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EP0826032A1 - PROCEDE BIOTECHNOLOGIQUE DE PRODUCTION D'ACIDE R-$g(a)-CARBOXYLIQUE DE PIPERAZINE ET D'AMIDE D'ACIDE S-$g(a)-CARBOXYLIQUE DE PIPERAZINE - Google Patents

PROCEDE BIOTECHNOLOGIQUE DE PRODUCTION D'ACIDE R-$g(a)-CARBOXYLIQUE DE PIPERAZINE ET D'AMIDE D'ACIDE S-$g(a)-CARBOXYLIQUE DE PIPERAZINE

Info

Publication number
EP0826032A1
EP0826032A1 EP96915025A EP96915025A EP0826032A1 EP 0826032 A1 EP0826032 A1 EP 0826032A1 EP 96915025 A EP96915025 A EP 96915025A EP 96915025 A EP96915025 A EP 96915025A EP 0826032 A1 EP0826032 A1 EP 0826032A1
Authority
EP
European Patent Office
Prior art keywords
microorganisms
piperazine
piperazinecarboxamide
formula
optionally substituted
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Withdrawn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
EP96915025A
Other languages
German (de)
English (en)
Inventor
Andreas Kiener
Jean-Paul Roduit
Klaus Heinzmann
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
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 Lonza AG filed Critical Lonza AG
Publication of EP0826032A1 publication Critical patent/EP0826032A1/fr
Withdrawn legal-status Critical Current

Links

Classifications

    • 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
    • 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
    • C12P41/006—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
    • C12R2001/38—Pseudomonas

Definitions

  • the invention relates to new microorganisms which are capable, optionally substituted, of (RS) - ⁇ -piperazinecarboxamides of the formula
  • microorganisms are capable of utilizing optionally substituted ⁇ -piperazinecarboxamides of the formula I above, in the form of their racemate or their optically active isomers, in particular R- ⁇ -piperazinecarboxamides, as the only nitrogen source.
  • These microorganisms or their cell-free enzymes are optionally substituted for a new process for the preparation of R- ⁇ -piperazinecarboxylic acids (formula II) and / or for the preparation of S- ⁇ -piperazinecarboxamides, optionally substituted, of the formula
  • R- ⁇ -piperazinecarboxylic acid of the formula II is an important intermediate for the preparation of (R) -2-carboxy-4- (3-phosphonopropyl) piperazine, a selective antagonist of N-
  • the object of the present invention is to provide a simple and technically viable biotechnological process for the production of optically pure R- ⁇ -piperazinecarboxylic acids, the S- ⁇ -piperazinecarboxamide also being able to be isolated in good purity at the same time.
  • 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 the only ones in a medium with an optionally substituted ⁇ -piperazinecarboxamide (formula I) in the form of its racemate or its optically active isomers
  • Nitrogen source preferably with an R- ⁇ -piperazinecarboxamide as the sole nitrogen source, and grown with a suitable carbon source in the usual way; b) then those selected from the culture obtained by cultivation are those which are stable and are capable, in (RS) - ⁇ -piperazinecarboxamides (formula I), of the R- ⁇ -piperazinecarboxamide into the corresponding R- ⁇ -piperazinecarboxylic acid (formula II ) to transfer.
  • the microorganisms can use, for example, sugar, sugar alcohols or carboxylic acids as a growth substrate as a carbon source.
  • Hexoses such as glucose or pentoses can be used as sugar.
  • Di- or tricarboxylic acids or salts thereof such as citric acid or succinate can be used as carboxylic acids.
  • glycerin can be used as the sugar alcohol.
  • a sugar alcohol such as glycerol is preferably used as the carbon source.
  • the selection and growth medium which can be used are those customary in the art, such as, for example, the mineral salt medium according to Kulla et al. (Arch. Microbiol., 135, 1-7, 1983) or that described in Table 1. Preferably, the one described in Table 1 is used.
  • Piperazine carboxamide can be used as an enzyme inducer.
  • the cultivation and selection is expediently carried out at a temperature of from 15 to 55 ° C., preferably from 20 to 45 ° C. and at a pH between pH 5 and pH 11, preferably between pH 6 and pH 10.
  • microorganisms with specific R-piperazinecarboxylic acid amidase activity are microorganisms of the genus Burkholde ⁇ a and their functionally equivalent variants and mutants.
  • Microorganisms of the genus Burkholderia as deposited on April 20, 1995 with the German Collection of Microorganisms and Cell Cultures GmbH, Mascheroder Weg lb, D-38124 Braunschweig, in accordance with the Budapest Treaty, and their functionally equivalent variants and mutants are particularly preferred.
  • Taxonomic properties of the microorganisms of the genus Burkholderia (DSM 9925)
  • “Functionally equivalent variants and mutants” are understood to mean microorganisms which have essentially the same properties and functions as the original microorganisms. Such variants and mutants can happen to z. B. are formed by UV radiation.
  • the corresponding R- ⁇ -piperazinecarboxamide is converted and isolated from the microorganisms into the corresponding R- ⁇ -piperazinecarboxylic acid by means of the specific microorganisms already described or by means of cell-free enzymes
  • Piperazinecarboxamides of the formula I can be used as the piperazinecarboxamides of the formula I.
  • Representatives of substituted piperazine carboxamides can be -C-C4-alkyl-substituted such.
  • Piperazinecarboxamide or 4-methylpiperazinecarboxamide is preferably used.
  • the enzymes for the cell-free system can be obtained by disrupting the microorganisms in the usual manner. For example, the ultrasonic, French press or lysozyme method can be used for this. These cell-free enzymes can also be immobilized on a suitable carrier material.
  • DSM 9925 The previously described specific microorganisms of the genus Burkholderia (DSM 9925) and their functionally equivalent variants and mutants are particularly suitable for the method.
  • the biotransformation can also be dormant
  • the medium used for the method with resting cells can be the facl-usual ones, such as, for example, the mineral salt medium described above according to KuUa et al., 1983 (ibid), low-molecular phosphate buffer, HEPES buffer, or the medium described in Table 1.
  • a medium containing a carbon and nitrogen source such as, for example, commercially available media or the medium according to Table 1, is usually used for the process with growing cells. The method is preferably carried out in the medium according to Table 1.
  • the biotransformation is expediently carried out with a single or continuous addition of corresponding (RS) - ⁇ -piperazinecarboxamide in such a way that the concentration of (RS) - ⁇ -piperazinecarboxamide does not exceed 20% by weight, preferably 10% by weight.
  • the pH of the medium can be in a range from pH 5 to pH 11, preferably from pH 6 to pH 10.
  • the biotransformation is expediently carried out at a temperature of from 15 to 55 ° C., preferably from 20 to 50 ° C.
  • the R- ⁇ -piperazinecarboxamide of the formula I has been converted completely to the R- ⁇ -piperazinecarboxylic acid, with S- ⁇ -piperazinecarboxamide also being obtained.
  • the R- ⁇ -piperazinecarboxylic acid obtained in this way and / or the S- ⁇ -piperazinecarboxylic acid amide can be prepared by conventional workup methods such as, for. B. isolated by acidification, electrodialysis, chromatography or extraction. The isolated S- ⁇ -piperazinecarboxamide can then be hydrolyzed chemically to the S- ⁇ -piperazinecarboxylic acid.
  • the A-N medium was used for the isolation of microorganisms which are capable of utilizing racemic piperazinamide as the sole nitrogen source. 100 ml of this medium was placed in a 300 ml Erlenmeyer flask and mixed with various soil samples (2 g) from the LONZA AG plant in Visp, Switzerland. The flasks were incubated at 30 ° C for 5 days at rest. Then 1 ml of the A-N medium was used to make a fresh one
  • the cells were grown in 11 A-N medium at 30 ° C. and then harvested and washed. 5 g cells (wet weight) were in
  • the cells were grown in A-N medium (Table 1) and then washed once with physiological saline. After resuspending in 69 mM phosphate buffer, pH 8.0 and setting a cell density of 10 at OD650, 20 gH (RS) -piperazinecarboxamide were added at a temperature of 47 ° C. Then it was incubated for 18 h (total volume:
  • Detector Hewlett-Packard diode array detector Buffer: 10 mM disodium hydrogen phosphate, 10 mM boric acid,
  • Electrolyte 900 ml buffer plus 100 ml methanol
  • Capillary HP Gl 600-61211 Electrical field: 20 kV current: approx. 24 - 30 ⁇ A
  • Oven temperature 20 ° C detector setting: 210 nm (bandwidth 5 nm) migration time: approx.17.1 min (S-acid) approx. 17.7 min (R-acid)

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Engineering & Computer Science (AREA)
  • Zoology (AREA)
  • Wood Science & Technology (AREA)
  • Health & Medical Sciences (AREA)
  • Genetics & Genomics (AREA)
  • Biotechnology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • General Engineering & Computer Science (AREA)
  • Microbiology (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Biomedical Technology (AREA)
  • Virology (AREA)
  • Tropical Medicine & Parasitology (AREA)
  • Medicinal Chemistry (AREA)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Micro-Organisms Or Cultivation Processes Thereof (AREA)

Abstract

L'invention concerne de nouveaux micro-organismes capables d'utiliser comme seule source d'azote des amides d'acide α-carboxylique de pipérazine sous forme du racémate ou de ses isomères optiquement actifs ayant la formule générale (I) et de transformer l'amide d'acide (RS)-α-carboxylique de pipérazine ayant la formule susmentionnée (I) en un acide R-α-carboxylique de pipérazine ayant la formule (II).
EP96915025A 1995-05-08 1996-05-07 PROCEDE BIOTECHNOLOGIQUE DE PRODUCTION D'ACIDE R-$g(a)-CARBOXYLIQUE DE PIPERAZINE ET D'AMIDE D'ACIDE S-$g(a)-CARBOXYLIQUE DE PIPERAZINE Withdrawn EP0826032A1 (fr)

Applications Claiming Priority (5)

Application Number Priority Date Filing Date Title
CH131795 1995-05-08
CH1317/95 1995-05-08
CH233795 1995-08-15
CH2337/95 1995-08-15
PCT/EP1996/001905 WO1996035775A1 (fr) 1995-05-08 1996-05-07 PROCEDE BIOTECHNOLOGIQUE DE PRODUCTION D'ACIDE R-α-CARBOXYLIQUE DE PIPERAZINE ET D'AMIDE D'ACIDE S-α-CARBOXYLIQUE DE PIPERAZINE

Publications (1)

Publication Number Publication Date
EP0826032A1 true EP0826032A1 (fr) 1998-03-04

Family

ID=25687314

Family Applications (1)

Application Number Title Priority Date Filing Date
EP96915025A Withdrawn EP0826032A1 (fr) 1995-05-08 1996-05-07 PROCEDE BIOTECHNOLOGIQUE DE PRODUCTION D'ACIDE R-$g(a)-CARBOXYLIQUE DE PIPERAZINE ET D'AMIDE D'ACIDE S-$g(a)-CARBOXYLIQUE DE PIPERAZINE

Country Status (6)

Country Link
US (1) US6214604B1 (fr)
EP (1) EP0826032A1 (fr)
JP (1) JPH11508761A (fr)
AU (1) AU5693996A (fr)
CA (1) CA2217067A1 (fr)
WO (1) WO1996035775A1 (fr)

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
FR2825717B1 (fr) * 2001-06-08 2005-02-18 Rhodia Chimie Sa Preparation stereoselective de l-acides amines cycliques
JP5265513B2 (ja) * 2007-02-19 2013-08-14 株式会社カネカ 光学活性３−アミノピペリジン又はその塩の製造方法
WO2021219523A1 (fr) * 2020-04-28 2021-11-04 F. Hoffmann-La Roche Ag Procédé de préparation d'un acide pipérazine-2-carboxylique chiral

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
LU74142A1 (fr) * 1976-01-08 1977-07-22
NL8403487A (nl) * 1984-11-15 1986-06-02 Stamicarbon Werkwijze voor de enzymatische scheiding van dl-alfa-aminozuuramides.
GB8703749D0 (en) * 1987-02-18 1987-03-25 Sandoz Ltd Piperazinecarboxylic acid
FR2626288B1 (fr) * 1988-01-27 1990-05-18 Rhone Poulenc Sante

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
See references of WO9635775A1 *

Also Published As

Publication number Publication date
JPH11508761A (ja) 1999-08-03
AU5693996A (en) 1996-11-29
US6214604B1 (en) 2001-04-10
CA2217067A1 (fr) 1996-11-14
WO1996035775A1 (fr) 1996-11-14

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