WO1998023769A1 - Procede de preparation de n-benzyl-3-pyrrolidinol - Google Patents

Procede de preparation de n-benzyl-3-pyrrolidinol Download PDF

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Publication number
WO1998023769A1
WO1998023769A1 PCT/JP1997/004300 JP9704300W WO9823769A1 WO 1998023769 A1 WO1998023769 A1 WO 1998023769A1 JP 9704300 W JP9704300 W JP 9704300W WO 9823769 A1 WO9823769 A1 WO 9823769A1
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WO
WIPO (PCT)
Prior art keywords
benzyl
pyrrolidinol
layer
reaction
pyrrolidinone
Prior art date
Application number
PCT/JP1997/004300
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English (en)
Japanese (ja)
Inventor
Yoshihiko Yasohara
Junzo Hasegawa
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Kaneka Corporation
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Publication date
Application filed by Kaneka Corporation filed Critical Kaneka Corporation
Publication of WO1998023769A1 publication Critical patent/WO1998023769A1/fr

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    • 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

Definitions

  • the present invention relates to a method for producing optically active N-benzyl-3-pyrrolidinol, which is useful as an intermediate for the synthesis of pharmaceuticals such as / -lactam antibiotics and dihydropyridine compounds.
  • Optically active N-benzyl 3-pyrrolidinol is useful as a synthetic intermediate for pharmaceuticals.
  • Known methods for producing optically active N-benzyl-3-pyrrolidinol include a method of synthesizing from an optically active compound, a method of asymmetric synthesis starting from a prochiral compound, and a method of optical resolution.
  • Japanese Patent Application Laid-Open No. 6-141876 discloses that N-benzyl-3 is used in the presence of an enzyme having an activity of stereoselectively reducing N-benzyl-3-pyrrolidinone.
  • a method for producing optically active N-benzyl-3-pinolidinol by stereoselectively reducing pyrrolidinone has been disclosed. However, this method was not practical for practical use because of its low substrate charge concentration and low conversion rate from substrate to product. Summary of the Invention
  • an object of the present invention is to provide a more efficient method for producing optically active N-benzyl-3-pyrrolidinol by an enzymatic reaction for stereoselectively reducing N-benzyl-3-pyrrolidinone. is there.
  • the present invention relates to a method for producing optically active N-benzyl-3-pyrrolidinol by stereoselective reduction of N-benzyl-3-pyrrolidinone by an enzymatic reaction, wherein the enzymatic reaction is carried out using an enzyme-containing water.
  • a method for producing optically active N-benzyl-3-pyrrolidinol in a two-layer system comprising a layer and an organic solvent layer forming a two-layer with the aqueous layer. Replacement form (Rule 26)
  • the present inventors have investigated the stability of N-benzyl-3-pyrrolidinone, which is a substrate for the enzymatic reaction, in the enzymatic reaction conditions, that is, in water, and found that it is very unstable.
  • N-benzyl-3-pyrrolidinol a product of the enzymatic reaction
  • the organic solvent layer in the two-layer system consisting of the aqueous layer and the organic solvent layer.
  • enzymes and various components required for the expression of enzyme activity are generally water-soluble compounds, and thus can be expected to be mostly present in the aqueous layer. Therefore, since the chance of contact with the substrate or product is reduced, inhibition of the enzyme activity by the substrate or product generally caused by the enzymatic reaction can be expected, so that a low substrate concentration and a decrease in the conversion rate of the enzymatic reaction can be expected.
  • the present inventors provide a process for producing optically active N-benzyl-3-pyrrolidinol using an enzyme that stereoselectively reduces N-benzyl-3-pyrrolidinone. Layer and an organic solvent layer that forms two layers with this aqueous layer, the resulting N-benzyl-13-pyrrolidinol can be compared with the case where the reaction is performed only in water containing the enzyme. It has also been found that the optical purity of the product is improved.
  • N-benzyl-3-pyrrolidinone as a substrate is stereoselectively reduced by an enzymatic reaction.
  • N-benzyl-3-pyrrolidinone can be synthesized by the method disclosed in Japanese Patent Application Laid-Open No. 54-166666. That is, a 3-ethylalanine derivative obtained by Michael addition of benzylamine and ethyl acrylate is reacted with ethyl ethyl acetate in the presence of a base. The obtained compound is cyclized in the presence of sodium metal to obtain N-benzyl-4-carboetkin-13-pyrrolidone. This is decarboxylated with hydrochloric acid to give N-benzyl-1-pyrrolidinone.
  • the enzymatic reaction is carried out in a two-layer system comprising an aqueous layer containing the enzyme and an organic solvent layer forming a two-layer with the aqueous layer.
  • the enzyme is not particularly limited as long as it has an ability to stereoselectively reduce the N-benzyl-3-pyrrolidinone.
  • the enzyme is exemplified in Japanese Patent Application Laid-Open No. 6-141876. Enzymes and the like.
  • microbial cells, cultures, or processed products thereof having the ability to stereoselectively reduce N-benzyl-3-pyrrolidinone can also be used.
  • the microorganism is not particularly limited.
  • the genus Depodascus (Dep0 dascus)
  • the genus Debaryomyces the genus Cryptoococcus
  • the genus Pichia the genus Richidosporium (Rh genus odsporidi um, genus Trichosporon, genus Komagataera (K 0 maga t_ ae 11a), genus Og ataea, genus Zyg'o sacchar omy es, genus E scherichia), Micrococcus (W), Genus Pseud omo nas, C andida, C.
  • microorganisms and the like belonging to the genus can generally be obtained from a stock that is easily available or purchased. It can also be separated from nature. In addition, it is necessary to obtain mutations in these microorganisms to obtain strains having more advantageous properties for this reaction. Replacement paper (Rule 26) Can also. Moreover, those derived from these microorganisms by recombinant DNA, genetic engineering such as cell fusion, or biotechnological techniques may be used.
  • the treated product of the above cells is not particularly limited, and examples thereof include a dried product of the cells, a surfactant or an organic solvent-treated product, a lysed enzyme-treated product, an immobilized cell or an enzyme extract extracted from the cells, and the like. Can be mentioned.
  • the processed product of the culture is not particularly limited, and examples thereof include a concentrate, a dried product, a processed product of a surfactant or an organic solvent, a processed product of a lytic enzyme, and the like. Further, the enzyme may be purified from the cultured cells or culture and used.
  • the organic solvent constituting the organic solvent layer an aqueous layer and a two-layer are formed, the N-benzyl-3-pyrrolidinone and the product N-benzyl-3-pyrrolidinol are dissolved, and the activity of the enzyme is reduced.
  • the organic solvent constituting the organic solvent layer
  • an aqueous layer and a two-layer are formed, the N-benzyl-3-pyrrolidinone and the product N-benzyl-3-pyrrolidinol are dissolved, and the activity of the enzyme is reduced.
  • esters such as acetate and butyrate
  • alcohols such as 1-butanol and 1-octanol
  • aromatics such as benzene and toluene
  • Ethers such as diisopropyl ether, diisopropyl ether, etc .; hydrogenated hydrocarbons such as chloroform and methylene chloride; aliphatic hydrocarbons such as n-hexane and n-decane; ketones such as methyl ethyl ketone and methyl isobutyl ketone And the like.
  • hydrogenated hydrocarbons such as chloroform and methylene chloride
  • aliphatic hydrocarbons such as n-hexane and n-decane
  • ketones such as methyl ethyl ketone and methyl isobutyl ketone And the like.
  • the ratio between the aqueous layer and the organic solvent layer in the two-layer system is not particularly limited, but is preferably in the range of 95/5 to 5Z95 on a weight basis.
  • the stereoselective reduction of N-benzyl-3-pyrrolidinone by the enzymatic reaction is specifically performed by mixing an aqueous medium containing the enzyme with the organic solvent and stirring or shaking the mixture. Can be.
  • the enzyme reaction requires reduced nicotinamide * adenine dinucleotide (NADH) and reduced nicotinamide / adenine dinucleotide phosphate (NADPH) as coenzymes in addition to the above enzymes. It is necessary to add these or add a reaction system that produces ADH, NADPH, etc. to the reaction system.
  • a reaction in which formate dehydrogenase produces NADH from NAD when producing carbon dioxide and water from formic acid and a method in which glucose dehydrogenase replaces glucose with glucono (Rule 26)
  • a reaction for producing NADH from NAD or NADPH from NADP can be used.
  • a coenzyme generation system that the microorganisms originally have in their own cells can be used as it is.
  • the above enzyme reaction is preferably performed at a reaction temperature of 0 to 70 ° C and a pH of 4 to 9. More preferably, the temperature is 20 to 50 ° C.
  • the time for the above enzyme reaction varies depending on the substrate concentration, the amount of the enzyme, the amount of the capture enzyme used, the reaction temperature and the like, but is usually from 1 to 100 hours. Further, it is preferable that the enzymatic reaction is carried out with stirring to such an extent that the organic solvent layer and the aqueous layer are mixed. It is determined as appropriate depending on the ratio, progress of the reaction, and the like.
  • N-benzyl 3-pyrrolidinone 10 mg was weighed into a test tube with a stopper, and 100 mM phosphate buffer (pH 6.5) 0.5 ml and the organic solvent shown in Table 1 were added. 5 ml was added and the mixture was stirred well. Three of these were prepared, and one of them was added 4 ml of ethyl acetate and sodium bicarbonate immediately after stirring until the aqueous layer became saturated, and then stirred well. A part of this organic layer was subjected to gas chromatography to analyze the amount of N-benzyl-13-pyrrolidinone. The remaining two tubes were shaken at 30 ° C.
  • a liquid medium having the following composition was prepared, dispensed into large test tubes in 5 ml increments, and steam sterilized at 20 ° C for 20 minutes.
  • Nicotinamide 'adenine dinucleotide phosphate 275 mg Nicotinamide 'adenine dinucleotide phosphate 275 mg
  • Glucose dehydrogenase (manufactured by Amano Pharmaceutical Co., Ltd.) 84 units
  • Table 2 summarizes the conversion to the product and the optical purity of the product.
  • a microbial cell suspension was prepared in the same manner as in Example 2, and the reaction was carried out without adding butyl acetate. Table 3 summarizes the results.
  • a liquid medium having the following composition was prepared, dispensed into a large test tube in an amount of 10 ml, and sterilized with steam at 120 ° C for 20 minutes.
  • a cell suspension of Escherichiaco 1 I FO 127 7 34 was prepared in the same manner as in Example 3, and the reaction was carried out without adding butyl acetate to the reaction.
  • the optical purity was 7% and the optical purity was (S) 58% ee.
  • Example 2 The same operations as in Example 2 were performed on the microorganisms shown in Table 4, and the results are summarized in Table 4.
  • Example 3 The same operation as in Example 3 was performed on the microorganisms shown in Table 5, and the results are summarized in Table 5.
  • a liquid medium having the composition shown in Example 3 was prepared, and 25 tubes of 100 ml were poured into a 500 ml volume flask, and sterilized with steam at 120 ° C for 20 minutes. Was performed. Each of them was aseptically inoculated with 2 ml of a culture solution of Pseudomonas diminut-a IF 0 126 997 cultured in the same manner as in Example 3. Shaking culture was performed at 30 ° C for 24 hours. Cells were collected from the resulting culture by centrifugation and suspended in 500 ml of 10 OmM phosphate buffer (pH 6.5).
  • a liquid medium having the composition shown in Example 2 was prepared, and 50 ml of a 500 ml dispensed volume was placed in a 500 ml volumetric flask, and steam sterilized at 120 ° C for 20 minutes. Natsuta. Each of them was aseptically inoculated with 1 ml of a culture solution of Pichiame's membrane fashion (Pichiamembranaefaciens) IFO 0182, and cultured at 30 ° C for 24 hours. The cells were cultured with shaking for hours. The cells were collected from the obtained culture solution by centrifugation, and suspended in 100 ml of 100 mM phosphate buffer (pH 6.5). Add 5 g of N-benzyl-3-pyrrolidinone and glucose
  • a liquid culture medium having the composition shown in Example 2 was prepared, and 50 ml of 500 ml dispensed into E-Saka Lofrasco was prepared, and sterilized by steam at 120 ° C for 20 minutes. Was performed. Each of them was aseptically inoculated with a culture solution lm1 of Trichosporon fermentans ATC C10675, which was cultured in the same manner as in Example 2, and incubated at 30 ° C for 24 hours. The cells were cultured with shaking for an hour. The cells were collected from the resulting culture by centrifugation, and suspended in 100 mM phosphate buffer (pH 6.5) (500 ml). The cells were disrupted with a brown cell disrupter under ice cooling, and the supernatant obtained by centrifugation was used as a cell-free extract and used as the following reaction solution components.
  • Nicotinamide adenine dinucleotide phosphate 26 mg
  • the method for producing N-benzyl-3-pyrrolidinol of the present invention has the above-mentioned constitution, it is possible to efficiently produce optically active N-benzyl-3-pyrrolidinol on an industrial scale. .
  • the optically active N-benzyl-3-pyrrolidinol obtained by the present invention has a high optical purity and is an important intermediate of a compound useful as a pharmaceutical such as a 3-lactam antibiotic ⁇ dihydropyridine compound. is there. Replacement form (Rule 26)

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  • Organic Chemistry (AREA)
  • Chemical & Material Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Wood Science & Technology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Microbiology (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biotechnology (AREA)
  • Health & Medical Sciences (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • General Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Pyrrole Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation efficace de N-benzyl-3-pyrrolidinol optiquement actif consistant à réduire stéréosélectivement le N-benzyl-3-pyrrolidinol par réaction enzymatique. Le procédé de la présente invention consiste à réduire stéréosélectivement le N-benzyl-3-pyrrolidinol par une réaction enzymatique se produisant dans un système à deux couches composé d'une couche aqueuse contenant un enzyme et d'une couche organique pouvant former un système à deux couches avec la couche aqueuse.
PCT/JP1997/004300 1996-11-26 1997-11-26 Procede de preparation de n-benzyl-3-pyrrolidinol WO1998023769A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP8/331468 1996-11-26
JP33146896A JPH10150998A (ja) 1996-11-26 1996-11-26 Ｎ−ベンジル−３−ピロリジノールの製造方法

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WO1998023769A1 true WO1998023769A1 (fr) 1998-06-04

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015610A1 (fr) * 1998-09-17 2000-03-23 Samsung Fine Chemicals Co., Ltd. PREPARATION DE DERIVES D'HYDROXYCYCLOALKYLAMINE A SUBSTITUTION $i(N)
EP1130109A1 (fr) * 2000-02-29 2001-09-05 Pfizer Products Inc. Procédé microbien pour la préparation de dérivés optiquement actifs de 3-hydroxypyrrolidine
WO2002010399A1 (fr) * 2000-08-01 2002-02-07 Kaneka Corporation Nouvelle carbonyl reductase, son gene et son procede d'utilisation

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP4753273B2 (ja) * 1999-07-21 2011-08-24 株式会社カネカ 光学活性ピリジンエタノール誘導体の製造方法

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5416466A (en) * 1977-07-07 1979-02-07 Shionogi & Co Ltd Novel 3-hydroxypyrrolldine-3-carboxylic derivative
JPH05219967A (ja) * 1991-10-23 1993-08-31 E R Squibb & Sons Inc ハロフェニルアルコールの立体選択的製造法
JPH06141876A (ja) * 1992-11-10 1994-05-24 Kyowa Hakko Kogyo Co Ltd 光学活性なｎ−ベンジル−３−ピロリジノールの製造法

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS5416466A (en) * 1977-07-07 1979-02-07 Shionogi & Co Ltd Novel 3-hydroxypyrrolldine-3-carboxylic derivative
JPH05219967A (ja) * 1991-10-23 1993-08-31 E R Squibb & Sons Inc ハロフェニルアルコールの立体選択的製造法
JPH06141876A (ja) * 1992-11-10 1994-05-24 Kyowa Hakko Kogyo Co Ltd 光学活性なｎ−ベンジル−３−ピロリジノールの製造法

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2000015610A1 (fr) * 1998-09-17 2000-03-23 Samsung Fine Chemicals Co., Ltd. PREPARATION DE DERIVES D'HYDROXYCYCLOALKYLAMINE A SUBSTITUTION $i(N)
EP1130109A1 (fr) * 2000-02-29 2001-09-05 Pfizer Products Inc. Procédé microbien pour la préparation de dérivés optiquement actifs de 3-hydroxypyrrolidine
WO2002010399A1 (fr) * 2000-08-01 2002-02-07 Kaneka Corporation Nouvelle carbonyl reductase, son gene et son procede d'utilisation
US7033808B2 (en) 2000-08-01 2006-04-25 Kaneka Corporation Carbonyl reductase, gene thereof and method of using the same
JP4880859B2 (ja) * 2000-08-01 2012-02-22 株式会社カネカ 新規カルボニル還元酵素、その遺伝子、およびその利用法

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JPH10150998A (ja) 1998-06-09

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