EP0944730A1 - Verfahren zur herstellung von d-prolinderivaten - Google Patents

Verfahren zur herstellung von d-prolinderivaten

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Publication number
EP0944730A1
EP0944730A1 EP97953805A EP97953805A EP0944730A1 EP 0944730 A1 EP0944730 A1 EP 0944730A1 EP 97953805 A EP97953805 A EP 97953805A EP 97953805 A EP97953805 A EP 97953805A EP 0944730 A1 EP0944730 A1 EP 0944730A1
Authority
EP
European Patent Office
Prior art keywords
proline
general formula
proline derivative
meaning given
microorganisms
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.)
Withdrawn
Application number
EP97953805A
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German (de)
English (en)
French (fr)
Inventor
Martin Sauter
Daniel Venetz
Oleg Werbitzky
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.)
Lonza AG
Original Assignee
Lonza AG
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Filing date
Publication date
Application filed by Lonza AG filed Critical Lonza AG
Publication of EP0944730A1 publication Critical patent/EP0944730A1/de
Withdrawn legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/16—Hydrolases (3) acting on ester bonds (3.1)
    • C12N9/18—Carboxylic ester hydrolases (3.1.1)
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N1/00—Microorganisms, e.g. protozoa; Compositions thereof; Processes of propagating, maintaining or preserving microorganisms or compositions thereof; Processes of preparing or isolating a composition containing a microorganism; Culture media therefor
    • C12N1/20—Bacteria; Culture media therefor
    • C12N1/205—Bacterial isolates
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N9/00—Enzymes; Proenzymes; Compositions thereof; Processes for preparing, activating, inhibiting, separating or purifying enzymes
    • C12N9/14—Hydrolases (3)
    • C12N9/78—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5)
    • C12N9/80—Hydrolases (3) acting on carbon to nitrogen bonds other than peptide bonds (3.5) acting on amide bonds in linear amides (3.5.1)
    • 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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/04—Alpha- or beta- amino acids
    • C12P13/24—Proline; Hydroxyproline; Histidine
    • 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
    • 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
    • C12P41/006—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by reactions involving C-N bonds, e.g. nitriles, amides, hydantoins, carbamates, lactames, transamination reactions, or keto group formation from racemic mixtures
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12R—INDEXING SCHEME ASSOCIATED WITH SUBCLASSES C12C - C12Q, RELATING TO MICROORGANISMS
    • C12R2001/00—Microorganisms ; Processes using microorganisms
    • C12R2001/01—Bacteria or Actinomycetales ; using bacteria or Actinomycetales

Definitions

  • the present invention relates to new microorganisms which are capable of a proline derivative in the form of the racemate or its optically active isomers of the general formula
  • R 1 is alkyl, acyl or hydrogen
  • R 2 is hydrogen or hydroxy
  • R is -NH 2 , aryloxy, or alkoxy to be used as the only nitrogen source, the only carbon source or the only carbon and nitrogen source.
  • D-proline and its derivatives are important intermediates for the manufacture of pharmaceuticals (J Org Chetn, 1994, 59, 7496 - 7498)
  • JP-A-92183399 describes a process for the preparation of D-proline starting from (DL) -proline using microorganisms of the genus Candida or Trichospora Dies
  • JP-A-07127354 describes a process for the preparation of D-proline starting from ornithine by means of microorganisms of the species Proteus mitajiri.
  • a disadvantage of this process is that on the one hand the educt ornithine is too expensive, and on the other hand that D-proline in poor yield is obtained
  • JP-A-07289275 describes a process for the preparation of D-proline starting from L-proline.
  • L-proline is racemized by means of microorganisms of the genus Escherichia, which have racemase activity, to (DL) -proline, which is then raced with L -Proline-degrading microorganisms are cultivated in order to obtain D-proline.
  • DL genus Escherichia
  • L-Proline-degrading microorganisms are cultivated in order to obtain D-proline.
  • a disadvantage of this process is that the D-proline obtained in this way has to be purified further and this is associated with high losses in yield
  • DE-A-43 30 678 encompasses a process for the preparation of N-carbamoyl-D-proline starting from a bicyclic hydantoin.
  • the bicyclic hydantoin is converted to N-carbamoyl-D-proline by means of the microorganisms Agrobacterium radiobacter the disadvantage that the reaction time is too long, and on the other hand that the corresponding D-proline derivative is only obtained in moderate yield
  • the object of the present invention is to isolate microorganisms which can be used for a simple and technically viable process for the preparation of D-proline derivatives of the general formulas II and VI.
  • the corresponding products should be isolated in good yield with good enantiomeric purity
  • microorganisms according to the invention can be isolated from soil samples, sludge or waste water with the aid of customary microbiological techniques. According to the invention, these microorganisms are isolated in such a way that they are present in a medium containing a proline derivative of the general formula I in the form of the racemate or one of its optically active isomers
  • the radical R 1 in the proline derivative of the general formula I means alkyl, acyl or hydrogen.
  • the radical R 2 means hydrogen or hydroxy.
  • the radical R means -NH 2 , alkoxy or aryloxy
  • Alkyl is hereinafter referred to a C ⁇ alkyl group, substituted or unsubstituted, as defined Suitable substituents are for example halogen, in particular fluorine, chlorine and bromine, and examples of an unsubstituted hydroxy C ⁇ - 5 alkyl group are methyl, ethyl, propyl, isopropyl, butyl , Isobutyl, Tertiarbutyl, Pentyl, Isopentyl, (Isoamyl) Examples of a substituted C ⁇ - 5 alkyl group are chloromethyl, trifluoromethyl, 2-bromopropyl and hydroxymethyl
  • Acyl is defined below as acetyl, formyl, propionyl, butyryl, pentyryl, benzoyl or phenylacetyl
  • Alkoxy is defined below as a C] - 5 alkoxy group, substituted or unsubstituted. Suitable substituents are, for example, the substituents mentioned above for alkyl. Examples of an unsubstituted C] - 5 alkoxy group are methoxy, ethoxy, propoxy, isopropoxy, butoxy, pentoxy , Isopentoxy or Isobutoxy Examples of a substituted C 5 alkoxy group are trifluoromethoxy, chloromethoxy, 2-chloropropoxy and hydroxymethoxy
  • Aryloxy is defined below as benzyloxy and phenyloxy
  • the microorganisms can use, for example, sugar, polyols, peptones, carboxylic acids or amino acids as a growth substrate as a suitable carbon source.
  • Hexoses such as glucose or fructose
  • pentoses such as xylose
  • disaccharides such as maltose or sucrose
  • glycols, glycerol, sugar alcohols such as mannitol can be used as polyols
  • Sorbitol or inositol can be used.
  • the carboxylic acids used are di- or tricarboxylic acids or their salts, such as, for example, oxalic acid, malonic acid, succinic acid, glutaric acid, adipic acid, pimelic acid, azelaic acid, sebacic acid, maleic acid, fumaric acid, sorbic acid, 1,2, citric acid, agaric acid 3- propanetricarboxylic acid, citrate, fumarate, oxalate or malate
  • amino acids or their salts all proteinogenic amino acids or their salts, such as aspartic acid, glutamic acid, aspartate, glutamate, glutamine, asparagine, alanine, valine, leucine, isoleucine, proline, Tryptophan, phenylalanine, methioni n, glycine, serine, tyrosine, threonine, cysteine, histidine, arginine can be used
  • a sugar or sugar alcohol is preferably used as the
  • the microorganisms can use, for example, ammonium compounds or amino acids or their amides as a suitable nitrogen source.
  • ammonium chloride, ammonium sulfate, ammonium carbonate or ammonium acetate can be used as the ammonium compound.
  • the amino acid can be alanine, valine, leucine, isoleucine, proline, tryptophan, phenylalanine, methionine, glycine, serine , Tyrosine, threonine, cysteine, asparagine, glutamine, lysine, arginine or histidine.
  • Appropriate representatives of the amino acid amides are prolinamide, alanine amide, glycinamide, serine amide and valine amide
  • Pipecolinic acid amide can be used as the piperidinecarboxylic acid amide, nicotinic acid amide as the pyridinecarboxylic acid amide and lactic acid amide as the hydroxycarboxylic acid amide
  • the selection and cultivation medium which can be used are those customary in the art, for example that described in Table 1
  • the active enzymes of the microorganisms are expediently induced during the cultivation and selection.
  • L- and DL-lactic acid amide or their N-methylated derivatives such as N-methyl-L-lactic acid amide and N, N-dimethyl-L-lactic acid amide can preferably be used as the enzyme inducer the L-enantiomer used
  • the inductor concentration is expediently between 0.05 and 10 g / 1, preferably between 0.5 and 3 g / 1
  • the cultivation and selection is usually carried out at a temperature of 10 to 40 ° C., preferably 25 to 35 ° C. and at a pH between pH 4 and pH 10, preferably between pH 6 and pH 8
  • Preferred microorganisms are L-proline-utilizing the genus Aureobacterium, Klebsiella, Aeromonas, Serratia or Pseudomonas
  • microorganisms of the species Klebsiella pneumoniae, Aeromonas sobria, Serratia plymuthica, Pseudomonas fluorescens or Aureobacterium sp LS10 (DSM 10203), as well as their functionally equivalent variants and mutants isolated The microorganisms Aureobacterium sp LS10 were deposited on 29 August 1995 with the DSM-German Collection of Microorganisms and Cell Cultures GmbH, Mascheroderweg 1 b, D-38124 Braunschweig, according to the Budapest contract
  • “Functionally equivalent variants and mutants” are understood to mean microorganisms or enzymes which have essentially the same properties and functions as the original microorganisms or the enzymes obtained from them. Variants and mutants of this type can be formed accidentally, for example by UV radiation become
  • the enzymes according to the invention the L-prolinester hydrolases or L-prolinamide hydrolases, which are capable of hydrolyzing proline derivatives of the formula I can be obtained, for example, by digestion of the microorganisms which is customary in the art.
  • the ultrasonic, French press or Lysozyme method can be used
  • an L-proline derivative of the general formula is expediently used
  • racemized can either be carried out in a known manner, for example in accordance with EP-A-0 057 092, or the racemization takes place in a strongly alkaline environment
  • the second stage, the esterification, the production of amides or the alkylation or acylation on the nitrogen atom, of the racemic proline derivative to the proline derivative of the general formula I is likewise carried out in a manner known per se.
  • the esterification can be carried out by reaction with an alcohol in accordance with the organic agent, 1976 , S 498ff, the preparation of the amides, for example by ammonolysis with ammonia according to Organikum, 1976, S 509ff, the alkylation on the nitrogen atom by reacting, for example, with an alkyl halide
  • microorganisms of the genus Aureobacterium, Klebsiella, Aeromonas, Serratia or Pseudomonas described above are particularly suitable for the method.
  • the microorganisms of the genus Aureobacterium such as Aureobacterium sp LS10 (DSM 10203) or its functionally equivalent variants and mutants are suitable for the biotransformation
  • the biotransformation can be carried out with resting cells (non-growing cells which no longer require a carbon and energy source) or with growing cells.
  • the biotransformation is preferably carried out with resting cells
  • biotransformation media customary in the art can be used, such as, for example, low-molar phosphate buffers, Tris buffers, or the medium described in Table 1.
  • the biotransformation is preferably carried out in the medium in accordance with Table 1
  • the biotransformation is expediently carried out with a single or continuous addition of the proline derivative of the formula I in such a way that the concentration does not exceed 40% by weight, preferably 20% by weight
  • the pH of the medium can be in a range from 4 to 10, preferably in a range from 5 to 8.
  • the biotransformation is expediently carried out at a temperature of 10 to 50 ° C., preferably 20 to 40 ° C.
  • the biotransformation can be carried out in the absence of the alcohols formed in the prolinester hydrolysis, preferably in the absence of ethanol, propanol, butanol, isopropanol, isobutanol, isopentyl alcohol (isoamyl alcohol) and benzyl alcohol.
  • the corresponding alcohols can be removed, for example, by adsorption
  • the process is preferably carried out without isolation of the racemic proline derivative of the formula V.
  • the proline derivatives according to formula VI are prepared by hydrolysis of the proline derivatives according to formula II.
  • the hydrolysis is carried out in a manner customary in the art, for example according to Organikum S 476 and S 477
  • Vitamin solution 1.0 ml / 1 pH 7.0
  • Fructose (5 g / 1) was added as a carbon source (C source).
  • C source carbon source
  • N source nitrogen source
  • Different batches were then inoculated with soil samples from different locations and incubated (30 ° C, 120 rpm) until clearly visible growth was evident. An aliquot of this culture was then inoculated into an equal volume of fresh medium and incubated again until it became cloudy This process was repeated three times.
  • the enriched microorganisms were then separated and purified on a solid medium (same composition as liquid medium, only addition of 20 g / 1 agar agar). In this way, more than 20 different bacterial isolates were obtained which were capable of prolinamide to be used as the only N source
  • Example 2 Example 2:
  • the isolates obtained with the method described in Example 1 were propagated in the medium described there, but using L-prolinamide (1 g / 1) as an N source and a small amount of yeast extract (0.2 g / 1)
  • the cells thus produced were harvested by centrifugation and then resuspended in buffer solution (50 mM phosphate buffer, pH 7.0) and washed. After resuspending in buffer again, the ability to hydrolize L-prolinamide was tested with resting cells.
  • Klebsiella pneumoniae, Aeromonas sobria, Serratia plymuthica, Pseudomonas fluorescens and Aureobacterium sp were found with a high enantioselectivity
  • Aureobacterium sp LS 10 was grown in the minimal medium described in Table 1 with glucose (10 g / 1) as the C source and some yeast extract (0.2 g / 1).
  • Various N sources (2 g / 1, except peptone 10 g / l) were added, such as amino acids and acid amides.
  • Cultures which achieved a good cell density (OD 50 > 0.5 in 48 h) were analyzed for their enzymatic activity (hydrolysis of L-proline butyl ester). The activity after cultivation with L-prolinamide as the N source was used as the 100% value Table 2
  • Aureobacterium sp LS10 was able to use a wide variety of C sources, but preferred sugar and sugar alcohols. The enzymatic activity was only influenced when amino acids were used as C sources (see Table 3)
  • Aureobacterium sp LS10 was grown in the minimal medium described in Table 1 with yeast extract (2 g / 1) as the N source and glucose (10 g / 1) as the C source. In addition, the cultures were grown after reaching a sufficient cell density their enzymatic activity (hydrolysis of L-proline butyl ester) was analyzed, L-lactic acid amide or other compounds structurally related to L-lactic acid amide were added (each 1 g / 1) to test their potency as an inducer of L-proline ester hydrolase In addition to the racemate of lactic acid amide, only the N-methylated derivatives of L-lactic acid amide showed an inducing effect (see Table 4) Table 4 Enzymatic activity of Aureobacterium sp. LSIO when grown with various potential inductors
  • Aureobacterium sp LSIO was grown as described under 4a).
  • L-lactic acid amide, DL-lactic acid amide or N-methyl-L-lactic acid amide was used as an inducer in various concentrations and, after reaching a good cell density, the enzymatic activity (hydrolysis of L-proline butyl ester) was determined .
  • the enzymatic activity at 1 g / 1 L-lactic acid amide was used as a 100% value
  • N-methyl-L-lactic acid amide reaches an activity plateau, since the rate of hydrolysis is likely to be significantly reduced.
  • N-methyl-L-lactic acid amide is only effective at higher concentrations than L-lactic acid amide, made possible at the optimum (3.0 g / 1 ) but higher enzymatic activity
  • Aureobacterium sp LSIO was grown in the minimal medium described in Table 1 with glucose (10 g / 1) as the C source, L-lactic acid amide (2 g / 1) as the N source and some yeast extract (0.2 g / 1) Cultured After reaching a sufficient cell density, the culture was harvested, the cells were washed and resuspended in saline solution (0.9%). Aliquots of this bacterial suspension were tested for their hydrolysis activity against L- or D-proline butyl ester by varying various parameters
  • the enzymatic activity of the L-prolinester hydrolase is largely temperature-dependent. An increase in temperature by 15 ° C leads to a quadrupling of the activity. Increasing pH also leads to increased activity, but only to a relatively small extent. Increasing the cell density is almost proportional Achieving increased activity.
  • the stereoselectivity is largely independent of temperature. The most important parameter here is the pH value, which should be as low as possible. A high cell density also contributes slightly to improved selectivity. This experiment shows that at low pH, high cell density and high temperature the best compromise between enzymatic activity and stereoselectivity can be achieved
  • Example 6 For this purpose, Aureobacterium sp LSIO in the minimal medium described in Table 1 with glucose (10 g / 1) as the C source, L-lactic acid amide (2 g / 1) as the N source and some yeast extract (0.2 g / 1 ) attracted After reaching a sufficient cell density, the culture was harvested, the cells were washed and resuspended in saline solution (0.9%). The enzymatic activity against various L- or D-proline esters was then determined.
  • the hydrolysis was determined as 100% of L-proline butyl ester used at pH 7.0
  • the stereoselectivity of the enzyme was determined on the basis of the ratio of the activity towards the L-proline esters and the corresponding D-proline esters n determined (E value)
  • FIG. 3 shows the enzymatic activity of the L-proline ester hydrolase with various L-proline esters as a function of the pH
  • Proline isopropyl ester which had proven to be the cheapest substrate, was to be used to investigate which product concentrations can be achieved.
  • Aureobacterium sp LSIO was used in the minimal medium described in Table 1 with glucose (10 g / 1) as the C source, L-lactic acid amide (2 g / 1) as N source and some yeast extract (0.2 g / 1) grown. After reaching a sufficient cell density, the culture was harvested. The cells were then washed in saline solution (0.9%) and finally resuspended therein The test was carried out with DL-proline isopropyl ester as a substrate in various concentrations, while the other parameters were kept constant (25 ° C., pH 6.0, OD 650 ca 15). At different times, aliquots were taken, which were determined by HPLC to determine their content D- and L-proline isopropyl esters were analyzed
  • Aureobacterium sp LSIO was in a Chemap fermenter (working volume 5 1) in minimal medium (see Tab 1) with glucose (30 g / 1) and L-lactic acid amide (4 g / 1) as a C or N source at 30 ° C grown In order to facilitate the growth of the cells, the medium also contained a small amount of yeast extract (0.7 g / 1). During the course of the cultivation, further L-lactic acid amide was added as required by the cells until a sufficiently high cell density (OD 650 ca 23) and a good specific enzyme activity (> 1.2 ⁇ mol L-proline butyl ester hydrolyzed / min x OD 650 ) was achieved.
  • Aureobacterium sp LS10 was in a Chemap fermenter (working volume 2 1) in mineral medium (see Tab 1) with glucose (20 g / 1) as a C source and yeast extract (15 g / 1) as a N source at 30 ° C dressed In addition, the medium contained N-methyl-L-lactic acid amide (3 g / 1) as an inducer. After reaching a sufficient cell density (OD 650 ca 30), the cells were harvested by centrifugation After washing and resuspending in saline solution, the cells had good activity (approx.
  • racemic proline 160 g (1.39 mol) of L-proline was dissolved in 600 ml (10.49 mol) of acetic acid and 20 g (277 mmol) of butanal were added. This solution was dissolved in a
  • proline could also be racemized in an alkaline aqueous solution (see part of the one-pot reaction in 10 3)
  • DL-proline isopropyl ester from L-proline can also be prepared in a one-pot process.
  • 80 g (695 mmol) of L-proline in 26 ml of 4 N NaOH (104 mmol ) and 148.5 g of water was dissolved.
  • This solution was then heated in an autoclave to 160 ° C., a pressure of about 5 bar being reached, and kept at this temperature for 14 hours.
  • the water was then passed through as well as possible Distillation removed, using the effect of azeotropic distillation after the addition of 250 ml of isopropanol to remove residual amounts of water.

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EP97953805A 1996-12-16 1997-12-12 Verfahren zur herstellung von d-prolinderivaten Withdrawn EP0944730A1 (de)

Applications Claiming Priority (3)

Application Number Priority Date Filing Date Title
CH308096 1996-12-16
CH308096 1996-12-16
PCT/EP1997/007006 WO1998027222A1 (de) 1996-12-16 1997-12-12 Verfahren zur herstellung von d-prolinderivaten

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EP0944730A1 true EP0944730A1 (de) 1999-09-29

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EP (1) EP0944730A1 (cs)
JP (1) JP2001506500A (cs)
AU (1) AU5757498A (cs)
CA (1) CA2274896A1 (cs)
CZ (1) CZ213199A3 (cs)
WO (1) WO1998027222A1 (cs)

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EP1737818A2 (en) * 2003-12-04 2007-01-03 Pfizer, Inc. Methods for the preparation of stereoisomerically enriched amines
CN111621541A (zh) * 2019-02-27 2020-09-04 上海艾美晶生物科技有限公司 使用电渗析技术拆分光学异构体的方法

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JPS5840473B2 (ja) * 1978-06-29 1983-09-06 財団法人野田産業科学研究所 新規なプロリンアシラ−ゼ及びその製法
JPS5571491A (en) * 1978-11-24 1980-05-29 Noda Sangyo Kagaku Kenkyusho Preparation of proline acylase
JPH06740B2 (ja) * 1984-08-16 1994-01-05 三菱レイヨン株式会社 光学活性カルボン酸アミドの製造法
JPH0783712B2 (ja) * 1987-09-18 1995-09-13 ダイセル化学工業株式会社 新規なプロリンアシラーゼ及びその製造法
DE3929570A1 (de) * 1989-09-06 1991-03-07 Degussa Mikrobiologisch hergestellte n-acyl-l-prolin-acylase, verfahren zu ihrer gewinnung und ihre verwendung
CA2150526C (en) * 1994-06-09 2005-11-15 Andreas Kiener Biotechnological process for the preparation of cyclic s-.alpha.-amino carboxylic acids and r-.alpha.-amino carboxamides
AU2155797A (en) * 1996-03-13 1997-10-01 Lonza A.G. Process for producing n-protected d-proline derivatives

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Title
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CZ213199A3 (cs) 1999-11-17
JP2001506500A (ja) 2001-05-22
CA2274896A1 (en) 1998-06-25
WO1998027222A1 (de) 1998-06-25
AU5757498A (en) 1998-07-15

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