WO2002020821A2 - Procede de preparation d'amines enantiomeriquement enrichies - Google Patents

Procede de preparation d'amines enantiomeriquement enrichies Download PDF

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Publication number
WO2002020821A2
WO2002020821A2 PCT/NL2001/000643 NL0100643W WO0220821A2 WO 2002020821 A2 WO2002020821 A2 WO 2002020821A2 NL 0100643 W NL0100643 W NL 0100643W WO 0220821 A2 WO0220821 A2 WO 0220821A2
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WO
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Prior art keywords
group
amine
enantiomerically enriched
formula
substituted
Prior art date
Application number
PCT/NL2001/000643
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English (en)
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WO2002020821A3 (fr
Inventor
Vytautas-Juozapas Kajetono Svedas
Dorel Teodor Guranda
Andrei Iaroslavonich Khimiouk
Roger Arthur Sheldon
Frederik Van Rantwijk
Lukas Michaël VAN LANGEN
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Dsm N.V.
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Publication date
Application filed by Dsm N.V. filed Critical Dsm N.V.
Priority to AU2001294378A priority Critical patent/AU2001294378A1/en
Publication of WO2002020821A2 publication Critical patent/WO2002020821A2/fr
Publication of WO2002020821A3 publication Critical patent/WO2002020821A3/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
    • C12P13/00—Preparation of nitrogen-containing organic compounds
    • C12P13/002—Nitriles (-CN)
    • 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
    • C12P13/008—Preparation of nitrogen-containing organic compounds containing a N-O bond, e.g. nitro (-NO2), nitroso (-NO)
    • 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
    • C12P13/02—Amides, e.g. chloramphenicol or polyamides; Imides or polyimides; Urethanes, i.e. compounds comprising N-C=O structural element or polyurethanes
    • 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
    • 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
    • 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
    • C12P41/007—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 by reactions involving acyl derivatives of racemic amines

Definitions

  • the invention relates to a process for the preparation of an enantiomerically enriched acylated amine of Formula 1 ,
  • R 6 and R 4 is OH or a substituted or unsubstituted alkyl group, aryl group, alkoxy group or amino group
  • X is NH 2 , OH, halogen, alkoxy with preferably 1-3 C atoms or alkyl with preferably 1-3 C atoms
  • R 5 is a phenyl group, that may be substituted with substituents chosen from the group of halogen, hydroxy, nitro, alkoxy with preferably 1-5 C atoms or alkyl with preferably 1-5 C atoms, in which process an enantiomerically enriched compound according to Formula 2, wherein X and R 5 are as defined above and wherein Z represents NH 2 , NH-OH, NH-NH 2 , NH-R 6 and R 6 is an alkyl group of preferably 1-6 C atoms, is contacted with a mixture of enantiomers of the corresponding amine H ⁇ CR ⁇ a, where R-i,R 2 and R 3 are as
  • WO-A-98/50575 discloses the enantioselective acylation of ⁇ - amino acids with the aid of Pen-G acylases using for example phenylacetic acid derivatives as acylating agent.
  • an enantiomercally enriched compound according to Formula 2 presents the added advantage that the reactions usually proceed more rapidly or that less enzyme is needed and/or that a higher yield is obtained compared with reactions wherein phenylacetic acid is used as acylating agent.
  • An added advantage is that when an enantiomerically enriched compound according to Formula 2 is used, that usually a higher S/H ratio (ratio of synthesis of acylated product to hydrolysis of the enantiomerically enriched compound according to Formula 2) is achieved in the acylation.
  • Another advantage of the application of an enantiomerically enriched compound according to formula 2 as acyl donor is that in most cases acylated amines of Formula 1 are crystalline products.
  • the invention also relates to a process for the preparation of an enantiomerically enriched amine through hydrolysis of a compound of Formula 1.
  • the (acylated) amines obtained in the process according to the invention preferably have an enantiomeric excess (ee) > 90%, in particular > 95%, more in particular > 98%.
  • enantiomerically enriched amines are prepared of the formula H 2 NCR 1 R 2 R 3 , where R ⁇ ,R 2 ,R 3 are as described above.
  • the (hetero)alkyl groups in R ⁇ R;* and R 3 preferably have 1-20, in particular 1-10 C atoms; the (hetero)cycloalkyl, (hetero)aryl, (hetero)alkylaryl, (hetero)alkylaryl, (hetero)arylalkyl groups preferably have 3-20, in particular 3-12 C atoms.
  • At least one of the groups Ri, R 2 or R 3 contains an aromatic ring.
  • Amines that may particularly suitably be prepared or split with the process according to the invention are for example phenylalkyl amines, in particular 1- phenyl-ethylamine, l-(p-CI-phenyl) ethylamine, 1-(1-naphthyl) ethylamine, 1-(2- naphthyl) ethylamine, 2-amino-4-phenylbutane, 1,1 ,1-trifluoro-2-amino-3- phenylpropane, 1 -phenyl-1 -amino-2-ethanol.
  • An enantiomerically enriched compound according to formula 2 is applied as an acyl donor in the process according to the invention.
  • the applied enantiomerically enriched enantiomer of the compound according to formula 2 preferably has as high an enantiomeric purity as possible, for example an ee (enantiomeric excess) > 90%, preferably > 95%, in particular greater than 98%.
  • the acyl donor is enantiomerically enriched mandelic acid amide, most preferably R-mandelic acid amide or enantiomerically enriched phenylglycine, most preferably D-phenylglycine amide.
  • the acylation is preferably carried out at a high pH, for example at a pH between 6 and 11 , in particular between 8 and 11.
  • the molar ratio of acyl donor to amine preferably is between 0.5 and 5, in particular between 1 and 3.
  • the pH at which the hydrolysis is carried out preferably is between 4 and 8, in particular between 5 and 8.
  • the temperature at which the acylation and hydrolysis are carried out is not especially critical and is for example between 0 and 50°C, in particular between 0 and 30°C. Preferably the reactions are carried out at room temperature.
  • Pen-G acylases that may be applied in the processes according to the invention are for example Pen-G acylases originating from Acetobacter, in particular Acetobacter pasteurianum. Aeromonas, Alcaligenes, in particular Alcaligenes faecalis. Aphanocladium, Bacillus sp.. in particular Bacillus megaterium, Cephalosporium, Escherichia, in particular Escherichia coli, Flavobacterium, Fusarium.
  • the enzyme may be applied in immobilised form.
  • immobilised enzymes that are commercially obtainable are for example the Escherichia coli enzyme supplied by Boehringer Mannheim GmbH, which is commercially obtainable under the name Enzygel(®), the immobilised Pnicillin-G acylase supplied by Recordati and the immobilised Pnicillin-G acylase supplied by Pharma Biotechnology Hannover.
  • enzymes may also be used in crystalline form (CLECsTM).
  • a Pen-G acylase originating from Alcaligenes faecalis is applied..
  • Such enzymes are obtainable via commonly known technologies.
  • the enzyme preparation as used in the present invention is not limited by purity and so forth and may be a crude enzyme solution or a purified enzyme, but it may also consist of (permeabilized and/or immobilized) cells that possess the desired activity or of a homogenate of cells possessing such activity.
  • the enzyme may also be used in immobilized form or in a chemically modified form.
  • the invention is in no way limited by the form in which the enzyme is used for the present invention.
  • use may of course also be made of an enzyme or a variant thereof originating from a microorganism that is genetically modified with or without recombinant DNA techniques.
  • the acylation and hydrolysis are preferably carried out in water that is optionally mixed with an organic solvent, for example acetonitrile or a lower (C1-C5) alcohol.
  • a mixture of the enantiomers of the amine to be split is acylated enantioselectively with a Pen-G acylase using an enantiomerically enriched compound according to Formula 2, for example phenylglycine amide, subsequently the acylated amine (mainly the one enantiomer of the amine) is separated from the non-acylated amine, and next the enantiomerically enriched, acylated amine is hydrolyzed in accordance with a second aspect of the invention, in which process there is formed a mixture of enantiomerically enriched amine and in the example phenylglycine, which corresponds to the applied phenylglycine amide, with the enanti
  • the acylated amine of Formula 1 obtained as intermediate product, may first be crystallized, it being possible for the diastereomeric excess of the acylated amine to be increased further.
  • the separation of the acylated amine and the non-acylated amine may be carried out in a known manner, for example through crystallization, extraction or phase separation, depending on the reaction conditions and the chosen substrate.
  • amines are split by first enantioselectively acylating a mixture of the enantiomers, for example chemically or enzymatically with the aid of a lipase in an organic solvent, then isolating the acylated amine from the non-acylated amine, and subsequently hydolyzing the acylated amine according to the invention with the aid of a Pen-G acylase .
  • Example II Example II
  • a pH-stat Radiometer RTS-622, Copenhagen, Denmark or Titrino 718, Metrohm, Switzerland
  • the aqueous system in most cases a homogeneous solution, sometimes emulsion or solution over a precipitate of non dissolved acyl donor contained 0.2 M racemic amine ((R,S)-6-amino-2-methyl-2-heptanol, (R,S)- 2-amino-1-butanol, (R,S)-1-phenylethylamine in table 1, (R,S)-1-phenylglycinol, (R,S)-2-amino-4-phenylbutane, (R,S)-Ieucinol, (R,S)-phenylalaninol in table 2) and 0.2-0.3 M acyl donor (phenylacetamide, D-phenylglycine amide, R- or S-mandelic acid amide) in the following experiments was used.
  • acyl donor phenylacetamide, D-phenylglycine amide, R- or S-mandelic acid amide
  • the concentration of penicillin acylase from Alcaligenes faecalis in the reaction mixture was 2-6 ⁇ M. Maximal yield of amide was observed in 10-60 min in different experiments. At appropriate time intervals samples of the heterogeneous reaction mixture were taken, diluted by eluent about 1000 times and subjected to HPLC analysis. The results of these exmperiments are shown in Table 1 and 2.

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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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

L'invention concerne un procédé pour préparer une amine acylée énantiomériquement enrichie. Ce procédé consiste à mettre en contact un amide de phénylglycine énantiomériquement enrichi, substitué ou non substitué, avec un mélange d'énantiomères de l'amine correspondante H2NCR1R2¿R¿3 en présence d'une acylase Pen-G, R1, R2 et R3 étant distincts et représentant chacun indépendamment H, CN, un groupe (cyclo)alkyle substitué ou non substitué, un groupe aryle, un groupe alkylaryle ou arylalkyle, un groupe hétéroalkyle ou hétéroaryle cyclique ou non cyclique comportant un ou plusieurs atomes de N, O ou S ou (CH2)n-COR4, n étant égal à 0, 1 ...6 et R4 représentant OH ou un groupe alkyle substitué ou non substitué, un groupe aryle, un groupe alcoxy ou un groupe amino, ou R1 et R2 (et R3) formant, avec l'atome C auquel ils sont liés, un groupe (bi)cyclique pouvant contenir, mais pas obligatoirement, un ou plusieurs atomes de N, O ou S. L'invention concerne également un procédé de préparation d'une amine énantiomériquement enrichie de formule H2NCR1R2R3, dans laquelle R1, R2 et R3 ont les significations susmentionnées, ce procédé consistant à mettre en contact une amine acylée avec une acylase Pen-G. De préférence, une acylase Pen-G dérivée d'Alcaligenes faecalis est utilisée.
PCT/NL2001/000643 2000-09-08 2001-08-31 Procede de preparation d'amines enantiomeriquement enrichies WO2002020821A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
AU2001294378A AU2001294378A1 (en) 2000-09-08 2001-08-31 Process for the preparation of enantiomerically enriched amines

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NL1016127 2000-09-08
NL1016127 2000-09-08

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Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067291B2 (en) 2002-12-20 2006-06-27 Pfizer Inc. Biocatalytic preparation of enantiomerically enriched aminopentanenitrile

Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0007205A1 (fr) * 1978-07-03 1980-01-23 Eli Lilly And Company Phénéthanolamines avec activité optique, leurs compositions, leur utilisation et leur préparation
EP0176068A2 (fr) * 1984-09-25 1986-04-02 Roche Diagnostics GmbH Procédé de préparation des stéréoisomères des acides 1-amino-alkylphosphoniques ou 1-amino-alkylphosphiniques
WO1994002628A1 (fr) * 1992-07-17 1994-02-03 Merrell Dow Pharmaceuticals Inc. RESOLUTION ENZYMATIQUE D'UN MELANGE RACEMIQUE D'INHIBITEURS D'ACIDE η-AMINOBUTYRIQUE TRANSAMINASE (GABA-T) STEREOSPECIFIQUES
WO1998050575A1 (fr) * 1997-05-01 1998-11-12 G.D. Searle & Co. Procede et appareil de preparation de beta amino-acides chiraux
NL1009814C2 (nl) * 1998-08-06 2000-02-08 Dsm Nv Werkwijze voor de bereiding van een N-geacyleerd aminonitril.
NL1010506C2 (nl) * 1998-11-06 2000-05-09 Dsm Nv Werkwijze voor de bereiding van bêta-lactam antibiotica.

Patent Citations (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0007205A1 (fr) * 1978-07-03 1980-01-23 Eli Lilly And Company Phénéthanolamines avec activité optique, leurs compositions, leur utilisation et leur préparation
EP0176068A2 (fr) * 1984-09-25 1986-04-02 Roche Diagnostics GmbH Procédé de préparation des stéréoisomères des acides 1-amino-alkylphosphoniques ou 1-amino-alkylphosphiniques
WO1994002628A1 (fr) * 1992-07-17 1994-02-03 Merrell Dow Pharmaceuticals Inc. RESOLUTION ENZYMATIQUE D'UN MELANGE RACEMIQUE D'INHIBITEURS D'ACIDE η-AMINOBUTYRIQUE TRANSAMINASE (GABA-T) STEREOSPECIFIQUES
WO1998050575A1 (fr) * 1997-05-01 1998-11-12 G.D. Searle & Co. Procede et appareil de preparation de beta amino-acides chiraux
NL1009814C2 (nl) * 1998-08-06 2000-02-08 Dsm Nv Werkwijze voor de bereiding van een N-geacyleerd aminonitril.
NL1010506C2 (nl) * 1998-11-06 2000-05-09 Dsm Nv Werkwijze voor de bereiding van bêta-lactam antibiotica.

Non-Patent Citations (8)

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Title
C. KASHIMA ET AL.: "Lithium aluminium hydride reduction of chiral benzoylformamides derived from chiral amino alcohols" J. CHEM. SOC., PERKIN TRANS. I, 1997, pages 1495-1499, XP002190073 LONDON, GB *
D. SEEBACH ET AL.: "Scope and limitations of the TiCl4-mediated additions of isocyanides to aldehydes and ketones with formation of alpha-hydroxycarboxylic acid amides" CHEMISCHE BERICHTE, vol. 121, 1988, pages 507-517, XP002190075 VCH VERLAGSGESELLSCHAFT, WEINHEIM, DE *
D.T. GURANDA ET AL. : "High efficiency and enantioselective enzymatic acylation of amines in aqueous mdedium" TETRAHEDRON: ASYMMETRY, vol. 12, no. 11, 4 July 2001 (2001-07-04), pages 1645-1650, XP002189974 PERGAMON PRESS, ELSEVIER SCIENCE, NY, US *
J. L\FFLER AND R. SCHOBERT: "2(3H)-Oxazolones from alpha-hydroxy amides and keteneylidenetriphenylphosphorane via a phosphorous ylide cascade" LIEBIGS ANN. ORG. BIOORG. CHEM., EUROPEAN JOURNAL, 1997, pages 217-220, XP002190074 VCH VERLAGSGESELLSCHAFT, WEINHEIM, DE *
KAJFEZ F ET AL: "A NEW SYNTHESIS OF AMPICILLIN AND RELATED INVESTIGATIONS" JOURNAL OF HETEROCYCLIC CHEMISTRY, vol. 13, no. 3, 1976, pages 561-566, XP002166875 ISSN: 0022-152X *
L.M. VAN LANGEN ET AL.: "Penicillin acylase-catalyzed resolution of amines in aqueous organic solvents" TETRAHEDRON: ASYMMETRY, vol. 11, no. 22, November 2000 (2000-11), pages 4593-4600, XP002166874 PERGAMON PRESS, ELSEVIER SCIENCE, NY, US *
ROSSI D ET AL: "APPROACH TO THE USE OF BENZYL PENICILLIN ACYLASE FOR CONFIGURATIONAL CORRELATIONS OF AMINO COMPOUNDS" JOURNAL OF ORGANIC CHEMISTRY, vol. 43, no. 13, 1978, pages 2576-2581, XP002166877 EN ISSN: 0022-3263 *
SVEDAS VYTAS ET AL: "Kinetic study of penicillin acylase from Alcaligenes faecalis." FEBS LETTERS, vol. 417, no. 3, 17 November 1997 (1997-11-17), pages 414-418, XP002166876 ISSN: 0014-5793 *

Cited By (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7067291B2 (en) 2002-12-20 2006-06-27 Pfizer Inc. Biocatalytic preparation of enantiomerically enriched aminopentanenitrile

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WO2002020821A3 (fr) 2002-08-08
AU2001294378A1 (en) 2002-03-22

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