FIELD OF THE INVENTION
The present invention relates to a simple and novel process for the preparation of N-(trans-4-isopropyl-cyclohexylcarbonyl)-D-phenylanine (Nateglinide), which is a cost effective, atom aeconomy and eco-friendly process. Nateglinide is depicted as formula (I)

Background of Invention
Nateglinide (N-(trans-4— isopropyl - cyclohexyl carbonyl)-D-phenylanine) has been shown to be effective for the treatment of type -2 diabetes mellitus.
The first report of anti diabetic property of Nateglinide appeared in EP 0196222 Bl and US RE 34,878, which disclosed that the Nateglinide reduced the diabetes in a rat model. These patents also reported that Nateglinide prepared by reacting D-phenyl alanine methylester hydrochloride (A) with a N-hydroxy succinamide ester of trans-4-isopropyl cyclohexyl carboxylic acid (B) and subsequent hydrolysis of ester intermediate (C) to afford the desired product as mentioned in Scheme-A.


In US RE 34,878, Example No.31 The preparation of the intermediate of N-hydroxy succinimide ester of trans-4-isopropyl cyclohexyl carboxylic acid involves the condensation of N-hydroxy succinimide with trans-4-isopropyl cyclohexyl carboxylic acid in presence of Dicyclohexylcarbodiimide (DCC). This preparation is not economical on a large-scale synthesis because N-hydroxy succinimide and DCC are expensive reagents and results in large amount of byproducts as effluent. The Dicyclohexylurea and Succinimide generated as by products will increase the solid waste during the course of reactions mainly due to usage of DCC and N-hydroxy succinimide. From this process the yields and purity of the ester intermediate are found to be low. The impure ester intermediate produces nateglinide that is low in purity as it is contaminated with opposite L- enantiomer to be used as an active pharmaceutical ingredient. Additional purification

steps are required to render the Nateglinide pharmaceutical^ acceptable and less suitable to production.
An alternative process for the preparation of D-phenylalanine derivatives was mentioned in RE34, 878 example No. 1 patents uses the Schotten-Baumann procedure to produce ester intermediate of Nateglinide. However, careful simultaneous addition of acid chloride and NaOH is required for pH control. Any failure in the addition leads to rapid decomposition of acid chloride to acid, which renders in the formation of ester intermediate in low yield and purity. A batch preparation the equipment, maintenance or sophisticated mechanical expertise for careful flow control would be preferable for a large-scale commercial process for the manufacturing of Nateglinide. In addition of above mentioned problem of low yield and purity problem, The production of substantially pure Nateglinide is problematic because of the formation of byproducts derived form the impurities present in the starting materials. Three such impurities have same chemical reactivities similar to Trans-4- isopropyl-cyclohexylcarbony chloride and D-phenyl alanine methyl ester and are carried through the process of the 34,878 patent to form side products that must be removed before the Nateglinide can be used as an active ingredient in a pharmaceutical composition, cis-4—isopropyl cyclohexyl carboxylic acid and 4-isopropyl benzoic acid are common impurities present in commercially available trans-4-isopropyl cyclohexyl carboxylic acid, cis-4-isopropyl cyclohexyl carboxylic acid originating in trans-4-isopropyl cyclohexyl carboxylic acid is transformed by esterification with N-hydroxy succinimide or by chlorination and subsequent reaction with D-phenyl alanine methyl ester to N-(cis-4—isopropyl cyclohexyl carbonyl)-D~ phenyl alanine methyl ester, which on hydrolysis to result N-(Cis-4-isopropyl cyclohexyl carbonyl)~D-phenyl alanine. 4-Isopropyl benzoic acid originating in trans-4-isopropyl cyclohexyl carboxylic acid is transformed by esterification with N-hydroxy succinimide or by chlorination and

subsequent reaction with D~phenyl alanine methyl ester hydrochloride to N-(4-isopropyl
benzoyl)-D-phenyl alanine methyl ester, which on hydrolysis to result N-(4—isopropyl benzoyl)-
D-phenyl alanine. Another troublesome impurity in Nateglinide derives from the L-phenylalanine
methyl ester hydrochloride, which is commonly present in minor amounts in D-phenylalanine
methyl ester hydrochloride obtained from commercial process.
The process described in the example 31 of RE 34,878 inherently suffers with the re-esterification
of hydrolysed product in the presence of methanol.
Summary of invention :
In accordance with the present invention a new, simple and an improved process for the synthesis
of N-(trans-^-isopropyl cyclohexylcarbonyl)-D-phenylalanine as depicted in the Scheme-B
relates to hypoglycemic agent useful as antidiabetic drug.


The synthesis of N-(trans—4-isopropyl-cyclohexylcarbonyl)-D-phenylalanine is affected in simple
solvents and reagents.
In a more preferred embodiment of the present invention the synthesis of Formula I is achieved by
the condensation of D-phenyl alanine methyl ester with trans-4-isopropyl-cyclohexylcarboxylic
acid chloride in the presence of halo alkane solvent.
The present invention describes and also incorporates the usage of inexpensive solvents like
methanol, chloroform and isopropanol and reagents like triethylamine, thionyl chloride. The
solvents which are used in this process can be recovered and reused, which makes the process
economic and environment friendly.

D - phenylalanine and trans- 4-isopropyl cyclohexyl carboxylic acid were main key raw materials
for the preparation of N-(trans-4-isopropyl cyclohexyl carbonyl)-D-phenyl alanine. Therefore the
main objective of the present invention is cost effective, substantially pure, easy scaleable, atom
economy and environment friendly process.
Detailed Description of the invention :
Accordingly the present invention provides a novel process for the preparation of N- (trans - 4 -
isopropyl cyclohexyl -1- carbony) -D- phenyl alanine methyl ester which comprises:
a. reacting 4 - trans - isopropyl cyclohexyl carbonyl chloride with D - phenyl alanine
methyl ester hydrochloride in halo alkane solvent like chloroform and methylene chloride
preferably chloroform in the presence of C] - C4 alkyl tertiary amines preferably
triethylamine;
b. stirring the solution at 20 - 60°C preferable at 25 - 35°C, till the reaction is substantially
complete;
c. washing the reaction mass with IN HC1 to remove the unreacted D - Phenyl alanine methyl
ester;
d. distillation of excess chloroform solvent under reduced pressure;
e. addition of C1-C4 alcohol preferably methanol to the solid residue and stir at 0 - 20°C
preferably at 0-10°C;
f. Filtration off the solid and optionally washing the solid with C1-C4 alcohol preferably
methanol;


The present invention, hence, provides a simple and improved process for the preparation of N-(trans - 4 - isopropyl cyclohexyl -1- carbonyl) -D- phenyl alanine.
a. reacting N - (trans - 4 - isopropyl cyclohexyl -1- carbonyl) -D- phenyl alanine methyl ester
with IN aqueous metal hydroxides preferably sodium hydroxide in the presence of Ci - C4
alcohol preferably isopropanol.
b. stirring the reaction solution at 20-40°C preferably at 25-35°C till the reaction completes
substantially.
c. treating the above basic solution with HC1 at 20 - 40°C preferably at 25 - 35°C to pH 1.5 to
2.5 to get N-(trans-4-isopropyl cyclohexyl-l-Carbonyl)-D-phenyl alanine
d. filtering the separated crystalline salt at 0 - 35°C preferably at 0 - 10°C to afford N-(trans-
4-isopropyl cyclohexyl-l-carbonyl)-D-phenyl alanine.
e. drying the filtered wet cake at 90°C under vacuum to get N - (trans - 4 - isopropyl
cyclohexy 1-1-carbonyl) -D- phenyl alanine substantially free from opposite L- enantiomer
and Cis- isomer.
Keeping in view, the above mentioned facts, the present invention hence, delivers a simple improved cost effective, industrially scaleable and environment friendly process for the synthesis of N - (trans -4 - isopropyl cyclohexyl -1- carbonyl) - D - phenyl alanine.
Examples :
The following specific examples are further illustrative of the present invention .

Example -1 :
N-(trans-4-isopropyl cyclohexyl carbonyl)-D-phenylalanine methyl ester :
Take 50 grams (0.294 moles) of trans-4-isopropylcyclohexylcarboxylicacid in 200 ml of
chloroform and add 71.0 grams (0.50 moles) of Thionyl chloride at room temperature. Stir the
reaction mass at an ambient temperature for 6 hours and distill of excess Thionyl chloride under
reduced pressure to get oily residue. Dissolve the oily residue in 100 ml chloroform and add to the
solution of 64.0 grams (0.29 moles) of D - Phenyl alanine methyl ester hydrochloride, 75.0 grams
(0.74 moles) of Triethylamine in 500 ml chloroform at room temperature stir the reaction mass at
ambient temperature for 10 hours and wash the reaction mass with 270 ml IN HC1 solution and
evaporate the chloroform under vaccum to get residue. Add 350 ml methanol to the residue cool to
0 - 10°C, filter and wash with 50 ml of methanol to get desired compound 70.0 grams (71 %) N -
(trans -4- isopropyl- cyclohexyl carbonyl) - D - Phenyl alanine methyl ester Substantially free
from cis content.
M.R. : 123-129°C
[a]25D : 7.7
cis Isomer content: < 0.05%
Example : 2
N - (trans - 4 - isopropyl cyclohexyl carbonyl) - D - phenylalanine :
Take 60 grams (0.18 moles) of N - (trans - 4 - isopropyl - cyclohexyl carbonyl) - D -
phenyalanine methyl ester in 300 ml of IN NaOH solution and stir for 15 - 20 minutes at room
temperature. Add 600 ml of isopropanol and stir the reaction mass at ambient temperature for 6
hours, add 600 ml of water and acidify with HC1 till pH attain to 2.0. Cool the reaction mass, filter

and wash with at 90°C to get 53.7 grams (93.4 %) of N - (trans - 4 - iso propyl cyclohexyl
carbonyl) - D - Phenyl alanine substantially free from cis and L - Enantiomer impurities.
Cis isomer : < 0.05%
L-enatiomer: < 0.05%
We claim:
1. A novel process for the preparation of N-(trans-4-isopropylcyclohexyl carbonyl)-D-
phenylalanine (Nataglinide) which is substantially free from cis and L-enantiomers,Which
comprises:
a. reacting 4 - trans - isopropyl cyclohexyl carbonyl chloride (which can be prepared by known
processes from the corresponding acid) with D - phenyl alanine methyl ester hydrochloride in
halo alkane solvent like chloroform and methylene chloride preferably chloroform in the prese
nce of C1 - C4 alkyl tertiary amines preferably triethylamine;
b. stirring the solution at 20 - 60°C preferable at 25 - 35°C, till the reaction is substantially
complete ;
c. washing the reaction solution with IN HC1 to remove the unreacted D - Phenyl alanine methyl
ester hydrochloride;
d. distillation of excess chloroform solvent under reduced pressure;
e. addition of C1-C4 alcohol preferably methanol to the solid residue and stir at 0-20°C preferably
at0-10°C;
f filtration off the solid and optionally washing the solid with Q-C4 alcohol preferably methanol;
g. dissolving the wet product to CI-C4 alcohol preferably methanol at reflux temperature;

h. cooling the solution to precipitate the desired N-(trans 4-isopropyl cyclohexyl-l-Carbonyl)-D-
phenyl alanine methyl ester; i. hydrolysis of N-(trans-4-isopropylcyclohexyl carboxy)-D-phenylalanine methyl ester in C1-C4
alcohols preferably in isopropyl alcohol to get the desired compound. 2. A novel process accirding to claim 1, for the preparation of compound of Formula (I) contains
the N-(Cis-4-isopropylcyclohexyl carboxyl)-D-phenylalanine less than 0.5%.
A novel process accirding to claiml, for the preparation of compound of Formula (I) contains
the N-(trans-4-isopropylcyclohexyl carboxyl)-L-phenylalanine content less the 0.5%. 4. A novel process for the preparation of Nateglinide is substantially as herein described and
examplified.