FIELD OF THE INVENTION:
The present invention relates to improved, safe and industrially applicable enantioselective enzymatic process for preparing (S)-Ethyl-3-cyano-5-methylhexanoate
BACKGROUND OF THE INVENTION:
(S)-Ethyl-3-cyano-5-methylhexanoate of formula-1 is used as an intermediate for the synthesis of active pharmaceutical ingrediënt.
Formufa-1
There are many approaches to synthesis recemic as wel! as enantiomerically pure compound in prior art.
Biocatalysis is becoming one of the greenest technologies for the synthesis of pharmaceutical intermediates due to its high enantioselectivity, mild reaction conditions, and environmental friendliness. Biocatalysis, as a reaction between organic components, has wide application in recent years.
Microbial enzymes mediate intermediate product formation in the chemical enzymatic synthesis of drugs. Indeed, physiologically active molecules in pharmaceutical formulations exist as enantiomers. Unlike commonly used physico-chemical reactions for the separation of racemic mixtures, the use of enantiomer specific enzymes offers a good alternative for particular enantiomers.
Improvement of environmental profile of manufacturing process for synthesis of active pharmaceutical ingredients is one of the important goals in pharmaceutical industry. This includes use of eco friendly chemicals, enhancing efficiency and yield in order to minimize waste, reduction of solvent usage and reactants and to develop operational friendly processes.
The present invention relates to develop an eco friendly, cost effective process for (S)-Ethyl-3-cyano-5-methylhexanoate.

SUMMARY OF THE INVENTION:
One aspect of the present invention provides process for preparing Diethyl 2-(3-niethy lbut> lident)malonate of formula-4 comprises;
(a) Condensing 3-tvtethylbutanal with Diethyl .malonate in presence of gl.acetic acid, di-n-propylamine, solvent
(b) Refluxing azeotropically
(c) Isolating Diethyl 2-(3-methylbutylidene)malonate
One aspect of the present invention provides a process for preparing Diethyl 2-(l-cyano-3-Methylbutyl) malonate of Formula-5 comprising the steps of;
(a) Reacting Diethyl 2-(3-methylbutylidene) malonate with Sodium cyanide in tert-butanol
(b) Isolating Diethyl 2-(l-cyano-3-Methylbutyl) malonate
One another aspect of the present invention provides a process for preparing Ethyl 3-cyano-5-methylhexanoate of formula-6 comprising the steps of;
(a) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with salt in presence of solvent
(b) Isolating Ethyl 3-cyano-5-methyIhexanoate
One another aspect of the present invention provides a process for preparing Ethyl 3-cyano-5-methylhexanoate of formula-6 comprising the steps of;
(a) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with base in presence of solvent
(b) Isolating Ethyl 3-cyano-5-methylhexanoate
One another aspect of the present invention provides a process for preparing Ethyl 3-cyano-5-methylhexanoate of formula-6 comprising the steps of;
(a) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with base in presence of solvent and phase transfer catalyst
(b) Isolating Ethyl 3-cyano-5-methylhexanoate
One another aspect of the present invention provides selective enzymatic hydrolysis process for preparing (S)-methyl 3-cyano-5-methylhexanoate of Formula-1 comprising the steps of; • (a) Reacting Methyl 3-cyano-5methyIhexanoate with enzyme in presence of buffer, base (b) Isolating (S)-methyl 3-cyano-5-methylhexanoate

One another aspect of the present invention provides racemisation process for preparing Racemic Ethyl 3-Cyano-5-methyl hexanoate of formula-6 comprising
(a) Combining (R)-Ethyl-3-cyano-5-Methylhexanoic acid sodium salt with sodium ethoxide and acetic acid in presence of solvent
(b) Isolating recemic Ethyl-3-cyano-5-Methylhexanoate
DETAIL DESCRIPTION OF THE INVENTION:
The present invention relates to improved, safe, economical and industrially applicable process for the preparation of (S)-Ethyl-3-cyano-5-methylhexanoate of formula-1
One aspect of the present invention provides well-known naming reaction Knoevengal reaction for preparing Diethyl 2-(3-methylbutylidene)malonate of formula-4 comprises;
(a) Condensing 3-Methylbutanal with Diethyl malonate in presence of gl.acetic acid, di-n-propylamine, solvent
(b) Refluxing azeotropically
(c) Isolating Diethyl 2-(3-methylbutylidene)malonate
The process for preparation of Diethyl 2-(3-methylbutylidene)malonate of Formula-4
given in the below reaction scheme-1

Scheme-1
The solvent used for step (a) is non-polar solvents and selected from the group consisting of Cyclohexane.Hexane, Dichloromethane, Toluene and mixture thereof. One aspect of the present invention provides a process for preparing Diethyl 2-(l-cyano-3-Methylbutyl) malonate of Formula-5 comprising the steps of;
Formula-5
(a) Reacting Diethyl 2-(3-methylbutylidene) malonate with Sodium cyanide in solvent
(b) Isolating Diethyl 2-(l-cyano-3-Methylbutyl) malonate
The process for preparation of Diethyl 2-(l-cyano-3-Methylbutyl) malonate of Formula-5 ,
given in the below reaction scheme-2
Sodium Cyanide was used instead of Potassium Cyanide that is recommended in the reported procedure. NaCN is much safer to handle as compared to K.CN in industrial use.
The solvent used for step (a) is alcohol solvents and selected from the group consisting of t-butanol, ethanol, methanol, isopropyl alcohol and mixture thereof.
One another aspect of the present invention provides a process for preparing Ethyl 3-cyano-5-methylhexanoate of formula-6 comprising the steps of;

(a) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with salt in presence of solvent
(b) Isolating Ethyl 3-cyano-5-methylhexanoate
The process for preparation of Ethyl 3-cyano-5-methyïhexanoate of formula-6 given in the below reaction scheme-3
Scheme-3
The solvent used for step (a) is selected from the group consisting of Cyclohexane, Hexane, Dichloromethane, Toluene and methyl tert butyl ether mixture thereof.
The salt for step (a) is inorganic salt. The inorganic salt is selected from the group consisting of Lithium chloride, Calcium sulphate, Calcium chloride, Calcium carbonate, Calcium bicarbonate, Potassium sulphate, Potassium nitrate, Potassium chloride, Potassium carbonate, Potassium bicarbonate, Sodium sulphate, Sodium nitrate, Sodium chloride, Sodium carbonate, Sodium bicarbonate, Magnesium sulphate, Magnesium nitrate, Magnesium chloride, Magnesium carbonate, Magnesium bicarbonate.
One another aspect of the present invention provides a process for preparing Ethyl 3-cyano-5-methyIhexanoate of formula-6 comprising the steps of;
Formula-6
(a) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with base in presence of solvent
(b) Isolating Ethyl 3-cyano-5-methylhexanoate

The base used in step (a) is inorganic base. The inorganic base is selected from hydroxides Hke sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonate salts of alkali and alkaline earth metais like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and mixture thereof.
The solvent used for step (a) is selected from the group consisting of Cyclohexane, Hexane, Dichloromethane, Toluene and methyl tert butyl ether mixture thereof.
The process for preparation of Ethyl 3-cyano-5-methylhexanoate of formuIa-6 given in the ;
below reaction scheme-4
Scheme-4
One another aspect of the present invention provides a process for preparing Ethyl 3-cyano-5-methylhexanoate of formula-6 comprising the steps of;
Formula-6
(a) Reacting Diethyl 2-(l-cyano-3-methylbutyl)maIonate with base in presence of solvent and phase transfer catalyst
(b) Isolating Ethyl 3-cyano-5-methy!hexanoate

The process for preparation of Ethyl 3-cyano-5-methylhexanoate of formula-6 given in the below reaction scheme-5
The phase-transfer catalysts used in step (a) is selected from the group consisting of tetrabutylammnoium bromide, n-butylammonium bromide, tetrabutylammonium chloride, tetrabutylammonium hydrogen Sulfate, tetrabutylphospho nium chloride, trioctylmethyl ammonium chloride and mixture thereof.
The base used in step (a) is inorganic base. The inorganic base is selected from hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and mixture thereof.
The solvent used for step (a) is selected from the group consisting of Cyclohexane, Hexane, Dichloromethane, Toluene and methyl tert butyl ether mixture thereof.
One another aspect of the present invention provides selective enzymatic hydrolysis process for preparing (S)-methyl 3-cyano-5-methylhexanoate of Formula-1 comprising the steps of;

Formuta-1
(a) Reacting Methyl 3-cyano-5methyIhexanoate with enzyme in presence of buffer, base
(b) Isolating (S)-methyl 3-cyano-5-methylhexanoate
The process for preparation of (S)-methyl 3-cyano-5-methylhexanoate of formula-1 given in the below reaction scheme-4
Scheme-6
The use of enzymes makes the process more efficiënt, easy, ecofriendly, economical. Enzymes can be recycled. Isolation of the enzyme from the reaction mixture is simple.
The base used in step (a) is inorganic base. The inorganic base is selected from hydroxides like sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and mixture thereof.
The enzyme used for step (a) is selected from the group consisting of Lipozyme TL100L, Addzyme TL100L, Addzyme CAL B7L, Iosynth Lipozyme TL100L (ECR 1030IM), losynth Lipozyme TL100L (ECR 88061M), losynth NS 42183, Novozymes Promea, Novozymes Standard Lipolase.
The enantioselectivity and activity of enzymes can be remarkably influenced by pH. The buffer provides pH suitable for the enzyme activity. Hence Enzymes are often used in a

combination with buffer. The buffer in present invention provides pH of about 6 to 9, more preferably about 6 to 7.
The buffer used for step (a) is selected from the group consisting of calcium acetate, magnesium acetate, sodium acetate, potassium acetate, potassium hydrogen phosphate, sodium hydrogen phosphate.
One another aspect of the present invention provides racemisatibn process for preparing Racemic Ethyl 3-Cyano-5-methyl hexanoate of formula-6 comprising
(a) Combining (R)-Ethyl-3-cyano-5-Methylhexanoic acid sodium salt with sodium ethoxide solution/ sodium ethoxide powder and acetic acid in presence of solvent
(b) Isolating recemic Ethyl-3-cyano-5-Methylhexanoate
The solvent for step (a) is selected from the group consisting of methyl tert butyl ether, Dichloromethane, isopropylacetate, ethyl acetate.
The following examples explain various other embodiments without limiting the scope of the present invention.
Example-1: Preparation of Diethyl 2-(3-methylbutyIidene)malonate
Diethyl malonate & 3-Methylbutanal were dissolved in cyclohexane. Added di-n-propyl amine and acetic acid to the mixture. The reaction mixture heated to 70-90°C and maintained for 4h. Removed water azeotropically and added second lot of di-n-propyl amine and acetic acid. Reaction mass was maintained for another 4 hr. After completion of reaction, quenched the mass with water, separated the layer. Collected organic layer and distilled to get 96% Diethyl 2-(3-methyIbutylidene)malonate.
GC Purity: -94.0 %
Example-2: Preparation of Diethyl 2-(l-cyano-methylbutyl) malonate
Sodium cyanide was suspended in /m-butanol foliowed by addition of Diethyl 2-(3-methylbutylidene) malonate at 30±5°C. Heated the mass and maintained for next 24h at 45-50°C. After completion of reaction, acetic acid, water & cyclohexane were added. Stirred the reaction mass and settled the layer. Separated the layer to collect upper organic layer. The organic layer washed with sodium thiosulfate (5%) solution & water. Distilled organic layer under vacuüm to get 94% Diethy! 2-(l-cyano-methylbutyl) malonate.

HPLC Purity: -96.4
Example-3: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged into water and DMSO and stirred for 10 minutes. Added Calcium chloride and heated the reaction mass at 120-160°C for 30-35h. After completion of reaction. reaction mass was cooled to room temperature and extracted by using Toluene. DistiJled of toiuene under vacuüm at 55-60°C to obtain Ethyl 3-Cyano-methylhexanoate.
GC Purity: -98%
Example-4: Preparation of (S)-methyI3-cyano-5-methylhexanoate
Calcium acetate was charged into water foliowed by addition HpozymeTLlOO. pH of the
reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the
reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime
solution. After completion of reaction, layers were separated. Organic layer was extracted
with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-
methylhexanoate.Other isomer was further used for re-racemization.
Example-5: Preparation of (S)-methyl 3-cyano-5-methylhexanoate
Calcium acetate was charged into water foliowed by addition Addzyme TL100L. pH of the
reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the
reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime
solution. After completion of reaction, layers were separated. Organic layer was extracted
with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-
methylhexanoate.Other isomer was further used for re-racemization.
Example-6: Preparation of (S)-methyl 3-cyano-5-methylhexanoate
Calcium acetate was charged into water foliowed by addition Addzyme CAL B7L. pH of the
reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the
reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime
solution. After completion of reaction, layers were separated. Organic layer was extracted
with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-
methylhexanoate.Other isomer was further used for re-racemization.
Example-7: Preparation of (S)-methyl 3-cyano-5-methylhexanoate
Calcium acetate was charged into water foliowed by addition Iosynth Lipozyme TL100L
(ECR 1030IM). pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-

5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-methyIhexanoate.Other isomer was further used for re-race mi zation.
Example-8: Preparation of (S)-methyl 3-cyano-5-methylhexanoate Calcium acetate was charged into water foliowed by addition Iosynth Lipozyme TL100L (ECR 8806IM). pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with tolüene and distilled off to give desired compound (S)-methyl 3-cyano-5-methylhexanoate.Other isomer was further used for re-racemization.
Example-9: Preparation of (S)-methyl 3-cyano-5-methy1hexanoate Calcium acetate was charged into water foliowed by addition Iosynth NS 42183. pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-methylhexanoate.Other isomer was further used for re-racemization. Example-10: Preparation of (S)-methyl 3-cyano-5-methyIhexanoate Calcium acetate was charged into water foliowed by addition Novozymes Promea. pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-methylhexanoate.Other isomer was further used for re-racemization. Example-11: Preparation of (S)-methyl 3-cyano-5-methylhexanoate Calcium acetate was charged into water foliowed by addition Novozymes Standard Lipolase. pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-methvlhexanoate.Other isomer was further used for re-racemization.

Example 12: Preparation of Racemic Ethyl 3-Cyano-5-methyl hexanoate
(R)-Ethyl-3-cyano-5-Methylhexanoate was charged into 20% Sodium ethoxide solution. Reaction mass was heated to 65-85°C and maintained for next I8h. After completion of racemisation, acetic acid was charged foliowed by distillation off ethanol under vaccum completly. Treated with sulphuric acid in ethanol. After complete distillation, Methyl tertiary butyl ether was charged foliowed by filteration of the unwanted salt, Filtrate was distilled off under vaccum to obtain racemic- Ethyl 3- Cyano -5-Methyl hexanoate.
Example 13: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged into water . Reaction mass was stirred for next 10 minutes. Calcium chloride was added into the reaction mass and temperature of the reaction mass at 120-160 °C for 30-35h. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using Toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methyl hexanoate.
Example 14: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged into water . Reaction mass was stirred for next 10 minutes. Lithium chloride was added into the reaction mass and temperature of the reaction mass at 120-I60°C for 30-35h. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using Toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 15: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged into water . Reaction mass was stirred for next 10 minutes. Magnesium chloride was added into the reaction mass and temperature of the reaction mass at 120-160°C for 30-35h. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using Toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 16: Preparation of Ethyl 3-cyano-5-methylhexanoate

Diethyl 2-(I-cyano-3-methyibutyl)malonate was charged into water . Reaction mass was stirred for next 10 minutes. Calcium chloride was added into the reaction mass and temperature of the reaction mass at 120-160°C for 30-35h. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using toluene. Distilled of all toluene under vacuüm at 55-60°C temp to fumish Ethyl 3-Cyano-methylhexanoate.
Example 17: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethy! 2-(l-cyano-3-methylbutyl)malonate was charged into water . Reaction mass was I
stirred for next 10 minutes. Lithium chloride was added into the reaction mass and temperature of the reaction mass at 120-160°C for 30-35h. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 18: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged into water . Reaction mass was stirred for next 10 minutes. Magnesium chloride was added into the reaction mass and temperature of the reaction mass at 120-160°C for 30-35h. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using toluene. Distilled of all toluene under vacuüm at 55-60°C temp to fumish Ethyl 3-Cyano-methylhexanoate.
Example 19: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged foliowed by intermittent addition of sodium hydroxide solution. Reaction mass was stirred for next 3h. After completion of reaction, sodium chloride was added into the reaction mass foliowed by toluene and temperature of the reaction mass at 120-ï60°C for 6-1 Oh. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using Toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 20: Preparation of Ethyl 3-cyano-5-methylhexanoate

Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged foliowed by intermittent addition of j
potassium hydroxide solution. Reaction mass was stirred for next 3h. After completion of
reaction, sodium chloride was added into the reaction mass foliowed by toluene and
temperature of the reaction mass at 120-160°C for 6-10h. After completion of reaction,
Reaction mass was cooled to room temperature. Reaction mass was extracted by using
Toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-
methylhexanoate.
Example21: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyI)malonate was charged foliowed by intermittent addition of sodium hydroxide solution. Reaction mass was stirred for next 3h. After completion of reaction, sodium chloride was added into the reaction mass foliowed by toluene and temperature of the reaction mass at 65-120°C for 6-1 Oh. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using toluene. Distilled of all toluene under vacuüm at 55-60°C temp to fumish Ethyl 3-Cyano-methylhexanoate.
Example 22: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate was charged foliowed by intermittent addition of potassium hydroxide solution. Reaction mass was stirred for next 3h. After completion of reaction, sodium chloride was added into the reaction mass foliowed by toluene and temperature of the reaction mass at I20-160°C for 6-lOh. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 23: Preparation of Ethyl 3-cyano-5-methyIhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate and tetra-n-butylammonium bromide was charged foliowed by intermittent addition of potassium hydroxide solution. Reaction mass was stirred for next 3h. After completion of reaction, sodium chloride was added into the reaction mass foliowed by toluene and temperature of the reaction mass at 120-160°C for 6-lOh. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using Toluene. Distilled of all toluene under vacuüm at 55-60°C temp

Example 24: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate and tetra-n-butylammonium bromide was |
charged foliowed by intermittent addition of sodium hydroxide solution. Reaction mass was |
stirred for next 3h. After completion of reaction, sodium chloride was added into the reaction j
mass foliowed by toluene and temperature of the reaction mass at 120-160°C for 6-1 Oh. After I
completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was
extracted by using Toluene. Distilled of all toluene under vacuüm at 55-60°C temp to fumish
Ethyl 3-Cyano-methylhexanoate. J
i Example 25: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate and tetra-n-butylammonium bromide was charged foliowed by intermittent addition of sodium hydroxide solution. Reaction mass was stirred for next 3h. After completion of reaction," sodium chloride was added into the reaction mass foliowed by toluene and temperature of the reaction mass at 120-160°C for 6-1 Oh. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using toluene. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 26: Preparation of Ethyl 3-cyano-5-methylhexanoate
Diethyl 2-(l-cyano-3-methylbutyl)malonate and tetra-n-butylammonium bromide was charged foliowed by intermittent addition of potassium hydroxide solution. Reaction mass was stirred for next 3h. After completion of reaction, sodium chloride was added into the reaction mass foliowed by toluene and temperature of the reaction mass at 120-160°C for 6-lOh. After completion of reaction, Reaction mass was cooled to room temperature. Reaction mass was extracted by using methyl tert butyl ether. Distilled of all toluene under vacuüm at 55-60°C temp to furnish Ethyl 3-Cyano-methylhexanoate.
Example 27: Preparation of Racemic Ethyl 3-Cyano-5-methyl hexanoate
(R)-Ethyl-3-cyano-5-Methylhexanoate was charged into 20%.Sodium ethoxide solution. Reaction mass was heated to 65-85°C and maintained for next I8h. After completion of racemisation, acetic acid was charged foliowed by distillation off ethanol under vaccum completly. After complete distillation, dichloromethane was charged foliowed by filteration of the unwanted salt, Filtrate was distilled off under vaccum to obtain racemic- Ethyl 3-

Example 28: Preparation of Racemic Ethyl 3-Cyano-5-methyl hexanoate
(R)-Ethyl-3-cyano-5-Methylhexanoate was charged into 20% Sodium ethoxide solution. Reaction mass was heated to 65-85°C and maintained for next I8h. After completion of racemisation, acetic acid was charged foliowed by distillation off ethanol under vaccum completly. Treated with sulphuric acid in ethanol. After complete distillation, isopropylacetate was charged foliowed by filteration of the unwanted salt, Filtrate was disïilled off under vaccum to obtain racemic- Ethyl 3- Cyano -5-Methyl hexanoate.
Example 29: Preparation of Racemic Ethyl 3-Cyano-5-methyl hexanoate
(R)-Ethyl-3-cyano-5-Methylhexanoate was charged into 20% Sodium ethoxide solution. Reaction mass was heated to 65-85°C and maintained for next 18h. After completion of racemisation, acetic acid was charged foliowed by distillation off ethanol under vaccum completly. After complete distillation, Ethylacetate was charged folio wed by filteration of the unwanted salt, Filtrate was distilled off under vaccum to obtain racemic- Ethyl 3- Cyano -5-Methyl hexanoate.
Example-30: Preparation of (S)-methyl 3-cyano-5-methylhexanoate
Sodium dihydrogen phosphate was charged into water foliowed by addition Addzyme TL100L. pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-methylhexanoate.Other isomer was further used for re-racemization. Example-31: Preparation of (S)-methyl 3-cyano-5-methylhexanoate Sodium dihydrogen phosphate was charged into water foliowed by addition Addzyme CAL B7L. pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic layer was extracted with toluene and distilled off to give desired compound (S)-methyl 3-cyano-5-methylhexanoate.Other isomer was further used for re-racemization. Example-32: Preparation of (S)-methyl 3-cyano-5-methylhexanoate Sodium dihydrogen phosphate was charged into water foliowed by addition Novozymes Promea. pH of the reaction mass was maintained at 7-8. Methyl 3-cyano-5methylhexanoate was added into the reaction mass. Reaction mass was maintained for next 24-30h at pH 7-8 by adding 30% Lime solution. After completion of reaction, layers were separated. Organic

layer was extracted with toluene and distilled off to give desired compound (S)-methyJ 3-cyano-5-methyl hexanoate. Other isomer was further used for re-racemization. Example 33: Preparation of Racemic Ethyl 3-Cyano-5-methyl hexanoate (R)-Ethyl-3-cyano-5-Methylhexanoate was charged into 20% Sodium ethoxide solution. Reaction mass was heated to 65-85°C and maintained for next 18h. After completion of racemisation, acetic acid was charged foliowed by distillation off ethanol under vaccum completly. Treated with sulphuric acid in ethanol. After complete distillation, dichloromethane was charged foliowed by filteration of the unwanted salt, Filtrate was distilled off under vaccum to obtain racemic- Ethyl 3- Cyano -5-Methyl hexanoate. Example 34: Preparation of Racemic Ethyl 3-Cyano-5-methyl hexanoate (R)-Ethyl-3-cyano-5-Methylhexanoate was charged into 20% Sodium ethoxide solution. Reaction mass was heated to 65-85°C and maintained for next 18h. After completion of racemisation, acetic acid was charged foliowed by distillation off ethanol under vaccum completly. Treated with sulphuric acid in ethanol. After complete distillation, toluene was charged foliowed by filteration of the unwanted salt, Filtrate was distilled off under vaccum to obtain racemic- Ethyl 3- Cyano -5-Methyl hexanoate.

Claims:
1. A process for preparing of Ethyl-3-cyano-5-methylhexanoate of Formula-6
comprising
l CN O
Formula-6
(a) Condensing 3-Methylbutanal with Diethyl malonate in presence of gl.acetic acid, di-n-propylamine, solvent
(b) Refluxing azeotropically
(c) Isolating Diethyl 2-(3-methylbutylidene)malonate
(d) Reacting Diethyl 2-(3-methylbutylidene) malonate with Sodium cyanide in tert-butanol in presence of solvent
(e) Isolating Diethyl 2-(l-cyano-3-Methylbutyl) malonate
(f) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with salt in presence of solvent
(g) Isolating Ethyl 3-cyano-5-methylhexanoate
2. A process for preparing of Ethyl-3-cyano-5-methylhexanoate of Formula-6
comprising
l CN O
Formula-6
(a) Condensing 3-Methylbutanal with Diethyl malonate in presence of gl.acetic acid, di-n-propylamine, solvent
(b) Refluxing azeotropically
(c) Isolating Diethyl 2-(3-methylbutylidene)malonate
(d) Reacting Diethyl 2-(3-methyIbutylidene) malonate with Sodium cyanide in tert-butanol in presence of solvent
(e) Isolating Diethyl 2-(l-cyano-3-Methylbutyl) malonate

(f) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with base in presence of solvent
(g) Isolating Ethyl 3-cyano-5-methylhexanoate
3. A process for preparing of Ethyl-3-cyano-5-methylhexanoate of Formula-6 comprising
(a) Condensing 3-Methylbutanal with Diethyl malonate in presence of gl.acetic acid, di-n-propylamine, solvent
(b) Refluxing azeotropically
(c) Isolating Diethyl 2-(3-methylbutylidene)malonate
(d) Reacting Diethyl 2-(3-methylbutylidene) malonate with Sodium cyanide in tert-butanol in presence of solvent
(e) Isolating Diethyl 2-(l-cyano-3-Methylbutyl) malonate
(f) Reacting Diethyl 2-(l-cyano-3-methylbutyl)malonate with base in presence of Phase transfer catalyst
(g) Isolating Ethyl 3-cyano-5-methylhexanoate
4. A process for preparing (S)-methyl 3-cyano-5-methylhexanoate of Formula-l comprising the steps of;
(a) Reacting Methyl 3-cyano-5methylhexanoate with enzyme in presence of buffer, base
(b) Isolating (S)-methyl 3-cyano-5-methylhexanoate
5. A racemisation process for preparing Racemic Ethyl 3-Cyano-5-methyl hexanoate of formula-6 comprising

(a) Combining (R)-Ethyl-3-cyano-5-Methylhexanoic acid sodium salt with sodium ethoxide and acetic acid in presence of solvent
(b) ïsolating recemic Ethyl-3-cyano-5-Methylhexanoate

6. The process according to any of the preceding claims where in the solvent is selected from the group consisting of cyclohexane, hexane, dichloromethane, toluene, methyl tert butyl ether and mixture thereof.
7. The process according to any of the preceding claims where in the base is selected from the group consisting of sodium hydroxide, potassium hydroxide, lithium hydroxide, carbonate salts of alkali and alkaline earth metals like potassium carbonate, potassium bicarbonate, sodium carbonate, sodium bicarbonate, cesium carbonate and mixture thereof.
8. The process according to any of the preceding claims wherein the phase transfer catalyst tetrabutylammnoium bromide, n-butylammonium bromide, tetrabutylammonium chloride, tetrabutylammoniurn hydrogen Sulfate, tetrabutylphospho nium chloride, trioctylmethyl ammonium chloride and mixture thereof.
9. The process according to any of the preceding claims wherein the salt is selected from the group consisting of Lithium chloride, Calcium sulphate, Calcium chloride, Calcium carbonate, Calcium bicarbonate, Potassium sulphate, Potassium nitrate, Potassium chloride, Potassium carbonate, Potassium bicarbonate, Sodium sulphate, Sodium nitrate, Sodium chloride, Sodium carbonate, Sodium bicarbonate, Magnesium sulphate, Magnesium nitrate, Magnesium chloride, Magnesium carbonate, Magnesium bicarbonate and mixture thereof.
10. The process according to any of the preceding claims wherein the enzyme is selected
from the group consisting of Lipozyme TL100L, Addzyme TL100L, Addzyme CAL
B7L, losynth Lipozyme TL100L (ECR 1030IM), losynth Lipozyme TL100L (ECR
8806IM), losynth NS 42183, Novozymes Promea, Novozymes Standard Lipolase.