FIELD OF INVENTION
The present invention relates to an improved process for the synthesizing highly pure nateglinide form B directly from nateglinide alkyl ester.
More particularly, the present invention relates to the process for synthesizing highly enantiomerically pure nateglinide form B.
BACKGROUND OF THE INVENTION
Nateglinide, of formula-I is marketed as starlix and is a useful therapeutic agent for the treatment of type II diabetes mellitus [also known as non-insulin dependent diabetes mellitus (NIDDM) or adult-onset diabetes].
(Figure Remove) Formula I
Nateglinide is an amino-acid derivative that lowers blood glucose levels by stimulating insulin secretion from the pancreas and is chemically known as V-(trans-4-isopropylcyclohexylcarbonyl)-D-phenyl alanine.
U.S. Patent 4,816,484 (referred herein as '484) and its subsequent reissue (U.S. Patent Re 34,878) disclosed hypoglycemic agents including nateglinide. Several methodologies have been disclosed for the preparation of hypoglycemic agents including nateglinide. In one of the methodologies, carboxylic acid is treated with N ~ hydroxysuccinimide in the presence of dicyclohexylcarbodiimide (DCC) to prepare the corresponding A-hydroxysuccinimide ester, which is further reacted with D-phenylalanine methyl ester hydrochloride to yield the corresponding D-phenylalanine
methyl ester derivative which on subsequent base assisted hydrolysis followed by acidification with a dilute acid results in the formation of desired product.
In the above patent the preparation of nateglinide from the corresponding trans-4-isopropylcyclohexane carboxylic acid is not exemplified using the above methodology. An example is given using cumic acid for the preparation of TV-cumoyl-D-phenylalanine and it is mentioned that following similar methodology, nateglinide can be prepared starting with trans-4-isopropylcyclohexane carboxylic acid in place of cumic acid.
As cumic acid is a planer compound and trans-4-isopropylcyclohexane carboxylic acid is a trans isomer so both are different in nature; therefore their corresponding D-phenylalanine derivatives can behave differently. Also the above patent fails to characterize the intermediates formed during the process of manufacture of nateglinide from trans-4-isopropylcyclohexane carboxylic acid. It has been observed that the given process and purification techniques used for the preparation of N-cumoyl-Z)-phenylalamne do not come off with the process for the preparation of nateglinide in high purity.
It is further disclosed that nateglinide can be recrystallized from methanol-water to give nateglinide in an overall yield of 65% starting from trans-4-isopropyl cyclohexane carboxylic acid but purity is not mentioned.
We have found that following the methodology given in '484 patent during crystallization from water-methanol system as per the reported condition, nateglinide undergoes esterification to the form unacceptably higher levels of the nateglinide methyl ester as an impurity. Thus nateglinide is contaminated with the corresponding methyl ester, undesirable amounts of corresponding cis isomer as well as unacceptable levels of £-enantiomer that were usually above 0.15%. The
enantiomeric purity being determined with the help of high performance liquid chromatography (HPLC) using chiral columns.
The aforesaid patent fails to mention the crystal nature and purity of nateglinide, although subsequent United States Patent no. 5,463,116 refers to the crystalline form of nateglinide formed according to '484 as B-type crystals.
Further, it was observed that during scale up, the process described in '484 generates B-type crystals that are contaminated with polymorphic H-type crystals.
U.S. Patent application No. 2006/0148902 Al describes a process for the direct conversion of nateglinide methyl ester into nateglinide form B by carrying out the hydrolysis in a mixture of water and toluene in the presence of a phase transfer catalyst and potassium hydroxide followed by addition of dilute hydrochloric acid, filtration, and drying to afford B-type crystals of nateglinide.
US Patent application 2003/0229249 Al describes a process for the conversion of H-type crystals of nateglinide into B-type crystals from a mixture of water and ethanol and drying first at 40- 45°C till the moisture content has come down to 1% and finally crystal modification at 90°C under vacuum for 12 hours. The method again suffers from the disadvantage of formation of the nateglinide ethyl ester though free of H-type crystals.
US Patent application 2004/0181089 Al discloses that the initially crystallized material formed by crystallization from methanol and water, as mentioned in '484, is isolated as a hydrate or a methanolate, which has been described as Z and E form respectively, that upon further drying gets converted into nateglinide form B.
Several alternate processes for generating nateglinide form B via crystallization of the nateglinide from different solvent systems have been reported, but there is hardly a
process which would directly convert the nateglinide alkyl ester into pure nateglinide
form B.
Above mentioned drawbacks urgently demand for a new, improved and reliable
process of preparing pure nateglinide form B, which are free from other forms as well
as from nateglinide ester impurity that will be suitable for large-scale preparation in
terms of simplicity, chemical yield, chemical as well as enantiomeric purity of the
product.
The object of the present invention, thus, is to provide an industrially advantageous
process for the preparation of pure nateglinide form B, without allowing other forms
to coexist, with low levels of Z-nateglinide enantiomer and other impurities, and
unique with respect to its simplicity, cost effectiveness, scalability.
Another object of the present invention is to provide an improved process for
synthesizing highly pure nateglinide intermediates using novel purification
techniques. The present invention also characterizes certain crucial intermediates
useful for the preparation of nateglinide in exceptionally high purity.
SUMMARY OF THE INVENTION
One aspect of the present invention relates to an improved process for the preparation of morphologically uniform nateglinide form B, directly from 7V-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine alkyl ester of formula II
(Figure Remove)in the presence of a mixture of water and water miscible solvents and alkali metal hydroxide.
Another aspect of the present invention relates to an improved process for preparing nateglinide polymorphic form B, comprising crystallizing any polymorphic form other than B-type crystals of nateglinide, from suitable solvents and isolating morphologically uniform nateglinide form B.
Yet another aspect of the present invention relates to an improved process for preparing nateglinide form B, comprising dissolving any polymorphic form of nateglinide, in a suitable solvent followed by the addition of antisolvent and isolating morphologically uniform nateglinide form B.
Yet another aspect of the present invention relates to an improved process for preparing nateglinide in high yield and purity using novel purification processes for intermediates.
BRIEF DESCRIPTION OF THE DRAWINGS
Figure 1 illustrates the powder X-ray diffraction pattern for nateglinide form B. Figure 2 illustrates the differential scanning calorimetry for nateglinide form B.
DETAILED DESCRIPTION OF THE INVENTION
More particularly, the present invention describes an improved process for the preparation of nateglinide form B in high yield and purity.
Nateglinide form B, encompassed by the present invention may be characterized by at least one of X-Ray power diffraction (XRD), FT-infrared spectroscopy (FTIR) or differential scan calorimetry (DSC) techniques.

The XRD patterns of polymorphic form B is measured on PANalytical X'Pert Pro diffractometer with Cu radiation and expressed in terms of two-theta, d-spacing and relative intensities.
Melting point is measured using Polmon MP Apparatus MP 96 with a sample weight of about lOmg.
DSC is conducted using standard conditions under Na gas flow at a temperature of 10°C/minute.
In one embodiment of the present invention, Ar-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II



Formula II
(Figure Remove)wherein Alk is C/-Q alkyl
can directly be converted to pharmaceutically pure nateglinide form B. The alkyl ester is selected from C\-C$ alkyl which can be straight chain or branched chain and preferably ethyl and methyl esters are used. Typically, 7V-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II (Alk is methyl) is added to a stirred solution of large volumes of demineralized water, a suitable solvent and alkali metal hydroxide preferably sodium hydroxide at 2-15 °C, over a period of few minutes with constant stirring. Suitable solvent can preferably be selected from, but not limited to solvents like ether, alkyl alcohols, allyl nitriles,

formamides and the like or mixtures thereof. In the preferred embodiment, the solvents used are tetrahydrofuran, methanol, acetonitrile or mixtures thereof.
The reaction works with equal efficiency of aqueous sodium hydroxide solution added to a suspension of nateglinide methyl ester in a mixture of water and organic solvent mentioned above. The amount of sodium hydroxide used varies between 1.1 to 3.0 molar equivalents, but preferably 2-2.5 molar equivalents are used. The ratio of organic solvent and water used varies from 0.1:0.9 to 0.9:0.1, but is preferably from 0.3:0.7 to 0.4:0.6. Total quantity of solvents may vary depending upon the solvent and reaction condition and can be between 10 times to 200 times, preferably between 20 times to 100 times..
The temperature of the reaction mass is slowly raised to 25±5°C over a period of about a few minutes to a few hours, preferably for a period of about 1-2 hours. The reaction mass is further stirred for 6-12 hours at 25±5°C and progress of the reaction can be monitored by high performance liquid chromatography or thin layer chromatography. The solution is checked for clarity and the reaction mixture is cooled to 15-20°C, filtered to remove suspended particles and stirred for additional one hour at that temperature. The solution is further cooled to 5 to 15°C and the pH of the mixture is adjusted to 7.0 - 7.5 with dropwise addition of cooled hydrochloric acid. The mixture is further stirred for about an hour and then additional hydrochloric acid is added at 0-20°C, preferably at a temperature of 10-15°C to adjust the pH of the reaction mass to 1.5-2.5 with stirring for a period of about 60 minutes. The strength of the hydrochloric acid used may vary between 0.1 N to 6 N, preferably between 0.5 Nto3.5N.
It is advantageous to carry out the acidification at below 20°C to avoid the formation of mixture of different polymorphic forms. The precipitated solid is quickly filtered

under vacuum, washed successively with excess of water. It is first suck dried for a period of about 1-4 hours and then dried in oven at 40°C for about 10-15 hours till the moisture content is between 25-50%. Finally the precipitated solid is dried at 60-65°C under vacuum till the moisture content is below 0.5% to provide nateglinide in high yield and purity greater than 99.5%. Alternatively, filtered material can be straightaway subjected to drying at 60- 70°C under vacuum or under normal atmosphere conditions. The nateglinide thus isolated is of pharmaceutical grade in which no unidentified impurity is above 0.15% and displays physicochemical characteristics which corresponds to that of form B of nateglinide.
More importantly the invention results in the preparation of highly pure nateglinide form B without the contamination by any other polymorphic form, wherein the residual solvents levels are as per the ICH guidelines and which does not require any additional step of purification,
Another embodiment of the present invention encompasses methods for preparing nateglinide form B comprising dissolving nateglinide in a suitable solvent to form solution and then evaporating the solvent and collecting the precipitate.
More particularly, B-type crystals of nateglinide or any other form or mixture there of was dissolved in a suitable solvent and filtered to remove suspended particles. The solvent used can be selected from, but not limited to ethers. In the preferred embodiment, the solvent used is tetrahydrofuran, dimethyl ether, diethyl ether and the like. Nateglinide form B can then be isolated by conventional methods. Although specific illustrations of suitable separation and isolation procedures can be had by reference to the examples herein below. However, other equivalent separation or isolation procedures could, of course, also be used.

Typically, the ether solvent, preferably tetrahydrofuran is evaporated under vacuum and the sample is dried under vacuum for 1-5 hours till the solvent has completely evaporated. The material is finally dried under vacuum at 60-70°C to afford nateglinide which displays characteristic patterns which correspond to that of nateglinide form B.
Another embodiment of the invention encompasses a method of preparing nateglinide form B comprising dissolving nateglinide in a solvent to form a mixture, cooling the mixture, adding an anti-solvent to precipitate nateglinide form B, and collecting the precipitate.
More particularly, nateglinide H-type crystals of nateglinide or any other form or mixture thereof is dissolved in a suitable solvent and the mixture is cooled to 3-20°C, preferably 5-10°C. Suitable solvent can preferably be selected from, but not limited to water miscible ethers, alcohols, nitriles or mixtures thereof. In the preferred embodiment, the solvent used is tetrahydrofuran, methanol or acetonitrile. This is followed by slow addition of anti-solvent to the solution and the mixture is stirred for 2 hours at 5-15°C. The anti-solvent is preferably water. Crystallization may occur spontaneously without any inducement. Another way of accelerating crystallization is by seeding with a crystal of nateglinide form B or scratching the inner surface of the crystallization vessel with a glass rod. The precipitated solid is isolated preferably by filtration, washed with excess of water, and dried at 60-70°C to afford nateglinide which displays characterization patterns which correspond to that of nateglinide form B.
Yet another embodiment of the present invention provides a novel process for preparing pure 7V-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II
(Figure Remove)by stirring suspension of trans-4-isopropylcyclohexyl-l-carboxylic acid of formula HI,

(Figure Remove)Formula III
and N-hydroxysuccinimide in a suitable halogenated solvent preferably dichloromethane, at about ambient temperature, a suitable organic base is added and this mixture is stirred The organic base can be selected from triethylamine, diisopropyl ethyl amine, tri isopropyl amine, tributyl amine, pyridine or substituted pyridines, preferably triethylamine is used. The mixture is then cooled to a temperature of below 15°C and TV.JV-dicyclohexylcarbodiimide is dissolved in dichloromethane is slowly added to the reaction mixture and the mixture is stirred at that temperature for few minutes to few hours preferably 30 minutes. The temperature is slowly raised to 30-50°C, preferably 38-40°C and the reaction mixture is stirred for 2-8 hours. Preferably the reaction mixture is stirred for 4-6 hours. The reaction completion is indicated by gas chromatographic analysis. The reaction mixture is cooled to ambient temperature followed by the addition of acetic acid and the reaction
mixture is stirred for few minutes to few hours. Preferably the reaction mixture is stirred for 60-90 minutes. The reaction mass is further cooled to a temperature of below 15°C and precipitated dicyclohexyl urea, formed as a side product via the hydrolysis of A^TV-dicyclohexylcarbodiirnide, is removed by conventional procedures viz. filtration. The filtrate is successively washed with dilute hydrochloric acid, sodium bicarbonate solution and water, and the solvent is distilled off at 38-42°C and then completely removed under vacuum to give crude trans-4-isopropylcyclohexyl-l-carboxylate-jV-hydroxysuccinimide ester of formula IV,
(Figure Remove)Formula IV
as a pale yellow solid having GC purity of 80-90% which is then purified from alkyl esters (preferably ethyl acetate) or C\-C^ alcohols (preferably methanol) or mixtures of alcohols and aliphatic alkanes (preferably mixtures of methanol or n-heptane). The trans-4-isopropylcyclohexyl-l-carboxylate-./V-hydroxysuccinimide ester of formula IV is characterized with the help of proton NMR, 13C- NMR, FTIR and other spectroscopic methods.
Trans-4-isopropylcyclohexyl-l-carboxylic acid of formula III used as starting material can be prepared by the methods known in prior art or can be procured from market.
According to yet another embodiment of the present invention, the crude trans-4-isopropylcyclohexyl-l-carboxylate-A'-hydroxysuccinimide ester of formula IV can be purified from a suitable solvent selected from alcohols, esters, alkanes, ketones or mixture thereof. The alcohol can be selected from C\-Cj alcohols and alkane can be
selected from Cs-C? alkane. The esters can be selected from esters formed by Ci-Cs alcohols and C\-C^ acids. Ketones can be selected from acetone, diethyl ketone, methylisobutyl ketone etc. Preferably, methanol, ethyl acetate, n-heptane, acetone or combination thereof can be used.
More particularly, crude trans-4-isopropylcyclohexyl-l-carboxylate-Af-hydroxy succinimide ester of formula IV is added to the suitable solvent and the mixture is heated with stirring at 50-75°C for a period of 1-4 hours. Preferably, the reaction mass is heated at 60-65°C for about 1 hour. The mixture is slowly cooled to a temperature of below 15°C, stirred for few minutes to few hours. Preferably the reaction mixture is stirred for 60-90 minutes, filtered, slurry washed with solvent/ solvent mixture and dried to yield pure trans-4-isopropylcyclohexyl-l-carboxylate-./V-hydroxysuccinimide ester of formula IV as a white to off white crystalline solid having GC purity greater than 96%.
According to yet another embodiment of the present invention, trans-4-isopropylcyclohexyl-1-carboxylate-JV-hydroxysuccinimide ester of formula IV can be converted to AL(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II





(Figure Remove)•wherein Alk is C/-Q alkyl

Formula II

Generally, a mixture of A^-trans-4-isopropylcyclohexyl-1 -carboxylate-jV-hydroxy succinimide ester of formula IV and Z)-phenylalanine alkyl ester of formula V or salt thereof
(Figure Remove)and a suitable base preferably triethylamine in halogenated solvent is reacted at 10-45 °C with continuous stirring over a period of 05-72 hours. The quantity of the solvent used may vary depending upon the nature of the alkyl ester used and reaction conditions. Generally solvent is used from 3-50 times v/w and preferably 5-20 times v/w of the intermediate of formula IV.
D-Phenylalanine alkyl ester or salt thereof used in the above reaction can be procured from market or can be prepared by the methods known in prior art. Preferably, the reaction mixture in dichloromethane is heated at 10°C-reflux temperature for 05-60 hours and progress of the reaction is monitored by gas chromatographic analysis. After the completion of the reaction, the reaction mixture is successively washed with dilute solution of hydrochloric acid, sodium bicarbonate solution and water at temperature below 25°C. The dichloromethane layer is dried over sodium sulphate, filtered and distilled at 38 - 40°C to afford crude JV-(trans-4-isopropylcyclohexyl-l-carboxyl)-Z)-phenylalanine methyl ester as off white to pale yellow solid.
According to yet another embodiment of the present invention, JV-(trans-4-isopropylcyclohexyl-1-carboxyl)-D-phenylalanine alkyl ester of formula II can be
purified from a suitable solvent selected from alcohols, ketones, ethers or mixture thereof. The alcohol can be selected from Q-Cs alcohols, the ketones may be acetone, diethyl ketone, methyl isobutyl ketone, the ethers could be tetrahydrofuran, 1,4-dimethoxy furan or alkyl ethers like diethyl ethers, diisopropyl ether, or a suitable mixture thereof.
Typically, the crude A^-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II ( Alk is methyl) is dissolved in alcoholic or a ketonic solvent and the mixture is cooled to a temperature of below 10°C preferably at 5-8°C and is stirred for about an hour at the same temperature. The solid that precipitates out is filtered, washed with chilled alcohol or ketone and dried to afford pure 7V-(trans-4-isopropylcyclohexyl-1- carboxyl)-£)-phenylalanine methyl ester as a white to off white crystalline solid in high yield and purity greater than 98%.
In an alternative process, 7V-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine alkyl ester of formula II (Alk is methyl) is dissolved in a mixture of alcohol and an aliphatic alkane solvent. It is observed that purification can best be conducted in a mixture of n- heptane and methanol at ambient temperature and the mixture is slowly heated to 50-65°C with constant stirring for 1 hr at that temperature. The mixture is then cooled to a temperature of below 10°C, stirred for 1 hour, filtered, washed with same solvent mixture, and dried under vacuum to yield pure JV-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester as a white to off white crystalline solid in high yield and purity greater than 98% by high performance liquid chromatography.
Af-(trans-4-isopropylcyclohexyl-l-carboxyl)-£>-phenylalanine alkyl ester of formula II can be converted to pharmaceutically pure Nateglinide of formula I by conventional procedures known in the prior art or by the processes described in the present invention.
Major advantages realized in the present invention are:
1. The process leads to the formation of highly pure intermediates which upon
hydrolysis lead to very high chemically and stereochemically pure nateglinide
in high yield.
2. Formation of impurities like L-nateglinide or alkyl ester is minimized under
the reaction conditions employed.
3. The process provides Nateglinide polymorphic form B of very high chemical
and stereochemical purity directly from nateglinide alkyl ester.
4. No purification or crystallization is required to prepare pure Nateglinide
polymorphic form B
The present invention will now be illustrated by the following examples, which are not intended to limit the effective scope of the claims. Consequently, any variations of the invention described above are not to be regarded as departure from the spirit and scope of the invention as claimed. The present invention has been described in terms of its specific embodiments and various modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of present invention.
EXAMPLES
Preparation of trans-4-isopropylcyclohexyl-l -carboxylate-yV-hydroxy
succinimide ester
To a stirred suspension of trans-4-isopropylcyclohexyl-l-carboxylic acid (100 g) and A'-liydroxysuccinimide (81.17 g, 1.2 molar eq) in dichloromethane (1200 ml), triethyl amine (20.45 ml) was added at 25 to 30°C and the mixture was stirred till clear solution was obtained. The clear solution was cooled to 5-10°C and /V,/V-dicyclohexylcarbodiimide (146.64 g ) dissolved in dichloromethane (300 ml) was
slowly added to the reaction mixture and the mixture was stirred at same temperature for 30 minutes. The temperature was slowly raised to 38- 40°C and stirred for 4-6 hours till the reaction was complete. The mixture was then cooled to 25-30°C and acetic acid (130 ml) was added to the reaction mixture and stirred for 60-90 minutes. The reaction mass was further cooled to 10-15°C and the precipitated dicyclohexyl urea was filtered off. The dichloromethane filtrate was successively washed with aqueous sodium bicarbonate solution (1 x2.5 L), IN hydrochloric acid (1 xl L) and demineralized water (3 x 1.0 L) and dried over sodium sulfate. Dichloromethane was distilled off at 38-40°C and then completely removed under vacuum to give 154.0 g of the title compound as a pale yellow solid having purity 86.66% by gas chromatography.
Purification of crude trans-4-isopropylcyclohexyl-l-carboxylate-./V-hydroxy succinimide ester
Example 1
To the crude trans-4-isopropyl cyclohexyl-l-carboxylate-TV-hydroxysuccinimide ester (154 g), n-heptane (540 ml) and methanol (160 ml) were added and the mixture was heated with stirring to 60-65°C for 1 hour. The mixture was slowly cooled to 5-10°C, stirred for 60-90 minutes, filtered, slurry washed with a cooled mixture of n-heptane and methanol ((9:1; 200 ml) and dried under vacuum at 50°C for 10-12 hours to yield 146g of trans^-isopropylcyclohexyl-l-carboxylate-A^hydroxysuccinimide ester as a white to off white crystalline solid having purity of 96.7% by gas chromatography. Example 2
To the crude trans-4-isopropyl cyclohexyl(-l-carboxylate-N-hydroxy succinimide ester (154 g), ethyl acetate (1.0 L) was added and the mixture was heated with stirring to 60-65°C for 1 hour. The mixture was slowly cooled to 5-10°C, stirred for 60-90 minutes, filtered through hyflo bed to remove the suspended particles and the filtrate was evaporated under vacuum at 45-50°C. The residue thus obtained was
further dried under vacuum at 50°C till most of ethyl acetate had been removed, n-Heptane was then added to the residue and the after stirring for 1 hour at 45-50°C the product was filtered and dried under vacuum at 45-50°C for 10-12 hours to yield 139.55 g of trans-isopropyl cyclohexyl-(-l-carboxylate-Af-hydroxy succinimide ester as a off white to pale yellow crystalline solid having purity of 96.2% by gas chromatography.
Example 3
Crude trans-isopropyl cyclohexy^-l-carboxylate-W-hydroxy succinimide ester (154 g) was dissolved in methanol (600 ml) at 55-60 °C and the mixture was cooled to 5-8°C and stirred for 1 hour. The crystallized solid was then filtered under vacuum, slurry washed with chilled methanol (2 xlOO ml) and dried under vacuum at 50°C for 10-12 hrs to yield 130.0 g of trans-isopropylcyclohexyl(-l-carboxylate-N-hydroxy succinimide ester as a white to off white crystalline solid having purity of 97.84 % by gas chromatography.
Preparation of A^-(trans-4-isopropylcyclohexyl-l-carbonyl)-D-phenyIalanine methyl ester
Example 1
A mixture of A^-(trans-4-isopropylcyclohexyl-l-carboxylate jV-hydroxysuccinimide ester (70 g ), £)-phenylalanine methyl ester hydrochloride (63 g, 1.1 mol eq.) and triemylamine (127.6 ml, 3.5 mol eq.) in dichloromethane (1400 ml) was heated 38-40°C with continuous stirring over a period of 40-48 hours and progress of the reaction was monitored by gas chromatography. After the reaction was over, the mixture was cooled to 15-20°C and successively washed with IN hydrochloric acid(3 x 400 ml), sodium bicarbonate solution (3 x400 ml) and water (3 x 400 ml). The dichloromethane was dried over sodium sulfate, filtered and distilled at 38-40°C to afford 85.5 g of the title compound as a pale yellow solid.

Example 2
A mixture of 7V-(trans-4-isopropylcyclohexyl-l-carboxylate jV-hydroxysuccinimide ester (100 g ), D-phenylalanine methyl ester hydrochloride ( 88.78 g, 1.1 mol eq.) and tri ethyl ami ne (182.4 ml, 3.5 mol eq.) in dichloromethane (500 ml) was stirred at 15-20°C for 20-24 hours and progress of the reaction was monitored by gas chromatography. After the reaction was over, the mixture was washed with IN hydrochloric acid (3 x 500 ml), sodium bicarbonate solution (3 x500 ml) and water (3 x 500 ml). The dichloromethane was dried over sodium sulfate, filtered and distilled at 38-40°C to afford 110 g of the title compound as a pale yellow solid.
Purification of crude 7V-(trans-4-isopropylcyclohexyl-l-carbonyl)-D-phenyl-alanine methyl ester
Example 1
Crude Af-(trans-4-isopropylcyclohexyl-l-carboxyl)-D-phenylalanine methyl ester (85.5g) was dissolved in methanol (550 ml) and the mixture was cooled to 5-8°C and stirred for 1 hour. The precipitated solid was filtered, slurry washed with chilled methanol (5°C, 2 x 70 ml) and dried under vacuum at 45 -50°C for 5-8 hours to afford 63.35 g of pure /V-(trans-4-isopropylcyclohexyl-l-carbonyl)-D-phenylalanine methyl ester as a white to off white crystalline solid having purity of 98.8 % by high performance liquid chromatography.
Example 2
Crude jV-(trans-4-isopropylcyclohexyl-l- carboxyl)-D-phenylalanine methyl ester (85.0 g) was added to n- heptane (448 ml) and methanol ( 112 ml) at 25-30°C and the mixture was slowly heated to 55-60°C and stirred for 1 hour. The mixture was then cooled to 5-10°C, stirred for 1 hour, filtered, slurry washed with a mixture of chilled n-heptane and methanol solution (4:1, 70 ml), and dried under vacuum at 45-50°C for 10-12 hours to yield 68. 5 g of pure 7V-(trans-4-isopropylcyclohexyl-l-

carboxyl)-D-phenylalanine methyl ester as a white to off white crystalline solid having purity of 98.18% by'high performance liquid chromatography.
Example 3
Crude 7V-(trans-4-isopropylcyclohexyl-l- carboxyl) - D-phenylalanine methyl ester obtained above was dissolved in acetone (680 ml) at 50-55 °C and stirred further and the mixture was cooled to 5-8°C (maintain for 1 hour) and stirred for 1 hour at that temperature. The precipitated solid was filtered, slurry washed with chilled acetone ( 5°C, 70 ml) and dried under vacuum at 45-50°C for 5-8 hours to afford 62.22 g ofN-(trans-4-isopropylcyclohexyl-l-carboxyl)-Z)-phenylalanine methyl ester as a white to off white crystalline solid which displays HPLC purity of 98.25%.
Preparation of pure Nateglinide form B from nateglinide methyl ester Example 1
To a stirred solution of demineralized water (2400 ml), methanol (2400 ml) and sodium hydroxide (18.12 g, 2.5 mol eq.) at 5-8°C, pure 7V-(trans-4-isopropylcyclohexyl-1-carboxyl)-£)-phenylalanine methyl ester (60.0 g) was added over a period of 3- 5 minutes and stirred for 15 minutes, the temperature was slowly raised to 26±2°C over a period of 60-90 min. The reaction mass was stirred for 8 hours at 26±2°C and progress of the reaction was monitored by high performance liquid chromatography. During this time the reaction mass became clear. The reaction mixture was cooled to 10-15°C, filtered to remove suspended particles and stirred for additional one hour at that temperature and pH of the mixture was adjusted to 7.0 -7.5 with drop wise addition of cooled IN hydrochloric acid (10-15°C). The mixture was stirred for 1 hr. at pH 7.0 - 7.5 and then additional 1 N hydrochloric acid was added at 10-15°C to adjust the pH to 1.5 - 2.5 and stirred for 30 minutes. The precipitated solid was quickly filtered under vacuum, successively slurry washed with cooled (10-15°C) mixture of methanol and demineralized water (50:50, 2 x 600 ml)

and demineralized water (6 x 600 ml). The filtered material was first suck dried for 2 hours and then at dried in oven at 40 - 45°C for 12 hours (till the moisture content was between 11-50%) and then finally dried at 60-65°C under vacuum (till the moisture content was below 0.5%) to yield 48.3 g of nateglinide form B having purity 99.95% by high performance liquid chromatography.
Example 2
To a stirred solution of purified water ( 1500 ml), tetrahydrofuran (400 ml) and sodium hydroxide (0.45 mol, 18.12 g, 1.5 m. eq.) at 5-10 °C, pure powdered N-(trans-4-isopropylcyclohexyl-l- carboxyl)-D-phenylalanine methyl ester (100 g, 0.30 moles) was added over a period of 3- 5 minutes. The temperature was slowly raised to 20-22 °C and reaction mass was stirred at 20-22 °C for 8-10 hours when the high performance liquid chromatography indicated the reaction to be complete. The reaction mass was filtered, further cooled to 5-8 °C and pH was adjusted to 7.0-7.5 with drop wise addition of cooled (10-15°C) 1 N hydrochloric acid. The mixture was stirred for 1 hr. at pH 7.0-7.5 and then additional 1 N hydrochloric acid was added at 5-8°C to adjust the pH to 1.5 - 2.5 and stirred for 60 min. The precipitated solid was filtered under vacuum, successively slurry washed with cooled purified water (3 x 500 ml), suck dried for 2 hrs and then dried in oven at 40-45°C for 12 hours till the m/c between 11-50%. The product was then finally dried at 60-65°C under vacuum till the moisture content was below 0.5% to afford 91.0 g of nateglinide form B as a white crystalline solid having purity of 99.85% by high performance liquid chromatography.
Example 3
To a stirred solution of purified water ( 50 ml), tetrahydrofuran (12.5 ml), acetonitrile (12.5 ml) and sodium hydroxide (0.9 g, 0.225 M.) at 5-10°C, pure powdered N-(trans-4-isopropylcyclohexyl-l- carboxyl)-D-phenylalanine methyl ester (5.0 g, 0.015

moles) was added and after stirring for 15- 20 min at 5-10 °C the temperature was slowly raised to 20-22°C and reaction mixture was stirred at 20-22 °C for 8-10 hrs when the thin layer chromatography indicated the reaction to be complete. The reaction mass was filtered, further cooled to 5-8 °C and pH was adjusted to 1.5 to 2.5 with drop wise addition of cooled (10-15°C)1N hydrochloric acid and the reaction mixture was stirred for 60 minutes. The precipitated solid was filtered under vacuum, successively slurry washed with cooled purified water (5 x 50 ml), suck dried for 2 hrs and then dried in oven at 40°C for 12 hours till the m/c between 11-50%). The product was then finally dried at 60-65°C under vacuum till the moisture content was below 0.5% to afford 4.5 g of nateglinide form B as a white crystalline solid. (Yield 94.73 %) having purity of 99.85% high performance liquid chromatography
Conversion of nateglinide to pure Nateglinide form B Example 1
Nateglinide (100.0 g) was dissolved in tetrahydrofuran (250 ml) and the mixture was cooled to 5-8°C. Methanol (250 ml) was the added and the mixture was stirred at 5-8°C for 5 minutes. Water (2000 ml was slowly added to the solution and the mixture was stirred for 2 hrs at 5-10°C. The precipitated solid was filtered, washed with water (3 xlOOO ml) and dried at 60 -70°C to afford nateglinide form B.
Example 2
Nateglinide (5.0 g) was dissolved in tetrahydrofuran (25 ml) and filtered to remove suspended particles. Tetrahydrofuran was then evaporated under vacuum and the sample was dried under vacuum for 2- 3 hrs till the solvent had completely evaporated. The material was scrapped from the walls of the flask and finally dried under vacuum at 60 -70°C to afford 4.8 g of B-type crystals of nateglinide.

Example 3
Nateglinide (5.0 g, polymorphic form H ) was dissolved in tetrahydrofuran (25 ml) and filtered to remove suspended particles. Tetrahydrofuran was then evaporated under vacuum and the sample was dried under vacuum for 2- 3 hours till the solvent had completely evaporated. n-Heptane was added to the flask and after stirring for 30 minutes, the powder was filtered, washed with n-heptane, and dried under vacuum at 60-70°C to afford 4.75 g of nateglinide form B.
Example 4
Nateglinide (100.0 g, polymorphic form H) was dissolved in tetrahydrofuran (500 ml) and the mixture was cooled to 5-8°C. Water (2000 ml) was slowly added to the solution and the mixture was stirred for 2 hours at 5-10°C. The precipitated solid was filtered, washed with water, and dried at 60-70°C to afford B-type crystals of nateglinide.
Example 5
Nateglinide (5.0 g, polymorphic form H) was dissolved in tetrahydrofuran (12.5 ml) at 25-35°C and acetonitrile (12.5 ml) was added and mixture was filtered to remove the suspended particles. After stirring for 5 min the mixture was cooled to 5-10 °C and purified water 100 ml) was slowly added to the reaction mixture. After stirring for 1 hour at that temperature, the precipitated solid was filtered and washed with cold water (5 x 50 ml), dried at 60-70°C under vacuum for 24 hours to afford 4.79 g of nateglinide form B as a white crystalline solid.

WE CLAIM
1. A process for the preparation of highly pure nateglinide form B comprises:
suspending V-(trans-4-isopropylcyclohexyl) carbonyl] £)-phenylalanine alkyl ester of formula II,
(Figure Remove) Formula II
wherein Alk is Cy-CV alkyl
in a mixture of water, a suitable solvent and alkali metal hydroxide,
stirring the above suspension at 0-35 °C, preferably at 10-30 °C,
optionally filtering the solution to remove the suspended particles, cooling the
filtrate,
treating the reaction mass with dilute acid till the pH of the solution is 1.5- 2.5,
optionally stirring the solution and
isolating highly pure nateglinide Form B.
2. A process according to claim 1, wherein the alkyl ester is preferably methyl ester and ethyl ester; the suitable solvent is selected from water miscible solvents like ethers, alcohols, nitriles etc and the like or mixtures thereof, preferably tetrahydrofuran, methanol or acetonitrile or mixtures thereof.
3. A process for the preparation of nateglinide form B comprising crystallizing
nateglinide, in any polymorphic form other than B-type crystals, from suitable
solvents selected from ethers, alcohols, nitriles etc and the like or mixtures
thereof, evaporating the solvent and isolating morphologically uniform
nateglinide form B.
4. A process for the preparation of nateglinide form B comprising dissolving
nateglinide, in any polymorphic form other than B-type crystals, from a suitable
solvent such as alcohols, nitriles, ethers etc and the like followed by the addition
of water and isolating morphologically uniform nateglinide form B.
5. A process for the preparation of nateglinide of Formula-I,
comprises reacting trans-4-isopropylcyclohexyl-l-carboxylic acid of formula III,
(Figure Remove) Formula III
with JV-hydroxysuccinimide in the presence of an organic base and N,N-dicyclohexylcarbodiimide in a halogenated solvent selected from dichloromethane, chloroform, 1,2-dichloroethane etc, to form crude trans-4-isopropyl cyclohexylcarboxylate-7V-hydroxysuccinimide ester of Formula IV,
(Figure Remove) Formula IV
purifying crude ester of Formula IV from a suitable organic solvent,
reacting trans-4-isopropylcyclohexylcarboxylate-./V-hydroxysuccinimide ester of formula IV with D-phenylalanine alkyl ester of formula V ,
(Figure Remove) Formula V
wherein Alk is C/-CV alkyl
in a halogenated solvent in the presence of a base to form ./V-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine alkyl ester of Formula II,
(Figure Remove) wherein Alk is C/-Calkyl
purifying Ar-(trans-4-isopropylcyclohexyl) carbonyl] -Z)-phenylalanine alkyl ester of Formula II from a suitable organic solvent,
converting the same to nateglinide of Formula I.
6. A process according to claim 1, wherein, the organic base is selected from
triethylamine, diisopropyl ethylamine, tributylamine, tripropylamine etc.
7. A process according to claim 1, wherein the suitable organic solvent is selected
from Ci-C4 alcohols, water miscible ethers such as tetrahydrofuran or a
combination thereof.
8. A process for the purification of trans-4-isopropyl cyclohexylcarboxylate-W-
hydroxysuccinimide ester of formula IV,
(Figure Remove) Formula IV
which comprises:
dissolving trans-4-isopropyl cyclohexylcarboxylate-jV-hydroxysuccinimide ester of formula IV in a suitable organic solvent selected from alcohols, esters, alkanes, ketones, allylnitriles or mixture thereof,
heating the mixture with stirring at 50-75°C for a period of 1-4 hours, cooling the mixture to a temperature of below 15°C,
filtering, and isolating the pure trans-4-isopropyl cyclohexylcarboxylate-A^-hydroxysuccinimide ester of formula IV.
9. A process for the preparation of jV-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine alkyl ester of formula II,

Formula II

(Figure Remove) which comprises reacting trans-4-isopropylcyclohexylcarboxylate-./V-hydroxysuccinimide ester of formula IV,
(Figure Remove) Formula IV
with £)-phenylalanine alkyl ester of formula V ,



(Figure Remove) Formula V
in a halogenated solvent in the presence of a base to form 7V-(trans-4-isopropylcyclohexyl) carbonyl]-Z)-phenylalanine alkyl ester of Formula II,

10. A process for the purification of V-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine alkyl ester of formula II,

Formula II
(Figure Remove) wherein Alk is C/-Q alkyl comprises:
dissolving JV-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine methyl ester of formula II in suitable organic solvent selected from alcohols, esters, alkanes, ketones, allyl nitriles etc or mixtures thereof.
cooling the mixture to a temperature of below 1 5°C,
stirring, filtering, and isolating the pure 7V-(trans-4-isopropylcyclohexyl) carbonyl]-D-phenylalanine methyl ester of formula II.