Title of Invention	AN IMPROVED PROCESS FOR THE PREPARATION OF ANTIDIABETIC COMPOUNDS
Abstract	The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula(1). where R<sup>1</sup>represents alkyl group such as methyl, ethyl, isprophyl and the like.

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This application is a divisional application of 585/MAS/Ol, filed on 18thJuly 2001. Field of the invention The present invention relates to an improved process for the preparation of ant diabetic compounds having the formula (1). where R" represents alkyl group such as methyl, ethyl, propels, isopropyl and the like. The compound of formula (I) is useful in lowering the plasma glucose, triglyceride, total cholesterol (TC); increase high density lipoprotein (HDL) and decrease low density lipoprotein (LDL). The compound of formula (I) is also useful in reducing body weight and for the treatment and / or prophylaxis of diseases such as hypertension, coronary heart disease, atherosclerosis, stroke, peripheral vascular diseases and related disorders. The compound of formula (I) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes). Background of invention In our WTO application No. 2416/MAS/97 we have described a process for the preparation of a novel ant diabetic compound having the formula (1). The process described therein comprises of converting aldehydes of formula (2) where X represents hydrogen or halogen atom to a compound of formula (3) where all symbols are as defined above and R^ represents lower alkyl group, reducing the compound of formula (3) to produce a compound of formula (4), hydrolyzing the compound of formula (4) to obtain an acid of formula (5), converting the acid of formula (5) to an amide of the formula (6) and hydrolyzing the amide to produce Scheme-1 While developing the improved process we observed that the process for the preparation of the compounds of the formula (1) as disclosed in our above referred apphcation involves • the use of exotic reactions like Wittig-Homer reaction, which is a moisture sensitive reaction, to prepare the compound of the formula (3). Moisture sensitive reactions are difficult to handle in large scale manufacturing process. • tedious reaction steps employing expensive, tedious and time consuming column chromatographic methods • the overall yield of the compounds of the formula (1) is only -2.5% and time cycle required for the completion of the reaction sequence resulting in the compounds of the formula (1) is very long which makes the process very expensive for commercial application . In our co pending application No. 2431/MAS/98 we have described process for preparing the compound of formula (1). The reaction schemes are shown below: CO2R HO (7) CHO (8) CHO BnO (9) BnO CO2R OH (10) COzR"^ OR, (12a) COzR^ Ho-U OR, (13a) (6) o H Ph Scheme-2 Though it is convergent synthetic method, the compound of formula (10) is produced in racemes mixture, which has to be resolved to get the optically pure material. OR HO OH (20) OH OR OH OH BnO BnO BnO (12) (11) (10) Scheme-3 In this process too the resolution has to be carried out for compound of formula (10). Recognizing the importance of the new ant diabetic compound, we continued the research to develop a more efficient, simple and commercially viable stereos elective process for the preparation of the said novel compounds of the formula (1). Objective of present invention The main objective of the present invention is to provide a simple and robust process for the preparation of the compound of formula (1) with high chemical and chital purity. To overcome the problem of partial recompilation during the conversion of compound of formula (10) to compound of formula (11). To avoid the use of highly reactive, difficult to handle and expensive chemicals replace with simple, inexpensive chemicals such as diethylsulphate and potassium carbonate. Detailed description of the invention Accordingly, the present invention provides an improved process for the preparation of compounds of the formula (1), where R represents alkyl group such as methyl, ethyl, propels, isopropyl and the like, which comprises : i). reacting the compound of formula (la) with alkyl halo acetates in the presence of a base and a solvent at a temperature in the range of -10 °C to 60 °C (Darzen"s condensation) to yield the glycolic ester of compound of formula (lb), where R represents alkyl group, (ii). opening the peroxide group of the glycerin ester of the compound of the formula (lb) using reducing agent in the presence of a solvent to yield a compound of the formula (Ic) where R2 is as defined above, (iii). alkyl ting the compound of the formula (Ic) using alkyl ting agent in the presence of a solvent and a base to yield compound of the formula (Ih) where R and R are as defined above, (iv). hydrolysing the compound of formula (Ih) to yield acid of the formula (Ii) where R1" is as defined above in the presence of base and solvent, (v). resolving the compound of formula (Ii) using chiral amines in the presence of solvent to produce compound of (Ig) where R1 is as defined above, (vi). reacting the compound of formula (Ig) with L-arginine in the presence of a solvent to yield compound of formula (1) where R1 is as defined above and (vii). Isolating the compound of formula (I) formed by conventional methods. 7 The reaction of the compound of the formula (la) with alkyl halo acetates such as methyl chloroacetate, methylbromoacetate, ethylchloroacetate, ethylbromoacetate, and the like to yield glycolic ester of the formula (lb) may be carried out in the presence of base such as sodium hydroxide, potassium hydroxide, sodium methodize, sodium ethnocide and the like. The reaction may also be carried out in the presence of solvents such as 8 methanol, ethanol, propanol and the like at a temperature in the range of-10 °C to 60 °C and the duration of the reaction may range from 2 to 12 h. The opening up of peroxide group of the glycerin ester of the compound of the formula (lb) may be carried out using reagents such as Raney Nickel, H2/Pd-C, borate reagents, and the like. The reaction may be carried out in the presence of solvents such as methanol, ethanol, propanol, isopropenyl and the like. The reaction may be carried out at a temperature in the range of 0 °C to 50 °C and the duration of the reaction may range from 1 to 36 h. The alkylation of compound of formula (Ic) to obtain compound of formula (Ih) may be carried out using alkyl ting agents such as diethyl soleplate, ethyl iodide or ethanol, in the presence of solvents such as hydrocarbons like benzene, toluene, xylene and the like or DMF, DMSO, MIBK, ethyl acetate and the like in alkali such as NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOs, sodium met oxide and the like. The hydrolysis of compound of formula (Ih) may be carried out in polar solvents such as alcohols such as methanol, ethanol, propanol, isopropenyl and the like or kenotic solvents such as acetone, methyl ethyl ketene and the like using aqueous alkali bases such as sodium hydroxide or potassium hydroxide to yield compound of formula (li). The resolution of compound of formula (li) may be carried out using chiral amine such as R(+) a-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine, n-octylglucosamine and the like using solvents such as alkyl ester like methyl acetate, ethyl acetate, ethyl propionates, n-butylacetate and the like. The reaction of compound of formula (Ig) with L-arginine may be carried out in the presence of solvents like (C1-C6) alcohols such as aqueous methanol, ethanol, propanol, isopropenyl and the like at a temperature in the range of 10 - 40 °C, for a period in the range of 4-24 h. It is appreciated that in any of the above mentioned reactions, any reactive group in the substrate molecule may be protected according to conventional chemical practice. Suitable protecting groups in any of the above mentioned reactions are tertiarybutyl diethyl silylchloride, methoxymethyl chloride and the like. The methods of formation and removal of such protecting groups are those conventional methods appropriate to the molecule being protected. The invention is described in the examples given below which are provided by way of illustration only and therefore should not construed to limit the scope of the invention. Example Step (i) Preparation of ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2,3-epoxy propionate To a freshly prepared sodium ethoxy (prepared by dissolving 6.95g of sodium metal in 350 ml of absolute ethanol) 4-[2-(phenoxazin-10-yl)ethoxy]benzaldehyde (50 g, 0.015 M) was added. To this mixture ethyl chloral acetate (27.7 g, 0.22 M) was added while stirring at 25-30 °C in about 30 min time. The reaction was maintained at same temperature for 12 h. Cold water was added to the reaction mass, filtered and dried the product to yield the title compound (yield 56 g), Step (ii) Preparation of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propionate A solution of ethyl-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2,3-epoxy propionate (15 g) in methanol (150 ml) was hydrogenated over 5 % Pd-C (3 g) at 60 phi pressure for 12 h at room temperature. The catalyst was filtered and the solution was concentrated to yield the title compound as thick syrup (yield 12 g). Step (iii) Preparation of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propionate To a stirred solution of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-hydroxy propionate (5 g, 0.012 M) in xylene (50 ml), potassium carbonate (4.1 g, 0.03M) and diethyl caliphate (2.75 g, 0.018M) were added and heated under reflux for 10 h. The reaction mass was cooled to room temperature, water was added, stirred for 1 h and the two layers were separated. The organic layer was washed with water and concentrated to yield the title compound as thick syrup, 4.76 g, 91.2 %. Step (iv) 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy pyromaniac acid To a stirred solution of ethyl 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propionate (15.0 g) in methanol (150 ml) at 0 °C, 10 % aqueous NaOH solution (150 ml) was added slowly in about 15-20 min and then the reaction mixture was brought to room temperature and maintained at that temperature for 10 h. Water was added and the aqueous layer was washed with toluene, acidified with dilute sulfuric acid and extracted with toluene. The organic layer was washed with water and concentrated to yield the title compound as thick syrup (yield 15.5 g, 96.4 %, purity 97.2 %). Step (v) Preparation of (S)-3- [4- [2-(phenoxazin-10-yl)ethoxy] phenyl] -2-ethoxy pyromaniac acid To a stirred solution of racemes 3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy propane acid (5.0 g, 0.012 M) in toluene (100 ml) at room temperature, (-) ephedrine (2.09 g, 0.012 M) was added and stirred for 12 h. The precipitate was filtered and washed with toluene (25 ml). The precipitate was taken in a round-bottomed flask, stirred with toluene (20 ml) and diluted with euphoric acid (15 ml). The organic layer was washed with water. To the organic layer (-) ephedrine (1.0 g, 6.0 mmol) was added and stirred for 12 h. The precipitate was filtered and washed with toluene. The precipitate was treated with toluene (15 ml) and dilute sulfuric acid (10 ml). The organic layer was washed with water and concentrated to yield the title compound as thick syrup, which was triturated with n-heptane to a fine free flowing solid (yield 1.45 g, 29 %, purity 99.08 %, diastereomer 0.42 %). Step (vi) Preparation of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyi]-2-ethoxy pyromaniac acid L-arginine salt A solution of L-Arginine (1.16 g, 6.6 mmol) in warm water (3.7 ml) was added to a stirred solution of (S)-3-[4-[2-(phenoxazin-10-yl)ethoxy]phenyl]-2-ethoxy pyromaniac acid (2.8 g, 6.6 mmol) in isopropenyl (70 ml) at 50-55 °C. After complete addition, the reaction mass was heated under reflux for 18 h. The reaction mass was cooled to 50-55 °C and the compound was flitted, washed with isopropanol and dried under vacuum at 70 °C for 6 h to yield the title compound (yield 3.0 g, 75.0 %, purity 99.27, diastereomer 0.41 %). Advantages of the present process • A convergent synthesis of the compound of the formula (1), has been developed without employing exotic and expensive chemicals, which is commercially viable, simple and efficient with safe operations even in scale-up reactions. • An easy resolution method has been developed by preparing the chiral amine salts instead of the round about procedure of preparing the diastereomeric amide of the formula (6) followed by its tedious hydrolysis. • Wherever possible resolution has been avoided thereby reducing the number of steps and loss of compound. ABSTRACT The present invention relates to an improved process for the preparation of ant diabetic compounds having the formula (1). where R" represents alkyl group such as methyl, ethyl, propel, isopropyl and the like. where R" represents alkyl group selected from methyl, ethyl, propyl or isopropyl, which comprises : i). reacting the compound of formula (la) with halo acetates in the presence of a alkali metal base and a solvent selected from alcohol, ketenes, alkyl acetate or hydrocarbon at a temperature in the range of -10 °C to 60 °C, for a period in the range of 2 to 12 h to yield the glycerin ester of compound of formula (lb), where R1 represents alkyl group selected from methyl, ethyl, propyl or isopropyl, (ii). opening the epoxide group of the glycedic ester of the compound of the formula (lb) using reducing agent in the presence of a solvent at a temperature in the range of 0 °C to 50 °C for period in the range from 1 to 36 h, to yield a compound of the formula (Ic) 14 where R2 is as defined above, (iii). alkylating the compound of the formula (Ic) using calculating agent in the presence of a solvent and a base to vied compound of the formula (Ih) where R1 and R2 are as defined above, (iv). hydrolyzing the compound of formula (Ih) to yield acid of the formula (li) where R1 is as defined above in the presence of base and solvent, (v). resolving the compound of formula (li) using chiral amines in the presence of solvent to produce compound of (Ig) where R is (vi). reacting the compound of formula (Ig) with L-argentines in the presence of a solvent at a temperature in the range of 10 - 40 °C, for a period in the range of 4-24 h, to yield compound of formula (1) where R1 is as defined above and 2.. The process as claimed in claim 1, wherein the alkylhaloacetate used in step (i) is selected from methylchloroacetate, methylbromoacetate, ethylchloroacetate or ethylbromoacetate. 3. The process as claimed in claims 1 and 2, wherein the base used in step (i) is selected from sodium hydroxide, potassium hydroxide, sodium met oxide or sodium ethoxide. 4. The process as claimed in claims Ito 3, wherein the solvent used in step (i) is selected from methanol, ethanol or propanol. 5. The process as claimed in claims 1 to 4, wherein the reducing agent used in step (ii) is selected from Raney Nickel, H2/Pd-C or borane reagents. 6. The process as claimed in claims 1 to 5,wherein the solvent used in step (ii) is selected from methanol, ethanol, propanol or isopropanol. 7. The process as claimed in claims 1 to 6, wherein the alkylating agent used in step (iii) is selected from diethyl sulphate, ethyl iodide or ethanol. 8. The process as claimed in claims 1 to 7, wherein the solvent used in step (iii), is selected from hydrocarbons such as toluene, xylene or benzene or DMF, DMSO, MIBK or ethyl acetate. 9. The process as claimed in claims 1 to 8, wherein the base used in step (iii) is selected from NaH, NaOH, KOH, t-BuOK, K2CO3, NaHCOj or sodium methoxide. 10. The process as claimed in claims 1 to 9, wherein the solvent used in step (iv) is selected from alcohols such as methanol, ethanol, propanol or isopropanol or ketonic solvents such as acetone or methyl ethyl ketone. 11. The process as claimed in claims 1 to 10, wherein the base used in step (iv) is selected from sodium hydroxide or potassium hydroxide. 12. The process as claimed in claims 1 to 11, wherein the chiral amine used in step (v) is selected from R(+) a-methylbenzylamine, S(+)-phenylglycinol, cinchonidine, ephedrine or n-octylglucosamine. 13. The process as claimed in claims 1 to 12, wherein the solvent used in step (v) is selected from methyl acetate, ethyl acetate, ethyl propanoate or n-butyl acetate. 14. The process as claimed in claims 1 to 13, wherein the solvent used in step (vi) is selected from (CpCe) alcohols such as aqueous methanol, ethanol, propanol or isopropanol.

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