Title of Invention	AN IMPROVED PROCESS FOR PREPARING NATEGLINIDE
Abstract	An improved process for peparing(-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine of formula I.

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FIELD OF THE INVENTION The present invention relates to an improved process for preparing (-)-N- [(trans-4-isopropyIcyclohexane)carbonyl]-D-phenylalanine of Formula I. BACKGROUND OF THE INVENTION (-)-N-[(trans-4-isopropylcyclohexane)carbonyl]-D-phenylalanine of Formula I, which is generically known as nateglinide is an antidiabetic drug. Nateglinide is being marketed under the proprietary name STARLIX as an oral tablet. Nateglinide was first disclosed in RE 34,878 and the crystals thus produced in this patent are named as B-type crystals, in a subsequent patent US 5,463,116. In view of the importance of nateglinide as an antidiabetic compound, several synthetic methods have been reported in the literature to prepare nateglinide, which are as summarized below: RE 34,878 discloses a method of preparing nateglinide in example 31. The process comprises hydrogenating cumic acid to produce a cis/trans mixture of 4-isopropylcyclohexane carboxylic acid, wherein the cis isomer is in 3 parts and trans isomer in 1 part. This mixture is esterified and treated with sodium hydride to increase the trans isomer ratio to 6 parts to 1 part of cis isomer. This product is hydrolysed and coupled with D-phenylalanine methyl ester. The resulting product is desterified to give nateglinide. The process is as shown below: The above process is a multistep process, with low yields and poor quality of the nateglinide. Further, technology involved in some of the steps of above process are tedious to work-up. EP 1 535 900 Al discloses a process to prepare nateglinide, by reacting D-phenylalanine methyl ester or a salt thereof with trans-4-isopropyl cyclohexane carboxylic acid in presence of an acyl chloride in a water-miscible organic solvent or water non-miscible organic solvent to give nateglinide methylester. Nateglinide methylester thus obtained was hydrolysed to nateglinide and further converted to sodium salt of nateglinide. The sodium salt was further converted to nateglinide hydrochloride salt by treating with an hydrochloric acid. This process uses a toxic reagent thionyl chloride, which is corrosive, moisture sensitive and not eco-friendly. WO 2004/018408 A1 discloses a process to prepare nateglinide, by reacting trans-4-isopropyl cyclohexyl carboxylic acid in acetone with alkyl chloroformate in the presence of triethylamine to give a solution of trans-4-isopropyl cyclohexyl carboxylic acid alkylformate and was reacted with alkali solution of D-phenylalanine to give nateglinide and is further purified and then converted to H-type crystals. The yields of pure nateglinide B-type crystals are in the range of 50-60 %. This B-type crystals is further converted in to H-type crystals with an average yield of 45 %. We have now found an improved process to prepare nateglinide, which is industrially feasible, with good yields and good quality. In addition to the above processes, the present invention is easy to handle and economically viable. OBJECTIVE The objective of the present invention is to provide an improved process for preparing nateglinide. In yet another objective of the present invention is to provide an improved process for preparing nateglinide, which is simple, industrially applicable and economically viable. In yet another objective of the present invention is to provide an improved process for preparing nateglinide, with good yields and purity. In yet another objective of the present invention is to provide an improved process for preparing nateglinide, which is free of 2-[2-[(Trans-4- DETAILED DESCRIPTION OF THE INVENTION In an aspect of the invention the trans-4-isopropylcyclohexane carboxylic acid of Formula II is treated with a alkali base and a solvent, which is selected from toluene, acetone and mixtures thereof. The obtained product is treated with pivaloyl chloride to obtain trans-4-isopropylcyclohexyl pivalic anhydride of Formula III. The alkali base is selected from sodium hydroxide or potassium hydroxide. The base can be added as such or as an aqueous solution. The reaction is carried out at 0-30°C, preferably at 20-30°C. The trans-4-isopropylcyclohexyl pivalic anhydride of Formula III may be isolated from the reaction mass or can be directly treated with D-phenylalanine solution of Formula IV in the presence of alkali base at pH 10.0-14.0 and at 10-40°C to produce nateglinide of Formula I. Preferably the pH is at 11-13 and temperature at 20-30°C. The nateglinide isolated by the above process is free from H-type crystals and is further purified and dried to yield a single form preferably B-type crystals. Further, the nateglinide produced as per the process of the present invention is free of 2-[2-[(Trans-4-isopropylcyclohexanecarbonyl)amino]-3-phenylpropionylamino]-3-phenylpropionic acid (IPP) of Formula V, This is achieved by maintaining the reaction mass pH at 10.0-14.0 during condensation of trans-4-isopropylcyclohexyl pivalic anhydride of Formula III and D-phenylalanine solution of Formula IV. In another aspect of the present invention, the D-phenylalanine solution is prepared by treating D-phenylalanine with sodium hydroxide in the presence of a solvent and water. The solvent used to prepare sodium salt of D-phenylalanine is acetone. The invention is illustrated with the following examples, which are provided by way of illustration only and should not be construed to limit the scope of the invention. EXAMPLE 1 PREPARATION OF NATEGLINIDE Trans-4-isopropylcyclohexane carboxylic acid (50 g) was dissolved in acetone (300 ml) and treated with 40% w/w aqueous sodium hydroxide solution (30.81 g) at 20-30°C. The reaction mass was stirred for 30 min and cooled to 10-15°C. Pivoloyl chloride (39 g) was added to the reaction mass at 10-15°C and allowed to 20-25°C and stirred for 3 h, filtered and washed with acetone (25 ml). The filtrate containing trans-4-isopropylcyclohexyl carboxylic pivalic anhydride was added to the mixture of D-phenylalanine (53.4 g), DM water (300 ml), acetone (100 ml) and 10% w/w aqueous sodium hydroxide solution (130 g) at 20-25°C in 30 min while maintaining the reaction mass pH at 11.5-12.5 with 10% w/w aqueous sodium hydroxide solution (130 g). The reaction mass was stirred for completion of reaction and distilled out acetone under reduced pressure. The residue was diluted with DM water (750 ml) and acidified with 10% w/v aqueous hydrochloric acid till the pH 1.0-2.0. The precipitated product was filtered and washed with DM water (150 ml). The wet product was treated with DM water (2000 ml) followed by n-heptane (1000 ml) and dried to yield nateglinide as B-type crystals. Yield: 72 g (77.23%) EXAMPLE 2 PREPARATION OF NATEGLINIDE Trans-4-isopropylcyclohexane carboxylic acid (120 g) was dissolved in toluene (600 ml) and treated with 40% w/w aqueous sodium hydroxide solution (74.2 g) at 20-3 0°C. The reaction mass was heated to reflux temperature and water was separated azeotropically. Toluene was distilled out completely from the reaction mass under reduced pressure and cooled to 40-50°C. The reaction mass was treated with acetone (480 ml) followed by pivoloyl chloride (90.94 g) at 10-15°C. The reaction mass stirred for 5 h for completion of reaction at 25-30°C, filtered and washed with acetone (25 ml). The filtrate containing trans-4-isopropylcyclohexyl carboxylic pivalic anhydride was added to the mixture of D-phenylalanine (128.0 g), DM water (720 ml), acetone (240 ml) and 10% w/w aqueous sodium hydroxide solution (335 g) at 20-30°C in 30 min while maintaining the reaction mass pH at 11.5-12.5 with 10% w/w aqueous sodium hydroxide solution (335 g). The reaction mass was stirred for completion of reaction and distilled out acetone under reduced pressure. The residue was diluted with DM water (1800 ml) and acidified with 10% w/v aqueous hydrochloric acid till the pH 1.0-2.0. The precipitated product was filtered and washed with DM water (150 ml). The wet product was treated with DM water (10800 ml) followed by n-heptane (4320 ml) and dried to yield nateglinide as B-type crystals. Yield: 160 g (71.5%) Chromatographic purity: 99.94 %

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