Field of the invention
The present invention relates to an improved process for the preparation of antidiabetic compounds having the formula (1).

O where R represents (CI-CG) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl
and the like.
The compound of formula (1) 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 (1) 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 (1) is also useful for the treatment and/or prophylaxis of insulin resistance (type II diabetes).
Background of invention
In our WTO application No. 568/MAS/Ol we have described a process for the preparation of free acid of compound of the formula (1). The process described therein comprises of converting aldehyde of formula (10) where X represents hydrogen or halogen atom to a compound of formula (11) where R^ and R^ represents lower alkyl group, reducing the compound of formula (11) to a compound of formula (12). Condensing the compound of formula (12) with a pyrimidine derivative of formula (13) to obtain the compound of formula (14), hydrolyzing the compound of formula (14) to a compound of formula (15). Converting the acid of formula (15) to amide of formula (16) and hydrolyzing the amide of formula (16) to a compound of formula (1) where R^ is a lower alkyl group. The process is shown in scheme 1 below.


Scheme 1
The above discussed process involves
• the use of reactions like Wittig-Homer's, which is a moisture sensitive reaction, to
prepare the compound of the formula (11). Moisture sensitive reactions are difficuh
to handle in large scale manufacturing process.
• tedious reaction steps employing expensive, time consuming column chromatographic methods
• the process requires resolution to get the desired compound
• the overall yield of the compounds of the formula (1) is low 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.
Recognizing the importance of the new antidiabetic compound, we continued our research to develop a more efficient, simple and commercially viable process for the preparation of the said novel compounds of the formula (1).
Objective of the 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 purity.
Yet another objective of the present invention is to avoid the use of highly reactive, difficult to handle and expensive chemicals and replace them with simple, inexpensive chemicals such as diethylsulphate and potassium carbonate.
Detailed description of ttie invention
Accordingly, the present invention provides an improved process for the preparation of compounds of the formula (1),

where R represents (Ci-Ce) alkyl group such as methyl, ethyl, propyl, isopropyl, butyl,
isobutyl, t-butyl and the like, which comprises:
i. reacting propionitrile with dry HCl gas in the presence of a solvent at a
temperature range of 0 to 30 "^C for a period of 2 to 30 h followed by treating with methanolic ammonia at a temperature range of 0 to 30 °C for a period of 2 to 6 h to yield propionamidine hydrochloride of formula (2) ii. reacting propionamidine hydrochloride (2) with ethyl benzoyl acetate in the presence of a base and an organic solvent at a temperature range of 20 to 150 °C, for a period of 2 to 30 h, to give 2-ethyl-6-phenyl-4-pyrimidinonc of the formula (3).

reacting 2-ethyl-6-phenyl-4-pyrimidinone of the formula (3) with 2-
haloethanol in the presence of a base and an organic solvent at a temperature
range of 20 to 150 °C, for a period of 2-12 h to give a mixture of the N-
alkylated product (4a) and the 0-alkylated product (4b). These are separated
by column chromatography.
reacting the N-alkylated product of formula (4a) or the 0-alkylated product of
formula (4b) or a mixture of both with methanesulfonyl chloride in the
presence of an organic solvent and a base at a temperature range of 0 to 50 **C
for a period of 2 to 10 h, to give 2-ethyl 3-(l-methanesulfonyloxyethyl)-6-
phenyl-4-pyrimidinone of the formula (5).
condensing 2-ethyl 3-(l -methanesulfonyloxyethyl)-6-phenyl-4-pyrimidinone
of the formula (5) with a compound of formula (6) where R represents t-
butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R^ represents
hydrogen or (Ci-C6)alkyl group defined above in the presence of a base and
an organic solvent at a temperature range of 20 to 150 °C, for a period of 2 to
30 h, to give a compound of the formula (7) where R represents t-
butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group; R^ represents
hydrogen or (Ci-C6)alkyl group defined above.
desilylation followed by hydrolysis of the compound of formula (7) to a
compound of formula (8) in the presence of a base or an acid and a solvent at
a temperature range of 20 to 50 °C, for a period of 2 to 20 h.
converting the compound of formula (8) to a compound of formula (1) using
an ethylating agent in the presence of a base and a solvent at a temperature
range of -10 to 70 °C and for a period of 1 to 24 h.
the chiral purity of compound of formula (1) is enhanced by treating (1) with a
chiral amine in the presence of an organic solvent at a temperature in the
range of room temperature to the boiling point of the solvent employed for a
period of 2 to 12 h to obtain a compound of formula (9).
the salt of the formula (9) is suspended in a water immiscible organic solvent
and water and treated with aqueous mineral acid to pH 2-3 to obtain
compound of formula (1).

X. Isolating the compound of formula (1) formed, by conventional methods.
The reaction sequence is shown in scheme 2 below:

Scheme 2
Propionitrile dissolved in alcohol such methanol, ethanol, propanol, isopropanol , butanol and the like or a mixture thereof, is treated with HCl gas at a temperature range of 0 to 25 °C for a period of 2-30 h followed by treating with methanolic ammonia at a

temperature range of 0 to 30 ""C for a period of 2 to 6 h to yield propionamidine hydrochloride of formula (2).
Propionamidine hydrochloride having formula (2) is reacted with ethyl benzoyl acetate in the presence of a base such as sodium carbonate, potassium carbonate and the like, using solvents such as toluene, xylene and the like. The reaction is carried out at a temperature range of 20 to 150 **C for a period of 2 to 12 h.
2-Ethyl-6-phenyl-4-pyrimidinone of the formula (3) is reacted with 2-haloethanol such as 2-chloroethanol, 2-bromoethanol and the like in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, using solvents such as toluene, xylene, tetrahydrofuran, dimethylformamide, dimethylacetamide, diisopropyl ether, diphenylether, dimethylsulfoxide or alcohol such as methanol, ethanol, propanol, isopropanol, butanol and the like or a mixture thereof The reaction may be carried out at a temperature range of 20 to 150 "^C and the duration of the reaction may range from 2 to 12 h to provide a mixture of the N-alkylated product 2-ethyl-3-(l-hydroxyethyl)-6-phenyl-4-pyrimidinone of formula (4a) and the 0-alkylated product 2-(2-ethyl -6-phenyl —4-pyrimidinyloxy)ethanol of formula (4b). The N and O alkylated products are separated by column chromatography or used as such without separation for further reaction.
2-Ethyl-3-(l-hydroxyethyl)-6-phenyl-4-pyrimidinone of formula (4a) or 2-(2-ethyl -6-phenyl -4-pyrimidinyloxy)ethanol of formula (4b) or a mixture of (4a) and (4b) is reacted with methanesulfonyl chloride in the presence of a solvent such as chloroform, dichloromethane, dichloroethane, diisopropylether, diphenylether and the like or a mixture thereof and a base such trimethylamine, triethylamine and the like at a temperature in the range of 0 to 50 °C for a period in the range of 2 to 10 h.
Condensing 2-ethyl 3-(l-methanesulfonyloxyethyl)-6-phenyl-4'pyrimidinone of the formula (5) with a compound of formula (6) in the presence of a base such as sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide and the like, using solvents such as toluene, xylene, tetrahydrofuran, dimethylformamide, dimethylacetamide, diisopropylether, diphenylether, dimethylsulfoxide or alcohol such as methanol, ethanol, propanol, isopropanol, butanol and the like or a mixture thereof The

reaction may be carried out at a temperature in the range of 20 to 150 °C, for a period of from 2 to 30 h.
Desilylation of the compound of formula (7) is carried out under acidic conditions by using /^-toluene sulfonic acid, hydrochloric acid or an acidic resin such as amberlite or dowex and an alcohol such as methanol, ethanol, propanol, isopropanol butanol and the like or a mixture thereof at a temperature range of 0 to 30 °C for a period of 2 to 10 h. The crude product obtained is hydrolyzed in the presence of a base such as sodium hydride, sodium hydroxide, potassium hydroxide, potassium t-butoxide, potassium carbonate, sodium carbonate, sodium bicarbonate and the like or acids such as methane sulfonic acid, hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluene sulfonic acid and the hke. The hydrolysis may also be carried out in the presence of a solvent such as alcohol selected from methanol, ethanol, propanol, isopropanol, butanol and the like or a mixture thereof The reaction may be carried out at a temperature range of 20 to 50 "^C and the duration of the reaction may range from 2 to 20 h.
Converting the compound of formula (8) to a compound of formula (1) using an ethylating agent such as diethyl sulfate, ethyl iodide and the like in the presence of a solvent such as hydrocarbons like toluene, xylene and the hke or dimethylformamide, dimethylsulfoxide, methyl isobutyl ketone, ethyl acetate, N-methyl pyrrolidone and the like or a mixture thereof^ in the presence of a base such as sodium carbonate, potassium carbonate, sodium methoxide, sodium hydride, n-butyl lithium, lithium diisopropyl amine and the like. The reaction may be carried out at a temperature range of -10 to 70 °C for a period of 1 to 24 h.
The chiral purity of the compound of formula (1) is enhanced by treating (1) with a chiral base such as R(+) phenyl ethyl amine, S(+) phenylglycinol, cinchonidine, ephidrine, N-octylglucaramine, N-methylglucaramine and the like in the presence of a solvent such as toluene, xylene, methyl isobutyl ketone, ethyl acetate, acetonitrile, alcohol like methanol, ethanol, propanol, isopropyl alcohol and the like or a mixture thereof The reaction is carried out at temperature range of room temperature to the boiling point of the solvent employed for a period of 2 to 12h.

The compound of formula (1) is obtained by suspending the salt of formula (9) in a water immiscible organic solvent such as xylene, toluene, ethyl acetate and the like or a mixture thereof and water. The suspension is acidified to pH 2-3 by treating with a mineral acid such as aqueous hydrochloric acid, aqueous sulfuric acid and the like. The desired compound of formula (1) is obtained by concentrating the organic solvent.
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.

In a 2L four-necked round bottom flask with a mechanical stirrer, air condenser, guard tube, thermometer socket and a gas inlet are placed propionitrile (200g) and ethanol (236ml).The reaction mixture is cooled to 0-10 ^C and dry HCl gas (146g) is passed at the same temperature. Then the reaction mixture is allowed to reach room temperature and stirring is continued for about 24hrs. Methanolic ammonia (1200ml) is slowly added to the reaction mixture at 0-5 ^C and stirring is continued at room temperature for about 4h. The precipitated solid is filtered and the filtrate is evaporated to get the title compound (389g, yield 98.5%).

In a lOL three necked round bottom flask with a mechanical stirrer, Dean-Stark, condenser are placed, propionamidine hydrochloride obtained in preparation 1 (380g), toluene, ethyl benzoyl acetate (560g) and potassium carbonate (1006g). The reaction mixture is refluxed and water is removed azeotropically. Refluxing is continued further for 24 hrs. The reaction mixture is filtered under hot condition. Filtrate is dumped in

water and acidified with hydrochloric acid and stirred for one hour. The precipitated solid
is filtered and dried in oven (375g, yield 64.6%).
Preparation 3 2-EthyI-3-(l-HydroxyethyI)-6-phenyl-4-pyrimidinone(4a)(N-alkylated)
In a 5L four necked round bottom flask, with a mechanical stirrer, air condenser, guard tube and thermometer socket are placed, DMF, potassium carbonate (638g) and 2-ethyl-6-phenyl-4-pyrimidinone obtained in preparation 2 (370g). 2-choloroethanol (223.3g) is added drop wise at room temperature. Then reaction mixture is heated to 90-lOO^C. When the reaction is complete the reaction mixture is filtered and the filtrate is diluted with water and extracted with ethyl acetate. The combined organic layers are washed with water and evaporated (386g, yield 85.5%). Compoimds (4a) and (4b) were separated by column chromatography.

In a 5L four necked round bottom flask with a mechanical stirrer condenser, guard tube, thermometer socket and dropping furmel are placed DCM, 2-ethyl-3-(l-hydroxyethyl)-6-phenyl-4-pyrimidinone (4a) obtained in preparation 3 (380g) and triethylamine (267g). Methanesulfonyl chloride (267.4g) was added drop wise to the above reaction mixture between 0 to 10 **C. After the addition is complete the reaction mass is maintained at room temperature for two hours. The reaction mass is washed with water and the organic layer is evaporated to get the title compound. (417g, yield 83 %)


In a 5L four necked round bottom flask with a mechanical stirrer condenser, guard tube, thermometer socket and dropping funnel are placed DCM, 2-(2-ethyl -6-phenyl -4-pyrimidinyloxy -1-ethanol (4b) obtained in preparation 3 (380g) and triethylamine (267g). Methanesulfonyl chloride (267.4g) was added drop wise to the above reaction mixture between 0 to 10 ^C. After the addition is complete the reaction mass is maintained at room temperature for two hours. The reaction mass is washed with water and the organic layer is evaporated to get the title compound. (417g, yield 83 %)
III 1» ■*■ In a 5L four necked round bottom flask with a mechanical stirrer condenser, guard tube,
thermometer socket and dropping funnel are placed DCM, a mixture of 2-ethyl-3-(l-
hydroxyethyl)-6-phenyl-4-pyrimidinone (4a) and 2-(2-ethyl -6-phenyl -4-pyrimidinyloxy
-1-ethanol (4b) obtained in preparation 3 (total 380g) and triethylamine (267g).
Methanesulfonyl chloride (267.4g) was added drop wise to the above reaction mixture
between 0 to 10 "*€. After the addition is complete the reaction mass is maintained at room
temperature for two hours. The reaction mass is washed with water and the organic layer
is evaporated to get the title compound. (417g, yield 83 %)
Preparation 7
2-Hydroxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyH,6-dihydro-l-pyrimidinyl]ethoxy] phenyl] propionic acid


In a 500 ml 4 necked round bottom tlask arranged witn mecnamcai stirrer, uean-btarK, condenser are placed toluene, potassium carbonate (27.8g), methyl-2 (S)-tertiary butyl dimethyl silyloxy-3-(4-hydroxyphenyl)propionate (25g) and 2-ethyl-3-(l-methane sulfonyloxy ethyl)-6-phenyl-4-pyrimidinone obtained in preparation 4 (28.5g). Reaction mixture is heated to reflux and maintained for 15hrs. The reaction mass is cooled to room temperature and water is added. The aqueous layer separated is extracted with toluene. The combined organic layers are concentrated to get the compound. This crude compound is dissolved in methanol and PTSA is added. This reaction mass is maintained at room temperature for 4hrs. After completion of the reaction (desilylation), reaction mass is hydrolyzed by adding 10% aqueous sodium hydroxide solution dropwise at 0^ to lO^c. The reaction mass is maintained at room temperature for 5 hrs. After completion of the reaction, the reaction mass is diluted with water and washed with toluene. Aqueous layer is acidified with hydrochloric acid and extracted with ethylacetate. Ethyl acetate layer is concentrated and precipitated with pet ether. The resultant compound is filtered

Preparation 8
2-Hydroxy-3-[4-[2-[2-ethyI-6-oxo-4-phenyH ,6-dihydro-l-pyrimidinyl] eth oxy ]
phenyl] propionic acid


In a 500 ml 4 necked round bottom flask arranged with mechanical stirrer, Dean-Stark, condenser are placed toluene, potassium carbonate (51.0g), isopropyl-2 (S)-tertiary butyl dimethyl silyloxy-3-(4-hydroxyphenyl)propionate (25g) and 2-ethyl-3-( 1 -methane sulfonyloxy ethyl)-6-phenyl-4-pyrimidinone obtained in preparation 4 (26. Ig). Reaction mixture is heated to reflux and maintained for 15hrs. The reaction mass is cooled to room temperature and water is added. The aqueous layer separated is extracted with toluene. The combined organic layers are concentrated to get the compound. This crude compound is dissolved in methanol and PTSA is added. This reaction mass is maintained at room temperature for 4hrs. After completion of the reaction (desilylation), the reaction mass is hydrolyzed by adding 10% aqueous sodium hydroxide solution dropwise at 0^ C to lO^c. The reaction mass is maintained at room temperature for 5 hrs. After completion of the reaction, the reaction mass is diluted with water and washed with toluene. Aqueous layer is acidified with hydrochloric acid and extracted with ethylacetate. Ethyl acetate layer is concentrated and precipitated with pet ether. The resultant compound is filtered and dried. (23g, yield 92.1%)


In a 500ml 4 necked round bottom flask arranged with mechanical stirrer, reflux condenser are placed isopropyl alcohol, potassium carbonate (38.5g), isopropyl-2-hydroxy-3-(4-hydroxphenyl) propionate(25g) and 2-ethyl-3-(l-methane sulfonyloxy ethyl)-6-phenyl-4-pyrimidinone obtained in preparation 4 (36g). Reaction mixture is heated to reflux and maintained for 15hrs. The reaction mass is cooled to O^c and 10% and aqueous sodium hydroxide solution is added drop wise at 0 to lO^c. The reaction mass is maintained at room temperature for 5 hrs. After completion of the reaction the reaction mass is diluted with toluene and the layers are separated. Aqueous layer is discarded. Organic layer is diluted with water. The aqueous layer is washed with toluene, acidified with hydrochloric acid and extracted with ethyl acetate. Ethyl acetate layer is concentrated and precipitated with pet ether. The resultant compound is filtered and dried. (23 g, yield 87.3 %)

Example 1
2-Ethoxy-3-[4-[2-[2-ethyl-6-oxo-4-phenyl-l,6-dihydro-l-pyrimidmyllethoxy] phenyl]propioiiic acid

In a 500 ml round bottom flask arranged with a mechanical stirrer, condenser, guard tube are placed sodium hydroxide (12.7g) and toluene. To this diethyl sulfate (24.6g) is added dropwise at room temperature. After the addition is complete the reaction mass is stirred for Ihr and 2-hydroxy-3-[4-[2-[2-ethyl-4-phenyl-l,6-dihydro-l-pyrimidinyl]ethoxy]

phenyljpropionic acid obtained in preparations 5-7 (25g dissolved in NMP) is added maintaining the same temperature The reaction mass is kept for stirring at room temperature for 8hrs. The reaction mass is diluted with cold water and washed with toluene. The aqueous layer is separated, acidified with 25%.sulfuric acid and stirred for Ihr. The resulted compound is filtered and dried. (21 g, yield 78.6%).

Example 2 2-Ethoxy-3-[4-[2"[2-ethyl-6-oxo-4-phenyH,6-dihydro-l-pyrimidiiiyl]ethoxy]phenyl]
propionic acid
n
Step i.
In a 250 ml round bottom flask arranged with a mechanical stirrer, condenser, guard tube
are placed isopropyl alcohol and 2-ethoxy -3-[4-[2-[2-ethyl -6-oxo -4-phenyl -1,6-dihydro -l-pyrimidinyl]ethoxy]phenyl]propionic acid obtained in example 1 (20g). The reaction mass is heated to reflux to get a clear solution. Then R(+) phenyl ethyl amine is added (5.4g) drop wise and the reaction mixture is maintained at reflux for 2 hrs. Then the temperature is allowed to reach room temperature and maintained for 6 hrs. The resulted compound filtered and dried under vacuum. (14g)

step ii
The above salt is suspended in toluene and water to this 25% aqueous sulfuric acid is
added slowly drop wise with vigorous stirring to adjust the pH 2-3. The layers are separated and aqueous layer is extracted into toluene. The combined organic layers are washed with water and evaporated on rotavapour to 1/4 of its volume. Then n-heptane is added portion wise with vigorous stirring and stirring is continued for 2 hr. The precipitated compound is filtered and dried under vacuum.(!Og)
Advantages of the present process
• A new process for the preparation of the compound of 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.
• The N-alkylated product as well as the 0-alkylated product provide the same intermediate, hence it is not necessary to separate the alkylated products thereby not affecting the overall yield of the reaction sequence.
• The process provides the compound of formula (1) as a single enantiomer,
• Further purification to enhance the chiral purity does not drastically reduce the overall yield.

We claim:
1. An improved process for the preparation of compound of formula (1),

i. reacting propionitrile with HCl gas in the presence of alcohol as solvent at a
temperature range of 0 to 30 °C for a period of 2 to 30 h followed by treating with methanolic ammonia at a temperature range of 0 to 30 °C for a period of 2 to 6 h to yield propionamidine hydrochloride of formula (2)

ii. reacting propionamidine hydrochloride (2) with ethyl benzoyl acetate in the presence of an alkali metal carbonate base and a hydrocarbon as a solvent at a temperature range of 20 to 150 °C, for a period of 2 to 30 h, to give 2-ethyl-6-phenyl-4-pyrimidinone of the formula (3).

iii. reacting the compound of formula (3) with 2-haloethanol in the presence of an alkali metal carbonate or alkali metal hydroxide as a base and a hydrocarbon or ether or dialkylsulfoxide or alcohol as a solvent at a temperature range of 20 to 150 °C for a period of 2 to 12 h to provide a mixture of the N-alkylated product: 2-ethyl-3-(l-hydroxyethyl)-6-phenyl-4-pyrimidinone of formula (4a) and the 0-alkylated product 2-(2-ethyl -6-phenyl -4-pyrimidinyloxy)ethanol of formula (4b). The N and O alkylated products are separated by column chromatography or used as such without separation for further reaction.


iv. reacting 2-ethyl-3-(l-hydroxyethyl)-6-phenyl-4-pyrimidinone of formula (4a) or 2-(2-ethyl -6-phenyl -4-pyrimidinyloxy)ethanol of formula (4b) or a mixture of (4a) and (4b) with methanesulfonyl chloride in the presence of a chlorinated hydrocarbon or ether as a solvent and trialkyl amine as base at a temperature range of 0 to 50 °C for a period of 2 to 10 h to provide a compound of formula (5)

where R represents t-butyldimethyl silyl, trimethyl silyl or alkoxyalkyl group and R1 represents hydrogen or (C1-C6)alkyl selected from methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl or hexyl in the presence of an alkali metal carbonate or alkali metal hydroxide as a base and a hydrocarbon or ether or dialkylsulfoxide or alcohol as a solvent at a temperature range of 20 to 150 °C for a period of 2 to 30 h to provide a compound of formula (7)


vi. desilylation of the compound of formula (7) in the presence of a mineral acid or an organic acid or an acidic resin and an alcohol as solvent at a temperature range of 0 to 30 °C for a period of 2 to 10 h. The crude product obtained is hydrolyzed under alkaline or acidic conditions in the presence of an alkali metal hydride or alkali metal hydroxide or alkali metal alkoxide or alkali metal carbonate as base or mineral acid or organic acids as an acid and alcohol as a solvent to provide a compound of formula (8)

vii. etherification of the compound of formula (8) in the presence of diethyl sulfate or ethyliodide as an ethylating agent and alkali metal carbonate or alkali metal alkoxide, or alkyl lithium or alkali metal hydride as base and a hydrocarbon or a ketone or an ester or dialkylsulfoxide or dimethylformamide or N-methyl pyrrolidinone as a solvent at a temperature range of -10 to 70 °C for a period of 1 to 24 h to provide a compound of the formula (1)

viii. the chiral purity of the compound of formula (1) is enhanced by reacting the compound of formula (1) with a chiral amine in the presence of a hydrocarbon or ketone or alkylnitrile or ester or alcohol as a solvent at a temperature range of room temperature to the boiling point of the solvent employed for a period of 2 to 12h to provide the salt of formula (9)


ix. the salt of formula (9) is suspended in a water immiscible organic solvent and
water and acidified with a mineral acid to pH 2-3
X. isolating the compound of formula (1) formed, by conventional methods.
2. The process as claimed in claim 1 wherein the solvent used in step (i) is selected from alcohol like methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof
3. The process as claimed in claim 1 wherein the base used in step (ii) is selected from alkali metal carbonate like sodium carbonate or potassium carbonate.
4. The process as claimed in claim 1 wherein the hydrocarbon solvent used in step (ii) is selected from toluene or xylene.
5. The process as claimed in claim 1 wherein the haloethanol used in step (iii) is selected from 2-chloroethanol or 2-bromoethanol.
6. The process as claimed in claim 1 wherein the base used in step (iii) is selected from alkali metal carbonate like sodium carbonate or potassium carbonate; alkali metal hydroxide like sodium hydroxide or potassium hydroxide.

7. The process as claimed in claim 1 wherein the solvent used in step (iii) is selected from a hydrocarbon like toluene or xylene; ether like diisopropylether or diphenylether; dialkylsulfoxide like dimethylsulfoxide; alcohol like methanol, propanol, isopropanol, butanol or a mixture thereof.
8. The process as claimed in claim 1 wherein the solvent used in step (iv) is selected from a chlorinated hydrocarbon like chloroform, dichloromethane or dichloroethane; ether like diisopropylether or diphenylether.
9. The process as claimed in claim 1 wherein the base used in step (iv) is selected from trimethylamine or triethylamine,
10. The process as claimed in claim 1 wherein the base used in step (v) is selected from alkali metal carbonate hke sodium carbonate or potassium carbonate; alkali metal hydroxide like sodium hydroxide or potassium hydroxide.
11. The process as claimed in claim 1 wherein the solvent used in step (v) is selected from a hydrocarbon like toluene or xylene; ether like diisopropylether, diphenylether or tetrahydrofuran; dialkylsulfoxide like dimethylsulfoxide; alcohol like methanol, propanol, isopropanol, butanol or a mixture thereof

12. The process as claimed in claim 1 wherein the acid used for desilylation in step (vi) is selected from hydrochloric acid, p-toluene sulfonic acid or an acidic resin like amberlite or dowex.
13. The process as claimed in claim 1 wherein the solvent used for desilylation in step (vi) is selected from an alcohol like methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof
14. The process as claimed in claim 1, wherein the base used for hydrolysis in step (vi) is selected from an alkali metal hydride like NaH; alkali metal hydroxide like sodium hydroxide or potassium hydroxide; alkali metal alkoxide like potassium tertiary butoxide; alkali metal carbonate like sodium carbonate, potassium carbonate or sodium bicarbonate.
15. The process as claimed in claim 1, wherein the acid used for hydrolysis in step (vi) is selected from mineral acid like hydrochloric acid or sulfuric acid; organic acid like methane sulfonic acid,/?- toluene sulfonic acid or trifluoroacetic acid.
16. The process as claimed in claim 1, wherein the solvent used for hydrolysis in step (vi) is selected from alcohol like methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof
17. The process as claimed in claim 1, wherein the base used in step (vii) is selected from alkali metal carbonate like sodium carbonate or potassium carbonate; alkali metal alkoxide like sodium methoxide; alkyl lithium like n-butyl lithium or lithium diisopropyl amine; alkali metal hydride like sodium hydride.
18. The process as claimed in claim 1, wherein the solvent used in step (vii) is selected from a hydrocarbon like toluene or xylene; ketone like methyl isobutyl ketone; ester like ethyl acetate; dialkylsulfoxide like dimethylsulfoxide.
19. The process as claimed in claim 1, wherein the chiral amine used in step (viii) is selected from R(+) phenyl ethyl amine, S(+) phenylglycinol, cinchonidine, ephidrine, N-octylglucaramine or N-methylglucaramine.
20. The process as claimed in claim 1, wherein the solvent used in step (viii) is selected from hydrocarbon like toluene or xylene; ketone like methyl isobutyl ketone; alkylnitrile like acetonitrile; ester like ethyl acetate; alcohol like methanol, ethanol, propanol, isopropanol, butanol or a mixture thereof

21. The process as claimed in claim 1, wherein the water immiscible organic solvent used in step (ix) is selected from xylene, toluene or ethyl acetate.
22. The process as claimed in claim 1, wherein the mineral acid used in step (ix) is selected from hydrochloric acid or sulfuric acid.
23. A process for the preparation of compound of the formula (1) as described in claims 1-22, substantially as herein described with reference to examples 1-2.