Title of Invention	NOVEL PROCESS FOR THE PREPARATION OF OLEFINIC CHIRAL DIHYDROXY ACID CoA REDUCTASE INHIBITORS
Abstract	Novel process for the preparation of olefinic chiral dihydroxy acid HMG CoA reductase inhibitors. The olefinic chiral dihydroxy acid HMG CoA compounds of general formula (1)(i.e., for example Rosuvastatin calcium, Pitavastatin calcium, Fluvastatin sodium) is as follows Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor and may for example be Wherein "...." denotes single or double bond and M is H, Na+, K+, Mg+2, Ca+2.

Title of Invention

NOVEL PROCESS FOR THE PREPARATION OF OLEFINIC CHIRAL DIHYDROXY ACID CoA REDUCTASE INHIBITORS

Abstract

Novel process for the preparation of olefinic chiral dihydroxy acid HMG CoA reductase inhibitors. The olefinic chiral dihydroxy acid HMG CoA compounds of general formula (1)(i.e., for example Rosuvastatin calcium, Pitavastatin calcium, Fluvastatin sodium) is as follows Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor and may for example be Wherein "...." denotes single or double bond and M is H, Na+, K+, Mg+2, Ca+2.

Full Text	NOVEL PROCESS FOR THE PREPARATION OF OLEFINIC CHIRAL DIHYDROXY ACID HMG CoA REDUCTASE INHIBITORS Field of the Invention The present invention relates to a novel process for the preparation of Olefinic chiral clihydroxy acid and its pharmaceutically acceptable salts HMG CoA Reductase inhibitors of general formula (1). 1 Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor and may for example be (a) (b) (c) (d) wherein ‘ —’ denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2 Herein after the above compounds of formula (a),(b),(c),(d),(e),(f),(g)and (h) are referred as’R’ The compounds of the present invention inhibit the HMG-CoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis. Summary of the Invention The present invention relates to a novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts HMG CoA Reductase inhibitors of general formula (1). 1 wherein ‘ —’ denotes single or double bond and M is H, Na ,K ,Mg ,Ca The present invention is directed to the synthesis of chiral dihydroxy acid HMG CoA Reductase inhibitors of general formula (1) preferably via sulfide, sulfoxide and sulfone intermediates which is used in preparing a dihydroxy acid HMG CoA reductase inhibitor or lactone thereof. In one aspect of the process of the invention, a Julia-Modified olefination reaction is employed wherein the sulfone intermediate is reacted with carboxylaldehyde to form the desired olefin which be isolated in high yield and optical purity and which may be converted to the final HMG CoA reductase inhibitor. Background of the Invention Rosuvastatin and process for its preparation is disclosed in US Patent No: 5260440. The process disclosed therein involves four distinct chemical steps and the generation of the phosphoranes side chain requires expensive reagents and the process is both uneconomical and time consuming, and statin compounds preparation through wittig reaction leads to formation of ‘Z’ isomer, hence not suitable for commercial production. It is, therefore, desirable to provide an efficient process for the preparation of statins which improves the economics by employing less expensive reagents and is more productive. The alternate method for the preparation of olefinic compounds is Julia classical olefination, Julia modified olefination, Julia modified olefination process for the preparation of HMG CoA Reductase inhibitors, is disclosed and claimed in US 6875867, in this patent chiral diol sulfone (aliphatic chain of statins) intermediates used for the preparation of HMG CoA Reductase inhibitors, the disclosed chiral diol sulfones are not stable and low yields were observed when using aliphatic chiral diol sulfones when compare to aromatic sulfone derivatives. Poor solubility of calcium salt of statins has been observed in aqueous methanol with known processes for the preparation of calcium salt of statins. This is a major drawback in the synthesis of calcium salt of statins. The present invention provides a novel process which solves the above mentioned problems of known processes. The present invention provides a novel and advantageous process for the preparation of calcium salt of statins which solves solubility problem of the compound in aqueous methanol and gives free flow solid of calcium salt. The present invention provides a novel process which is simple and cost effective. Disadvantages of the prior art processes • Usage of hazardous reagents like phosphorous trihalides or phosphorous oxyhalides. • Usage of strong base like LDA / n-BuLi followed by usage of Na/Hg in Julia classical olefination reactions, which are highly pyrophoric in nature, hence those are not recommended for commercial scale up. • Usage of strong base like LDA / n-BuLi in Julia modified olefination reactions, which are highly pyrophoric in nature, hence those are not recommended for commercial scale up. • Chiral diol sulfone compounds which are prepared as per the procedure given in US Patent 6875867 are unstable intermediates. • Poor solubility of calcium salt compound of formula (1) in aqueous methanol. Brief description of the Invention In accordance with the present invention, a process is provided for preparing chiral dihydroxy acid HMG CoA reductase inhibitors which are useful as anti-cholesterol agents as described hereinafter. The first aspect of the present invention is to provide a novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a novel process is provided for preparing olefin dihydroxy acid compounds of general formula (1) 1 wherein «==-- denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2 A Novel process is provided for the preparation of olefin dihydroxy compound of general formula (1) via a Julia-Modified olefination, which comprises of the following steps, 1. Reacting a sulfone compound of general formula (2) with an aldehyde compound of formula (3) in the presence of an alkali and alkaline earth metal bases in a suitable polar aprotic solvent to provide olefin compound of general formula (4). 2. The olefininc compound of general formula (4) may be used to form a dihydroxy acid (or lactam thereof) HMG CoA reductase inhibitor by subjecting the olefin compound of formula 4 to acidic conditions to remove the acetonide and form diol compound, which upon treating with a base such as an alkali metal hydroxide to form the corresponding alkali metal salt then further treating with an organic amine base to form corresponding organic amine salt compound of general formula (5). 3. Converting the organic amine salt compound of formula 5 into free acid compound of formula 6 by treating the compound of formula 5 with an acid to give acid compound of formula (6). 4. The alkenyl double bond in acid compound of formula 6 may be hydrogenated (H2/PCI/C) to provide the saturated alkyl acid compound of formula (7). 5. Converting the olefinic chiral dihydroxy acid or its organic amine salt into its pharmaceutically acceptable salts of the general formula (1) by treating the organic amine compound of general formula (5) or acid compound of general formula (6) with an alkali base followed by treating with corresponding alkali or alkaline earth metal salts in a suitable solvent. The lactone compound of formula (8) may be prepared 8 By treating the olefin compound of formula 4 under acid conditions (for example, TFA, HC1) to effect conversion to lactone compound of formula (8). The saturated derivative of lactone 8 may be obtained by catalytic (Pd/C, Pt/C, Pd(OH)2) hydrogenation of compound of formula 8 to compound of formula 9. 9 Lactone compounds of formula 8 and 9 may be converted to the corresponding diols by saponification of 8 and 9 with aqueous base to form corresponding alkali salt compounds of formula 10 and 11. 11 The second aspect of the present invention is to provide novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a process provided for preparing olefin dihydroxy acid compound of general formula (1) 1 — denotes single or double bond and M is H, Na+ ,K+ ,Mg+2 ,Ca+2 A Novel process for the preparation of olefin dihydroxy compound of general formula (1) is provided via a Julia-Modified olefination, which comprises of the following steps, 1. Reacting a sulfoxide compound of general formula (12) with an aldehyde compound of formula (3) in the presence of an alkali and alkaline earth metal bases in a suitable polar aprotic solvent to provide olefin compound of general formula (4). 2. The olefininc compound of general formula (4) may be used to form a dihydroxy acid (or lactam thereof) HMG CoA reductase inhibitor by subjecting the olefin compound of formula 4 to acidic conditions to remove the acetonide and form diol compound, which upon treating with a base such as an alkali metal hydroxide to form the corresponding alkali metal salt then further treating with an organic amine base to form corresponding organic amine salt compound of general formula (5). 3. Converting the organic amine salt compound of formula 5 into free acid compound of formula 6 by treating the compound of formula 5 with an acid to give acid compound of formula (6). 4. The alkenyl double bond in acid compound of formula 6 may be hydrogenated (tk/Pd/C) to provide the saturated alkyl acid compound of formula (7). 5. Converting the olefinic chiral dihydroxy acid into its pharmaceutically acceptable salts of the general formula (1) by treating the organic amine compound of general formula (5) or acid compound of general formula (6) with an alkali base followed by treating with corresponding alkali or alkaline earth metal salts in a suitable solvent. The process of the present invention may be employed to prepare pravastatin, atorvastatin, cerivastatin, fluvastatin, rosuvastatin, nisvastatin (pitavastatin), simvastatin, lovastatin and other dihydroxy acid or lactone HMG CoA reductase inhibitors. The starting material aldehyde compound of formula (3) can be prepared as per the prior art processes, Ref : WO/49014; US 6844437; US 20040049036 and in US 2006/0004200 and Tetrahedron Letters, Vol.31, No. 18, pp 2545-2548,1990 The third aspect of the present invention is to provide a novel process for preparing a novel sulfone and sulfoxide compounds having general formula (2) and formula (12). which comprise of the following steps 1. Reacting a compound of general formula (13) with a thiol compound of general formula (14) in presence of a suitable base with or without a suitable solvent to provide a novel sulfide compound of general formula (15) 2. And oxidizing the sulfide compound of formula (15) with an oxidizing agent in presence of an appropriate catalyst in a suitable solvent, to provide a novel sulfone compound of general formula (2) and sulfoxide compound of formula (12) can be prepared by controlled oxidation of sulfide. The starting material compounds of general formula (13) can be prepared as per the prior art processes, Ref : US Patent 6627636; US 5763675 (Pitavastatin); US 5354772; US 4739073 (Fluvastatin); WO 03/097614; US2004/0176401 and WO03/006439. The fourth aspect of the invention is to provide a novel process for the preparation of calcium salt of statins which comprises of the following steps. (a) Converting the organic amine salt compound of general formula (5) into its corresponding alkali salt by treating with alkali base. (b) Setting the reaction mixture pH to 8.0 to 9.2 by expelling the organic amine followed by extraction or by extracting the organic amine with a suitable solvent or by adding an acid. (c) Adding the aqueous phase of the reaction mixture to a calcium source to give free flow calcium salt compound of general formula (1). 1 wherein M is Ca+2 In addition, in accordance with the present invention , the following intermediates prepared by the process of the invention are novel compounds. 1. Sulfide compounds of general formula (15) 15 where R and R2 are defined above. 2. Sulfone compounds of general formula (2) 2 where R and R2 are defined above. 3. Sulfoxide compounds of general formula (12) 12 where R and R2 are defined above. - Advantages of the present invention • No pyrophoric reagents used in present invention. • Usage of simple bases like potassium carbonate, sodium carbonate instead of using LDA / n-BuLi / LiHMDS / NaHMDS. • Sulfone compounds which are prepared as per the present invention are stable. • Yields are above 80% for all stages of the present invention. • Calcium salt compound of formula (la) is freely soluble in aqueous methanol. • Calcium slat compounds of statins prepared by the present invention are free flow solids. • The present invention is simple and cost effective. Detailed description of the Invention In accordance with the present invention, a process is provided for the preparation of chiral dihydroxy acid HMG CoA reductase inhibitors which are useful as anti-cholesterol agents as described hereinafter. The first aspect of the present invention is to provide a novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a novel process is provided for preparing olefinic dihydroxy acid compound of general formula (1) 1 — denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2 A Novel process is provided for the preparation of olefinic dihydroxy compound of general formula (1) via a Julia-Modified olefination, which comprises the steps of reacting a sulfone compound of general formula (2). 2 Wherein R is defined as above and R2 is Wherein R3 is alkyl, aryl, arylalkyl or cycloalkyl, R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2 R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy And X is O,N-H,N-alkyl or S; Herein after the above compounds of general formula (i),(j) and (k) are referred as ‘R2’ With an aldehyde compound of formula (3) 3 wherein R1 is alkyl,cycloalkyl,arylalkyl,aryl or carbonylbenzyloxy (cbz), preferably alkyl, more preferably tertiary butyl. In presence of an alkali and alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably cesium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide olefin compound of general formula (4). 4 The olefin compound of general formula (4) may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting olefin compound of formula 4 to acidic conditions such as using hydrochloric acid, acetic acid, sulfuric acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form the corresponding sodium salt then further treating with an organic amine base like methyl amine, dicyclohexyl amine, tertiary butyl amine, preferably dicyclohexylamine to form corresponding amine salt compound of formula (5). 5 Converting the organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula (1) by treating the organic amine compound of general formula (5) with an alkali base such as sodium hydroxide followed by treating with corresponding alkali or alkaline earth metal salts like calcium chloride, calcium acetate, sodium hydroxide in a suitable solvent such as water. 1 wherein M is H, Na+,K+,Mg+2,Ca+2. The second aspect of the present invention is to provide novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a process provided for preparing olefinic dihydroxy acid compound of formula (1) 1 wherein ‘ —’ denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2 , A Novel process for the preparation of olefin dihydroxy compound of formula (1) is provided via a Julia-Modified olefmation, which comprises the steps of reacting sulfoxide compound of general formula (12). 12 With an aldehyde compound of formula (3) 3 wherein Rj is alkyl,cycloalkyl,arylalkyl,aryl or carbonylbenzyloxy (cbz), preferably alkyl, more preferably tertiary butyl. in presence of strong base like amide bases such as sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide in a suitable polar aprotic solvents like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide olefin compound of general formula (4), 4 The olefin compound of general formula (4) may be used to form a dihydroxy acid HMG Co A reductase inhibitor by subjecting olefin compound of formula 4 to acidic conditions such as using hydrochloric acid, sulfuric acid, acetic acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form the corresponding sodium salt then further treating with an organic amine base like methyl amine, dicyclohexyl amine, tertiary butyl amine, preferably dicyclohexylamine to form corresponding amine salt compound of formula (5). 5 Converting the organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula (1) by treating the organic amine compound of general formula (5) with an alkali base such as sodium hydroxide followed by treating with corresponding alkali or alkaline earth metal salts like calcium chloride, calcium acetate, sodium hydroxide in a suitable solvent such as water. 1 where M is H, Na+,K+,Mg+2,Ca+2. The third aspect of the present invention further comprises the steps of forming a novel sulfone and sulfoxide derivatives having the general formula (2) and formula (12) of the following. 2 12- which comprises of treating a solution of the compound of general formula (13) R-L 13 Wherein L is a leaving group such as halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, preferably halogen, more preferably bromo with a thiol compound of general formula (14) R2SH 14 wherein R2 is defined as above in presence of a suitable base like sodium hydroxide with or without a suitable solvent, a suitable solvent selected from chloro solvents like methylene chloride, chloroform, carbon tetrachloride, keto solvents like acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, ester solvents like ethyl acetate, methyl acetate, tertiary butyl acetate, polar solvents like dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, water or mixtures thereof, preferably keto solvents, more preferably aceone to provide a novel sulfide compound of formula (15), 15 wherein R and R2 are defined as above And oxidizing a sulfide compound of formula (15) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride to provide the novel sulfone compound of general formula (2) and a novel sulfoxide compound of formula (12) can be prepared by controlled oxidation of sulfide. The fourth aspect of the invention is to provide a novel process for the preparation of calcium salt of statins, which comprises of the following steps. (a) Converting the organic amine salt compound of general formula (5) into its sodium salt by treating with sodium hydroxide. (b) Setting the reaction mixture pH to 8.0 to 9.2 by expelling the organic amine followed by extracting the reaction mixture with a suitable solvent such as ester solvents like ethyl acetate, methyl acetate, tertiary butyl acetate or by extracting the organic amine with a suitable solvent like ester solvents ethyl acetate, methyl acetate, tertiary butyl acetate, preferably tertiary butyl acetate to remove organic amine or by adding an acid like hydrochloric acid. (c) Adding the aqueous phase of the reaction mixture to a calcium source like calcium chloride or calcium acetate in a suitable solvent like water to give free flow calcium salt compound of general formula (1). 1 wherein M is Ca According to the present invention, a preferred process is provided for preparing the preferred olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts compound of formula (la). la wherein M is Ca+2 A novel process for the preparation of Olefin dihydroxy acid is provided via Julia-Modified olefination which comprises the steps of reacting sulfone compound of formula (2a) 2a With an aldehyde compound of formula (3a) 3a in the presence of cesium carbonate in dimethyl sulfoxide to provide olefin compound of general formula (4a). 4a The olefin compound of general formula (4a) may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting olefin compound of formula 4a to acidic conditions such as using hydrochloric acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form sodium salt then further treating with dicyclohexyl amine to form corresponding amine salt compound of formula (5a). 5a Converting the organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula (la) by treating the organic amine compound of general formula (5 a) with an alkali base such as sodium hydroxide and setting the pH of the reaction mixture by extracting the organic amine with tertiary butyl amine to 9.1 followed by adding the aqueous phase of the reaction mixture to a solution of calcium chloride or calcium acetate in a suitable solvent such as water. la +9 wherein M is Ca In accordance with the present invention, a preferred process is provided for preparing the preferred sulfone compound of formula 2a. Formula (2a) Which comprise of treating a solution of compound of formula (13a) 13a with difluoromethoxy benzimidazole-thiol compound of formula (14a) in presence of sodium hydroxide in dimethyl formamide or in acetone, 14a To provide a novel sulfide compound of formula (15a) 15a and methylating the compound of formula (15a) using methylating agent like dimethyl sulfate to provide N-methyl sulfide compound of formula (16). 16 17 And oxidizing the sulfide compound of formula (16) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride or oxidizing the sulfide compound of formula (15a) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride and then methylating the obtained sulfone compound of formula (17), to provide the novel sulfoxide compound of formula (12a). 2a In accordance with the present invention, a preferred process is provided for preparing the preferred sulfoxide compound of formula 12a. Formula (12a) Which comprises of treating a solution of the compound of formula (13a) 13a with difluoromethoxy benzimidazole-thiol compound of formula (14a) in presence of sodium hydroxide in dimethyl formamide or acetone, 14a To provide a novel sulfide compound of formula (15a) 15a and methylating the compound of formula (15a) using methylating agent to provide N-methyl sulfide compound of formula (16). 16 18 And controlled oxidation of sulfide compound of formula (16) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride or controlled oxidation of sulfide compound of formula (15a) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic - system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride and then methylating the obtained sulfoxide compound of formula (18), to provide the novel sulfoxide compound of formula (12a). The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention. Examples Example 1 : Preparation of sulfide compound of formula (15a) 47.56 gr of 5-(difluoromethoxy)-2-mercapto benzimidazole compound of formula (14a) is added to a aqueous sodiumhydroxide solution (9.61 gm sodium hydroxide in 200 ml water) at 25 to 35°C and stirred for 15 minutes, then added a solution of 400 ml of acetone and 100 gr of [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-Methyl-N-methane Sulphonyl amino pyrimidine-5yl] methyl bromide compound of formula (13a) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water and filtered the obtained precipitate and dried the compound at 60-65°C for 3 hours to get the title compound. Yield : 119.5 grams; M.R : 165-170°C Mass spectrum : M+l peak at 551 Example 2 : Preparation of N-methylated sulfide compound of formula (16) A solution of 10 gr of sulfide compound of formula (15a) prepared as per the example 1 and 100 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 2.9 gr of potassium carbonate to the above solution then added 3.0 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 3 hours. Yield : 8 grams ; M.R : 158-165°C. Mass spectrum : M+l peak at 566 Example 3 : Preparation of sulfone compound of formula (2a) A solution of 24 gr of N-methylated sulfide compound of formula (16) prepared as per the example 2, 120 ml of methylene chloride and 1.0 gr of Tetrabutyl ammonium bromide, is cooled to 0-5 °C. Added a mixture of 72 ml of 30% hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield : 24 grams. M.R : 145-154°C. Example 4 : Preparation of sulfone compound of formula (17) A solution of 117 gr of sulfide compound of formula (15a) prepared as per the example 1 and 585 ml of methylene chloride, is cooled to 0-5°C. Added a mixture of 240.6 ml of 30% hydrogen peroxide and 2.34 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 5 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes and heptane mix as a solvent medium. Dried the compound at 60-65°C for 3 hours.Yield : 122 grams. M.R : 105-135°C. Example 5 : Preparation of sulfone compound of formula (2a) A solution of 120 gr of sulfone compound of formula (17) prepared as per the example 4 and 600 ml of acetone at 3O-35°C. Added 31.24 gr of potassium carbonate to the above solution then added 21.39 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 30-35°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 110 grams. M.R : 145-155°C. Example 6 : Preparation of sulfoxide compound of formula (12a) A solution of 24 gr of N-methylated sulfide compound of formula (16) prepared as per the example 2 and 240 ml of methylene chloride, is cooled to 0-5 °C. Added a mixture of 36 ml of hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield: 24 grams. Mass spectrum : M+l peak at 582. Example 7 : Preparation of olefin compound of formula (4a) 34.67 gr of potassium carbonate is added to a solution of 25 gr of sulfone compound of formula (2a) prepared as per example 3 and 125 ml of dimethyl sulfoxide at 25 to 35°C. Added 10.8 gr of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yl]acetate compound of formula (3a). Stirred for 13 hours at 60 to 65°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45 °C for 6 hours . Yield : 13.5 grams. M.R : 148-155°C Mass spectrum : M+l peak at 578 Example 8 : Preparation of DCHA salt of dihydroxy acid compound of formula (5a) A solution of 25 gr of olefin compound of formula 4a prepared as per example 5 and 250 ml of acetonitrile, is cooled to 23 to 28°C. Added 70.75 ml of 1.0% hydrochloric acid solution slowly to the above contents of the reaction. Stirred the reaction mixture for 4 hours at 23 to 28°C. Added 37.5 ml of 10% sodium hydroxide solution to the reaction mixture and stirred to 2 hours at 30-35°C. Adjust the pH of the reaction mixture to 3.5 to 4.5 with 10% hydrochloride. Separated the organic phase and cooled to 0-10°C. Added 8.66 gr of dicyclohyxyl amine (DCHA) to the contents and stirred for 1 hour at 0-5 °C. Distilled the solvent completely and isolated the title compound using acetonitrile as a solvent. Dried the compound at 40-45°C for 5 hours. Yield: 18 grams. Example 9 : Preparation of calcium salt of olefin dihydroxy compound of formula (la) A solution of 15 gr of DCHA salt compound of formula (5a) and 75 ml of water, is cooled to 25-30°C. Added 8.5 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by extracting the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 2.55 gr of calcium chloride and 15 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45°C. Yield : 12 grams; M.R: 145-150 (Decomposed) ; Purity by HPLC is 99.50% Example 10 : Preparation of sulfide compound of formula (15b) 39.68 gr of 5-methoxy-2-mercapto benzimidazole compound of formula (14b) is added to aqueous sodium hydroxide solution(9.61 gm sodium hydroxide in 200 ml water) at 25 to 35°C and stirred for 15 minutes, then added a solution of 400 ml of acetone and 100 gr of [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-Methyl-N-methane Sulphonyl amino pyrimidine-5yl] methyl bromide compound of formula (13a) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 60-65°C for 3 hours to get the title compound. Yield :110 grams. M.R: 159-163°C. Example 11 : Preparation of sulfide compound of formula (15c) 33.07 gr of 2-mercapto benzimidazole compound of formula (14c) is added to an aqueous sodium hydroxide solution (9.61 gm of sodium hydroxide in 200 ml water) at 25 to 35°C and stirred for 15 minutes, then added a solution of 400 ml of acetone and 100 gr of [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-Methyl-N-methane Sulphonyl amino pyrimidine-5yl] methyl bromide compound of formula (13a) and stirred for 1.5 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 60-65°C for 2 hours to get the title compound. Yield : 106.0 grams. M.R : 188-195°C. Example 12 : Preparation of sulfone compound of formula (17a) A solution of 108 gr of sulfide compound of formula (15b) prepared as per the example 10, 540 ml of methylene chloride and 2.16 gr tetrabutyl ammonium bromide. Added a mixture of 237.5 ml of 30% hydrogen peroxide and 2.16 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 4 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 60-65°C for 3 hours. Yield : 114 grams. M.R : 100-132°C Example 13 : Preparation of sulfone compound of formula (17b) A solution of 105 gr of sulfide compound of formula (15c) prepared as per the example 11, 525 ml of methylene chloride and 2.1 gr tetrabutyl ammonium bromide. Added a mixture of 245.2 ml of 30% hydrogen peroxide and 2.1 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at60-65oCfor4hours. Yield : 107 grams.M.R : 98-128°C. Example 14 : Preparation of N-methylated sulfone compound of formula (2b) A solution of 3.0 gr of sulfone compound of formula (17a) prepared as per the example 12 and 15 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 0.88 gr of potassium carbonate to the above solution then added 0.6 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 1.7 grams. M.R : 122-130°C. Example 15 : Preparation of N-methy lated sulfone compound of formula (2c) A solution of 3.0 gr of sulfone compound of formula (17b) prepared as per the example 13 and 15 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 0.93 gr of potassium carbonate to the above solution then added 0.63 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 2.0 grams. M.R : 126-134°C Example 16 : Preparation of olefin compound of formula (4a) 8.4 gr of cesium carbonate is added to a solution of 10 gr of sulfone compound of formula (2b) prepared as per example 14 and 50 ml of dimethyl sulfoxide at 25 to 35°C. Added 4.5 gr of Tertiary butyl 2-[(4R,6S)-6-fomyl-2,2-dimethyl-l,3-dioxane-4-yljacetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45 °C for 6 hours. Yield: 6.0 grams. M.R: 148-155°C. Purity by HPLC > 96% Example 17 : Preparation of olefin compound of formula (4a) 8.4 gr of cesium carbonate is added to a solution of 10 gr of sulfone compound of formula (2c) prepared as per example 15 and 50 ml of dimethyl sulfoxide at 25 to 35°C. Added 4.5 gr of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yljacetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45 °C for 6 hours. Yield : 6.2 grams. M.R : 148-155°C. Purity by HPLC > 96% Example 18 : Preparation of calcium salt of olefin dihydroxy compound of formula (la) A solution of 15 gr of DCHA salt compound of formula (5a) and 75 ml of water, is cooled to 25-30°C. Added 8.5 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by extracting the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 4.3 gr of calcium acetate and 15 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45°C. Yield : 12 grams; M.R: 145-150 (Decomposed); Purity by HPLC is 99.50% Example 19 : Preparation of calcium salt of olefin dihydroxy compound of formula (la) A solution of 12.5 gr of methyl amine salt compound of formula (5b) and 65 ml of water, is cooled to 25-30°C. Added 9.5 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by expelling the methyl amine traces. Extracted the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 2.79 gr of calcium acetate and 12.5 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45°C. Yield: 9.5 grams Example 20 : Preparation of calcium salt of olefin dihydroxy compound of formula (la) A solution of 10.0 gr of methyl amine salt compound of formula (5b) and 50 ml of water, is cooled to 25-30°C. Added 7.8 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by expelling the methyl amine traces. Extracted the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 1.701 gr of calcium chloride and 10 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45 °C. Yield : 8.7 grams. HPLC Purity is 99% Example 21 : Preparation of sulfide compound of formula (15d) 15 gr of 5-(difluoromethoxy)-2-mercapto benzimidazole compound of formula (14a) is added to a 82.5 ml of 2.9% solution of sodium hydroxide at 25 to 35°C and stirred for 15 minutes, then added a mixture of 175 ml of dimethylformamide and 25 gr of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline compound of formula (13b) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 50-55°C for 6 hours to get the title compound.Yield : 32 grams. M.R : 117-125°C. Example 22 : Preparation of sulfone compound of formula (17c) A solution of 25 gr of sulfide compound of formula (15d), 100 ml of methylene chloride and 1.0 gr of tetrabutyl ammonium bromide, is cooled to 0-5°C. Added a mixture of 56 ml of 30% hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield : 23 grams. M.R : 150-160°C. Example 23 : Preparation of N-methylated sulfone compound of formula (2d) A solution of 3.0 gr of sulfone compound of formula (17c) prepared as per the example 22 and 15 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 0.93 gr of potassium carbonate to the above solution then added 0.63 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 3.5 grams. M.R : 158-162°C. Example 24 : Preparation of olefin compound of formula (4b) 5.2 gr of cesium carbonate is added to a solution of 3.5 gr of sulfone compound of formula (2d) and 20 ml of dimethyl sulfoxide at 25 to 35°C. Added 1.68 gr of Tertiary butyl 2-[(4R?6S)-6-formyl-2?2-dimethyl-l53-dioxane-4-yl]acetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield: 1.2 grams. M.R : 115-121°C. Example 25 : Preparation of sulfide compound of formula (lSe) 6.0 gr of 5-(difluoromethoxy)-2-mercapto benzimidazole compound of formula (14a) is added to a 36 ml of 2.9% solution of sodium hydroxide at 25 to 35°C and stirred for 15 minutes, then added a mixture of 30 ml of acetone and 10 gr of 2-(bromomethyl)-3-(4-fluorophenyl)-l-isopropyl-lH-indole compound of formula (13c) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 50-55°C for 6 hours to get the title compound. Yield: 10 grams. Example 26 : Preparation of sulfone compound of formula (17d) A solution of 10 gr of sulfide compound of formula (15e), 100 ml of methylene chloride and 0.5 gr of tetrabutyl ammonium bromide, is cooled to 0-5°C. Added a mixture of 14 ml of 30% hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield ; 6.0 grams. Example 27 : Preparation of N-methylated sulfone compound of formula (2e) A solution of 5.0 gr of sulfone compound of formula (17d) prepared as per the example 26 and 25 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 1.35 gr of potassium carbonate to the above solution then added 3.1 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield: 3.0 grams. Example 28 : Preparation of olefin compound of formula (4c) 2.7 gr of potassium carbonate is added to a solution of 3.0 gr of sulfone compound of formula (2e) prepared as per example 27 and 10 ml of dimethyl sulfoxide at 25 to 35°C. Added 1.5 gr of Tertiary butyl 2-[(4R>6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yl]acetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield: 0.6 grams

Full Text

NOVEL PROCESS FOR THE PREPARATION OF OLEFINIC CHIRAL DIHYDROXY ACID HMG CoA REDUCTASE
INHIBITORS

Field of the Invention
The present invention relates to a novel process for the preparation of Olefinic chiral clihydroxy acid and its pharmaceutically acceptable salts HMG CoA Reductase inhibitors of general formula (1).

1
Wherein R is a hydrophobic anchor or residue of an HMG CoA reductase inhibitor and may for example be (a)
(b)
(c)
(d)

wherein ‘ —’ denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2
Herein after the above compounds of formula (a),(b),(c),(d),(e),(f),(g)and (h) are referred
as’R’

The compounds of the present invention inhibit the HMG-CoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia, hyperlipoproteinemia, and atherosclerosis.
Summary of the Invention
The present invention relates to a novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts HMG CoA Reductase inhibitors of general formula (1).

1 wherein ‘ —’ denotes single or double bond and M is H, Na ,K ,Mg ,Ca
The present invention is directed to the synthesis of chiral dihydroxy acid HMG CoA Reductase inhibitors of general formula (1) preferably via sulfide, sulfoxide and sulfone intermediates which is used in preparing a dihydroxy acid HMG CoA reductase inhibitor or lactone thereof. In one aspect of the process of the invention, a Julia-Modified olefination reaction is employed wherein the sulfone intermediate is reacted with carboxylaldehyde to form the desired olefin which be isolated in high yield and optical purity and which may be converted to the final HMG CoA reductase inhibitor.
Background of the Invention
Rosuvastatin and process for its preparation is disclosed in US Patent No: 5260440. The process disclosed therein involves four distinct chemical steps and the generation of the phosphoranes side chain requires expensive reagents and the process is both uneconomical and time consuming, and statin compounds preparation through wittig reaction leads to formation of ‘Z’ isomer, hence not suitable for commercial production.
It is, therefore, desirable to provide an efficient process for the preparation of statins which improves the economics by employing less expensive reagents and is more productive.

The alternate method for the preparation of olefinic compounds is Julia classical olefination, Julia modified olefination, Julia modified olefination process for the preparation of HMG CoA Reductase inhibitors, is disclosed and claimed in US 6875867, in this patent chiral diol sulfone (aliphatic chain of statins) intermediates used for the preparation of HMG CoA Reductase inhibitors, the disclosed chiral diol sulfones are not stable and low yields were observed when using aliphatic chiral diol sulfones when compare to aromatic sulfone derivatives.
Poor solubility of calcium salt of statins has been observed in aqueous methanol with known processes for the preparation of calcium salt of statins. This is a major drawback in the synthesis of calcium salt of statins.
The present invention provides a novel process which solves the above mentioned problems of known processes.
The present invention provides a novel and advantageous process for the preparation of calcium salt of statins which solves solubility problem of the compound in aqueous methanol and gives free flow solid of calcium salt.
The present invention provides a novel process which is simple and cost effective.
Disadvantages of the prior art processes
• Usage of hazardous reagents like phosphorous trihalides or phosphorous
oxyhalides.
• Usage of strong base like LDA / n-BuLi followed by usage of Na/Hg in Julia
classical olefination reactions, which are highly pyrophoric in nature, hence those
are not recommended for commercial scale up.
• Usage of strong base like LDA / n-BuLi in Julia modified olefination reactions,
which are highly pyrophoric in nature, hence those are not recommended for
commercial scale up.
• Chiral diol sulfone compounds which are prepared as per the procedure given in
US Patent 6875867 are unstable intermediates.
• Poor solubility of calcium salt compound of formula (1) in aqueous methanol.

Brief description of the Invention
In accordance with the present invention, a process is provided for preparing chiral dihydroxy acid HMG CoA reductase inhibitors which are useful as anti-cholesterol agents as described hereinafter.
The first aspect of the present invention is to provide a novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a novel process is provided for preparing olefin dihydroxy acid compounds of general formula (1)

1 wherein «==-- denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2
A Novel process is provided for the preparation of olefin dihydroxy compound of general formula (1) via a Julia-Modified olefination, which comprises of the following steps,
1. Reacting a sulfone compound of general formula (2) with an aldehyde
compound of formula (3) in the presence of an alkali and alkaline earth
metal bases in a suitable polar aprotic solvent to provide olefin compound
of general formula (4).
2. The olefininc compound of general formula (4) may be used to form a
dihydroxy acid (or lactam thereof) HMG CoA reductase inhibitor by
subjecting the olefin compound of formula 4 to acidic conditions to
remove the acetonide and form diol compound, which upon treating with a
base such as an alkali metal hydroxide to form the corresponding alkali
metal salt then further treating with an organic amine base to form
corresponding organic amine salt compound of general formula (5).
3. Converting the organic amine salt compound of formula 5 into free acid
compound of formula 6 by treating the compound of formula 5 with an
acid to give acid compound of formula (6).

4. The alkenyl double bond in acid compound of formula 6 may be
hydrogenated (H2/PCI/C) to provide the saturated alkyl acid compound of
formula (7).
5. Converting the olefinic chiral dihydroxy acid or its organic amine salt into
its pharmaceutically acceptable salts of the general formula (1) by treating
the organic amine compound of general formula (5) or acid compound of
general formula (6) with an alkali base followed by treating with
corresponding alkali or alkaline earth metal salts in a suitable solvent.
The lactone compound of formula (8) may be prepared

8
By treating the olefin compound of formula 4 under acid conditions (for example, TFA, HC1) to effect conversion to lactone compound of formula (8). The saturated derivative of lactone 8 may be obtained by catalytic (Pd/C, Pt/C, Pd(OH)2) hydrogenation of compound of formula 8 to compound of formula 9.

9
Lactone compounds of formula 8 and 9 may be converted to the corresponding diols by saponification of 8 and 9 with aqueous base to form corresponding alkali salt compounds of formula 10 and 11.

11

The second aspect of the present invention is to provide novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a process provided for preparing olefin dihydroxy acid compound of general formula (1)

1 — denotes single or double bond and M is H, Na+ ,K+ ,Mg+2 ,Ca+2
A Novel process for the preparation of olefin dihydroxy compound of general formula (1) is provided via a Julia-Modified olefination, which comprises of the following steps,
1. Reacting a sulfoxide compound of general formula (12) with an aldehyde
compound of formula (3) in the presence of an alkali and alkaline earth
metal bases in a suitable polar aprotic solvent to provide olefin compound
of general formula (4).
2. The olefininc compound of general formula (4) may be used to form a
dihydroxy acid (or lactam thereof) HMG CoA reductase inhibitor by
subjecting the olefin compound of formula 4 to acidic conditions to
remove the acetonide and form diol compound, which upon treating with a
base such as an alkali metal hydroxide to form the corresponding alkali
metal salt then further treating with an organic amine base to form
corresponding organic amine salt compound of general formula (5).
3. Converting the organic amine salt compound of formula 5 into free acid
compound of formula 6 by treating the compound of formula 5 with an
acid to give acid compound of formula (6).
4. The alkenyl double bond in acid compound of formula 6 may be
hydrogenated (tk/Pd/C) to provide the saturated alkyl acid compound of
formula (7).
5. Converting the olefinic chiral dihydroxy acid into its pharmaceutically
acceptable salts of the general formula (1) by treating the organic amine

compound of general formula (5) or acid compound of general formula (6) with an alkali base followed by treating with corresponding alkali or alkaline earth metal salts in a suitable solvent.
The process of the present invention may be employed to prepare pravastatin, atorvastatin, cerivastatin, fluvastatin, rosuvastatin, nisvastatin (pitavastatin), simvastatin, lovastatin and other dihydroxy acid or lactone HMG CoA reductase inhibitors.
The starting material aldehyde compound of formula (3) can be prepared as per the prior art processes, Ref : WO/49014; US 6844437; US 20040049036 and in US 2006/0004200 and Tetrahedron Letters, Vol.31, No. 18, pp 2545-2548,1990
The third aspect of the present invention is to provide a novel process for preparing a novel sulfone and sulfoxide compounds having general formula (2) and formula (12). which comprise of the following steps
1. Reacting a compound of general formula (13) with a thiol compound of general
formula (14) in presence of a suitable base with or without a suitable solvent to
provide a novel sulfide compound of general formula (15)
2. And oxidizing the sulfide compound of formula (15) with an oxidizing agent in
presence of an appropriate catalyst in a suitable solvent, to provide a novel
sulfone compound of general formula (2) and sulfoxide compound of formula
(12) can be prepared by controlled oxidation of sulfide.
The starting material compounds of general formula (13) can be prepared as per the prior art processes, Ref : US Patent 6627636; US 5763675 (Pitavastatin); US 5354772; US 4739073 (Fluvastatin); WO 03/097614; US2004/0176401 and WO03/006439.
The fourth aspect of the invention is to provide a novel process for the preparation of calcium salt of statins which comprises of the following steps.
(a) Converting the organic amine salt compound of general formula (5) into
its corresponding alkali salt by treating with alkali base.
(b) Setting the reaction mixture pH to 8.0 to 9.2 by expelling the organic
amine followed by extraction or by extracting the organic amine with a
suitable solvent or by adding an acid.

(c) Adding the aqueous phase of the reaction mixture to a calcium source to give free flow calcium salt compound of general formula (1).

1 wherein M is Ca+2
In addition, in accordance with the present invention , the following intermediates prepared by the process of the invention are novel compounds.
1. Sulfide compounds of general formula (15)

15 where R and R2 are defined above.
2. Sulfone compounds of general formula (2)

2 where R and R2 are defined above.
3. Sulfoxide compounds of general formula (12)

12 where R and R2 are defined above.
-

Advantages of the present invention
• No pyrophoric reagents used in present invention.
• Usage of simple bases like potassium carbonate, sodium carbonate instead of
using LDA / n-BuLi / LiHMDS / NaHMDS.
• Sulfone compounds which are prepared as per the present invention are stable.
• Yields are above 80% for all stages of the present invention.
• Calcium salt compound of formula (la) is freely soluble in aqueous methanol.
• Calcium slat compounds of statins prepared by the present invention are free flow
solids.
• The present invention is simple and cost effective.
Detailed description of the Invention
In accordance with the present invention, a process is provided for the preparation of chiral dihydroxy acid HMG CoA reductase inhibitors which are useful as anti-cholesterol agents as described hereinafter.
The first aspect of the present invention is to provide a novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a novel process is provided for preparing olefinic dihydroxy acid compound of general formula (1)

1 — denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2
A Novel process is provided for the preparation of olefinic dihydroxy compound of general formula (1) via a Julia-Modified olefination, which comprises the steps of reacting a sulfone compound of general formula (2).

2
Wherein R is defined as above and R2 is
Wherein
R3 is alkyl, aryl, arylalkyl or cycloalkyl,
R4 is H, alkyl, aryl, arylalkyl, CF3, halo or NO2
R5 is H, alkyl, alkaoxy, haloalkyl, monohaloalkyloxy, dihaloalkyloxy And
X is O,N-H,N-alkyl or S;
Herein after the above compounds of general formula (i),(j) and (k) are referred as ‘R2’ With an aldehyde compound of formula (3)

3
wherein R1 is alkyl,cycloalkyl,arylalkyl,aryl or carbonylbenzyloxy (cbz), preferably alkyl, more preferably tertiary butyl.
In presence of an alkali and alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably cesium carbonate in a suitable polar aprotic solvent like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide olefin compound of general formula (4).

4

The olefin compound of general formula (4) may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting olefin compound of formula 4 to acidic conditions such as using hydrochloric acid, acetic acid, sulfuric acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form the corresponding sodium salt then further treating with an organic amine base like methyl amine, dicyclohexyl amine, tertiary butyl amine, preferably dicyclohexylamine to form corresponding amine salt compound of formula (5).
5
Converting the organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula (1) by treating the organic amine compound of general formula (5) with an alkali base such as sodium hydroxide followed by treating with corresponding alkali or alkaline earth metal salts like calcium chloride, calcium acetate, sodium hydroxide in a suitable solvent such as water.

1
wherein M is H, Na+,K+,Mg+2,Ca+2.
The second aspect of the present invention is to provide novel process for the preparation of Olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts, in accordance with the present invention, a process provided for preparing olefinic dihydroxy acid compound of formula (1)

1 wherein ‘ —’ denotes single or double bond and M is H, Na+,K+,Mg+2,Ca+2 ,
A Novel process for the preparation of olefin dihydroxy compound of formula (1) is provided via a Julia-Modified olefmation, which comprises the steps of reacting sulfoxide compound of general formula (12).

12 With an aldehyde compound of formula (3)

3
wherein Rj is alkyl,cycloalkyl,arylalkyl,aryl or carbonylbenzyloxy (cbz), preferably alkyl, more preferably tertiary butyl.
in presence of strong base like amide bases such as sodium bis (trimethyl silyl) amide, potassium bis (trimethyl silyl) amide, lithium bis (trimethyl silyl) amide in a suitable polar aprotic solvents like dimethylformamide, dimethylsulfoxide, dimethylacetamide or mixtures thereof, preferably dimethyl sulfoxide to provide olefin compound of general formula (4),
4
The olefin compound of general formula (4) may be used to form a dihydroxy acid HMG Co A reductase inhibitor by subjecting olefin compound of formula 4 to acidic conditions such as using hydrochloric acid, sulfuric acid, acetic acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form the corresponding sodium salt then further treating with an organic amine base like methyl amine, dicyclohexyl amine, tertiary butyl amine, preferably dicyclohexylamine to form corresponding amine salt compound of formula (5).
5
Converting the organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula (1) by treating the organic amine compound of general formula (5) with an alkali base such as sodium hydroxide followed by treating with corresponding alkali or alkaline earth metal salts like calcium chloride, calcium acetate, sodium hydroxide in a suitable solvent such as water.

1
where M is H, Na+,K+,Mg+2,Ca+2.
The third aspect of the present invention further comprises the steps of forming a novel sulfone and sulfoxide derivatives having the general formula (2) and formula (12) of the following.
2 12-
which comprises of treating a solution of the compound of general formula (13)
R-L
13
Wherein L is a leaving group such as halogen, trifluoromethanesulfonyloxy, methanesulfonyloxy, preferably halogen, more preferably bromo
with a thiol compound of general formula (14)
R2SH
14
wherein R2 is defined as above
in presence of a suitable base like sodium hydroxide with or without a suitable solvent, a suitable solvent selected from chloro solvents like methylene chloride, chloroform,

carbon tetrachloride, keto solvents like acetone, 2-butanone, methyl isobutyl ketone, methyl ethyl ketone, ester solvents like ethyl acetate, methyl acetate, tertiary butyl acetate, polar solvents like dimethyl formamide, dimethyl acetamide, dimethyl sulfoxide, water or mixtures thereof, preferably keto solvents, more preferably aceone to provide a novel sulfide compound of formula (15),

15
wherein R and R2 are defined as above
And oxidizing a sulfide compound of formula (15) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride to provide the novel sulfone compound of general formula (2) and a novel sulfoxide compound of formula (12) can be prepared by controlled oxidation of sulfide.
The fourth aspect of the invention is to provide a novel process for the preparation of calcium salt of statins, which comprises of the following steps.
(a) Converting the organic amine salt compound of general formula (5) into
its sodium salt by treating with sodium hydroxide.
(b) Setting the reaction mixture pH to 8.0 to 9.2 by expelling the organic
amine followed by extracting the reaction mixture with a suitable solvent
such as ester solvents like ethyl acetate, methyl acetate, tertiary butyl
acetate or by extracting the organic amine with a suitable solvent like
ester solvents ethyl acetate, methyl acetate, tertiary butyl acetate,

preferably tertiary butyl acetate to remove organic amine or by adding an acid like hydrochloric acid.
(c) Adding the aqueous phase of the reaction mixture to a calcium source like calcium chloride or calcium acetate in a suitable solvent like water to give free flow calcium salt compound of general formula (1).

1 wherein M is Ca
According to the present invention, a preferred process is provided for preparing the preferred olefinic chiral dihydroxy acid and its pharmaceutically acceptable salts compound of formula (la).

la wherein M is Ca+2
A novel process for the preparation of Olefin dihydroxy acid is provided via Julia-Modified olefination which comprises the steps of reacting sulfone compound of formula (2a)

2a With an aldehyde compound of formula (3a)

3a
in the presence of cesium carbonate in dimethyl sulfoxide to provide olefin compound of general formula (4a).

4a
The olefin compound of general formula (4a) may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting olefin compound of formula 4a to acidic conditions such as using hydrochloric acid to remove the acetonide and form diol compound, which upon treating with an alkali base such as sodium hydroxide to form sodium salt then further treating with dicyclohexyl amine to form corresponding amine salt compound of formula (5a).

5a
Converting the organic amine salt compound into pharmaceutically acceptable salts of olefin dihydroxy acid compound of general formula (la) by treating the organic amine compound of general formula (5 a) with an alkali base such as sodium hydroxide

and setting the pH of the reaction mixture by extracting the organic amine with tertiary butyl amine to 9.1 followed by adding the aqueous phase of the reaction mixture to a solution of calcium chloride or calcium acetate in a suitable solvent such as water.

la
+9
wherein M is Ca
In accordance with the present invention, a preferred process is provided for preparing the preferred sulfone compound of formula 2a.

Formula (2a) Which comprise of treating a solution of compound of formula (13a)

13a
with difluoromethoxy benzimidazole-thiol compound of formula (14a) in presence of sodium hydroxide in dimethyl formamide or in acetone,

14a To provide a novel sulfide compound of formula (15a)

15a
and methylating the compound of formula (15a) using methylating agent like dimethyl sulfate to provide N-methyl sulfide compound of formula (16).

16 17
And oxidizing the sulfide compound of formula (16) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride or oxidizing the sulfide compound of formula (15a) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol,

chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride and then methylating the obtained sulfone compound of formula (17), to provide the novel sulfoxide compound of formula (12a).

2a
In accordance with the present invention, a preferred process is provided for preparing the preferred sulfoxide compound of formula 12a.

Formula (12a) Which comprises of treating a solution of the compound of formula (13a)

13a
with difluoromethoxy benzimidazole-thiol compound of formula (14a) in presence of sodium hydroxide in dimethyl formamide or acetone,

14a To provide a novel sulfide compound of formula (15a)

15a
and methylating the compound of formula (15a) using methylating agent to provide N-methyl sulfide compound of formula (16).

16 18
And controlled oxidation of sulfide compound of formula (16) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride or controlled oxidation of sulfide compound of formula (15a) with an oxidizing agent like metachloro perbenzoic acid, sodium hypochlorite, hydrogen peroxide, tertiary butyl hydrogen peroxide, cumene hydroperoxide, preferably hydrogen peroxdide in the presence of an appropriate catalyst like ammonium molybdate in a single or biphasic
-

system in a suitable solvent selected from alcoholic solvents like methanol, 2-proponol, ethanol, chlorosolvents like methylene chloride, chloroform, carbon tetra chloride or mixture thereof, preferably chlorosolvents, more preferably methylene chloride and then methylating the obtained sulfoxide compound of formula (18), to provide the novel sulfoxide compound of formula (12a).

The processes described in the present invention were demonstrated in examples illustrated below. These examples are provided as illustration only and therefore should not be construed as limitation of the scope of the invention.
Examples
Example 1 : Preparation of sulfide compound of formula (15a)
47.56 gr of 5-(difluoromethoxy)-2-mercapto benzimidazole compound of formula (14a) is added to a aqueous sodiumhydroxide solution (9.61 gm sodium hydroxide in 200 ml water) at 25 to 35°C and stirred for 15 minutes, then added a solution of 400 ml of acetone and 100 gr of [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-Methyl-N-methane Sulphonyl amino pyrimidine-5yl] methyl bromide compound of formula (13a) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water and filtered the obtained precipitate and dried the compound at 60-65°C for 3 hours to get the title compound.
Yield : 119.5 grams; M.R : 165-170°C Mass spectrum : M+l peak at 551 Example 2 : Preparation of N-methylated sulfide compound of formula (16)
A solution of 10 gr of sulfide compound of formula (15a) prepared as per the example 1 and 100 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 2.9 gr of potassium carbonate to the above solution then added 3.0 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 3 hours. Yield : 8 grams ; M.R : 158-165°C. Mass spectrum : M+l peak at 566
Example 3 : Preparation of sulfone compound of formula (2a)
A solution of 24 gr of N-methylated sulfide compound of formula (16) prepared as per the example 2, 120 ml of methylene chloride and 1.0 gr of Tetrabutyl ammonium bromide, is cooled to 0-5 °C. Added a mixture of 72 ml of 30% hydrogen peroxide and

1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield : 24 grams. M.R : 145-154°C.
Example 4 : Preparation of sulfone compound of formula (17)
A solution of 117 gr of sulfide compound of formula (15a) prepared as per the example 1 and 585 ml of methylene chloride, is cooled to 0-5°C. Added a mixture of 240.6 ml of 30% hydrogen peroxide and 2.34 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 5 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes and heptane mix as a solvent medium. Dried the compound at 60-65°C for 3 hours.Yield : 122 grams. M.R : 105-135°C.
Example 5 : Preparation of sulfone compound of formula (2a)
A solution of 120 gr of sulfone compound of formula (17) prepared as per the example 4 and 600 ml of acetone at 3O-35°C. Added 31.24 gr of potassium carbonate to the above solution then added 21.39 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 30-35°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 110 grams. M.R : 145-155°C.

Example 6 : Preparation of sulfoxide compound of formula (12a)
A solution of 24 gr of N-methylated sulfide compound of formula (16) prepared as per the example 2 and 240 ml of methylene chloride, is cooled to 0-5 °C. Added a mixture of 36 ml of hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield: 24 grams. Mass spectrum : M+l peak at 582.
Example 7 : Preparation of olefin compound of formula (4a)
34.67 gr of potassium carbonate is added to a solution of 25 gr of sulfone compound of formula (2a) prepared as per example 3 and 125 ml of dimethyl sulfoxide at 25 to 35°C. Added 10.8 gr of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yl]acetate compound of formula (3a). Stirred for 13 hours at 60 to 65°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45 °C for 6 hours . Yield : 13.5 grams. M.R : 148-155°C Mass spectrum : M+l peak at 578

Example 8 : Preparation of DCHA salt of dihydroxy acid compound of formula (5a)
A solution of 25 gr of olefin compound of formula 4a prepared as per example 5 and 250 ml of acetonitrile, is cooled to 23 to 28°C. Added 70.75 ml of 1.0% hydrochloric acid solution slowly to the above contents of the reaction. Stirred the reaction mixture for 4 hours at 23 to 28°C. Added 37.5 ml of 10% sodium hydroxide solution to the reaction mixture and stirred to 2 hours at 30-35°C. Adjust the pH of the reaction mixture to 3.5 to 4.5 with 10% hydrochloride. Separated the organic phase and cooled to 0-10°C. Added 8.66 gr of dicyclohyxyl amine (DCHA) to the contents and stirred for 1 hour at 0-5 °C. Distilled the solvent completely and isolated the title compound using acetonitrile as a solvent. Dried the compound at 40-45°C for 5 hours. Yield: 18 grams.
Example 9 : Preparation of calcium salt of olefin dihydroxy compound of formula (la)
A solution of 15 gr of DCHA salt compound of formula (5a) and 75 ml of water,
is cooled to 25-30°C. Added 8.5 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by extracting the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 2.55 gr of calcium chloride and 15 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45°C. Yield : 12 grams; M.R: 145-150 (Decomposed) ; Purity by HPLC is 99.50%
Example 10 : Preparation of sulfide compound of formula (15b)
39.68 gr of 5-methoxy-2-mercapto benzimidazole compound of formula (14b) is added to aqueous sodium hydroxide solution(9.61 gm sodium hydroxide in 200 ml water) at 25 to 35°C and stirred for 15 minutes, then added a solution of 400 ml of acetone and 100 gr of [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-Methyl-N-methane Sulphonyl amino pyrimidine-5yl] methyl bromide compound of formula (13a) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 60-65°C for 3 hours to get the title compound. Yield :110 grams. M.R: 159-163°C.

Example 11 : Preparation of sulfide compound of formula (15c)
33.07 gr of 2-mercapto benzimidazole compound of formula (14c) is added to an aqueous sodium hydroxide solution (9.61 gm of sodium hydroxide in 200 ml water) at 25 to 35°C and stirred for 15 minutes, then added a solution of 400 ml of acetone and 100 gr of [4-(4-Fluoro phenyl) - 6 -isopropyl -2-(N-Methyl-N-methane Sulphonyl amino pyrimidine-5yl] methyl bromide compound of formula (13a) and stirred for 1.5 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 60-65°C for 2 hours to get the title compound. Yield : 106.0 grams. M.R : 188-195°C.
Example 12 : Preparation of sulfone compound of formula (17a)
A solution of 108 gr of sulfide compound of formula (15b) prepared as per the example 10, 540 ml of methylene chloride and 2.16 gr tetrabutyl ammonium bromide. Added a mixture of 237.5 ml of 30% hydrogen peroxide and 2.16 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 4 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 60-65°C for 3 hours. Yield : 114 grams. M.R : 100-132°C
Example 13 : Preparation of sulfone compound of formula (17b)
A solution of 105 gr of sulfide compound of formula (15c) prepared as per the example 11, 525 ml of methylene chloride and 2.1 gr tetrabutyl ammonium bromide. Added a mixture of 245.2 ml of 30% hydrogen peroxide and 2.1 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water.

Separated the organic phase and distilled the solvent at below 60°C under reduced
pressure. The title compound is isolated using hexanes as a solvent. Dried the compound
at60-65oCfor4hours.
Yield : 107 grams.M.R : 98-128°C.
Example 14 : Preparation of N-methylated sulfone compound of formula (2b)
A solution of 3.0 gr of sulfone compound of formula (17a) prepared as per the example 12 and 15 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 0.88 gr of potassium carbonate to the above solution then added 0.6 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 1.7 grams. M.R : 122-130°C.
Example 15 : Preparation of N-methy lated sulfone compound of formula (2c)
A solution of 3.0 gr of sulfone compound of formula (17b) prepared as per the example 13 and 15 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 0.93 gr of potassium carbonate to the above solution then added 0.63 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 2.0 grams. M.R : 126-134°C
Example 16 : Preparation of olefin compound of formula (4a)
8.4 gr of cesium carbonate is added to a solution of 10 gr of sulfone compound of formula (2b) prepared as per example 14 and 50 ml of dimethyl sulfoxide at 25 to 35°C. Added 4.5 gr of Tertiary butyl 2-[(4R,6S)-6-fomyl-2,2-dimethyl-l,3-dioxane-4-yljacetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium

chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45 °C for 6 hours. Yield: 6.0 grams. M.R: 148-155°C. Purity by HPLC > 96%
Example 17 : Preparation of olefin compound of formula (4a)
8.4 gr of cesium carbonate is added to a solution of 10 gr of sulfone compound of formula (2c) prepared as per example 15 and 50 ml of dimethyl sulfoxide at 25 to 35°C. Added 4.5 gr of Tertiary butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yljacetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45 °C for 6 hours. Yield : 6.2 grams. M.R : 148-155°C. Purity by HPLC > 96%
Example 18 : Preparation of calcium salt of olefin dihydroxy compound of formula (la)
A solution of 15 gr of DCHA salt compound of formula (5a) and 75 ml of water,
is cooled to 25-30°C. Added 8.5 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by extracting the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 4.3 gr of calcium acetate and 15 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45°C. Yield : 12 grams; M.R: 145-150 (Decomposed); Purity by HPLC is 99.50%

Example 19 : Preparation of calcium salt of olefin dihydroxy compound of formula (la)
A solution of 12.5 gr of methyl amine salt compound of formula (5b) and 65 ml
of water, is cooled to 25-30°C. Added 9.5 ml of 10% sodium hydroxide solution. Stirred
for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by expelling the methyl amine
traces. Extracted the reaction mixture thrice with tertiary butyl acetate. Added the
aqueous phase of the reaction mixture to a solution of 2.79 gr of calcium acetate and 12.5
ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at
40-45°C.
Yield: 9.5 grams
Example 20 : Preparation of calcium salt of olefin dihydroxy compound of formula (la)
A solution of 10.0 gr of methyl amine salt compound of formula (5b) and 50 ml
of water, is cooled to 25-30°C. Added 7.8 ml of 10% sodium hydroxide solution. Stirred for 1 hour. Adjusted the pH of the reaction mixture to 9.1 by expelling the methyl amine traces. Extracted the reaction mixture thrice with tertiary butyl acetate. Added the aqueous phase of the reaction mixture to a solution of 1.701 gr of calcium chloride and 10 ml of water at 35 to 45°C. Filtered off the precipitated compound. Dried the compound at 40-45 °C. Yield : 8.7 grams. HPLC Purity is 99%
Example 21 : Preparation of sulfide compound of formula (15d)
15 gr of 5-(difluoromethoxy)-2-mercapto benzimidazole compound of formula (14a) is added to a 82.5 ml of 2.9% solution of sodium hydroxide at 25 to 35°C and stirred for 15 minutes, then added a mixture of 175 ml of dimethylformamide and 25 gr of 3-(bromomethyl)-2-cyclopropyl-4-(4-fluorophenyl)quinoline compound of formula (13b) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 50-55°C for 6 hours to get the title compound.Yield : 32 grams. M.R : 117-125°C.

Example 22 : Preparation of sulfone compound of formula (17c)
A solution of 25 gr of sulfide compound of formula (15d), 100 ml of methylene chloride and 1.0 gr of tetrabutyl ammonium bromide, is cooled to 0-5°C. Added a mixture of 56 ml of 30% hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield : 23 grams. M.R : 150-160°C.
Example 23 : Preparation of N-methylated sulfone compound of formula (2d)
A solution of 3.0 gr of sulfone compound of formula (17c) prepared as per the example 22 and 15 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 0.93 gr of potassium carbonate to the above solution then added 0.63 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield : 3.5 grams. M.R : 158-162°C.
Example 24 : Preparation of olefin compound of formula (4b)
5.2 gr of cesium carbonate is added to a solution of 3.5 gr of sulfone compound of formula (2d) and 20 ml of dimethyl sulfoxide at 25 to 35°C. Added 1.68 gr of Tertiary butyl 2-[(4R?6S)-6-formyl-2?2-dimethyl-l53-dioxane-4-yl]acetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to

the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield: 1.2 grams. M.R : 115-121°C.
Example 25 : Preparation of sulfide compound of formula (lSe)
6.0 gr of 5-(difluoromethoxy)-2-mercapto benzimidazole compound of formula (14a) is added to a 36 ml of 2.9% solution of sodium hydroxide at 25 to 35°C and stirred for 15 minutes, then added a mixture of 30 ml of acetone and 10 gr of 2-(bromomethyl)-3-(4-fluorophenyl)-l-isopropyl-lH-indole compound of formula (13c) and stirred for 2 hours at 25 to 30°C. Quenched the reaction mass with chilled water filtered the obtained precipitate and dried the compound at 50-55°C for 6 hours to get the title compound. Yield: 10 grams.
Example 26 : Preparation of sulfone compound of formula (17d)
A solution of 10 gr of sulfide compound of formula (15e), 100 ml of methylene chloride and 0.5 gr of tetrabutyl ammonium bromide, is cooled to 0-5°C. Added a mixture of 14 ml of 30% hydrogen peroxide and 1.0 gr of ammonium heptamolybdate tetra hydrate. Stirred the mixture for 3 hours. Quenched the reaction mixture with chilled water and separated the organic layer and extracted the reaction mixture with methylene chloride twice. Washed the organic phase with 10% sodium sulfite solution and 5% sodium bicarbonate solution followed by washed with water. Separated the organic phase and distilled the solvent at below 60°C under reduced pressure. The title compound is isolated using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield ; 6.0 grams.
Example 27 : Preparation of N-methylated sulfone compound of formula (2e)
A solution of 5.0 gr of sulfone compound of formula (17d) prepared as per the example 26 and 25 ml of acetone, is cooled to 0-5°C under nitrogen atmosphere. Added 1.35 gr of potassium carbonate to the above solution then added 3.1 ml of dimethylsulfate to the above reaction mixture and stirred for 4 hours at 0-5°C. Quenched the reaction

mixture with chilled water and filtered the precipitated compound. Dried the compound at 50-55°C for 6 hours. Yield: 3.0 grams.
Example 28 : Preparation of olefin compound of formula (4c)
2.7 gr of potassium carbonate is added to a solution of 3.0 gr of sulfone compound of formula (2e) prepared as per example 27 and 10 ml of dimethyl sulfoxide at 25 to 35°C. Added 1.5 gr of Tertiary butyl 2-[(4R>6S)-6-formyl-2,2-dimethyl-l,3-dioxane-4-yl]acetate compound of formula (3a). Stirred for 3 hours at 25 to 35°C. Quenched the reaction mixture with chilled water slowly in 30 minutes. Extracted the reaction mixture twice with ethyl acetate. Separated and washed the organic phase with saturated sodium chloride solution. Distilled the solvent completely under reduced pressure at below 70°C. hexanes added to the residue and decanted twice then dissolved the residue in toluene and isolated the title compound using hexanes as a solvent. Dried the compound at 40-45°C for 6 hours. Yield: 0.6 grams

Documents:

805-CHE-2006 FORM-13 20-02-2008.pdf

805-CHE-2006 AMENDED CLAIMS 16-04-2012.pdf

805-CHE-2006 AMENDED PAGES OF SPECIFICATION 16-04-2012.pdf

805-CHE-2006 CORRESPONDENCE OTHERS.pdf

805-CHE-2006 CORRESPONDENCE PO.pdf

805-CHE-2006 EXAMINATION REPORT REPLY RECEIVED 16-04-2012.pdf

805-CHE-2006 FORM-13.pdf

805-CHE-2006 FORM-18.pdf

805-che-2006-abstract.pdf

805-che-2006-claims.pdf

805-che-2006-correspondence-others.pdf

805-che-2006-description(complete).pdf

805-che-2006-form1.pdf

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Patent Number

252200

Indian Patent Application Number

805/CHE/2006

PG Journal Number

18/2012

Publication Date

04-May-2012

Grant Date

01-May-2012

Date of Filing

03-May-2006

Name of Patentee

SHRI. MANNE SATYANARAYANA REDDY

Applicant Address

DR. MANNE SATYANARAYANA REDDY H.NO. 8-3-167/D/16 KALYAN NAGAR-1 HYDERABAD-500038

Inventors:

#	Inventor's Name	Inventor's Address
1	SHRI. MANNE SATYANARAYANA REDDY	H.NO. 8-3-167/D/16 KALYAN NAGAR-1 HYDERABAD-500038
2	SRINIVASAN THIRUMALAI RAJAN	SRINIVASAN THIRUMALAI RAJAN PLOT NO-12 & 13, LAKE VIEW ENCLAVE, MIYAPUR HYDERABAD, ANDHRA PRADESH
3	MARAMREDDY SAHADEVA REDDY	MARAMREDDY SAHADEVA REDDY H.NO.15-21-140 BALAJI NAGAR, KUKATPALLY HYDERABAD, ANDHRA PRADESH INDIA 500 078

PCT International Classification Number

C07D215/14

PCT International Application Number

N/A

PCT International Filing date

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1			NA