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WO2002057475A1 - Preparation stereoselective de 3-hydroxy-3-phenylpropionitrile - Google Patents

Preparation stereoselective de 3-hydroxy-3-phenylpropionitrile Download PDF

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Publication number
WO2002057475A1
WO2002057475A1 PCT/IN2001/000008 IN0100008W WO02057475A1 WO 2002057475 A1 WO2002057475 A1 WO 2002057475A1 IN 0100008 W IN0100008 W IN 0100008W WO 02057475 A1 WO02057475 A1 WO 02057475A1
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WO
WIPO (PCT)
Prior art keywords
hydroxy
lipase
methanol
acetate
alcohol
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.)
Ceased
Application number
PCT/IN2001/000008
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English (en)
Inventor
Ahmed Kamal
Gollapalli Bhasker Khanna
Maddamsetty Venkate Rao
Kondapuram Vijaya Raghavan
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Council of Scientific and Industrial Research CSIR
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Council of Scientific and Industrial Research CSIR
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 Council of Scientific and Industrial Research CSIR filed Critical Council of Scientific and Industrial Research CSIR
Priority to GB0317492A priority Critical patent/GB2387597B/en
Priority to JP2002558527A priority patent/JP2004520039A/ja
Priority to PCT/IN2001/000008 priority patent/WO2002057475A1/fr
Publication of WO2002057475A1 publication Critical patent/WO2002057475A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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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
    • C12P13/002—Nitriles (-CN)
    • C12P13/004—Cyanohydrins
    • 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 chemoenzymatic process for the stereoselective preparation of both R and S enantiomers of 3-hydroxy-3-phenylpropanenitrile.
  • This invention particularly relates to a chemoenzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3-phenylpropanenitrile a key intermediate for the synthesis of antipsychic drugs like (S)-fluoxetine and (R)-to ⁇ noxetine.
  • Fluoxetine, tomoxetine and related class of compounds are important for treating psychiatric disorders ( Figure-1 of accompanying drawing).
  • Tomoxetine is a norepinephrine reuptake inhibitor where as fluoxetine is a neuronal inhibitor of serotonin reuptake and are clinically effective in treating depression.
  • Fluoxetine in particular is a multifaceted drug used in treating migraine headache, chronic pain, obsessive compulsive disorders, sexual disfunctioning, memory disorders, sleep disorders etc.
  • fluoxetine and tomoxetine and their cognant compounds nisoxetine and norfluoxetine are therapeutically used in racemate form (Analytical Profiles of Drug Substances, vol.
  • the main objective of the present invention is to provide a chemoenzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3- phenylpropanenitrile.
  • Another objective of the present invention is to employ vicinal cyanohydrin as the substrate.
  • the present invention provides a chemoenzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3- phenylpropanenitrile which are the optically pure intermediates for the synthesis of (S)- fluoxetine and (R)-tomoxetine in high enantiomeric excess as they are promisingly more potent than their other enantiomers with less affinity for ⁇ -adrenergic receptors.
  • the present invention employs vicinal cyanohydrin as the substrate of choice, which is the key intermediate for the antianxiety and antidepressant drugs.
  • the present invention provides an enzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3-phenylpropanenitrile, a key intermediate for the synthesis of (S)-fluoxetine, (R)-tomoxetine and cognant compounds which comprises of reacting the cyanohydrin with acetylating agent in the presence of lipase followed by separation of (R)-acetate and (S)-alcohol obtained and by hydrolysing (R)-acetate in the presence of K 2 CO 3 in methanol to obtain the required enantiomers.
  • 3-hydroxy-3-phenylpropanenitrile (6) is formed by facile regioselective ring opening of styrene oxide (5) with alkali metal cyanide selected from sodium cyanide and potassium cyanide.
  • the 3-hydroxy-3-phenylpropanenitrile is selectively acetylated with vinyl acetate, isopropenyl acetate in the presence of lipases.
  • the alcohol and the ester formed in the kinetic resolution are separated by column chromatography, absolute configuration is ascertained by the values of optical rotation, and the enantiomeric purity was confirmed by HPLC employing chiral column.
  • sodium cyanide in aqueous alcoholic conditions is used as a source for cyanide for the nucleophilic rings opening.
  • 3-Hydroxy-3-phenylpropanenitrile is prepared by regioselective ring opening of styrene oxide between 20-40°C by stirring for
  • the reaction mixture is concentrated to about half the volume followed by extraction with ethyl acetate and this upon evaporation gave the residue.
  • the residue thus obtained is purified by column chromatography to give 3-hydroxy-3-phenylpropanenitrile more than 98 % yield.
  • racemic 3-hydroxy-3- phenylpropanenitrile is acetylated enzymatically employing different acetylating agents and various lipases in different solvents.
  • the acetylating agent is selected from vinyl acetate and isopropenyl acetate.
  • the lipase used is selected from
  • Pseudomonas cepacia lipase Amano PS
  • Candida rugosa lipase CRL
  • Porcine pancreas lipase PPL
  • the organic solvent is selected from the group consisting of diisopropyl ether, t-butylmethyl ether, diethyl ether, tefrahydrofuran, and toluene.
  • the presence of lipase (R)-3-hydroxy- 3-phenylpropanemtrile is selectively acetylated and the (R)-acetate and the (S)-alcohol are separated by column chromatography.
  • the enantiomeric excess is determined by HPLC employing chiral column.
  • Figure-1 represents the structures of norfluoxetine, fluoxetine, tomoxetine and nisoxetine
  • Figure-2 shows the schematic representation of this process towards the preparation of both enantiomers of 3-hydroxy-3-phenylpropanenitrile and their usefulness towards the synthesis of (S)-fluoxetine and (R)-tomoxetine.
  • Example 1 is given by way of illustration and they should not be construed to limit the scope of the present invention.
  • Example 2 Enzymatic Resolution of (SV3-hvdroxy-3-phenylpropanenitrile and its (R) acetate: To a solution of 3-hydroxy-3-phenylpropanenitrile (5 mmol) dissolved in diisopropyl ether (100 mL), Pseudomonas cepacia lipase (600 mg) and vinyl acetate (10 mmol) were added successively and incubated at 40°C in an orbital shaker. After 50% completion of the reaction (72-78 hrs) as indicated by TLC, the reaction mixture was filtered and solvent was evaporated under reduced pressure. The residue was subjected to column chromatography to separate the ester and the unreacted alcohol. The optical purity of these compounds were determined by HPLC.
  • Example 4 Chiral HPLC Analysis HPLC analysis was performed by employing chiral column (Chiralcel OD, Daicel). The racemic acetate was prepared by treating 3-hydroxy-3- phenylpropanenitrile with acetic anhydride in presence of pyridine as an authentic sample for comparison on HPLC. The mobile phase was hexane: isopropanol (90:10), flowrate 0.5 mL/min and monitored at UN 254 nm.
  • Vicinal cyanohydrins or 1,2-cyanohyrins are important and versatile compounds in organic synthesis as they could be easily transformed to amino alcohols, hydroxy amides, hydroxy esters, hydroxy acids etc., by employing simple methods, i recent years there has been an increasing demand for the optically pure forms of these vital intermediates which could lead to chirally pure compounds of biological importance.
  • 3-hydroxy-3-phenylpropanenitrile has been obtained by regioselective ring opening of styrene oxide in good yields. This is an exceptionally mild and simple procedure, which is carried out at 20-40°C. In this process chiral 1,2-cyanohydrin has been obtained by lipase mediated resolution in high enantiomeric excess.

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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 chimioenzymatique pour la préparation stéréosélective d'énantiomères (R) et (S) de 3-hydroxy-3-phénylpropionitrile, utiles comme intermédiaire clé pour la synthèse de (S)-fluoxétine, de (R)-tomoxétine et de composés apparentés, consistant à faire réagir de la cyanohydrine avec un agent d'acétylation en présence de lipase dans un solvant organique, à séparer le (R)-acétate et le (S)-alcool, à hydrolyser le (R)-acétate en présence de K2CO3 dans du méthanol, à filtrer le mélange réactionnel et à faire évaporer le solvant pour obtenir le (R)-alcool.
PCT/IN2001/000008 2001-01-22 2001-01-22 Preparation stereoselective de 3-hydroxy-3-phenylpropionitrile Ceased WO2002057475A1 (fr)

Priority Applications (3)

Application Number Priority Date Filing Date Title
GB0317492A GB2387597B (en) 2001-01-22 2001-01-22 Stereoselective preparation of 3-hydroxy-3-phenylpropionitrile
JP2002558527A JP2004520039A (ja) 2001-01-22 2001-01-22 ３−ヒドロキシ−３−フェニルプロパンニトリルの立体選択的調製
PCT/IN2001/000008 WO2002057475A1 (fr) 2001-01-22 2001-01-22 Preparation stereoselective de 3-hydroxy-3-phenylpropionitrile

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/IN2001/000008 WO2002057475A1 (fr) 2001-01-22 2001-01-22 Preparation stereoselective de 3-hydroxy-3-phenylpropionitrile

Publications (1)

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WO2002057475A1 true WO2002057475A1 (fr) 2002-07-25

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PCT/IN2001/000008 Ceased WO2002057475A1 (fr) 2001-01-22 2001-01-22 Preparation stereoselective de 3-hydroxy-3-phenylpropionitrile

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GB (1) GB2387597B (fr)
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Cited By (16)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2004055194A1 (fr) * 2002-12-16 2004-07-01 Council Of Scientific And Industrial Research Procede chimio-enzymatique de preparation stereoselective d'enantiomeres r et s de 2-hydroxy-3-(2-thienyl) propanenitrile
JP2006507234A (ja) * 2002-08-01 2006-03-02 ビーエーエスエフ アクチェンゲゼルシャフト （ｓ）−３−メチルアミノ−１−（チエン−２−イル）プロパン−１−オールの製造方法
WO2006064513A1 (fr) * 2004-12-18 2006-06-22 Council Of Scientific & Industrial Research Synthèse chimioenzymatique énantioconvergente de l'acide (r)-gamma-amino-bêta-hydroxybutyrique ((r)-gabob)
US7485754B2 (en) 2005-07-08 2009-02-03 Apotex Pharmachem Inc. Efficient method for preparing 3-aryloxy-3-arylpropylamines and their optical stereoisomers
EP2348120A1 (fr) * 2009-12-30 2011-07-27 Universität Wien Réduction enzymatique de 1-phénylpropanone et dérivés associés
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8545881B2 (en) 2004-04-19 2013-10-01 Eurand Pharmaceuticals, Ltd. Orally disintegrating tablets and methods of manufacture
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, Inc. Timed, sustained release systems for propranolol
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US10130580B2 (en) 2004-10-12 2018-11-20 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
CN109706194A (zh) * 2018-12-24 2019-05-03 浙江工业大学 一种基于流动化学酶促胺解反应在线合成苯乙醇类β-氨基醇衍生物的方法
US10471017B2 (en) 2004-10-21 2019-11-12 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
CN113219094A (zh) * 2021-05-07 2021-08-06 湖北欣泽霏药业有限公司 一种盐酸托莫西汀口服溶液光学异构体的液相色谱检测法
CN114058655A (zh) * 2021-11-30 2022-02-18 青岛科技大学 一种酶-化学一锅法合成(r)-乙酰胺基苯丙醇的方法

Families Citing this family (1)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113646293A (zh) * 2019-04-02 2021-11-12 赢创运营有限公司 制备3-羟基-3-甲基丁酸化物(hmb)及其盐的方法

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Cited By (36)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US8945618B2 (en) 1996-06-14 2015-02-03 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8956650B2 (en) 1996-06-14 2015-02-17 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US8071128B2 (en) 1996-06-14 2011-12-06 Kyowa Hakko Kirin Co., Ltd. Intrabuccally rapidly disintegrating tablet and a production method of the tablets
US9358214B2 (en) 2001-10-04 2016-06-07 Adare Pharmaceuticals, Inc. Timed, sustained release systems for propranolol
US9040086B2 (en) 2001-10-04 2015-05-26 Aptalis Pharmatech, Inc. Timed, sustained release systems for propranolol
JP2006507234A (ja) * 2002-08-01 2006-03-02 ビーエーエスエフ アクチェンゲゼルシャフト （ｓ）−３−メチルアミノ−１−（チエン−２−イル）プロパン−１−オールの製造方法
US7045341B2 (en) 2002-12-16 2006-05-16 Council Of Scientific And Industrial Research Chemoenzymatic process for stereoselective preparation of R and S enatiomers of 2-hydroxy-3-(2-thienyl) propanenitrile
WO2004055194A1 (fr) * 2002-12-16 2004-07-01 Council Of Scientific And Industrial Research Procede chimio-enzymatique de preparation stereoselective d'enantiomeres r et s de 2-hydroxy-3-(2-thienyl) propanenitrile
US8367111B2 (en) 2002-12-31 2013-02-05 Aptalis Pharmatech, Inc. Extended release dosage forms of propranolol hydrochloride
US8545881B2 (en) 2004-04-19 2013-10-01 Eurand Pharmaceuticals, Ltd. Orally disintegrating tablets and methods of manufacture
US9089490B2 (en) 2004-04-19 2015-07-28 Aptalis Pharmatech, Inc. Orally disintegrating tablets and methods of manufacture
US9730896B2 (en) 2004-04-19 2017-08-15 Adare Pharmaceuticals, Inc. Orally disintegrating tablets and methods of manufacture
US10568832B2 (en) 2004-10-12 2020-02-25 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US11452689B2 (en) 2004-10-12 2022-09-27 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10130580B2 (en) 2004-10-12 2018-11-20 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions
US10952971B2 (en) 2004-10-21 2021-03-23 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
US10471017B2 (en) 2004-10-21 2019-11-12 Adare Pharmaceuticals, Inc. Taste-masked pharmaceutical compositions with gastrosoluble pore-formers
WO2006064513A1 (fr) * 2004-12-18 2006-06-22 Council Of Scientific & Industrial Research Synthèse chimioenzymatique énantioconvergente de l'acide (r)-gamma-amino-bêta-hydroxybutyrique ((r)-gabob)
US9566249B2 (en) 2005-05-02 2017-02-14 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US10500161B2 (en) 2005-05-02 2019-12-10 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US10045946B2 (en) 2005-05-02 2018-08-14 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9161919B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US11147772B2 (en) 2005-05-02 2021-10-19 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9579293B2 (en) 2005-05-02 2017-02-28 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US9161918B2 (en) 2005-05-02 2015-10-20 Adare Pharmaceuticals, Inc. Timed, pulsatile release systems
US7485754B2 (en) 2005-07-08 2009-02-03 Apotex Pharmachem Inc. Efficient method for preparing 3-aryloxy-3-arylpropylamines and their optical stereoisomers
US8580313B2 (en) 2009-12-02 2013-11-12 Aptalis Pharma Limited Fexofenadine microcapsules and compositions containing them
US10729682B2 (en) 2009-12-02 2020-08-04 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US10166220B2 (en) 2009-12-02 2019-01-01 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
US9233105B2 (en) 2009-12-02 2016-01-12 Adare Pharmaceuticals S.R.L. Fexofenadine microcapsules and compositions containing them
EP2348120A1 (fr) * 2009-12-30 2011-07-27 Universität Wien Réduction enzymatique de 1-phénylpropanone et dérivés associés
CN109706194A (zh) * 2018-12-24 2019-05-03 浙江工业大学 一种基于流动化学酶促胺解反应在线合成苯乙醇类β-氨基醇衍生物的方法
CN109706194B (zh) * 2018-12-24 2021-04-06 浙江工业大学 一种基于流动化学酶促胺解反应在线合成苯乙醇类β-氨基醇衍生物的方法
CN113219094A (zh) * 2021-05-07 2021-08-06 湖北欣泽霏药业有限公司 一种盐酸托莫西汀口服溶液光学异构体的液相色谱检测法
CN114058655A (zh) * 2021-11-30 2022-02-18 青岛科技大学 一种酶-化学一锅法合成(r)-乙酰胺基苯丙醇的方法
CN114058655B (zh) * 2021-11-30 2023-08-29 青岛科技大学 一种酶-化学一锅法合成(r)-乙酰胺基苯丙醇的方法

Also Published As

Publication number Publication date
GB0317492D0 (en) 2003-08-27
GB2387597B (en) 2004-11-10
GB2387597A (en) 2003-10-22
JP2004520039A (ja) 2004-07-08

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