WO2002057475A1 - Stereoselective preparation of 3-hydroxy-3-phenylpropionitrile - Google Patents
Stereoselective preparation of 3-hydroxy-3-phenylpropionitrile Download PDFInfo
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- 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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- 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)
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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)
- C12P13/004—Cyanohydrins
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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
- 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.
Abstract
This invention relates to a Chemoenzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3-phenylpropanenitrile, useful as a key intermediate for synthesis of (S)-fluoxetine, (R)-tomoxetine and cognant compounds, which comprises reacting cyanohydrin with an acetylating agent in the presence of lipase in an organic solvent, followed by separation of (R)-acetate and (S) alcohol, hydrolyzing (R)-acetate in presence K2CO3 in methanol, filtering the reaction mixture and evaporating the solvent to obtain the (R) alcohol.
Description
STΞREOSELECTIVE PREPARATION OF 3-HYDR0XY-3 -PHENYLPR0PI0N--TRILE
Technical Field
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)-toιnoxetine. Background Art
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. Although fluoxetine and tomoxetine and their cognant compounds nisoxetine and norfluoxetine are therapeutically used in racemate form (Analytical Profiles of Drug Substances, vol. 19, p.193-219; Klaus Florey, Ed; Academic Press Inc., San Diego, 1990 and references cited therein), while there is some stereospecificity associated with their biological action. The current preference is for the use of enantiomerically pure drugs due to differences in metabolic behaviour and pharmacological activities displayed by individual enantiomers. Fluoxetine and tomoxetine have the same basic structural skeleton of 3-amino-propanol, but the need is for different enantiomers of high optical purity. These enantiomerically pure compounds have been prepared by using optically pure substrates (Synth. Commun., 1995, 25, 1231) or by employing a chiral reducing agents (J. Org. Chem., 1988, 53, 2916; J. Org. Chem., 1988, 53, 4081) or by chemoenzymatic synthesis. In chemoenzymatic synthesis either an oxo group is reduced by whole cells or microorganism (Tetrahedron Lett., 1991, 32, 1901; Chem. Lett., 1991, 1603) or by kinetic resolution of 3-chloro-l- phenyl-1-propanol (Tetrahedron: Asymmetry, 1992, 3, 525) or l-phenyl-3-buten-l-ol (Tetrahedron Lett., 1996, 37, 9253) using Upases. The reported methods employ chiral reducing agents and usually these reagents are not commercially available. Some methods involve tedious work-up procedure while others employ expensive starting materials.
Disclosure of the invention
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.
Summary of the invention
Accordingly, 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 β-adrenergic receptors. Also, the present invention employs vicinal cyanohydrin as the substrate of choice, which is the key intermediate for the antianxiety and antidepressant drugs. Detailed Description of the invention
Accordingly, 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 K2CO3 in methanol to obtain the required enantiomers. In an embodiment of the present invention 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. In another embodiment of the present invention, the 3-hydroxy-3-phenylpropanenitrile is selectively acetylated with vinyl acetate, isopropenyl acetate in the presence of lipases. In yet another embodiment of the present invention 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.
In an embodiment of the present invention, sodium cyanide in aqueous alcoholic conditions is used as a source for cyanide for the nucleophilic rings opening.
In yet another embodiment of the present invention, 3-Hydroxy-3-phenylpropanenitrile is
prepared by regioselective ring opening of styrene oxide between 20-40°C by stirring for
8-10 hrs.
In yet another embodiment of the present invention, the reaction mixture is concentrated to about half the volume followed by extraction with ethyl acetate and this upon evaporation gave the residue.
In yet another embodiment of the present invention, the residue thus obtained is purified by column chromatography to give 3-hydroxy-3-phenylpropanenitrile more than 98 % yield.
In yet another embodiment of the present invention, the racemic 3-hydroxy-3- phenylpropanenitrile is acetylated enzymatically employing different acetylating agents and various lipases in different solvents.
In yet another embodiment of the present invention, the acetylating agent is selected from vinyl acetate and isopropenyl acetate. i yet another embodiment of the present invention, the lipase used is selected from
Pseudomonas cepacia lipase (Amano PS), Candida rugosa lipase (CRL) and Porcine pancreas lipase (PPL).
In yet another embodiment of the present invention, the organic solvent is selected from the group consisting of diisopropyl ether, t-butylmethyl ether, diethyl ether, tefrahydrofuran, and toluene.
In yet another embodiment of the present invention, 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.
In yet another embodiment of the present invention, the enantiomeric excess is determined by HPLC employing chiral column.
In yet another embodiment of the present invention, the synthesis of (S) fluoxetine and (R) tomoxetine is performed conventionally.
Brief description of the accompanying drawings:
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.
The following examples are given by way of illustration and they should not be construed to limit the scope of the present invention.
Example 1
Preparation of 3-Hydroxy-3-phenylpropanenitrile: To a solution of styrene oxide (10 mmol) in ethanol (10-15 mL) water (50 mL) was added and stirred for 5 minutes. To this sodiumcyanide (12 mmol) was added and stirring was continued for 6-8hrs. After formation of the product as indicated by TLC, the reaction mixture was concentrated to about half the volume under reduced pressure. The residue was extracted with ethyl acetate washed with brine and dried over anhydrous sodium sulphate to give the product. This was further purified by column chromatography employing EtOAc/hexane as the eluent. (Yield 95%). 1H NMR (ODCl3); 7.35 (s, 5H), 4.90-5.0 (t, IH), 2.65-2.70 (d, 2H); MS: m/z
147(M+).
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. Yield of (S)-3-hydroxy-3-phenylpropanenitrile 49%, ee >99%; [α]20 D-60.5 (c 1, CHC13); Yield of (R) acetate(2-cyano-l-phenyl-l(R)-ethyl acetate) 48%, ee >99%, [α]20 D +71.9 (c 1, CHC13). 1H NMR (CDC13);7.35 (s, 5H), 5.85-5.95 (t, IH), 2.80-2.90 (d, 2H), 2.15 (s, 3H); MS: m/z 189 (M+); m.p. 97-100°C.
Example 3 Hydrolysis of (RVacetate to (R)-3-Hvdroxy-3-phenyIpropanenitrile: To a solution of (R)-acetate (3 mmol) in 30 mL of methanol was added K2CO3 (10 mmol) and stirred at room temperature for 6 hrs. After complete hydrolysis of ester as indicated by TLC, the reaction mixture was subjected to filteration. The residue is treated with ethyl acetate (2x15ml). The organic layers was combined and solvents were evaporated to get the (R)-3- hydroxy-3-phenylpropanenitrile in almost quantitative yields (98%), e.e > 99%.
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.
The main advantages of the present invention are:
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.
Claims
Claims
1) A chemoenzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3-phenylpropanenitrile, useful as a key intermediate for synthesis of (S)-fluoxetine, (R)-tomoxetine and cognant compounds, which comprises reacting cyanohydrin with an acetylating agent in the presence of lipase in an organic solvent, followed by separation of (R)-acetate and (S) alcohol, hydrolyzing (R)-acetate by adding K2CO3, in methanol, filtering the reaction mixture and evaporating the solvent to obtain the (R) alcohol and thereby obtaining the required enantiomers. 2) A process as claimed in claim 1 wherein, the cyanohydrin is obtained by reacting styrene oxide with a alkali metal cyanide selected from sodium cyanide and potassium cyanide.
3) A process as claimed in claiml wherein, Hydroxy-3-phenylpropanenitrile is prepared at a mild simple procedure, which is carried out a temperature ranging between 20-40°C and stirring for 8-10 hrs.
4) A process as claimed in claim 1 wherein, recycling is not required for these products as they are obtained by kinetic resolution since the enantiomeric excess is >99%.
5) A process as claimed in claim 1 wherein, the residue thus obtained is purified by column chromatography to give 3-hydroxy-3-phenylpropanenitrile more than 98 % yield.
6) A process as claimed in claim 1 wherein, the acetylating agent employed is selected from vinyl acetate and isopropenyl acetate.
7) A process as claimed in claim 1 wherein, the organic solvent used is selected from the group consisting of diisopropyl ether, t-butylmethyl ether, diethyl ether, tetrahydrofuran, methanol and toluene.
8) A process as claimed in claim 1 wherein, the lipase used is selected from Pseudomonas cepacia lipase (Amano PS), Porcine pancreas lipase (PPL) and Candida rugosa lipase (CRL). 9) A process as claimed in claim 1 wherein, the synthesis of (S) fluoxetine and (R) tomoxetine is performed conventionally.
AMENDED CLAIMS
[received by the International Bureau on 17 May 2002 ( 17.05.02); original claims 1-9 replaced by new claims 1-12 (2 pages)]
Claims:
1) A chemoenzymatic process for the stereoselective preparation of both (R) and (S) enantiomers of 3-hydroxy-3-phenylpropanenitrile, useful as a key intermediate for synethesis of (S)-fluoxetine, (R)-tomoxetine and cognant compounds, the said process comprising the steps of: a) reacting styrene epoxide with alkali cyanide in presence of an alcohol at an ambient temperature to obtain the cyanohydrin, b) treating the cyanohydrin of step (a) with an acylating agent in the presence of lipase enzyme in an organic solvent to obtain a mixture of (R)-3-acetoxy and (S)- 3-hydroxy-3-phenylpropionitrile, c) purifying the products of step (b) to obtain (R)-3-acetoxy phenylpropionitrile and (S)-3-hydroxyphenylpropionitrile, d) hydrolysing (R)-3-acetoxy phenylpropionitrile of step (c) with alkali carbonate and alcohol at a temperature ranging between 20 ° to 40 ° C for a period of 8-10 hrs, and e) filtering the reaction mixture of step (b), evaporating the filtrate, filtering the solid thus obtained to yield (R)-3-hydroxy-3-phenyl propionitrile of required enantiomeric purity.
2) A process as claimed in claim 1, wherein in step (a) the alkali metal cyanide used is selected from a group consisting of sodium cyanide and potassium cyanide.
3) A process as claimed in claim 1, wherein in step (a) the alcohol used is selected from methanol, ethanol or isopropanol and preferably methanol.
4) A process as claimed in claim 1, wherein the (R) and (S) isomer of 3-hydroxy-3- phenyl propionitrile is prepared by simple procedure under a mild condition.
5) A process as claimed in claim 1, wherein in step (b) the acylating agent is selected from vinyl acetate or isoprenyl acetate.
6) A process as claimed in claim 1, wherein in step (b) the lipase enzyme used is selected from Pseudomonas cepacia lipase (Amano PS), Porcine pancreas lipase (PPL) and Candida rugosa lipase (CRL).
7) A process as claimed in claim 1, wherein in step(b) the organic solvent used is selected from a group consisting of diisopropyl ether, t-butylmethyl ether, diethyl ether, tetrahydrofuran, methanol and toluene.
8) A process as claimed in claim 1, wherein in step (c) (R)-3-hydroxy-3-phenyl propiontrile is obtained in a yield of more than 98 %
9) A process as claimed in claim 1, wherein in step (d) the alkali carbonate used is selected from a group consisting of sodium bicarbonate, sodium carbonate, potassium bicarbonate or potassium carbonate and preferably potassium carbonate.
10) A process as claimed in claim 1, wherein in step (d) the alcohol used is selected from a group consisting of methanol, ethanol or isopropanol and preferably methanol.
11) A process as claimed in claim 1, wherein the (R) and (S) isomers of 3-hydroxy-3- phenyl propionitrile does not require recycling for purification as they are obtained by kinetic resolution having an enantiomeric excess greater than 99%.
12) A process as claimed in claim 1, wherein the synthesis of (S)-fluoxetine and (R)- tomoxetine is performed conventionally.
STATEMENT UNDER ARTICLE 19 (1)
The claims have been revised to make them more clear and definite. No new matter has been added in the revised claims. While revising the claims, the novel and non- obvious features such as preparation of racemic 3-Phenyl-3-hydroxy-propionitrile starting from styrene epoxide is not inferred, which is the starting material in the present invention and hydrolysis of the optically active (R)-3-acetoxy-3-phenyl propionitrile, using potassium carbonate and methanol to obtain R(-) alcohol retaining high enantiomeric purity has been outlined.
Though, the method for the preparation of (R)-acetate of 3-Phenyl-3-hydroxy- propionitrile can be inferred by these citations, but its hydrolysis using K2CO3/methanol cannot be envisaged in this citation. Use of an enzyme for the hydrolysis of acetyl function and a base for the same purpose provides a very different reaction condition to perform the hydrolysis of acetyl group to obtain the hydroxyl group. Use of an inorganic base to hydrolyze the acetyl group need not necessarily provide specificity in retaining the optical activity of the starting material. The hydrolysis carried out by chemical reaction conditions are known to destroy the optical active center by encountering inversion at the optically active center leading to racemic product. Thus, by overcoming this major problem of inversion, which is the main objective of the present invention and obtaining the optically active enantiomer having high purity, by using inexpensive and commonly available chemical is a significant achievement in the present invention.
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| JP2002558527A JP2004520039A (en) | 2001-01-22 | 2001-01-22 | Stereoselective preparation of 3-hydroxy-3-phenylpropanenitrile |
| GB0317492A GB2387597B (en) | 2001-01-22 | 2001-01-22 | Stereoselective preparation of 3-hydroxy-3-phenylpropionitrile |
| PCT/IN2001/000008 WO2002057475A1 (en) | 2001-01-22 | 2001-01-22 | Stereoselective preparation of 3-hydroxy-3-phenylpropionitrile |
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| EP3947336B1 (en) * | 2019-04-02 | 2023-03-15 | Evonik Operations GmbH | Process for preparing 3-hydroxy-3-methylbutyrate (hmb) and salts thereof |
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2001
- 2001-01-22 JP JP2002558527A patent/JP2004520039A/en active Pending
- 2001-01-22 GB GB0317492A patent/GB2387597B/en not_active Expired - Fee Related
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| 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 |
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Also Published As
| Publication number | Publication date |
|---|---|
| GB0317492D0 (en) | 2003-08-27 |
| JP2004520039A (en) | 2004-07-08 |
| GB2387597A (en) | 2003-10-22 |
| GB2387597B (en) | 2004-11-10 |
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