanese (ja)
Inventor
Takashi Adachi
Mayuma Ikeda
Takako Hadachi
Kazunori Hanada
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho 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 Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to AU24863/92A priority Critical patent/AU2486392A/en
Publication of WO1994004701A1 publication Critical patent/WO1994004701A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/12—Antihypertensives
    • 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
    • C12P17/12—Nitrogen as only ring hetero atom containing a six-membered hetero ring
    • 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
    • C12P41/00—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture
    • C12P41/003—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions
    • C12P41/005—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by ester formation, lactone formation or the inverse reactions by esterification of carboxylic acid groups in the enantiomers or the inverse reaction

Definitions

  • the present invention relates to a method for producing an intermediate for producing an optically active 1,4-dihydropyridine compound, and more particularly, to an important optically active 1,4 when producing an optically active 1,4 dihydropyridine compound which is extremely useful as a pharmaceutical.
  • the present invention relates to a method for producing a dihydropyridine intermediate.
  • the two carboxylic acid esters bonded to the 3- and 5-positions of the dihydropyridine ring of the 1,4-dihydropyridine compound are different from each other, they have an asymmetric carbon at the 4-position and there are two optical isomers I do.
  • a compound having such an asymmetric carbon is used as a drug, it is generally considered that only one isomer that is preferable as a drug is given to a living body from the viewpoint that no extra load is applied to the living body. It is becoming more and more.
  • the desired optical isomer can be obtained only with a maximum yield of 50% through complicated operations.
  • Compound A is expected to be a prophylactic and therapeutic agent for ischemic heart disease, hypertension, etc., because it has a selective coronary vasodilator effect, excellent sustained drug efficacy, and a c-GMP increasing effect Has been done. Further, it is expected that Compound A has an optical isomer in its structure, and only one of the isomers is preferable as a pharmaceutical.
  • the present inventors have diligently studied a method using an enzyme in producing optically active compound A.
  • hydrolyzing enzymes produced by microorganisms belonging to the genera Aspergillus, Benicillium, Streptomyces and Bacillus, and hydrolysis prepared from animal organs using compounds that can be easily produced as raw materials The present inventors have found that the use of an enzyme and a hydrolase prepared from a plant gives a production intermediate of compound A exhibiting a preferred optical rotation in high yield and high optical purity, and completed the present invention. .
  • the present invention relates to 2,6-dimethyl-14- (3-nitrophenyl) 1-1,4-dihydropyridine-13,5-dicarboxylic acid bis (2-nicotinylaminoethyl) ester or a salt thereof.
  • the salt is a hydrochloride, a sulfate or a nitrate.
  • the enzymes used in the present invention include enzymes produced by microorganisms belonging to Aspergillus, Benicillium, Streptomyces, and Bacillus, enzymes prepared from animal organs, and enzymes prepared from plants.
  • any object can be used as long as the object of the present invention can be achieved, and there is no particular limitation.
  • Some of these microbial enzymes are commercially available and are readily available. Specific examples of commercially available enzymes include, for example, enzymes derived from the genus Aspergillus (Aspergillus oryzae); protease A “Amano”, protease M “Amano”, enzymes derived from the genus Aspergillus (Aspergillus melleus); Mano ", Seabrose” Amano ", an enzyme derived from the genus Aspergillus (Aspergillus sp.); Cellulase A” Amano ", Acylase” Amano "1500, Piozyme A (registered trademark)” Amano ", Deamisym ( (Registered trademark) "Amano", an enzyme derived from the genus Penicillium sp .; nuclease "Amano” (above, manufactured by Amano Pharmaceutical Co., Ltd.), an enzyme derived from the genus Aspergillus
  • Specific examples of commercially available enzymes include, for example, pig liver esterase (manufactured by Sigma) and kidney lipase (manufactured by Tokyo Chemical Industry). Some enzymes prepared from plants are commercially available and are also readily available. Specific examples of commercially available enzymes include, for example, bean nut phospholipase (Phospholipase D) (manufactured by Lucerna Chem), and pine-atre proteases (Bromelain) (manufactured by Sigma).
  • various additives can be used in the enzyme reaction, and addition of 1,10-0-phenanthroline is particularly effective. By using this additive, the reaction rate can be improved and the amount of required enzyme can be reduced.
  • each is set according to the optimum conditions of the enzyme to be used.
  • the general reaction conditions will be described.
  • the reaction solution it is preferable to use a buffer such as a phosphate buffer or a Tris-HCl buffer in order to keep the pH of the reaction solution constant.
  • concentration of the buffer varies depending on the type of the buffer, but is preferably 2 M or less.
  • the reaction can be carried out without using a buffer.
  • the reaction conditions may be set according to the enzyme used.
  • various conditions when using protease P are such that the pH is 6.0 to 8.0, and most preferably, the pH is 7.0 to 7.5.
  • the reaction temperature is from 25 ° C to 50 ° C, most preferably from 30 ° C to 35 ° C.
  • the concentration of S substance in the reaction solution is 0.05 to 25% by weight based on the reaction solution.
  • the amount of enzyme used depends on the enzyme titer and the amount of substrate.
  • the reaction time may be set while confirming the progress of the reaction by TLC analysis or HPLC analysis.
  • organic solvents can be used as a substrate dissolution aid.
  • the organic solvent that can be added include acetone, methyl ethyl ketone, dimethyl sulfoxide, dioxane, N, dimethylformamide, and acetonitrile. These may be used alone or in combination of two or more.
  • the power that can be added at a concentration of 1 to 15% to the reaction solution is most preferably 4 to 6%.
  • the organic solvent may be added either at the beginning of the reaction or during the reaction.
  • surfactants such as sodium lauryl sulfate, triton 100, and Tween 80, and emulsifying agents such as polyethylene glycol # 400, gum arabic, and lecithin can also be used.
  • the substrate is added all at once in the early stage of the reaction when performing this enzyme reaction, the substrate precipitates and aggregates, and the progress of the reaction is inhibited.
  • a method of dissolving a substrate (hydrochloride, sulfate, or nitrate) in water and adding the solution to the enzyme solution little by little continuously showed a great effect.
  • the continuous addition of the substrate and the addition of the organic solvent are performed at the same time, it is preferable to add the organic solvent in the middle of the reaction rather than adding the organic solvent at the beginning of the reaction in which the substrate concentration is low.
  • the use of the substrate solubilizing agent and the continuous addition of the substrate can greatly increase the final substrate charge concentration.
  • the reaction rate can be increased and the amount of the enzyme used can be reduced.
  • the enzyme used was protease II, various organic reagents and metal ions were added and examined.
  • 1.10-0-funanthroline showed a particularly excellent effect.
  • 1,10— ⁇ -phenanthroline can be dissolved in an organic solvent such as dimethylsulfoxide or acetone and added to the enzyme solution. It is effective to add at a concentration of O mM, and the optimal concentration is 1 mM to 4 mM.
  • the desired product can be isolated by extraction with an organic solvent such as, for example, and, if necessary, purification by column chromatography or the like.
  • reaction products were confirmed by the TLC method and the HPLC method shown below.
  • Optical purity was determined by optical rotation measurement or HPLC analysis using a chiral column. HPLC analysis was performed under the following conditions.
  • the optical yield measured by the HPLC method was 100%.
  • the pH of the reaction solution decreased with the addition of the substrate, the pH was maintained at 7.5 by adding a 0.5 N aqueous sodium hydroxide solution according to the pH status. After 48 hours, when the addition of the substrate was completed, the progress of the reaction was confirmed by HPLC, and the substrate was almost completely eliminated.
  • the reaction mixture was adjusted to pH 5.0 by adding 1N phosphoric acid, and extracted twice with 300 ml of ethyl acetate. After the ethyl acetate layer was concentrated to 200 ml, it was extracted twice with 200 ml of a 1N aqueous sodium hydroxide solution.
  • the present invention it is possible to provide an intermediate for the production of a compound A which is simple, has a high yield, and is optically active (levorotatory) with high optical purity.
  • the raw material (prochiral compound) used and the product have a 1: 1 balance relationship, and the yield of the desired optical isomer is at most 50% as in the conventional optical resolution method.
  • the biggest feature is that it has no shortcomings.
  • the method of the present invention has the following advantages: the reaction proceeds under mild conditions, so that no special reactor is required, an expensive resolving agent is not required, and the waste liquid after the reaction is easily treated. It has very advantageous advantages over the method.
  • an optically active compound A can be produced extremely easily and in good yield. That is, the compound can be reacted with 3-nitrooxypropyl-111-bromide or 3-nitrooxypropyl alcohol to obtain an optically active compound A.
  • optically active compound A obtained here is a preferred isomer (Levorotary) as a pharmaceutical U
  • Levorotatory compound A is significantly more effective than racemic and dextrorotatory compound A in tests of calcium channel binding ability, coronary blood flow increasing action, heart rate inhibitory action and hypotensive action. Therefore, the compound A having an optical activity of levorotation produced by the intermediate of the present invention is extremely useful as a drug for preventing and treating angina pectoris, hypertension and the like.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Wood Science & Technology (AREA)
  • Zoology (AREA)
  • General Engineering & Computer Science (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Microbiology (AREA)
  • Biotechnology (AREA)
  • Veterinary Medicine (AREA)
  • Genetics & Genomics (AREA)
  • Cardiology (AREA)
  • Heart & Thoracic Surgery (AREA)
  • Medicinal Chemistry (AREA)
  • Biochemistry (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Procédé de production d'un 3-(2-nicotinoylaminoéthyl)ester optiquement actif d'acide (-) 2,6-diméthyl-4-(3-nitrophényl)-1,4-dihydropyridine-3,5-dicarboxylique par hydrolyse asymétrique de bis(2-nicotinoylaminoéthyl)2,6-diméthyle-4-(3-nitrophényl)-1,4-dihydropyridine-3,5-dicarboxylate, ou bien d'un sel de celui-ci, avec une enzyme qui peut hydrolyser asymétriquement les groupes carboxylates liés aux positions 3 et 5 d'un cycle 1,4-dihydropyridine. Le procédé selon l'invention permet de produire un intermédiaire très important, permettant d'obtenir seulement l'isomère optique pouvant être utilisé en tant que médicament, parmi les isomères de 3-(2-nicotinoylaminoéthyl)5-(3-nitroxypropyl)ester d'acide 2,6-diméthyl-4-(3-nitrophényl)-1,4-dihydropyridine-3,5-dicarboxylique.
PCT/JP1992/001074 1991-03-01 1992-08-26 Procede de production d'un compose de 1,4-dihydropyridine optiquement actif Ceased WO1994004701A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU24863/92A AU2486392A (en) 1991-03-01 1992-08-26 Process for producing optically active 1,4-dihydropyridine compound

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP12066991 1991-03-01
JP4030255A JPH0584089A (ja) 1991-03-01 1992-02-18 光学活性１，４−ジヒドロピリジン化合物の製造法

Publications (1)

Publication Number Publication Date
WO1994004701A1 true WO1994004701A1 (fr) 1994-03-03

Family

ID=26368581

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1992/001074 Ceased WO1994004701A1 (fr) 1991-03-01 1992-08-26 Procede de production d'un compose de 1,4-dihydropyridine optiquement actif

Country Status (3)

Country Link
JP (1) JPH0584089A (fr)
AU (1) AU2486392A (fr)
WO (1) WO1994004701A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0657429A4 (fr) * 1992-08-31 1996-03-27 Mercian Corp Compose a base de 1,4-dihydropyridine presentant une activite optique et procede de production.

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0211592A (ja) * 1988-06-29 1990-01-16 Nissan Chem Ind Ltd 光学活性なジヒドロピリジンホスホン酸エステル
JPH02223580A (ja) * 1988-11-24 1990-09-05 Taisho Pharmaceut Co Ltd １，４―ジヒドロピリジン誘導体

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPH0211592A (ja) * 1988-06-29 1990-01-16 Nissan Chem Ind Ltd 光学活性なジヒドロピリジンホスホン酸エステル
JPH02223580A (ja) * 1988-11-24 1990-09-05 Taisho Pharmaceut Co Ltd １，４―ジヒドロピリジン誘導体

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0657429A4 (fr) * 1992-08-31 1996-03-27 Mercian Corp Compose a base de 1,4-dihydropyridine presentant une activite optique et procede de production.

Also Published As

Publication number Publication date
AU2486392A (en) 1994-03-15
JPH0584089A (ja) 1993-04-06

Similar Documents

Publication Publication Date Title
JP7757278B2 (ja) （４ｓ）－（４－シアノ－２－メトキシフェニル）－５－エトキシ－２，８－ジメチル－１，４－ジヒドロ－１，６－ナフチリジン－３－カルボン酸のアシルオキシメチルエステルの製造方法
JP7001597B2 (ja) 新規なプロセスおよび中間体
EP1375495B1 (fr) Procede de fabrication d'un derive d'azetidinone-2
JPH0641075A (ja) 新規な１，４−ジヒドロピリジン化合物及びその製造方法
Winkler et al. Nitrilase‐Catalyzed Enantioselective Synthesis of Pyrrolidine‐and Piperidinecarboxylic Acids
WO1994004701A1 (fr) Procede de production d'un compose de 1,4-dihydropyridine optiquement actif
EP1206452A2 (fr) Procede de preparation de composes benzoperhydroisoindole
EP0844230B1 (fr) Procédé de dédoublement optique d'acide (plus, minus)-3,4,-dihydroxybutanoique
JP3491296B2 (ja) 光学活性１、５−ジ置換−２、４−ｏ−イソプロピリデン−２、４−ジヒドロキシペンタンおよびその製造法
JPH04299994A (ja) 光学活性１，４−ジヒドロピリジン化合物の製造法
KR100878035B1 (ko) 생체 촉매 효소를 이용한 선택적 가수분해방법
JPWO1996006829A1 (ja) １，４−ジヒドロピリジン誘導体
EP4276101B1 (fr) Procédé de préparation d'un dérivé de pyrrolopyridine
JPH0690790A (ja) 光学活性１，４−ジヒドロピリジン−３，５−ジカルボン酸・モノエステル誘導体の製造方法
JP3078597B2 (ja) Ｌ−スレオ−３−（３，４−ジヒドロキシフェニル）セリン誘導体の製造法
JP3078599B2 (ja) Ｌ−３，４−ジヒドロキシフェニルセリン誘導体の製造法
JPH05227991A (ja) 光学活性な３−ピロリジノール誘導体の製造法
KR100848935B1 (ko) 생체 촉매 효소를 이용한 광학 선택적 가수분해방법
WO1994005637A1 (fr) Compose a base de 1,4-dihydropyridine presentant une activite optique et procede de production
EP1737818A2 (fr) Procedes pour la preparation d'amines stereoisomeriquement enrichies
JPH07184685A (ja) 光学的に純粋なテトラヒドロキノリン誘導体の合成法
JPH05284986A (ja) 光学活性１，４−ジヒドロピリジン化合物の製造方法
EP0375394B1 (fr) Procédé de préparation d'antagonistes leucotriéniques
EP2264039A1 (fr) Procédé de préparation du fosinopril et ses intermédiaires
JPH0770066A (ja) 光学活性なジヒドロピリジン化合物及びその合成法

Legal Events

Date Code Title Description
AK Designated states

Kind code of ref document: A1

Designated state(s): AU CA KR US

AL Designated countries for regional patents

Kind code of ref document: A1

Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL SE

DFPE Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101)
121 Ep: the epo has been informed by wipo that ep was designated in this application
122 Ep: pct application non-entry in european phase
NENP Non-entry into the national phase

Ref country code: CA