Title of Invention

A PROCESS FOR RESOLUTION OF 2-SUBSTITUTED PHENYLGLYCINE ACIDS OR ESTERS THEREOF

Abstract

A process for resolution of methyl 2-substituted phenylglyclne esters and/or acids of the formula 1 by asymmetric transformation of diastereomeric salts comprising resolution of racemic 2-substituted phenylglycine esters and/or acids of formula (I)with L(+) tartaric acid in molar ratio of 0.9 to 1.4 in presence of solvent selected from acetone, methanol, ethanol, isopropyl alcohol and mixture thereof

Full Text

FIELD OF INVENTION The present invention relates to a highly efficient resolution process for 2-substituted phenyl glycine esters and/or acids, a valuable intermediate for the preparation of highly active antiplatelet aggregatory compounds known as clopidogrel More specifically the present invention relates to a process for the preparation of 2-substituted phenylglycine esters and acids of formula -I in high yield which is a valuable intermediate for the synthesis of highly active anti platelet aggregation drug clopidogrel and also a valuable unnatural amino acids for different biochemical activities. where R = H, alkyl(methyl,ethyl,propyl,isopropyl,butyl,phenyl) X=halogen,OR1S,R1 Where R,- H or alkyl ( C1-C3 carbons) = phenyl and optionally substituted phenyl. BACKGROUND AND PRIOR ART: Synthesis of phenyl glycine ( X=H ) and 3-substituted (meta) and 4-substituted ( para) compounds are reported in US 3,976680. The concept of asymmetric transformation of diasteriomeric salts was first reported by H.leuchs and J.Wutke in Ber 1913,46,2420 and was first popularized commercially in the case of D(-) phenylglycine and D(-)p-hydroxy phenylglycine in US 3,976,680.In this the unwanted isomer is rearranged in the process by forming schift base and the schift base is isomerised, which is resolved again to give net yields > 50% and are close to 90%. The 2- substituted phenylglycine like2-chlorophenylglycine has attained commercial importance recently because of the success of clopidogrel an anti platelet drug. This compound is reported to be resolved using with camphor sulphonic acid or tartaric acid. US 5,204,469 teaches preparation of racemic methyl alpha-(4,5,6,7-tetrahydro-5-thieno[3,2c]pyridil)(2-chlorophenyl) acetate, one of whose isomers is clopidogrel which is a useful platelet anti aggregating and anti thrombotic agent, by reacting a formylating agent with methyl alpha-(2-thienylethylamino) methyl alpha-amino(2-chlorophenyl) acetate. This methyl alpha- (2-thienylethylamino) methyl alpha-amino (2-chlorophenyl) acetate is formed from reaction of methyl alpha amino (2-chlorophenyl) acetate with thienyl derivative. This art teaches the resolving the racemic methyl alpha amino (2-chlorophenyl) acetate using tartaric acid, acetonitrile and methyl ethyl ketone as solvents at about 60°C. the compound is purified with acetonitrile and methanol. The yield is about 45.79%. WO 059128 and EP1353928, do not report the present compound I These patents describe the preparation of [3,2-c]pyridil derivatives and their racemic and optically active forms. Only thing reported in this patent was using of Tartaric acid for resolution for other compounds. US 6,635,763 claims the resolution of (2-chlorophenyl)(6,7-dihydro4H-thieno[3,2,c]pyrid-5yl) acetonitrile using tartaric acid also along with other resolving agents The resolution efficiency was of >40% but less than 48%. The disadvantages of the above resolution processes are 1. Handling of racemisation process which is a high temperature and potentially high-pressure reaction. 2. The efficiency of the process is only 40-45%, where handling of materials will be more (double). 3. Because the process efficiency is only 40-45%, one will be using high quantities of solvents, which is potentially hazardous. As the Clopidogrel is an effective antiplatelet drug and already attained a status of "block buster drug" there is a need for a novel efficient and high yielding process which can overcome the above problems. OBJECTS OF THE INVENTION Thus the main object of the present invention is to provide a resolution process for 2-substituted phenyl glycine esters and /or acids involving asymmetric transformation of diasteriomeric salts. A further object of the present invention is to provide a resolution process for 2-substituted phenyl glycine esters and acids so as to provide a high yield of the compound even at low temperatures. The present inventors have now found that resolution of the 2-substituted phenyl glycine esters and /or acids of compound I involving asymmetric transformation of diasteriomeric salts may be carried out using tartaric acid in defined ratio to the compound of formula I in specific solvents resulting in high yield of the said compound I even at low temperatures. In the processes of the prior art the required isomer is isolated as salt and the undesired isomer (50% of total quantity) are wasted in filtrate. Hence only 50% of the total quantity are utilized and accordingly the yield is low. The inventors have found that process of present invention involves conversion of undesired isomer also in situ to desired isomeric form thus utilizing both the isomers. The use of both the isomers gives yield of at least 86%. SUMMARY OF THE INVENTION Thus according to the main aspect of the present invention there is provided a process for the resolution of methyl 2-substituted phenylglycine esters and/or acids of the formula I by asymmetric transformation of diastereomeric salts comprising resolution of racemic 2-substituted phenylglycine esters and/or acids of formula (I) with L (+) tartaric acid in molar ratio of 1.1 to 1.2 in presence of solvent selected from acetone, ethanol, isopropyl alcohol, mixtures thereof and mixture of acetone and methanol. DETAILED DESCRIPTION OF THE INVENTION The present inventors have found a process of efficient resolution with high yield by using the technique asymmetric transformation of diastereomeric salts in situ to isomeric required form. In the process of present invention the racemic form is converted into the isomeric form using tartaric acid in defined ratio with the racemic salt in presence of solvents acetone and methanol in defined amount. The acetone used forms an intermediate with the unwanted isomer, which is converted to the racemic form by tartaric acid. Finally both the desired and undesired isomers are resolved to give high yields of (+) tartrate salts of 2-substituted phenylglycine esters and/or acids. More over the temperature used for the resolution with acetone and methanol varies from 15 to 25°C, preferably 20°C for 25 to 35 minutes, preferably 30 minutes when crystallization occurs. The temperature of reaction is then raised to 28-32° C, preferably 30 °C and maintained for about 16 to 24 hrs, preferably 20 hours. The resolution process is preferably carried out with the selective solvent mixture of methanol and acetone in the ratio of 4:5. The resolution process of the present invention provides a yield above 86% It is believed that acetone forms an "imine" in situ with chlorophenylglycine methyl ester of the undesired isomer which in the presence of tartaric acid gets converted in to a racemic isomer. The racemic isomer is resolved further. Thus total conversion of Dextro-Levo mixture to only isomeric form is called asymmetric transformation of diasteromeric salts. The ratio of the ester and/ or acid and tartaric acid used varies 0.9 to 1.4, preferably 1: 1.1. On increasing or decreasing the molar ratio of tartaric acid with respect to the ester the yield is less and the quality of the product is also poor. Both the solvents are used for the reaction .The solvents required for the process are in defined ratios. The ester and / or acid is dissolved in acetone and added to the solution of tartaric acid in methanol. The reaction is not favorable if it is started with premixed solvents (acetone and methanol mixture). The combination of methanol and acetone in the selected ratio only help the reaction to go to completion with highest yield. It is found that with methanol alone there is no reaction. Acetone alone also gives low yield compared to that of the combination of acetone and methanol but higher than those of the known processes. The best results are obtained by using the solvents at the selected ratio only are demonstrated in the examples. It has been found that the particular ratio Methanol: Acetone substantially in the region of 4:5 provides optimum resolution and that ratio outside the same does not give the desired yield. Methanol was replaced by ethanol and iso propyl alcohol. In case of ethanol yields are low, with iso propyl alcohol reaction completed only 50% after 40 hours of the reaction time. Other solvents mixtures like acetonitrile and MEK mixture followed by methanol addition is reported in US 5204469 for our ester using tartaric acid as resolving agent but with low yield of 45% on theory. The present inventors reproduced the same results. The optimum molar ratio of racemic methyl amino (2-chlorophenyl) acetate I to L (+) tartaric acid is studied. The effect of solvents A (acetone) and B (methanol) and the combination of A and B on the efficiency of resolution on I are also studied. The resolution process is then followed by the liberation of the free base by conventional reaction of dissolving compound I in methylene chloride, cooling adjusting pH, removal of methylene chloride under vacuum resulting free base of the compound I as oil. The details of the process of the present invention is described in the following examples which is provided by way of illustration only and therefore should not be construed to limit the scope of the invention. Example 1A: (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms, (1.1 mole, 1.1 eq on ester) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (-f)-tartrate of methyl (+)-alpha amino (2-chlorophenyl) acetate was isolated and dried at 55- 60 °C. Yield: 86% by theory based on ester, m.p: 163-167 °C, HPLC 98%, [a]D+88.5(c=l,CH3OH) Example 1 B: methyI(+)-alpha amino (2-chlorophenyl)acetate : (-t)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate of above example 1A was dissolved in 900-ml methylene chloride and cooled to 10 °C. D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes, allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuum resulting oil of methyl (+)-alpha amino (2-chlorophenyl) acetate, G.C: 99% [a] D +135.0 (c=I, CH3OH) Example 2A: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms, (1.1 mole, 1.1 eq on ester) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 50 -55 °C and maintained at 50-55 °C for 15 minutes. Temperature of the mass was reduced to 30 °C and maintained at 30 °C 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl) acetate was isolated and dried at 55-60 °C. Yield: 68.5% by theory based on ester, HPLC 98%, [a] D +87.5(c=l,CH3OH) Example 2B: Methyl (+)-alpha amino (2-chlorophenyl) acetate: ( + )-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate of above example 2A was dissolved in 720-ml methylene chloride and cooled to 10 °C . D.M. water 960 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes, allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuum resulting oil of methyl (+)-alpha amino (2-chlorophenyl) acetate, G.C: 99% [a] D +134.0 (c=l, CH3OH) The process illustrated in Examples 1 and 2 provides 2-substituted phenylglycine esters with yield of over 86 % and 68.5% respectively at low and high temperatures by the use of the acetate and tartaric acid at defined ratio in solvents acetone and methanol at definite ratio. Example 3A: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 75 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms, (1.1 mole, 1.1 eq on ester) in 800 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallization starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino (2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. Yield: 45.6% by theory based on ester, HPLC 98%, [a] D +80 (c=l, CH3OH) Example 3 B: methyl (+)-alpha amino(2-chlorophenyl)acetate: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate of above example 1A was dissolved in 480-ml methylene chloride and cooled to 10 °C. D.M. water 640 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes, allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuum resulting oil of methyl (+)-alpha amino (2-chlorophenyl) acetate G.C: 98% [a] D +130.0 (c=l, CH3OH) Example 4: (+)-tartrate of methyl (+)-a!pha amino (2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 135 gms, (0.9mole, 0.9 eq on ester) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl) acetate was isolated and dried at 55- 60 °C. Yield: 67.34% by theory based on ester, M.pl35-148°C, [oc] D -15 (c=l,CH3OH) Example 5: (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 142.5 gms, (0.95mole) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl) acetate was isolated and dried at 55- 60 °C. Yield: 78.9% by theory based on ester, M.pl42-146°C, [α] D +14.46 (c=l, CH3OH) Example 6: (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino (2-chlorophenyl) acetate 199.5 gms, (1 mole) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 150 gms, (1.0 mole) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl (+)-alpha amino (2-chlorophenyl) acetate was isolated and dried at 55- 60 °C. Yield: 62.7% by theory based on ester, M.pl62-164°C, [α] D +88.15 (c=l, CH3OH) Example 7A: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid ,180 gms,(l .2 mole, 1.2 eq on ester ) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 86% by theory based on ester, M.pl62-165°C, [ α ]D +87( c=l,CH3OH) Example 7 B : methyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 7A was dissolved in 900 ml methylene chloride and cooled to 10 °C . D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G.C : 99% [ α ]D +135.0 ( c-l,CH3OH) Example 8: (1 )-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 960 ml of acetone was added to pre cooled solution of (+)-tartaric acid ,210 gms,(1.4 mole, 1.4 eq on ester ) in 790 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 57.9% by theory based on ester, M.pl48-152°C, [ α ]D +14( c=l,CH3OH) That the optimum ratio of the acetate and the tartaric acid provides the compound of formula 1 at yields of 86% and above is illustrated in examples 4- 8. Thus it is observed that with various molar ratio of acetate and tartaric acid like 1.0: 0.9, 1.0:0.95, 1.0:1.0, 1.0:1.2, 1.0: 1.4 the yield is low and the purity less in case of molar ratio of less than 1.1 of tartaric acid for 1 mole of ester. In case of molar ratio of 1.0: 1.2 high yield is obtained where as low yield is obtained in case of increased molar ratio of tartaric acid. The ratio of 1:1 is provided in examples 1 and 2 where also the yield is high. Example 9: (H-)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 800 ml of acetone was added to pre cooled solution of (+)-tartaric acid ,165 gms,(l.l mole, 1.1 eq on ester ) in 1000 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 65% by theory based on ester, M.pl42-145°C, [α ]D +14( c=l,CH3OH) Example 10A: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl a!pha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 900 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,(l.l mole, 1.1 eq on ester) in 900 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 74.3% by theory based on ester, M.pl60-163°C, [ α ]D +80.27(c=l,CH3OH) Example 10 B : rnethyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 10A was dissolved in 900 ml methylene chloride and cooled to 10 °C . D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G.C : 98% [αx ]D +132.0 ( c=l,CH3OH) Example 11 A: (+)-tartrate of methyl (+)-a!pha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 1200 ml of acetone was added to pre cooled solution of (+)-tartaric acid , r ) 165 gms,(l.l mole, 1.1 eq on ester )in 600 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyI(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 71% by theory based on ester, M.P160-162°C, [ α ]D +85.5 ( c=l,CH3OH) Example 11 B : methyl(+)-alpha amino(2-chIorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 11A was dissolved in 900 ml methylene chloride and cooled to 10 °C . D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G.C : 98% [α ]D +130.0 ( c-l,CH3OH) Example 12A: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyI)acetate: A solution of racemic methyl a!pha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 1000 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,(l.l mole, 1.1 eq on ester) in 800 ml acetone at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 71.98% by theory based on ester, M.pl58-162°C, [ α]D +79.98 (c=l,CH3OH) Example 12 B : methyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 12A was dissolved in 900 ml methylene chloride and cooled to 10 °C . D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G.C : 98% [ α ]D +130.0 ( c-l,CH3OH) Example 13A: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 1000 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,(l.l mole, 1.1 eq on ester) in 1000 ml acetone at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 74.31% by theory based on ester, M.pl61-163°C, [ α ]D +83.76 (c=l,CH3OH) Example 13 B : methyl(+)-aIpha amino(2-chlorophenyl)acetate : ( + )-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate of above example 13A was dissolved in 900 ml methylene chloride and cooled to 10 °C . D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G.C : 98% [ α ]D +130.0 ( cH,CH3OH) Example 14A: (+)-tartrate of methyl (+)-a!pha amino(2-chlorophenyl)acetate; A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 2000 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,(l.l mole, 1.1 eq on ester) in 2000 ml acetone at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield : 71.98% by theory based on ester, M.pl61-163°C, [α ]D +81.28(c-l,CH3OH) Example 14 B : methyl(+)-alpha amino(2-chlorophenyl)acetate : (+)-tartrate of methyl(+)-a!pha amino(2-chlorophenyI)acetate of above example 14A was dissolved in 900 ml methylene chloride and cooled to 10 °C . D.M. water 1200 ml was added at 10 °C and pH of the mass was adjusted to 6.9 to 7.1 with aqueous ammonia solution. Reaction mass was stirred for 30 minutes , allowed to settle for 30 minutes and layers were separated. Methyl chloride was removed by distillation under vacuume resulting oil of methyl(+)-alpha amino(2-chlorophenyl)acetate, G.C : 98% [α ]D +130.0 ( c-l,CH3OH) Example 15: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 1000 ml of methanol was added to pre cooled solution of (+)-tartaric acid , 165 gms,(l.l mole, 1.1 eq on ester) in 800 ml methanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick, slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid was isolated and dried at 55-60 °C, found to be mixture of tatrate salt of racemic ester (starting material) and tartaric acid which confirms that the resolution is not taking place in presence of solvent methanol alone. Example 16: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole ) in 1000 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,(l.l mole, 1.1 eq on ester) in 800 ml ethanol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)~alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield :65% by theory based on ester, M.pl49-152°C, [ α]D +29.16 ( c-l,CH3OH) Example 17: (+)-tartrate of methyl (+)-alpha amino(2-chlorophenyl)acetate: A solution of racemic methyl alpha-amino(2-chlorophenyl)acetate 199.5 gms, (1 mole) in 1000 ml of acetone was added to pre cooled solution of (+)-tartaric acid, 165 gms,(l.l mole, 1.1 eq on ester) in 800 ml isopropyl alcohol at 20 °C and maintained at 20 °C for 30 minutes. During this period crystallisation starts and reaction mass becomes a thick slurry. Temperature of the reaction mass was raised to 30 °C and maintained 28-32 °C for 20 hours under stirring. Reaction mass was cooled to 10 °C and maintained at 10 °C to 15 °C for 1 hour. Solid (+)-tartrate of methyl(+)-alpha amino(2-chlorophenyl)acetate was isolated and dried at 55- 60 °C. yield :72% by theory based on ester, M.pl58-162°C, [ α]D +45.51 ( c=l,CH3OH) The various ratios of acetone and methanol are illustrated in examples 9-11.While examples 12, 13 and 14 illustrate the result using acetone alone as solvent and example 15 and 16 demonstrate the result using methanol alone. Use of acetone and isopropyl alcohol is illustrated in example 17. It is found that the yield with acetone alone as solvent is from 71.98 to 74.31% which is higher than the yield achieved by the prior art methods. But the best result in terms of yield of 86% and more is achieved by the mixture of solvents methanol and acetone in defined ratio of 4:5. The yield using different ratios of methanolracetone is summarized in Table 1. The yield using different mole ratios of ester vs L (+) tartaric acid is summarized in Table 2. The distinct advantages of this process are the following: i) Single stage process ii) Higher yields of reaction above 86% iii) Less consumption of raw materials and solvents so environment friendly iv) Efficient use of resolving agent I CLAIM: 1. An in situ process for resolution of methyl 2-substituted phenylglycine esters and/or acids of the formula I by asymmetric transformation of diastereomeric salts comprising resolution of racemic 2-substituted phenylglycine esters and/or acids of formula (I)with L(+) tartaric acid in molar ratio of 0.9 to 1.4 in presence of solvent mixture of methanol and acetone in the ratio of 4:5. 2. A process as claimed in claims 1 wherein the yield of compound of formula I on resolution is above 86% 3. A process as claimed in claim 1 where in said acid and /or ester and L(+)tartaric acid are in ratio of 1:1,1. 4. A process as claimed in claim 1 wherein the temperature of the reaction is in the region of 28-32° C, preferably 30 °C. 5. A process as claimed in any preceding claim wherein the time of reaction is 16-24 hrs preferably 20 hrs at a temperature of 30 °C . 6. A process as claimed in any preceding claim wherein the resolution is followed liberation of the free base by conventional reaction of dissolving compound 1 in methylene chloride, cooling adjusting pH, removal of methylene chloride under vacuum resulting free base of the compound I as oil. 7. A process for resolution of methyl 2-substituted phenylglycine esters and/or acids of the formula I by asymmetric transformation of diastereomeric salts as herein described with reference to the examples. Dated this 22nd day of December 2006 I CLAIM: 1. An in situ process for resolution of methyl 2-substituted phenylglycine esters and/or acids of the formula I by asymmetric transformation of diastereomeric salts comprising resolution of racemic 2-substituted phenylglycine esters and/or acids of formula (I)with L(+) tartaric acid in molar ratio of 0.9 to 1.4 in presence of solvent mixture of methanol and acetone in the ratio of 4:5. 2. A process as claimed in claims 1 wherein the yield of compound of formula I on resolution is above 86% 3. A process as claimed in claim 1 where in said acid and /or ester and L(+)tartaric acid are in ratio of 1:1,1. 4. A process as claimed in claim 1 wherein the temperature of the reaction is in the region of 28-32° C, preferably 30 °C. 5. A process as claimed in any preceding claim wherein the time of reaction is 16-24 hrs preferably 20 hrs at a temperature of 30 °C . 6. A process as claimed in any preceding claim wherein the resolution is followed liberation of the free base by conventional reaction of dissolving compound 1 in methylene chloride, cooling adjusting pH, removal of methylene chloride under vacuum resulting free base of the compound I as oil. 7. A process for resolution of methyl 2-substituted phenylglycine esters and/or acids of the formula I by asymmetric transformation of diastereomeric salts as herein described with reference to the examples. Dated this 22nd day of December 2006

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