WO2000012745A1 - Procede de preparation de derives de (2r)-piperidine - Google Patents

Procede de preparation de derives de (2r)-piperidine Download PDF

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Publication number
WO2000012745A1
WO2000012745A1 PCT/EP1999/006277 EP9906277W WO0012745A1 WO 2000012745 A1 WO2000012745 A1 WO 2000012745A1 EP 9906277 W EP9906277 W EP 9906277W WO 0012745 A1 WO0012745 A1 WO 0012745A1
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WO
WIPO (PCT)
Prior art keywords
general formula
microorganisms
pipecolinic acid
amino
reaction
Prior art date
Application number
PCT/EP1999/006277
Other languages
German (de)
English (en)
Inventor
Michael Petersen
Wolfgang Beck
Klaus Heinzmann
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
Priority to CA002341554A priority Critical patent/CA2341554A1/fr
Priority to JP2000567728A priority patent/JP2002523107A/ja
Priority to EP99944524A priority patent/EP1108053A1/fr
Priority to AU57415/99A priority patent/AU5741599A/en
Publication of WO2000012745A1 publication Critical patent/WO2000012745A1/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/20—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms
    • C07D211/22—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by singly bound oxygen or sulphur atoms by oxygen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/60—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • 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
    • C12P41/001—Processes using enzymes or microorganisms to separate optical isomers from a racemic mixture by metabolizing one of the enantiomers

Definitions

  • the present invention relates to a new process for the preparation of (2R) - piperidine derivatives of the general formulas
  • R 1 is hydroxy, amino or C ,. -AIkoxy and R 4 is hydroxy or amino
  • (2R) -piperidine derivatives of the general formula I are important synthesis building blocks for biologically active compounds, such as stimulants of growth hormone release (WO-A-9513069) or anti-anxiety agents (DE-A-37 02 943).
  • EP-A-686 698 describes a biotechnological process for the production of S- ⁇ -aminocarboxylic acids, for example S- ⁇ -pipecolinic acid, by reacting the racemic RS- ⁇ -aminocarboxylic acid amides with microorganisms of the genera Klebsiella and Pseudomonas, and also the corresponding ones R- ⁇ -aminocarboxylic acid amides are obtained In order to prepare the R- ⁇ -aminocarboxylic acid amides, however, the S- ⁇ -aminocarboxylic acids have to be separated off using relatively complex processes
  • JP-A-63 248 393 describes a process for the preparation of (R) -pipecolinic acid starting from racemic pipecolinic acid by means of microorganisms of the genera Pseudomonas, Kurthia or Alcaligenes. The long reaction times are disadvantageous in this process
  • the object of the present invention is to eliminate these disadvantages and to provide a simple process for the preparation of (2R) -piperidine derivatives, with which high yields can be achieved and which is feasible on an industrial scale
  • microorganisms which have the property of ⁇ -aminocarboxamides in foam of racemate or its optically active isomers of the general formula III,
  • microorganisms wherein A together with -NH and -CH represent an optionally substituted 5- or 6-membered saturated heterocyclic ring as the only nitrogen source that can be used.
  • Such microorganisms are known in the prior art and have already been described in detail in EP-A-686 698 Preferred microorganisms with the properties described above are microorganisms of the genera Klebsiella and Pseudomonas. Microorganisms of the species Pseudomonas putida, in particular those of the species Pseudomonas putida with the designation DSM 9923, and their functionally equivalent variants and mutants are particularly preferred
  • microorganisms of the species Pseudomonas putida with the designation DSM 9923 were on 20 04 1 95 at the German Collection for Microorganisms and Cell Cultures GmbH (DSM). Mascherodeweg lb, D-38124 Braunschweig, deposited in accordance with the Budapest Treaty
  • R "is hydroxyl, amino or d .c-alkoxy can decompose in the presence of trace elements and under aerobic conditions with ring cleavage and, in the case of microorganisms, can be used as the only source of carbon and energy. After a sufficient reaction time, usually after 1 to 48 hours, then there is little or no ring-shaped S- ⁇ -aminocarboxylic acid or other disruptive open-chain by-products such as S-2-aminoadipic acid in the reaction medium in the reaction medium.
  • the (2R) -piperidine derivatives of the general formula I accumulated during the reaction
  • R is hydroxy, amino or C
  • C] - f -Aikoxy has the meaning of a straight-chain or branched alkoxy group with 1 to 6 C atoms here and below. Methoxy, ethoxy, propoxy, isopropoxy, butoxy, isobutoxy should be mentioned. tert-butoxy, pentoxy and its isomers and hexoxy and its isomers
  • the enzymes for the cell-free system can be obtained by disrupting the microorganisms in a manner customary in the art. For example, the ultrasound, French press or lysozyme method can be used for this purpose. These cell-free enzymes can also be immobilized on a suitable carrier material
  • trace elements are, for example, zinc, manganese, cobalt, copper, nickel, molybdenum, calcium, magnesium, boi.
  • Zinc and manganese are preferred.
  • Boron, iron and sulfur »emeinsa 'sge sets
  • the most preferred substrates of the general formula II are (RS) -pipecolinic acid, (RS) -pipecolinic acid ethyl ester, (RS) -pipecolinic acid isopropyl ester and (RS) -pipecolinic acid amide
  • Aerobic conditions are understood to mean culture conditions in which the microorganisms are supplied with oxygen. This can be experienced, for example, in shake culture by atmospheric oxygen or in submerged culture by blowing in molecular oxygen or atmospheric oxygen
  • the reaction can be carried out without conventional cultivation directly by adding the microorganisms to (RS) -piperidine derivatives of the general formula II.
  • the reaction can be carried out after conventional cultivation of the microorganisms with a suitable carbon and energy source Sugar.
  • Carboxylic acids, sugar alcohols or amino acids can be used.
  • sugars hexoses such as glucose or pentoses can be used
  • glutamate can be used
  • reaction is preferably carried out without customary cultivation directly by adding the microorganisms to (RS) -piperidine derivatives of the general Foimel II
  • the microorganisms can use the (S) -isomer of the (RS) -piperidine derivative of the general formula II as the only carbon and energy source and as the only nitrogen source
  • the medium customary in the art can be used as the medium for the process according to the invention, such as mineral salt media, for example the mineral salt medium according to Kulla et al (Arch Microbiol 135, 1-7. 1983), the media described in Table 1 or low-molar buffers such as 10 to 100 mM phosphate buffer to which the necessary trace elements have been added.
  • the process is preferably carried out in the media according to Table 1
  • the conditions are expediently chosen such that the S-isomer of the (RS) -piperidine derivatives of the formula II is preferably used by the microorganisms as a carbon and energy source.
  • the medium therefore preferably does not contain any compounds other than compound II that are easily usable as a carbon and energy source links
  • the reaction is carried out expediently with a single, repeated or continuous addition of (RS) -piperidine derivatives of the general formula II.
  • the addition of (RS) -piperidine derivatives of the general formula II is carried out in such a way that the concentration is 30% by weight, preferably 10% by weight %, particularly preferably 5% by weight, not exceeded
  • the pH of the medium is expediently in a range from 4 to 9, preferably from 6 to 8
  • the reaction is expedient at a temperature of from 15 to 80 ° C., preferably from 25 to 40 ° C. by 'saw 1 -f
  • (2R) -pipecolinic acid amide or (2R) -pipecolinic acid is obtained from (RS) -pipecolinic acid amide can be controlled, for example, via the reaction time.
  • the (2R) initially Pipecolinic acid amide which can be isolated if necessary
  • the acid is formed from the (2R) -pipecolinic acid amide.
  • the reaction can be followed analytically, e.g. chromatographically. The same applies to the reaction of (RS) -pipecolinic acid esters, in which the (2R ) -Pipecolinic acid ester and then the acid accumulates
  • the (2R) -piperidine derivatives of the general formula I preferably the (R) -pipecolinic acid, the (R) -pipecolinic acid amide and the (R) -pipecolinic acid ethyl and isopropyl esters, become very high to quantitative Yield obtained in the medium
  • the (2R) -piperidine derivatives of the general formula I obtained in this way can be isolated by customary work-up methods such as, for example, by separating off the biomass, acidification, chromatography, electrodialysis or crystallization
  • the course of the reaction can also be regulated via the supply of oxygen.
  • the reaction is expedient until the (R) -pipecolinic acid amide or the like is accumulated (R) -pipecolinic acid esters as above described carried out under aerobic conditions and then the oxygenation adjusted, after which the acid is formed
  • R has the meaning given above, which can be temporarily accumulated in the medium with increasing enantiomeric excess and, if appropriate, isolated. If the (R) -pipecolinic acid derivative according to formula VI is to be prepared from the (RS) -pipecolinic acid derivative according to formula V, it will after accumulation isolated If the (R) -pipecolinic acid according to formula IV is to be produced from the (RS) -pipecolinic acid derivative according to formula V, the reaction is expediently carried out under aerobic conditions until the accumulation of the (R) -pipecolinic acid derivative according to formula VI and then the oxygen supply is stopped
  • reaction can be followed analytically, for example by chromatography Implementation should be stopped as soon as the accumulation of the (R) -p ⁇ pecol ⁇ nsaurede ⁇ ⁇ ats according to formula VI is reached
  • Another component of the invention is the further implementation, the reduction, of the (2R) - Pipecolmsaurede ⁇ vate dei general formula VI to the (2R) -P ⁇ pe ⁇ d ⁇ nde ⁇ ⁇ aten of the general Foimel VII
  • R is Hvdroxv or Amino
  • an alkali metal hydride or an alkaline earth metal hydride such as, for example, is used as the reducing agent Potassium or
  • the reduction is expediently carried out at a temperature of 0 to 100 ° C., preferably at the reflux temperature of the corresponding solvent
  • the reduction can be carried out in a polar organic solvent, for example in an ethei. Diethyl ether, dipropylethei, tetrahydrofuran or 1,4-dioxane are suitable as ethers, for example
  • the desired products of the general formula VII such as the (R) -2- (aminomethyl) p; per ⁇ d ⁇ n or the (R) -2- (hydroxymethyl) p ⁇ pe ⁇ d ⁇ n, can then be isolated by known processing methods Table 1
  • Pseudomonas putida DSM 9923 was grown on medium 3 with 20 g / l glutamate overnight in the fermenter. At OD650 of 14, 1% (RS) -pipecolinic acid amide was added. According to GC analysis, after 2 hours there was practically enantiomerically pure (R) -pipecolinic acid amide before pipecolinic acid was not to prove

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (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)
  • Analytical Chemistry (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)
  • Hydrogenated Pyridines (AREA)

Abstract

L'invention concerne un procédé de préparation de dérivés de (R)-pipéridine de formule générale (I) et (VII), dans laquelle R1 représente hydroxy, amino ou C¿1-6?-alcoxy et R?4¿ représente hydroxy ou amino. Les dérivés de (R)-pipéridine sont obtenus à partir de (RS)-pipéridine de formule générale (II), dans laquelle R2 représente hydroxy, amino ou C¿1-6?-alcoxy, en présence d'éléments traces et en utilisant des micro-organismes ou des enzymes acellulaires issus de ces micro-organismes.
PCT/EP1999/006277 1998-08-26 1999-08-26 Procede de preparation de derives de (2r)-piperidine WO2000012745A1 (fr)

Priority Applications (4)

Application Number Priority Date Filing Date Title
CA002341554A CA2341554A1 (fr) 1998-08-26 1999-08-26 Procede de preparation de derives de (2r)-piperidine
JP2000567728A JP2002523107A (ja) 1998-08-26 1999-08-26 （２ｒ）−ピペリジン誘導体の製造方法
EP99944524A EP1108053A1 (fr) 1998-08-26 1999-08-26 Procede de preparation de derives de (2r)-piperidine
AU57415/99A AU5741599A (en) 1998-08-26 1999-08-26 Method for preparing (2r)-piperidine derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
EP98116061.7 1998-08-26
EP98116061 1998-08-26

Publications (1)

Publication Number Publication Date
WO2000012745A1 true WO2000012745A1 (fr) 2000-03-09

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EP (1) EP1108053A1 (fr)
JP (1) JP2002523107A (fr)
AU (1) AU5741599A (fr)
CA (1) CA2341554A1 (fr)
WO (1) WO2000012745A1 (fr)

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2348107A2 (fr) 2003-02-18 2011-07-27 Metabolic Explorer Procédé de préparation de microorganismes évolués permettant la création ou la modification de voies métaboliques

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63248393A (ja) * 1987-04-02 1988-10-14 Agency Of Ind Science & Technol 微生物によるｄ−ピペコリン酸の製造法
EP0686698A2 (fr) * 1994-06-09 1995-12-13 Lonza Ag Procédé biotechnologique pour la préparation des acides S-alpha-aminocarboxyliques et des amides d'acides R-alpha-aminocarboxyliques

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS63248393A (ja) * 1987-04-02 1988-10-14 Agency Of Ind Science & Technol 微生物によるｄ−ピペコリン酸の製造法
EP0686698A2 (fr) * 1994-06-09 1995-12-13 Lonza Ag Procédé biotechnologique pour la préparation des acides S-alpha-aminocarboxyliques et des amides d'acides R-alpha-aminocarboxyliques

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
DATABASE WPI Section Ch Week 198847, Derwent World Patents Index; Class B03, AN 1988-334671, XP002124625 *
FRANZEN V: "Asymmetric catalysis of the intramolecular Cannizzaro reaction.", CHEMISCHE BERICHTE., vol. 90, 1957, pages 2036 - 2039, XP002124624, ISSN: 0009-2940 *
MOCHIZUKI K ET AL: "Simultaneous Production of D-Pipecolic Acid and L-alpha-Aminoadipic Acid from DL-Pipecolic Acid Using a Microorganism", AGRICULTURAL AND BIOLOGICAL CHEMISTRY., vol. 52, no. 5, 1988, pages 1113 - 1116, XP002124623, ISSN: 0002-1369 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP2348107A2 (fr) 2003-02-18 2011-07-27 Metabolic Explorer Procédé de préparation de microorganismes évolués permettant la création ou la modification de voies métaboliques

Also Published As

Publication number Publication date
JP2002523107A (ja) 2002-07-30
EP1108053A1 (fr) 2001-06-20
AU5741599A (en) 2000-03-21
CA2341554A1 (fr) 2000-03-09

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