WO2008038050A2 - Réduction des alpha-halocétones - Google Patents

Réduction des alpha-halocétones Download PDF

Info

Publication number
WO2008038050A2
WO2008038050A2 PCT/GB2007/050590 GB2007050590W WO2008038050A2 WO 2008038050 A2 WO2008038050 A2 WO 2008038050A2 GB 2007050590 W GB2007050590 W GB 2007050590W WO 2008038050 A2 WO2008038050 A2 WO 2008038050A2
Authority
WO
WIPO (PCT)
Prior art keywords
group
alkyl
optionally substituted
alkylaryl
aryl
Prior art date
Application number
PCT/GB2007/050590
Other languages
English (en)
Other versions
WO2008038050A3 (fr
Inventor
Jonathan Wiffen
Brian Adger
Original Assignee
Almac Sciences Limited
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 Almac Sciences Limited filed Critical Almac Sciences Limited
Publication of WO2008038050A2 publication Critical patent/WO2008038050A2/fr
Publication of WO2008038050A3 publication Critical patent/WO2008038050A3/fr

Links

Classifications

    • 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
    • C12P7/00—Preparation of oxygen-containing organic compounds
    • C12P7/02—Preparation of oxygen-containing organic compounds containing a hydroxy group
    • 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
    • C12P13/22—Tryptophan; Tyrosine; Phenylalanine; 3,4-Dihydroxyphenylalanine
    • C12P13/222—Phenylalanine
    • 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
    • C12P41/004—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 alcohol- or thiol groups in the enantiomers or the inverse reaction

Definitions

  • the present invention relates to a method for reducing alpha-halo ketones to alpha-halo alcohols. More specifically, the present invention is concerned with the use of isolated enzymes for reduction of alpha-halo ketones to corresponding alpha-halo alcohols.
  • the selectivity is not sufficiently good for the intended purpose of the end products, particularly those that are going to be used in pharmaceutical or food applications. This means that further work up and purification procedures are required. There is therefore a need for a process which can provide an alpha-haloalcohol in good yield from the corresponding ketone. It is an aim to do this in a stereoselective manner. Desirably, such a reaction will have a good volume efficiency. It is also an aim of the present invention to provide a reaction in which the selectivity is strongly directed towards one or other enantiomer.
  • R 1 and R 2 are independently selected from the group comprising: H; Ci -7 alkyl;
  • Ci -7 alkylaryl, C 2 . 7 alkenylaryl and P is a protecting group; wherein each of the foregoing groups may where chemically possible be optionally substituted by 1 to 4 substituents independently selected from the group comprising: Ci -7 alkyl, Ci- 7 haloalkyl, -SR 5 , -OR 6 , -NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3 ;
  • each of R 3 to R 6 is independently selected from the group comprising: H, Ci -7 alkyl, C 2 - 7 alkenyl, C 2 - 7 alkynyl, -CF 3 , -CH 2 F, -CHF 2 , CH 2 CF 3 , CH 2 OCi_ 7 alkyl, CH 2 SCi- 7 alkyl, phenyl, benzyl, and 2-phenethyl, wherein each of phenyl, benzyl, or 2-phenethyl may be optionally substituted by 1 to 3 substituents independently selected from the group comprising: d- 7 alkyl, -SR 5 , -OR 6 , -NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3 ; and / or independently any two of the R 2 to R 13 groups joined to the same carbon, may together with the carbon to which they are attached form a ring of
  • het is selected from the group comprising: C-linked pyrrolyl, imidazolyl, triazolyl, thienyl, furyl, thiazolyl, oxazolyl, thiadiazolyl, oxadiazolyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, quinolinyl, isoquinolinyl, benzimidazolyl, quinazolinyl, phthalazinyl, benzoxazolyl and quinoxalinyl;
  • X is a leaving group
  • n is from O to 5;
  • n is from O to 5.
  • X is halo or sulphonate.
  • Halo means fluoro, chloro, bromo, or iodo. More preferably X is halo.
  • X is chloro or bromo. Most preferably, X is chloro.
  • the method uses an isolated enzyme.
  • the invention also relates to novel compounds of Formula (I) whether produced by the process of the invention or otherwise. These compounds can most easily be produced by the process of the invention. Preferred novel compounds are those produced by the preferred embodiments described below.
  • R 1 is selected from the group comprising: Ci -7 alkyl; Ci -7 alkylaryl; and ZR or ZP where Z is NH and R is Ci -7 alkyl, C 2 7 alkenyl, C 2 7 alkynyl, Ci -7 alkylaryl and P is a protecting group; wherein each of the foregoing groups may where chemically possible be optionally substituted by 1 to 3 substituents independently selected from the group comprising: Ci -7 alkyl, Ci- 7 haloalkyl, -SR 5 , -OR 6 , -NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3
  • R 1 is selected from the group comprising: ZR or ZP.
  • P is a benzyl or trityl group.
  • R 2 is selected from the group comprising: Ci -7 alkyl; aryl; Ci -7 alkylaryl; het; and Ci -7 alkylhet, wherein each of the foregoing groups may where chemically possible be optionally substituted by 1 to 4 substituents independently selected from the group comprising: Ci -7 alkyl, Ci- 7 haloalkyl, -SR 5 , - OR 6 , -NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3 .
  • R 2 is selected from the group comprising: aryl and het. Most preferably R 2 is aryl.
  • Aryl includes any aromatic carbocyclic ring or ring system comprising one or more rings which may be fused, conjugated or isolated from one another and containing up to 24 carbon atoms in the ring system skeleton.
  • Aryl thus includes systems such as phenyl, naphthyl, anthracyl, bisphenyl, phenanthryl, and indenyl. Most preferably, aryl is optionally substituted phenyl.
  • R 3 is selected from the group comprising: H, and optionally substituted Ci -7 alkyl. Preferably R 3 is H.
  • R 4 is selected from the group comprising: H, and optionally substituted Ci- 7 alkyl. Preferably R 4 is H.
  • R 5 is selected from the group comprising: H, and optionally substituted Ci -7 alkyl.
  • R 5 is H.
  • R 6 is selected from the group comprising: H, and optionally substituted Ci -7 alkyl.
  • R 6 is H.
  • n 1
  • n 0.
  • the isolated enzymes are ketone reductase enzymes and are commercially available from Biocatalytics lnc of 129 N. Hill Avenue, Suite 103, Pasadena, CA 91106 USA (web address www.biocatalytics.com).
  • the alpha-halo ketone is an alpha-chloro ketone derived from phenyl alanine
  • the amino group is protected by a suitable protecting group.
  • suitable protecting groups include benzyloxycarbonyl and triphenylmethyl (trityl) group. Other suitable protecting groups are known in the art.
  • the present invention also relates to the use of an isolated enzyme for the reduction of an alpha-halo ketone.
  • the use of an isolated enzyme for the reduction of an alpha-halo ketone derived from phenyl alanine is of particular interest.
  • alpha-halo ketones The enantioselective reduction of alpha-halo ketones is of particular interest because it provides valuable intermediates that can be produced as chiral building blocks in organic synthesis. Although the bioreduction of alpha-halo ketones has been described previously, to date this has been done using whole cell systems.
  • a further aspect of the invention relates to entiomeric or diastereomeric enrichment of an alpha-halo ketone of formula I. This is achieved by the use of a hydrolase enzyme derived from a resting cell. We have found that the treatment of alpha-halo alcohols with hydrolase provides up to 99% enantiomeric or diastereomeric excess, the latter being the case in which a new chiral centre is created in a molecule which is already optically active.
  • a further aspect of the invention relates to a process for the entiomeric or diastereomeric enrichment of an alpha-halo ketone as defined above in Formula I using a hydrolase enzyme derived from a resting cell.
  • the enrichment is achieved in greater than 80% ee or de, and more preferably greater than 90% ee or de.
  • the present invention discloses the use of isolated ketoreductase enzymes for the diastereoselective reduction of certain chloroketone substrates, as outlined elsewhere in the application.
  • Such enzymes are typically produced by a process that starts with the fermentation of a genetically manipulated host microorganism that overexpresses the ketoreductase. Following fermentative production of the enzyme by the host, the enzyme is retained either within the cell (in soluble form or as inclusion bodies) or transported into the external medium, and is isolated by commonly practised downstream processing techniques.
  • a soluble enzyme that is retained in the cell (which may be in a recombinant form or a native wild-type enzyme) it is usual to recover the cell biomass first by centrifugation, then to resuspend the cells in an appropriate buffer solution. The cells are then broken open to release the enzyme- this may be done by mechanical or chemical means, then the cell debris is removed, again by centrifugation or by addition of a flocculant followed by filtration or centrifugation.
  • the resulting cell-free extract may be further purified (for example by salt precipitation techniques or by chromatography), or it may be used as directly recovered in a semi-purified form.
  • the enzyme may be concentrated at this stage, for example by ultrafiltration, or it may be processed into a powder form, for example by lyophilisation. It will be understood by those skilled in the art that this invention could be adapted to use other less pure forms of the enzyme, such as the whole-cells themselves. However, the use of isolated enzymes is preferred in accordance with the invention.
  • the biocatalyst may also exist as a whole cell-containing preparation that has been deliberately or otherwise treated to cause release of the enzymes from the cells. In some cases the use of solvents or high concentrations of the substrate itself can cause the cells to leak their contents into the surrounding medium.
  • biocatalyst are equally applicable and useful as the lyophilised enzymes that are used in this application.
  • Table 3 shows the results of conventional hydrogenation reactions such as a transfer hydrogenation performed using known transfer hydrogenation catalysts and a sodium borohydride reduction.
  • CATHy is a registered trademark of Avecia Limited and NPIL Pharmaceuticals Limited and refers to a transfer hydrogenation catalyst produced and sold by those companies.
  • IPA as hydrogen source: Potassium hydroxide (4 mg) and Ru(mesitylene)(TSDPEN) catalyst (4mg) was added to a solution of chloroketone (200mg) in isopropanol under nitrogen atmosphere then heated at 6O 0 C for 60hrs. Reaction was diluted with water (1OmL), extracted into ethyl acetate (2x 2OmL), dried (Na 2 SO 4 ) and concentrated.
  • Triethylammonium formate (0.4 mL) was added to a solution of chloroketone (200mg) in degassed ethyl acetate (2mL) followed by addition of Ru(mesitylene)(TSDPEN) catalyst (4mg) then stirred at 3O 0 C for 60hrs. Reaction was diluted with water (1OmL), extracted into ethyl acetate (2x 2OmL), dried (Na 2 SO 4 ) and concentrated.
  • the enantiomeric excess of the haloalcohol product is enhanced by lipase catalysed transesterification
  • the enantioenriched alcohol (2.5g, 7.8mmol, typically an 85:15 to 90:10 mixture of diastereomers, but can be lower) was dissolved in methyl t-butylether (50ml) with stirring, and one equivalent of acyl donor (7.8 mmol) added. Vinyl acetate, vinyl butyrate, vinyl stearate and succinic anhydride were used as acyl donors.
  • Lipase (0.625g, AE07, Mann-Associates, Cambridge, UK) was added and the heterogeneous mixture stirred at ambient temperature. After 48 hrs the reactions were sampled. The enzyme was removed by filtration, and the filtrate diluted one in four into hexane. The solutions were analysed by HPLC.
  • the process of the invention has utility in preparing intermediate compounds which in turn can be used in the preparation of a number of pharmaceutically active compounds as well as other materials.
  • actives which can be prepared from intermediates produced using the present invention include amprenavir, atazanavir and fosamprenavir.
  • amprenavir finds utility in the second of the following sequence of steps from compound XVIII to XIX in the process to produce amprenavir:
  • Sensitive functional groups may need to be protected and deprotected during synthesis of a compound of the invention. This may be achieved by conventional methods, for example as described in "Protective Groups in Organic Synthesis” by TW Greene and PGM Wuts, John Wiley & Sons lnc (1999), and references therein.
  • the isolated enzyme is capable of catalyzing the reduction of a ketone.
  • the isolated enzyme is a ketoreductase.
  • the process can be conducted in the presence of a reducing agent.
  • the reducing agent may be NADPH or NADP.
  • the ketoreductase may be an NADPH dependent ketoreductase.
  • the ketoreductase may also be an NADH dependent ketoreductase.
  • R alkyl, substituted alkyl, preferably -CH 2 Ph.
  • the alkyl group may have from 1 to 10 carbon atoms and may be optionally substituted by one or more groups such as phenyl.
  • P is a protecting group and X is a halo group.
  • R is an alkyl group which may have from 1 to 10 carbon atoms and which may be optionally substituted by one or more groups such as phenyl. Suitable types of hydrolase which can be used include lipase, protease and aminoacylase.
  • R 1 is selected from the group comprising: H; Ci -7 alkyl; C 2 7 alkenyl; C 2 7 alkynyl; aryl; Ci -7 alkylaryl; C 2 7 alkenylaryl; het; and Ci -7 alkylhet;
  • R 2 is selected from the group comprising: H; Ci -7 alkyl; C 2 7 alkenyl; C 2 . 7 alkynyl; aryl; Ci -7 alkylaryl; C 2 . 7 alkenylaryl; het; and Ci -7 alkylhet; wherein each of the foregoing groups defined for R 1 and R 2 may where chemically possible be optionally substituted by 1 to 4 substituents independently selected from the group comprising: Ci -7 alkyl, Ci- 7 haloalkyl, -SR 5 , - OR 6 , -NR 6 R 6 , -NO 2 , SCF 3 , halogen, -C(O)R 7 , -CN, and -CF 3 ; and P is a protecting group.
  • R 1 is optionally substituted Ci -7 alkyl, and more prefereably it is Me.
  • R 2 is optionally substituted Ci -7 alkyl; aryl; or Ci -7 alkylaryl, and more preferably it is Ci -7 alkylaryl. Most preferably it is benzyl.
  • P is preferably a benzyl or BOC group.

Landscapes

  • 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)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Preparation Of Compounds By Using Micro-Organisms (AREA)

Abstract

La présente invention se rapporte à un procédé de réduction des alpha-halocétones en alcools alpha-halo. Elle concerne plus spécifiquement l'utilisation d'enzymes isolées pour la réduction d'alpha-alocétones en alcools alpha-halo correspondants. L'alcool alpha-halo est obtenu à partir de la cétone correspondante de manière stéréosélective avec un rendement correct. La réaction est conduite en présence d'une enzyme isolée ou d'une cellule au repos.
PCT/GB2007/050590 2006-09-29 2007-09-28 Réduction des alpha-halocétones WO2008038050A2 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
GB0619240A GB0619240D0 (en) 2006-09-29 2006-09-29 Reduction of alpha-halo ketones
GB0619240.5 2006-09-29

Publications (2)

Publication Number Publication Date
WO2008038050A2 true WO2008038050A2 (fr) 2008-04-03
WO2008038050A3 WO2008038050A3 (fr) 2008-06-26

Family

ID=37434924

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/GB2007/050590 WO2008038050A2 (fr) 2006-09-29 2007-09-28 Réduction des alpha-halocétones

Country Status (2)

Country Link
GB (1) GB0619240D0 (fr)
WO (1) WO2008038050A2 (fr)

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
DE102012017026A1 (de) 2012-08-28 2014-03-06 Forschungszentrum Jülich GmbH Sensor für NADP(H) und Entwicklung von Alkoholdehydrogenasen
US8796002B2 (en) 2009-06-22 2014-08-05 Codexis, Inc. Polypeptides for a ketoreductase-mediated stereoselective route to alpha chloroalcohols
US9080192B2 (en) 2010-02-10 2015-07-14 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
WO2017001907A1 (fr) * 2015-06-29 2017-01-05 Teva Pharmaceuticals International Gmbh Procédés biocatalytiques de préparation de vilantérol
CN113185429A (zh) * 2021-04-12 2021-07-30 江苏海洋大学 一种抗hiv蛋白酶抑制剂中间体的制备方法

Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0779366A1 (fr) * 1995-06-19 1997-06-18 Kaneka Corporation Procede pour produire des derives 1-halo-3-amino-4-phenyl-2-butanol optiquement actifs
USH1893H (en) * 1996-07-23 2000-10-03 Bristol-Myers Squibb Company Enzymatic reduction method for the preparation of halohydrins
WO2006013801A1 (fr) * 2004-08-06 2006-02-09 Kaneka Corporation Nouvelle carbonyl réductase, gène de celle-ci et procédé d'utilisation de celle-ci
WO2006061137A1 (fr) * 2004-12-09 2006-06-15 Wacker Chemie Ag Gdh mutante ayant une stabilité chimique améliorée
WO2006127180A1 (fr) * 2005-05-25 2006-11-30 Bristol-Myers Squibb Company Procede pour preparer du butane (2r,3s)-1,2-epoxy-3-(protege)amino-4-substitue et des intermediaires de celui-ci

Patent Citations (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0779366A1 (fr) * 1995-06-19 1997-06-18 Kaneka Corporation Procede pour produire des derives 1-halo-3-amino-4-phenyl-2-butanol optiquement actifs
USH1893H (en) * 1996-07-23 2000-10-03 Bristol-Myers Squibb Company Enzymatic reduction method for the preparation of halohydrins
WO2006013801A1 (fr) * 2004-08-06 2006-02-09 Kaneka Corporation Nouvelle carbonyl réductase, gène de celle-ci et procédé d'utilisation de celle-ci
WO2006061137A1 (fr) * 2004-12-09 2006-06-15 Wacker Chemie Ag Gdh mutante ayant une stabilité chimique améliorée
WO2006127180A1 (fr) * 2005-05-25 2006-11-30 Bristol-Myers Squibb Company Procede pour preparer du butane (2r,3s)-1,2-epoxy-3-(protege)amino-4-substitue et des intermediaires de celui-ci

Non-Patent Citations (4)

* Cited by examiner, † Cited by third party
Title
DATABASE CAPLUS CHEMICAL ABSTRACTS SERVICE, COLUMBUS, OHIO, US; 14 October 2003 (2003-10-14), KATAOKA ET AL.: "Conjugated polyketone reductase from Candida parapsilosis" XP002465384 retrieved from STN accession no. 2003:804796 *
KALUZNA ET AL: "Ketoreductases: stereoselective catalysts for the facile synthesis of chiral alcohols" TETRAHEDRON: ASYMMETRY, PERGAMON, OXFORD, GB, vol. 16, no. 22, 14 November 2005 (2005-11-14), pages 3682-3689, XP005180018 ISSN: 0957-4166 *
PATEL R N ET AL: "Diastereoselective microbial reduction of (S)-[3-chloro-2-oxo-1-(phen ylmethyl)propyl]carbamic acid, 1,1-dimethylethyl ester" TETRAHEDRON: ASYMMETRY, ELSEVIER SCIENCE PUBLISHERS, AMSTERDAM, NL, vol. 14, no. 20, 17 October 2003 (2003-10-17), pages 3105-3109, XP004464019 ISSN: 0957-4166 *
PATEL R N: "BIOCATALYTIC SYNTHESIS OF CHIRAL INTERMEDIATES FOR ANTIVIRAL AND ANTIHYPERTENSIVE DRUGS" JOURNAL OF THE AMERICAN OIL CHEMISTS' SOCIETY, AOCS PRESS, CHAMPAIGN, IL, US, vol. 76, no. 11, 1999, pages 1275-1281, XP002946859 ISSN: 0003-021X *

Cited By (14)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9296992B2 (en) 2009-06-22 2016-03-29 Codexis, Inc. Ketoreductase-mediated stereoselective route to alpha chloroalcohols
US9404092B2 (en) 2009-06-22 2016-08-02 Codexis, Inc. Ketoreductase-mediated stereoselective route to alpha chloroalcohols
US8796002B2 (en) 2009-06-22 2014-08-05 Codexis, Inc. Polypeptides for a ketoreductase-mediated stereoselective route to alpha chloroalcohols
US9029112B2 (en) 2009-06-22 2015-05-12 Codexis, Inc. Ketoreductase-mediated stereoselective route to alpha chloroalcohols
US9394551B2 (en) 2010-02-10 2016-07-19 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
US9080192B2 (en) 2010-02-10 2015-07-14 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
US9714439B2 (en) 2010-02-10 2017-07-25 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
US10196667B2 (en) 2010-02-10 2019-02-05 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
US10604781B2 (en) 2010-02-10 2020-03-31 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
US11193157B2 (en) 2010-02-10 2021-12-07 Codexis, Inc. Processes using amino acid dehydrogenases and ketoreductase-based cofactor regenerating system
DE102012017026A1 (de) 2012-08-28 2014-03-06 Forschungszentrum Jülich GmbH Sensor für NADP(H) und Entwicklung von Alkoholdehydrogenasen
WO2014032777A1 (fr) 2012-08-28 2014-03-06 Forschungszentrum Jülich GmbH Capteur de nadp(h) et développement d'alcool déshydrogénases
WO2017001907A1 (fr) * 2015-06-29 2017-01-05 Teva Pharmaceuticals International Gmbh Procédés biocatalytiques de préparation de vilantérol
CN113185429A (zh) * 2021-04-12 2021-07-30 江苏海洋大学 一种抗hiv蛋白酶抑制剂中间体的制备方法

Also Published As

Publication number Publication date
WO2008038050A3 (fr) 2008-06-26
GB0619240D0 (en) 2006-11-08

Similar Documents

Publication Publication Date Title
JP3789938B2 (ja) 酵素触媒作用アシル化による１級及び２級のヘテロ原子置換アミンのラセミ体分割
Vongvilai et al. Direct asymmetric dynamic kinetic resolution by combined lipase catalysis and nitroaldol (Henry) reaction
WO2008038050A2 (fr) Réduction des alpha-halocétones
WO2005073388A1 (fr) Processus de fabrication methylpyrrolidine-2 substitue-1 optiquement actifs et alternatives
US7727751B2 (en) Method for the preparation of mycophenolate mofetil by enzyme tranesterification
JP2000509254A (ja) 治療用アミドの立体選択的調製のための酵素的方法
US20060148046A1 (en) Enzymatic process for the preparation of an intermediate compound and use thereof for the synthesis of tamsulosin hydrochloride
JPWO2007026860A1 (ja) 光学活性α−ヒドロキシカルボン酸の製造方法
JP5093248B2 (ja) 光学活性インドリン−２−カルボン酸類またはその誘導体の製造方法
US20080249310A1 (en) Process For the Preparation of (2R,3R)-2-Hydroxy-3-Amino-3-Aryl-Propionamide and (2R,3R)-2-Hydroxy-3-Amino-3-Aryl-Propionic Acid Alkyl Ester
EP0792936B1 (fr) Procédé de préparation de 2-halo-1-(phényle substitué) éthanol optiquement active
JP5092466B2 (ja) 光学活性ピペコリン酸またはその誘導体の製造方法。
CA2054773C (fr) Methode de protection de la fonction hydroxyde lors de la separation d'alcool et d'ester
JP3814766B2 (ja) 光学活性な２−ハロ−１−（置換フェニル）エタノールの製造法
US8008062B2 (en) Production of (R)- and (S)-4-(1-aminoethyl) benzoic acid methyl ester sulfate by lipase acylation of racemic 4-(1-aminoethyl) benzoic acid methyl ester and sulfuric acid precipitation
WO2003085120A1 (fr) Procede de production soit d'acide $g(b)-amine n-substitue optiquement actif et d'ester d'acide $g(b)-amine n-substitue optiquement actif, soit d'acide 2-homopipecolique n-substitue optiquement actif et d'ester d'acide 2-homopipecolique n-substitue optiquement actif
MXPA06002944A (es) Sintesis enzimatica de intermediarios enantiopuros mediante colesterol esterasa a partir de levadura.
CA2410438A1 (fr) Procede de resolution optique d'un acide carboxylique heterocyclique alpha-substitue racemique a l'aide d'enzymes
JP5092465B2 (ja) ピペコリン酸の立体選択的なエステル化方法
US7439036B2 (en) Process for producing optically active octahydro-1H-indole-2-carboxylic acid
JP4257975B2 (ja) 光学活性アミノインダノール類及びアミノテトラリノール類の製造法
KR100527231B1 (ko) 무수숙신산에 의한 광학활성 1,2-디올 유도체와 이의 에스테르 제조방법
JP2006021999A (ja) 光学活性β−アミノニトリル化合物およびその対掌体アミド化合物の製造方法
JPH04197197A (ja) 光学活性ハロヒドリン誘導体の製造方法
GB2299332A (en) Esters of (R) 2-(2-hydroxybutyl)-3-chlorothiophene and a process for the resolution of (S) 2-(2-hydroxybutyl)-3-chlorothiophene

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 07804493

Country of ref document: EP

Kind code of ref document: A2

NENP Non-entry into the national phase in:

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 07804493

Country of ref document: EP

Kind code of ref document: A2