Indian Patents. 238331:A NOVEL PROCESS FOR THE PREPARATION OF (+)-(3R-5S)-7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N-METHYL-N-METHANESULFONYLAMINO)PYRIMIDIN -5-YL]-3,5-DIHYDROXY-6-(E)-HEPTENOIC ACID CALCIUM SALT

Title of Invention	A NOVEL PROCESS FOR THE PREPARATION OF (+)-(3R-5S)-7-[4-(4-FLUOROPHENYL)-6-ISOPROPYL-2-(N-METHYL-N-METHANESULFONYLAMINO)PYRIMIDIN -5-YL]-3,5-DIHYDROXY-6-(E)-HEPTENOIC ACID CALCIUM SALT
Abstract	A novel process for the preparation of a compound of formula

Full Text	A novel process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yI]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1). FIELD OF THE INVENTION This invention relates to a novel chemical process, and more particularly it relates a novel chemical process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluoro phenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1). Formula I Which is pharmaceutically useful in the treatment of, inter alia, hypercholesterolemia hyperlipoproteinemia and antherosclerosis. The invention further includes the novel starting material used in said process and the use of the process in the manufacture of an HMG CoA reductase inhibitor. BACKGROUND FO THE INVENTTON European patent 0521 471 Bl disclosed that (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6- (E)-heptenoic acid and its pharmaceutically acceptable salts and process for it's preparation. It is illustrated below. R= H, Na+, Ca+2 (Hereinafter referred to collectively as "The Agent" as inhibitors of HMG CoA reductase). The process for the preparation comprises of reduction of ethyl [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-methyl-N-methane sulphonyl amino pyrimidin-5-carboxylate with DIBAL-H to give hydroxy compound. Hydroxy compound is oxidized with 4-methyl morpholin -N-oxide and TPAP to give an aldehyde. Aldehyde is further condensed with (3R)-3-(tert-butyl dimethyl silyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoic acid derivative to give an olefin compound and tert-butyl dimethyl silyl group is removed by the hydrolysis with hydrogen halide and it is further reacted with diethyl methoxy borane and sodium borohydride to give dihydroxy compound. Dihydroxy compound is hydrolyzed with base to form free acid of the title compound. Calcium salt of title compound is prepared from the acid by using calcium chloride. The generation of the phosphorane side chain requires eight synthetic steps and involves expensive reagents. The process is both uneconomical and time consuming, hence not suitable for commercial production. Therefore, the main objective of the present invention is to prepare formula-1 in novel method, which is cost-effective, commercially viable and non-hazardous. The formula-1 is prepared in the present invention; in a novel process that is cost effective and suitable for commercial scale up. SUMMARY OF THE INVENTION The present invention provides a process and novel intermediates for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl -N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid and its pharmaceutically acceptable salts with less number of stages and the using commercially available raw materials as well as cost effective. According to the present invention yields and quality of the product are found good. According to the present invention formula-1 is prepared by using ethyl -4-chloro-3-hydroxy butanoate as a key starting material. Hydroxy group is protected with the reaction of tert-butyl dimethyl silyl chloride in presence of a acid trapping agent to give compound (a). It is reacted with sodium acetate in presence of phase transfer catalyst to give compound (b). Compound (b) is hydrolyzed to give compound (c) and it is further oxidized with a mild oxidizing agent like sodium hypochlorite in presence of TEMPO (2,2,6,6-tetramethyl piperidinyloxy free radical) to give the compound (d). Compound (d) is condensed with an aromatic compound (e) (it is disclosed in the prior art) in the presence of a strong base to give compound (f). It is further condensed with tert-butyl acetate in the presence of a strong base like Na HMDS to give compound (g). Compound (g) is under goes selective reduction to give compound (h), it is further hydrolyzed and to give the acid compound of the title compound. It is further converted into a salt (i) with reaction of a organic base of which a Nitrogen containing one or two alkyl or cyclo alkyl or aryl alkyl or cyclo alkyl having hetero atoms, for example, substiuents like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine, Morpholine or alkyl amines such as isopropyl amine, disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as, phenyl ethyl amine, phenyl propyl amine. This salt optionally re crystallized in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol. The purpose of salt conversion with organic base and re crystalisation is to get higher purity (i.e >99%, preferably >99.8% of purity), particularly diene impurity, and any other impurities which is to be level of more than 0.2% is washed out at the level of below 0.1%. The organic amine salt formation and crystallization can be done for the acid compound of Formula-I to get higher purity, irrespective of the synthetic route. Finally it is converted into calcium salt with calcium chloride. Synthetic scheme is as follows. DETAILED DESCRIPTION OF THE INVENTION According to the present invention there is provided a process for preparing formula-1, which comprises protection of ethyl-4-chloro-3-hydroxy butanoate with tertiary butyl dimethyl silyl chloride in appropriate solvent like tetrahydrafuran or dichloro methane with a acid trapping agent such as organic base like triethyl amine, DIPEA or a inorganic base like sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate. The above reaction is carried out -30 to 70°C, preferably at around room temperature, for 10 minutes to 10 hrs, preferably for 30 minutes 3hrs. The obtained protected compound (a) is subjected to reaction with sodium acetate in presence of tetrabutyl ammonium bromide in toluene as a solvent to give the compound (b). The reaction is performed for 1-30 hrs preferably for 10-15 hrs under reflux condition. Compound (b) has the following structure. The compound (b) is subjected to hydrolysis in appropriate solvent such as an alcoholic solvent like methanol, ethanol isopropyl alcohol, butanol, in the presence of a base to give the compound (c). Compound ( c) has the following structure. The compound (c) is oxidized with a mild oxidizing agent like sodium hypochlorite in presence of a free radical initiator in appropriate solvent such as dichloromethane, toluene, tetrahydrofuran. This reaction is conducted preferably at -30 to 50°C and more preferably at -10 to 20°C for 10 minutes to 5 hrs, preferably for 30 minutes to 2 hrs to give compound (d ), Compound ( d) has the following structure. Compound (d) is further condensed with an aromatic intermediate i.e. Diphenyl (4-(4-fluoro phenyl)-6-isopropyl-2-(N-methyl-N-methane sulphonylamino) pyridin-yl methyl) phosphine oxide (e) (Preparation of this compound is disclosed in the prior art) in the presence of a strong base to give the compound (f) . The reaction is illustrated below. (e) (f) The process is carried out in a suitable solvent or mixture of solvent for example ethereal or aromatic solvents as mixtures thereof. Particularly suitable solvents like Tetrahydrofuran (THF), dimethoxy ethane and toluene, or mixtures thereof. Preferably THF or THF and toluene. Suitable bases for use in the process like amide bases, alkyl metals and metal hydrides. Particular bases include, for example, sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide, and butyllithium and sodium hydride. Particularly more preferred base is for example sodium bis (trimethyl silyl) amide (Na HMDS). The reaction may be carried out at a temperature in the range of, for example, -20°C to -90°C, such as -40°C to - 90°C, for example -40°C to-80°C preferably -75to -80°C. A convenient temperature at which to carried out the reaction is, for example, that of a mixture of acetone and solid carbon dioxide.(about - 75°C.) Compound (f) is further condensed with tertiary butyl acetate to give compound (g), in appropriate solvent such as ethers, hexanes, dioxane, toluene, cyclohexane, or any other inert organic solvent. The organic solvent is most preferably tetrahydrofuran. The reaction is carried out with strong base like, NaNHb, KHMDS, KNH2, a lithium amide compound such as lithium di isopropyl amide or Li HMDS, most preferably LiHMDS. The reaction is carried out at a temperature of from about 25 °C to about -90°C, most preferably from about -40°C to about-78°C, and it is conducted under an inert atmosphere such as nitrogen or argon. Compound (g) has the following structure. Compound (g) is further reduced by using a reducing agent which include sodium borohydride, zinc borohydride, lithium borohydride, preferably sodium borohydride. It is preferred in this step to prepare a compound of formula (h) having the preferred stereoisomeric configuration. Stereospecificity of the reduction reaction may be achieved by the use of a hydride reducing agent. Particularly high stereospecificity may be achieved by the use of a combination of sodium borohydride and a trialkyl borane. The reducing agent employed is most preferably a mixture if triethyl borane or an alkoxydialkylborane such as methoxy diethyl borane and sodium borhydride. The stereospecific reduction is preferably carried out by addition of borane reagent followed by sodium borohydride, at the end of the reduction, the formed borane complex may be hydrolyzed by a peroxide such as hydrogen peroxide or by alkaline solution. The reaction is carried out at a temperature of from about -30 °C to about -90°C? most preferably from about -60°C to about-80°C, and it is conducted under an inert atmosphere such as nitrogen or argon. Compound (h) has the following structure. Compound (h) in which ester group is hydrolyzed to acid under basic condition and neutralization to get free acid, then reacts with a organic base to give compound (i). which comprising of, cleavage of the tert-butyl ester group under basic conditions for example by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in ethanol or acetonitrile to form the sodium salt, followed by neutralization to give an acid compound of the formula-1, it is further reacted with a organic base like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as isopropyl amine,disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine, phenyl propyl amine to give a salt of compound of formula (i). This salt optionally recrystallined in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol. The product of above salt was analyzed by HPLC, using a liquid chromatograph equipped with variable wavelength UV-Detector, set at 242 nm. The coloumn is inertsil, CI8 ODS-3V 250X 4.6 mm; 5 μm and the eluent 20% acetonitrile,40% methanol,40% 0.05 M Na H2P04 2 H20 buffer at pH 2.0, flow rate of 1.0 ml per minute, injection volume 20 microliters. The sample is prepared by diluting 0.025 gm of the sample to 100 ml with 4:5:1 water, acetonitrile, methanol. The product peak elutes at 11-14 minutes and diene impurity elutes at RRT ~1.1. The invention is further illustrated, but not limited by the following examples. Examples: Example: 1 Preparation of (S) -4-chloro-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester (formula-a). A solution of (S)-4-chloro -3- hydroxy butanoic acid ethyl ester (50 gm) is diluted with dichloro methane (100 ml) and triethyl amine (25 ml) and cooled to 20°C and added the solution of tert-butyl dimethyl silyl chloride (68 gm) and dichloromethane (50 ml) slowly in 45 minutes. Reaction is maintained for 2 hrs at 25°C. Reaction mass is filtered and removed the byproduct and the organic layer is washed water(2xl00 ml) and separated the organic layer and water layer. Organic layer is dried with sodium sulfate and distilled the solvent completely under vacuum. Residue weight (67 gm), which is carried forward to the next stage without further purification. Example:2 Preparation of (S) -4 -Acetyl -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester (formula-b). 50 gms of (S) -4-chloro-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester,toluene (200 ml)5 sodium acetate (44 gm) and tetrabutyl ammonium bromide (118 gm) are heated to reflux and maintained for 12 hrs at reflux. Reaction mass is quenched with chilled water and stirred for 20 minutes. Organic layer separated and washed with water(50ml) and dried with sodium sulfate and distilled the solvent completely under vacuum. Wash the residue with hexane and decant the hexane layer, yield (35 gm). Example:3 Preparation of (S) -4 -hydroxy -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester (formula-c). 50 gms of (S) -4-acetyl-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester is dissolved in methanol (250 ml), and charged potassium carbonate and cooled to 0-5°C, maintained the reaction mass at 0-5 °C for 2 hrs Reaction mass is quenched with chilled water and stirred for 20 minutes. Reaction mass is extracted with ethyl acetate (3x100 ml) and organic layer washed with brine and water(50ml) and dried with sodium sulfate and distilled the solvent completely under vacuum, yield (35 gm). Example:4 Preparation of (S) -3 -formyl -3 - tert-butyl dimethyl silyloxy propanoic acid ethyl ester (formula-d). (S) -4 -hydroxy -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester (25 gm) is dissolved in dichloromethane and cooled to 0-5°C. KBr (lgm), TEMPO (0.1 gm) (2,2,6,6-tetramethyl piperidinyloxy free radical) were added to the same R.B.Flask. The pH of NaOCl solution was adjusted to 9.2 with saturated NaHC03 in another R.B.Flask and this solution is added into the above reaction mass at 0-5°C in 60 minutes and maintained for another 30 minutes at 0-5°C. The reaction mass is quenched with sodiumthiosulphate solution 10% solution (50 ml), separated the organic layer and washed the organic layer with water (50 ml Organic layer is dried with sodium sulfate and distilled completely under vacuum, yield (10 gm). Example:5 Preparation of (+) -5- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3 S) hydroxy-(E)-5- pentenoic acid ethyl ester (formula-e). A mixture of Diphenyl (4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methane sulphonylamino) pyridin-yl methyl) phosphine oxide (12 gm) (DPPO) and THF (120 ml) were warmed briefly to 40°C until a clear solution had formed then inserted by the sequential application of vacuum and nitrogen. The mixture was immersed in an acetone / CO2 bath cooling the contents to -75°C. Sodium bis (trimethyl silyl) amide (30 ml) was added to the reaction mixture over 30 minutes dropping funnel maintaining the temperature below -75 °C and forming a red solution of the anion. THF (10 ml) was rinsed through the dropping funnel into the mixture and the mixture stirred a further 1 hr at -70°C to -75°C forming a red suspension. (S) -3 -formyl -3 - tert-butyl dimethyl silyloxy propanoic acid ethyl ester (6 gm in 50 ml of toluene) was added in portions in the suspension over 30 minutes from dropping funnel maintaining the temperature below -70°C and stirred the mixture further 15 minutes at -70°C to -75°C. The chilling bath was lowered and the suspension allowed to warm to 10°C over 1.0 hr. quenched the reaction mass with glacial Acetic acid (3 ml) in water (30 ml) and raise the temperature to 18°C to dissolve all solids. The reaction mixture stirred further 5 minutes. Reaction mass diluted further with water and separated the organic layer. Washed the organic layer with sodium bicarbonate solution (10%) 60 ml and followed by washing with saturated sodium chloride solution (50 ml). Distill the organic layer under high vacuum and crude product isolated in n-hexane. Recovery DPPO isolated by slurry of above crude in diisopropyl ether at room temperature by filtration. Filtrate is concentrated by distillation under vacuum. Obtained residual product. Yield (8 gm). Example:6 Preparation of Tert- butyl (+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl- N-methyl sulfonyl amino) pyrimidin-5 yl ] -(5 S) hydroxy -3- oxo-(E)-6-heptenoate (formula-g). 850 ml of 1 molar LiHMDS solution is cooled to -75°C and tert-butyl acetate (70 ml) is added slowly in 45 minutes and maintained for 30 minutes at -75°C. (+) -5- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3 S) hydroxy pentanoic acid ethyl ester (50 gm) solution in tetrahydrofuran (250 ml) is added in 45 minutes at -75°C and maintained for 4 hrs at -75°C. Reaction mass is quenched with chilled water and hydrochloric acid solution. Separated the organic layer and washed with 10% sodium bicarbonate solution (100 ml) followed by water (100 ml) and brine solution. Finally dried the organic layer with sodium sulfate and distilled the solvent completely under vacuum. Residue is purified with pet-ether at -10 to -5°. Yield (70 gm). Example:7 Preparation of Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (formula-h). Tert- butyl (+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] ~(5 S) hydroxy -3- oxo-(E)-6-heptenoate (50 gm) is dissolved in 250 ml of tetrahydrofuron and cooled to -75°C and diethyl methoxy borane (60 ml) is added slowly in 45 minutes to the reaction mass. Maintained the reaction mass at -75°C for another 30 minutes and sodium borohydride is added in 5 lots. Maintained the reaction for 3 hrs at -75°C. Then the reaction mass is quenched with hydrogen peroxide solution and separated the organic layer and washed with 10% sodium bicarbonate solution followed by water and brine solution. Finally organic layer is dried with sodium sulfate and solvent completely distilled under vacuum. Residual material recrystallised in acetonitrile solvent.Yield( 38 gm). M.R: 130-136°C. Example:9 Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid dicyclohexyl amine (formula-i) Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R55S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile (100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Reaction mass is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Dicyclohexyl amine(3 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). It is re crystallized in mixture of acetonitrile and isopropyl alcohol solvents and dried the obtained product at 40-45°C for 5 hrs. Yield (7.5 gm). HPLC Purity: 99.84%, Example: 10 Preparation of (+)-(3R,5S)-7-[4-(4-FIuorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid dicyclohexyl amine (formula-i) (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1) of HPLC Purity is 98% and diene impurity: 1.2% ( 25gm) is dissolved in acetonitrile (250 ml) and cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Dicyclohexyl amine 10 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 200 ml of acetonitrile and raised the temperature to 25-30°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at 40-45°C for 5 hrs. Yield (28.5 gm). HPLC purity 99.8%, diene impurity (RRT: -1.1) 0.08%. Example: 11 Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid phenyl ethyl amine (formula-i) Tert-butyl-(H-) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile (100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Reaction mass is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Phenyl ethyl amine (3.5 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at 40-45°C for 5 hrs. Yield ( 8.0 gm) HPLC purity: 99.78%. Example: 12 Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid phenyl ethyl amine (formula-i) (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1) ( 25gm) is dissolved in acetonitrile (250 ml) and cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution, phenyl ethyl amine (12gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 200 ml of acetonitrile and raised the temperature to 25-30°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at 40-45°C for 5 hrs. Yield (25 gm). Example: 13 Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid tert-butyl amine (formula-i) Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile (100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Reaction mass is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Tert-butyl amine (3 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at40-45°Cfor5hrs. Yield (7.0 gm). Example: 14 Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1) (formula-I) Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile(100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Distilled the solvent completely under vacuum at below 50°C. Reaction mass is diluted with D.M.Water (150 ml). Calcium chloride (15 gm) in D.M.Water(50 ml) solution is added in 15-20 minutes to the reaction mass and mass is maintained for another 45 minutes and filtered the cake and washed with D.M.Water (50 ml). Dried the obtained product at 40-45°C for 15 hrs. Yield (7 gm). Claims: 1. Novel process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:l),which comprises of, i. Protecting the hydroxy group in ethyl -4-chloro-3-hydroxy butanoate with tertiary butyl dimethyl silyl chloride in appropriate solvent like tetrahydrafuron or dichloro methane with an acid trapping agent, such as organic base like triethyl amine or an inorganic base like sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate and it is carried out at a temperature in the range of-30 to 0°C for 10 minutes to 10 hrs. ii. Acylation of (S) -4-chloro-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester obtained in the step-i, with sodium acetate in presence of phase transfer catalyst like tetra butyl ammonium bromide in a solvent having boiling point more than 60°C or without solvent and the reaction is carried out at a temperature in the range of 0 to 120 °C for 1 to 30 hrs. iii. Hydrolyzing the (S) -4 -Acetyl -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester obtained in step-ii, in an appropriate solvent such as an alcoholic solvent like methanol, ethanol isopropyl alcohol, butanol, in the presence of a base like sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate and it is carried out at a temperature in the range of -10 to 50 °C for 1 to 30 hrs. iv. Oxidizing the (S)-4 -hydroxy -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester obtained in step-iii, with a mild oxidizing agent like sodium hypochlorite, M11O2, PCC, with or without free radical initiator namely TEMPO inappropriate solvent such as dichloromethane, toluene, tetrahydrofuron, it is conducted at -30 to 50°C and for 10 minutes to 5 hrs. v. Condensation of (S) -3 -formyl -3 - tert-butyl dimethyl silyloxy propanoic acid ethyl ester obtained in the step-iv with an aromatic intermediate i.e, Diphenyl (4-(4-fluorophenyl)-6-isopropyl-2-(N-Methyl-N-methanesulphonylamino)pyridin-yl methyl) phosphine oxide or Diethyl (4-(4-fluorophenyl)-6-isopropyl-2-(N-Methyl-N-methane sulphonylamino) pyridin-yl methyl) phosphine oxide in the presence of a strong base sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide, and butyllithium and sodium hydride and the process is carried out in a suitable solvent, or mixture of solvent for example ethereal or aromatic solvents as mixtures thereof, at temperature in the range of, - 20°C to -90°C. vi Condensation of (+) -5- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3 S) hydroxy-(E)-5- pentenoic acid ethyl ester obtained from step-v with tertiary butyl acetate in the presence of strong base like NaNIfe, KHMDS, KNH2, a lithium amide compound such as lithium di isopropyl amide or Li HMDS, and in an appropriate solvent such as ethers,hexanes,dioxane, toluene, cyclohexane, or any other inert organic solvent, reaction is carried out at a temperature about 25 °C to -90°C and it is conducted under an inertatmosphere such as nitrogen or argon. vii. Reducing the compound obtained in the step-vi stereoselectively in an inert atmosphere such as nitrogen or argon, by using a reducing agent in presence of trialkyl or dialkyl alkoxy borane such as sodium borohydride, and the trialkyl or alkoxydialkylborane such as triethyl borane or methoxy diethyl borane preferably methoxy diethyl borane, at temperature about -30 °C to -90°C. viii. Hydrolyzing of the compound obtained in the step-vii under basic conditions for example by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in polar solvent like ethanol,acetonitrile,ethyl acetate,THF, preferably acetonitrile to form the sodium salt and subsequently neutralizing with organic or inorganic acid agents to get acid of Formula- I. xi. Salt formation of the compound obtained in the step-viii ,with organic base, like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine, etc, which can be optionally re crystalised in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol, obtained compound purity is not less than 99.8% and any individual impurity is not more than 0.1%. x. Substituting the organic amine salt with inorganic alkali metal salt, namely lithium, sodium, potassium, preferably sodium salt and subsequently reacting with anions having calcium atom such as calcium halides, calcium acetate, calcium hydroxide, calcium sulfate, preferably calcium chloride, reaction is carried out at a temperature from about 0 °C to 50°C. 2. A process according to step-iv of claim 1 the oxidizing agent is sodium hypochlorite.. 3. A process according to step-iv of claim 1 where in free radical initiator is TEMPO. 4. A process according to step-v of claim 1 where in the base is Na HMDS. 5. A process according to step-vi of claim 1 where the base is used as Li HMDS. 6. A salt of the compound, (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2- (N-methyl-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid, wherein the salt is an like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as isopropyl amine, disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine,phenyl propyl amine and it's analogues. 7. According to claim I of xi, where in any individual impurity is not more than 0.1%, in which any individual impurity means, specifically diene, lactone, Z-isomer and amide derivatives (from respective amines) of formula-I. 8. A process for the preparation of formula-(i) 9. A compound of diene impurity of compound of formula-I 10. A process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2- (N-methyl)-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)- heptenoic acid calcium salt (2:1), as here in described and exemplified.

Full Text

A novel process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yI]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1).
FIELD OF THE INVENTION
This invention relates to a novel chemical process, and more particularly it relates a novel chemical process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluoro phenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1).

Formula I
Which is pharmaceutically useful in the treatment of, inter alia, hypercholesterolemia hyperlipoproteinemia and antherosclerosis. The invention further includes the novel starting material used in said process and the use of the process in the manufacture of an HMG CoA reductase inhibitor.

BACKGROUND FO THE INVENTTON
European patent 0521 471 Bl disclosed that (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-
(E)-heptenoic acid and its pharmaceutically acceptable salts and process for it's preparation. It is illustrated below.

R= H, Na+, Ca+2 (Hereinafter referred to collectively as "The Agent" as inhibitors of HMG CoA reductase). The process for the preparation comprises of reduction of ethyl [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-methyl-N-methane sulphonyl amino pyrimidin-5-carboxylate with DIBAL-H to give hydroxy compound. Hydroxy compound is oxidized with 4-methyl morpholin -N-oxide and TPAP to give an aldehyde. Aldehyde is further condensed with (3R)-3-(tert-butyl dimethyl silyloxy)-5-oxo-6-triphenyl phosphoranylidene hexanoic acid derivative to give an olefin compound and tert-butyl dimethyl silyl group is removed by the hydrolysis with hydrogen halide and it is further reacted with diethyl methoxy borane and sodium borohydride to give dihydroxy compound. Dihydroxy compound is hydrolyzed with base to form free acid of the title compound. Calcium salt of title compound is prepared from the acid by using calcium chloride.

The generation of the phosphorane side chain requires eight synthetic steps and involves expensive reagents. The process is both uneconomical and time consuming, hence not suitable for commercial production.
Therefore, the main objective of the present invention is to prepare formula-1 in novel method, which is cost-effective, commercially viable and non-hazardous. The formula-1 is prepared in the present invention; in a novel process that is cost effective and suitable for commercial scale up.
SUMMARY OF THE INVENTION
The present invention provides a process and novel intermediates for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl -N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid and its pharmaceutically acceptable salts with less number of stages and the using commercially available raw materials as well as cost effective. According to the present invention yields and quality of the product are found good.
According to the present invention formula-1 is prepared by using ethyl -4-chloro-3-hydroxy butanoate as a key starting material. Hydroxy group is protected with the reaction of tert-butyl dimethyl silyl chloride in presence of a acid trapping agent to give compound (a). It is reacted with sodium acetate in presence of phase transfer catalyst to give compound (b). Compound (b) is hydrolyzed to give compound (c) and it is further oxidized with a mild oxidizing agent like sodium hypochlorite in presence of TEMPO (2,2,6,6-tetramethyl piperidinyloxy free radical) to give the compound (d). Compound (d) is condensed with an aromatic compound (e) (it is disclosed in the prior art) in the presence of a strong base to give compound (f).

It is further condensed with tert-butyl acetate in the presence of a strong base like Na HMDS to give compound (g). Compound (g) is under goes selective reduction to give compound (h), it is further hydrolyzed and to give the acid compound of the title compound. It is further converted into a salt (i) with reaction of a organic base of which a Nitrogen containing one or two alkyl or cyclo alkyl or aryl alkyl or cyclo alkyl having hetero atoms, for example, substiuents like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine, Morpholine or alkyl amines such as isopropyl amine, disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as, phenyl ethyl amine, phenyl propyl amine. This salt optionally re crystallized in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol. The purpose of salt conversion with organic base and re crystalisation is to get higher purity (i.e >99%, preferably >99.8% of purity), particularly diene impurity, and any other impurities which is to be level of more than 0.2% is washed out at the level of below 0.1%. The organic amine salt formation and crystallization can be done for the acid compound of Formula-I to get higher purity, irrespective of the synthetic route. Finally it is converted into calcium salt with calcium chloride. Synthetic scheme is as follows.

DETAILED DESCRIPTION OF THE INVENTION
According to the present invention there is provided a process for preparing formula-1, which comprises protection of ethyl-4-chloro-3-hydroxy butanoate with tertiary butyl dimethyl silyl chloride in appropriate solvent like tetrahydrafuran or dichloro methane with a acid trapping agent such as organic base like triethyl amine, DIPEA or a inorganic base like sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate.

The above reaction is carried out -30 to 70°C, preferably at around room temperature, for 10 minutes to 10 hrs, preferably for 30 minutes 3hrs. The obtained protected compound (a) is subjected to reaction with sodium acetate in presence of tetrabutyl ammonium bromide in toluene as a solvent to give the compound (b). The reaction is performed for 1-30 hrs preferably for 10-15 hrs under reflux condition. Compound (b) has the following structure.

The compound (b) is subjected to hydrolysis in appropriate solvent such as an alcoholic solvent like methanol, ethanol isopropyl alcohol, butanol, in the presence of a base to give the compound (c). Compound ( c) has the following structure.

The compound (c) is oxidized with a mild oxidizing agent like sodium hypochlorite in presence of a free radical initiator in appropriate solvent such as dichloromethane, toluene, tetrahydrofuran. This reaction is conducted preferably at -30 to 50°C and more preferably at -10 to 20°C for 10 minutes to 5 hrs, preferably for 30 minutes to 2 hrs to give compound (d ), Compound ( d) has the following structure.

Compound (d) is further condensed with an aromatic intermediate i.e. Diphenyl (4-(4-fluoro phenyl)-6-isopropyl-2-(N-methyl-N-methane sulphonylamino) pyridin-yl methyl) phosphine oxide (e) (Preparation of this compound is disclosed in the prior art) in the presence of a strong base to give the compound (f) . The reaction is illustrated below.

(e) (f)
The process is carried out in a suitable solvent or mixture of solvent for example
ethereal or aromatic solvents as mixtures thereof. Particularly suitable solvents like
Tetrahydrofuran (THF), dimethoxy ethane and toluene, or mixtures thereof. Preferably
THF or THF and toluene.

Suitable bases for use in the process like amide bases, alkyl metals and metal hydrides. Particular bases include, for example, sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide, and butyllithium and sodium hydride. Particularly more preferred base is for example sodium bis (trimethyl silyl) amide (Na HMDS).
The reaction may be carried out at a temperature in the range of, for example, -20°C to -90°C, such as -40°C to - 90°C, for example -40°C to-80°C preferably -75to -80°C. A convenient temperature at which to carried out the reaction is, for example, that of a mixture of acetone and solid carbon dioxide.(about - 75°C.)
Compound (f) is further condensed with tertiary butyl acetate to give compound (g), in appropriate solvent such as ethers, hexanes, dioxane, toluene, cyclohexane, or any other inert organic solvent. The organic solvent is most preferably tetrahydrofuran. The reaction is carried out with strong base like, NaNHb, KHMDS, KNH2, a lithium amide compound such as lithium di isopropyl amide or Li HMDS, most preferably LiHMDS. The reaction is carried out at a temperature of from about 25 °C to about -90°C, most preferably from about -40°C to about-78°C, and it is conducted under an inert atmosphere such as nitrogen or argon. Compound (g) has the following structure.

Compound (g) is further reduced by using a reducing agent which include sodium borohydride, zinc borohydride, lithium borohydride, preferably sodium borohydride. It is preferred in this step to prepare a compound of formula (h) having the preferred stereoisomeric configuration. Stereospecificity of the reduction reaction may be achieved by the use of a hydride reducing agent. Particularly high stereospecificity may be achieved by the use of a combination of sodium borohydride and a trialkyl borane.

The reducing agent employed is most preferably a mixture if triethyl borane or an alkoxydialkylborane such as methoxy diethyl borane and sodium borhydride.
The stereospecific reduction is preferably carried out by addition of borane reagent followed by sodium borohydride, at the end of the reduction, the formed borane complex may be hydrolyzed by a peroxide such as hydrogen peroxide or by alkaline solution.
The reaction is carried out at a temperature of from about -30 °C to about -90°C? most preferably from about -60°C to about-80°C, and it is conducted under an inert atmosphere such as nitrogen or argon. Compound (h) has the following structure.

Compound (h) in which ester group is hydrolyzed to acid under basic condition and neutralization to get free acid, then reacts with a organic base to give compound (i).

which comprising of, cleavage of the tert-butyl ester group under basic conditions for example by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in ethanol or acetonitrile to form the sodium salt, followed by neutralization to give an acid compound of the formula-1, it is further reacted with a organic base like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as isopropyl amine,disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine, phenyl propyl amine to give a salt of compound of formula (i). This salt optionally recrystallined in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol.
The product of above salt was analyzed by HPLC, using a liquid chromatograph equipped with variable wavelength UV-Detector, set at 242 nm. The coloumn is inertsil, CI8 ODS-3V 250X 4.6 mm; 5 μm and the eluent 20% acetonitrile,40% methanol,40% 0.05 M Na H2P04 2 H20 buffer at pH 2.0, flow rate of 1.0 ml per minute, injection volume 20 microliters. The sample is prepared by diluting 0.025 gm of the sample to 100 ml with 4:5:1 water, acetonitrile, methanol. The product peak elutes at 11-14 minutes and diene impurity elutes at RRT ~1.1.
The invention is further illustrated, but not limited by the following examples.

Examples:
Example: 1
Preparation of (S) -4-chloro-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl
ester (formula-a).
A solution of (S)-4-chloro -3- hydroxy butanoic acid ethyl ester (50 gm) is diluted with dichloro methane (100 ml) and triethyl amine (25 ml) and cooled to 20°C and added the solution of tert-butyl dimethyl silyl chloride (68 gm) and dichloromethane (50 ml) slowly in 45 minutes. Reaction is maintained for 2 hrs at 25°C. Reaction mass is filtered and removed the byproduct and the organic layer is washed water(2xl00 ml) and separated the organic layer and water layer. Organic layer is dried with sodium sulfate and distilled the solvent completely under vacuum. Residue weight (67 gm), which is carried forward to the next stage without further purification.
Example:2
Preparation of (S) -4 -Acetyl -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl
ester (formula-b).
50 gms of (S) -4-chloro-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester,toluene (200 ml)5 sodium acetate (44 gm) and tetrabutyl ammonium bromide (118 gm) are heated to reflux and maintained for 12 hrs at reflux. Reaction mass is quenched with chilled water and stirred for 20 minutes. Organic layer separated and washed with water(50ml) and dried with sodium sulfate and distilled the solvent completely under vacuum. Wash the residue with hexane and decant the hexane layer, yield (35 gm).

Example:3
Preparation of (S) -4 -hydroxy -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl
ester (formula-c).
50 gms of (S) -4-acetyl-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester is dissolved in methanol (250 ml), and charged potassium carbonate and cooled to 0-5°C, maintained the reaction mass at 0-5 °C for 2 hrs Reaction mass is quenched with chilled water and stirred for 20 minutes. Reaction mass is extracted with ethyl acetate (3x100 ml) and organic layer washed with brine and water(50ml) and dried with sodium sulfate and distilled the solvent completely under vacuum, yield (35 gm).
Example:4
Preparation of (S) -3 -formyl -3 - tert-butyl dimethyl silyloxy propanoic acid ethyl
ester (formula-d).
(S) -4 -hydroxy -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester (25 gm) is dissolved in dichloromethane and cooled to 0-5°C. KBr (lgm), TEMPO (0.1 gm) (2,2,6,6-tetramethyl piperidinyloxy free radical) were added to the same R.B.Flask. The pH of NaOCl solution was adjusted to 9.2 with saturated NaHC03 in another R.B.Flask and this solution is added into the above reaction mass at 0-5°C in 60 minutes and maintained for another 30 minutes at 0-5°C. The reaction mass is quenched with sodiumthiosulphate solution 10% solution (50 ml), separated the organic layer and washed the organic layer with water (50 ml Organic layer is dried with sodium sulfate and distilled completely under vacuum, yield (10 gm).

Example:5
Preparation of (+) -5- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl
sulfonyl amino) pyrimidin-5 yl ] -(3 S) hydroxy-(E)-5- pentenoic acid ethyl ester
(formula-e).
A mixture of Diphenyl (4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methane sulphonylamino) pyridin-yl methyl) phosphine oxide (12 gm) (DPPO) and THF (120 ml) were warmed briefly to 40°C until a clear solution had formed then inserted by the sequential application of vacuum and nitrogen. The mixture was immersed in an acetone / CO2 bath cooling the contents to -75°C. Sodium bis (trimethyl silyl) amide (30 ml) was added to the reaction mixture over 30 minutes dropping funnel maintaining the temperature below -75 °C and forming a red solution of the anion. THF (10 ml) was rinsed through the dropping funnel into the mixture and the mixture stirred a further 1 hr at -70°C to -75°C forming a red suspension. (S) -3 -formyl -3 - tert-butyl dimethyl silyloxy propanoic acid ethyl ester (6 gm in 50 ml of toluene) was added in portions in the suspension over 30 minutes from dropping funnel maintaining the temperature below -70°C and stirred the mixture further 15 minutes at -70°C to -75°C. The chilling bath was lowered and the suspension allowed to warm to 10°C over 1.0 hr. quenched the reaction mass with glacial Acetic acid (3 ml) in water (30 ml) and raise the temperature to 18°C to dissolve all solids. The reaction mixture stirred further 5 minutes. Reaction mass diluted further with water and separated the organic layer. Washed the organic layer with sodium bicarbonate solution (10%) 60 ml and followed by washing with saturated sodium chloride solution (50 ml).
Distill the organic layer under high vacuum and crude product isolated in n-hexane. Recovery DPPO isolated by slurry of above crude in diisopropyl ether at room temperature by filtration. Filtrate is concentrated by distillation under vacuum. Obtained residual product. Yield (8 gm).

Example:6
Preparation of Tert- butyl (+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-
N-methyl sulfonyl amino) pyrimidin-5 yl ] -(5 S) hydroxy -3- oxo-(E)-6-heptenoate
(formula-g).
850 ml of 1 molar LiHMDS solution is cooled to -75°C and tert-butyl acetate (70 ml) is added slowly in 45 minutes and maintained for 30 minutes at -75°C. (+) -5- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3 S) hydroxy pentanoic acid ethyl ester (50 gm) solution in tetrahydrofuran (250 ml) is added in 45 minutes at -75°C and maintained for 4 hrs at -75°C. Reaction mass is quenched with chilled water and hydrochloric acid solution. Separated the organic layer and washed with 10% sodium bicarbonate solution (100 ml) followed by water (100 ml) and brine solution. Finally dried the organic layer with sodium sulfate and distilled the solvent completely under vacuum. Residue is purified with pet-ether at -10 to -5°. Yield (70 gm). Example:7
Preparation of Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (formula-h).
Tert- butyl (+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] ~(5 S) hydroxy -3- oxo-(E)-6-heptenoate (50 gm) is dissolved in 250 ml of tetrahydrofuron and cooled to -75°C and diethyl methoxy borane (60 ml) is added slowly in 45 minutes to the reaction mass. Maintained the reaction mass at -75°C for another 30 minutes and sodium borohydride is added in 5 lots. Maintained the reaction for 3 hrs at -75°C. Then the reaction mass is quenched with hydrogen peroxide solution and separated the organic layer and washed with 10% sodium bicarbonate solution followed by water and brine solution. Finally organic layer is dried with sodium sulfate and solvent completely distilled under vacuum. Residual material recrystallised in acetonitrile solvent.Yield( 38 gm). M.R: 130-136°C.

Example:9
Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid dicyclohexyl amine (formula-i)
Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R55S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile (100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Reaction mass is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Dicyclohexyl amine(3 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). It is re crystallized in mixture of acetonitrile and isopropyl alcohol solvents and dried the obtained product at 40-45°C for 5 hrs. Yield (7.5 gm). HPLC Purity: 99.84%,
Example: 10
Preparation of (+)-(3R,5S)-7-[4-(4-FIuorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid dicyclohexyl amine (formula-i)
(+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1) of HPLC Purity is 98% and diene impurity: 1.2% ( 25gm) is dissolved in acetonitrile (250 ml) and cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Dicyclohexyl amine 10 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 200 ml of acetonitrile and raised the temperature to 25-30°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at 40-45°C for 5 hrs. Yield (28.5 gm). HPLC purity 99.8%, diene impurity (RRT: -1.1) 0.08%.

Example: 11
Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid phenyl ethyl amine (formula-i)
Tert-butyl-(H-) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile (100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Reaction mass is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Phenyl ethyl amine (3.5 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at 40-45°C for 5 hrs. Yield ( 8.0 gm) HPLC purity: 99.78%.
Example: 12
Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid phenyl ethyl amine (formula-i)
(+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1) ( 25gm) is dissolved in acetonitrile (250 ml) and cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution, phenyl ethyl amine (12gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 200 ml of acetonitrile and raised the temperature to 25-30°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at 40-45°C for 5 hrs. Yield (25 gm).

Example: 13
Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid tert-butyl amine (formula-i)
Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile (100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Reaction mass is cooled to 0-10°C and pH is adjusted to 4 with 10% hydrochloric acid and organic layer washed with brine solution. Tert-butyl amine (3 gm) is added to the reaction mass at 0-10°C and reaction mass is further diluted with 100 ml of acetonitrile and raised the temperature to 25-35°C, further maintained for 2 hrs at 25-35°C, filtered the cake and washed with acetonitrile (50 ml). Dried the obtained product at40-45°Cfor5hrs. Yield (7.0 gm).
Example: 14
Preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:1) (formula-I)
Tert-butyl-(+) -7- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3R,5S) -dihydroxy -(E)-6-heptenoate (10 gm) is dissolved in acetonitrile(100 ml) and cooled to 25-30°C. Sodiumhydroxide (1.5 gm) in D.M.Water (75 ml) solution is added slowly in 20 minutes and maintained the reaction for 3 hrs at 30-35°C. Distilled the solvent completely under vacuum at below 50°C. Reaction mass is diluted with D.M.Water (150 ml). Calcium chloride (15 gm) in D.M.Water(50 ml) solution is added in 15-20 minutes to the reaction mass and mass is maintained for another 45 minutes and filtered the cake and washed with D.M.Water (50 ml). Dried the obtained product at 40-45°C for 15 hrs. Yield (7 gm).

Claims:
1. Novel process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl)-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic acid calcium salt (2:l),which comprises of,

i. Protecting the hydroxy group in ethyl -4-chloro-3-hydroxy butanoate with tertiary
butyl dimethyl silyl chloride in appropriate solvent like tetrahydrafuron or dichloro methane with an acid trapping agent, such as organic base like triethyl amine or an inorganic base like sodium carbonate, sodium bicarbonate, potassium carbonate or potassium bicarbonate and it is carried out at a temperature in the range of-30 to 0°C for 10 minutes to 10 hrs.
ii. Acylation of (S) -4-chloro-3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester obtained in the step-i, with sodium acetate in presence of phase transfer catalyst like tetra butyl ammonium bromide in a solvent having boiling point more than 60°C or without solvent and the reaction is carried out at a temperature in the range of 0 to 120 °C for 1 to 30 hrs.
iii. Hydrolyzing the (S) -4 -Acetyl -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester obtained in step-ii, in an appropriate solvent such as an alcoholic solvent like methanol, ethanol isopropyl alcohol, butanol, in the presence of a base like sodium carbonate, sodium bicarbonate, potassium carbonate or

potassium bicarbonate and it is carried out at a temperature in the range of -10 to 50 °C for 1 to 30 hrs.
iv. Oxidizing the (S)-4 -hydroxy -3 - tert-butyl dimethyl silyloxy butanoic acid ethyl ester obtained in step-iii, with a mild oxidizing agent like sodium hypochlorite, M11O2, PCC, with or without free radical initiator namely TEMPO inappropriate solvent such as dichloromethane, toluene, tetrahydrofuron, it is conducted at -30 to 50°C and for 10 minutes to 5 hrs.
v. Condensation of (S) -3 -formyl -3 - tert-butyl dimethyl silyloxy propanoic acid ethyl ester obtained in the step-iv with an aromatic intermediate i.e, Diphenyl (4-(4-fluorophenyl)-6-isopropyl-2-(N-Methyl-N-methanesulphonylamino)pyridin-yl methyl) phosphine oxide or Diethyl (4-(4-fluorophenyl)-6-isopropyl-2-(N-Methyl-N-methane sulphonylamino) pyridin-yl methyl) phosphine oxide in the presence of a strong base sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide, and butyllithium and sodium hydride and the process is carried out in a suitable solvent, or mixture of solvent for example ethereal or aromatic solvents as mixtures thereof, at temperature in the range of, - 20°C to -90°C.
vi Condensation of (+) -5- [4 - (4-fluoro phenyl)-6 isopropyl-2- (N-methyl-N-methyl sulfonyl amino) pyrimidin-5 yl ] -(3 S) hydroxy-(E)-5- pentenoic acid ethyl ester obtained from step-v with tertiary butyl acetate in the presence of strong base like NaNIfe, KHMDS, KNH2, a lithium amide compound such as lithium di isopropyl amide or Li HMDS, and in an appropriate solvent such as ethers,hexanes,dioxane, toluene, cyclohexane, or any other inert organic solvent, reaction is carried out at a temperature about 25 °C to -90°C and it is conducted under an inertatmosphere such as nitrogen or argon.

vii. Reducing the compound obtained in the step-vi stereoselectively in an inert atmosphere such as nitrogen or argon, by using a reducing agent in presence of trialkyl or dialkyl alkoxy borane such as sodium borohydride, and the trialkyl or alkoxydialkylborane such as triethyl borane or methoxy diethyl borane preferably methoxy diethyl borane, at temperature about -30 °C to -90°C.
viii. Hydrolyzing of the compound obtained in the step-vii under basic conditions for example by using a solution of a metallic hydroxide in a polar solvent, such as using aqueous sodium hydroxide in polar solvent like ethanol,acetonitrile,ethyl acetate,THF, preferably acetonitrile to form the sodium salt and subsequently neutralizing with organic or inorganic acid agents to get acid of Formula- I.
xi. Salt formation of the compound obtained in the step-viii ,with organic base, like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine, etc, which can be optionally re crystalised in the solvents like acetone, acetonitrile or mixture of acetonitrile and isopropyl alcohol, obtained compound purity is not less than 99.8% and any individual impurity is not more than 0.1%. x. Substituting the organic amine salt with inorganic alkali metal salt, namely lithium, sodium, potassium, preferably sodium salt and subsequently reacting with anions having calcium atom such as calcium halides, calcium acetate, calcium hydroxide, calcium sulfate, preferably calcium chloride, reaction is carried out at a temperature from about 0 °C to 50°C.
2. A process according to step-iv of claim 1 the oxidizing agent is sodium hypochlorite..
3. A process according to step-iv of claim 1 where in free radical initiator is TEMPO.
4. A process according to step-v of claim 1 where in the base is Na HMDS.
5. A process according to step-vi of claim 1 where the base is used as Li HMDS.
6. A salt of the compound, (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-

(N-methyl-N-methanesulfonylamino) pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-heptenoic
acid, wherein the salt is an like cyclic amines such as cyclo propyl amine, cyclo pentyl amine, cyclo hexyl amine, dicyclohexyl amine, pyrrolidine or morpholine or alkyl amines such as isopropyl amine, disiopropyl amine, tert-butyl amine, n-octyl glucamine or aryl amines such as phenyl ethyl amine,phenyl propyl amine and it's analogues.
7. According to claim I of xi, where in any individual impurity is not more than 0.1%,
in which any individual impurity means, specifically diene, lactone, Z-isomer and
amide derivatives (from respective amines) of formula-I.
8. A process for the preparation of formula-(i)

9. A compound of diene impurity of compound of formula-I

10. A process for the preparation of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-
(N-methyl)-N-methanesulfonylamino)pyrimidin-5-yl]-3,5-dihydroxy-6-(E)-
heptenoic acid calcium salt (2:1), as here in described and exemplified.

Documents:

0782-che-2005-abstract.pdf

0782-che-2005-claims.pdf

0782-che-2005-correspondnece-others.pdf

0782-che-2005-correspondnece-po.pdf

0782-che-2005-description(complete).pdf

0782-che-2005-form 1.pdf

782-che-2005 abstract 19-08-2009.pdf

782-che-2005 description (complete) 19-08-2009.pdf

782-CHE-2005 DRAWINGS 19-08-2009.pdf

782-CHE-2005 EXAMINATION REPORT REPLY RECIEVED 19-08-2009.pdf

782-CHE-2005 FORM-2 19-08-2009.pdf

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Patent Number

238331

Indian Patent Application Number

782/CHE/2005

PG Journal Number

6/2010

Publication Date

05-Feb-2010

Grant Date

28-Jan-2010

Date of Filing

22-Jun-2005

Name of Patentee

MANNE STYANARAYANA REDDY

Applicant Address

DR. MANNE SATYANARAYANA REDDY, CHAIRMAN AND MANAGING DIRECTOR, MSN LABORATORIES LIMITED, FACTORY:SY.NO.317&323, RUDRARAM (VIL), PATANCHERU(MDL), MEDAK(DIST), AP-502329

Inventors:

#	Inventor's Name	Inventor's Address
1	MANNE SATYANARAYANA REDDY	DR. MANNE SATYANARAYANA REDDY, CHAIRMAN AND MANAGING DIRECTOR, MSN LABORATORIES LIMITED, FACTORY:SY.NO.317&323, RUDRARAM (VIL), PATANCHERU(MDL), MEDAK(DIST), AP-502329
2	MUPPA KISHORE KUMAR	MUPPA KISHORE KUMAR, LIG-34, DHARMAREDDY COLONY, PHASE 1, NEAR JNTUC, HYDERABAD, AP
3	SRINIVASAN THIRUMALAI RAJAN	SRINIVASAN THIRUMALAI RAJAN, PLOT NO.12&13, LAKE VIEW ENCLAVE, MIYAPUR, HYDERABAD 500 049
4	MARAM REDDY SAHADEVA REDDY	MARAM REDDY SAHADEVA REDDY, H.NO 15-21-140, BALAJI NAGAR, KUKATPALLY, HYDERABAD 500078, AP

PCT International Classification Number

A61K 31/505

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA