Title of Invention	NOVEL PROCESS FOR THE PREPARATION OF PITAVASTATIN AND ITS PHARMACEUTICALLY ACCEPTABLE SALTS
Abstract	Novel Process for the Preparation of Pitavastatin and its Pharmaceutically Acceptable Salts having the following formula (1) Wherein M is H, Na+,K+,Mg+2,Ca+2.

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Novel Process for the preparation of Pitavastatin and its pharmaceutically acceptable salts Field of the Invention The present invention relates to a novel process for the preparation of Pitavastatin and its pharmaceutically acceptable salts, preferably Pitavastatin calcium which is chemically known as (3R, 5S)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3, 5-dihydroxy-6(E)-heptenoic acid calcium salt having the following formula (I) Formula I Wherein M is H, Na+,K+,Mg+2,Ca+2. Pitavastatin is a synthetic lipid-lowering agent that acts as an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (HMG-CoA Reductase inhibitor). This enzyme catalyzes the conversions of HMG-CoA to mevalonate, inhibitors are commonly referred to as “statins”. Statins are therapeutically effective drugs used for reducing low density lipoprotein (LDL) particle concentration in the blood stream of patients at risk for cardiovascular disease. Pitavastatin is used in the treatment of hypercholesterolemia (heterozygous familial and nonfamilial) and mixed dyslipidemia (Fredrickson Type IIa and IIb). The compound of the present invention inhibits 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. Background of the Invention US Patent 5856336 claimed quinoline type mevalonolactones, specifically Pitavastatin. The disclosed process using an expensive reagent like sodium hydride, n-butyl lithium and borane derivates, reagents that are difficult to use on a commercial scale. Accordingly, there remains a need for a novel process for the preparation of quinoline derivatives such as Pitavastatin that reduces the problems of the prior art on a commercial scale in a convenient and cost efficient manner. US 2005/0124639 claim the process for the preparation of Rosuvastatin and its intermediates using Wittig reagent. EP 0521471 Patent describes a process for the synthesis of the calcium salt of Rosuvastatin, the final stage of which is the conversion of the sodium salt of the Rosuvastatin into the calcium salt. The calcium salt thus formed is then collected and dried and may be processed further as required. This conversion of the sodium salt into the calcium salt, followed by collection and drying is also described in an international patent application WO 00/49014. Brief description of the Invention In accordance with the present invention, a novel process is provided for the preparation of quinoline derivatives such as Pitavastatin (HMG-CoA) inhibitors, more specifically, the present invention provides a novel process for the preparation of Pitavastatin using Wittig reagents. The first aspect of the present invention is to provide a Novel process for the preparation of Pitavastatin and its pharmaceutically acceptable salt compound of formula (1), preferably Calcium salt, in accordance with the present invention, a novel process is provided for preparing Pitavastatin and its pharmaceutically acceptable salt compound of general formula (1) Formula (1) Wherein M is H, Na+,K+,Mg+2,Ca+2. A novel process is provided for the preparation of pitavastatin and its pharmaceutically acceptable salt compound of a general formula (1) via Wittig reaction, which comprises the following steps, 1. Reacting the Bromo compound of formula (2) with Wittig reagent in a suitable solvent to provide bromide salt compound of formula (3). 2. Reacting the bromide salt compound of formula (3) with an aldehyde compound of formula (4) in presence of an alkali or alkaline earth metal bases in a suitable polar aprotic solvent to provide an olefin compound of formula (5) 3. The olefinic compound of formula (5) may be used to form a dihydroxy acid by subjecting olefin compound of formula (5) 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 formula (6). 4. Converting the organic amine salt compound of formula (6) into its pharmaceutically acceptable salts of the general formula (1) by treating the organic amine 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 second aspect of the invention is to provide a novel process for the preparation of calcium salt of statins specifically pitavastatin which comprises of the following steps. (a) Converting the organic amine salt compound of formula (6) into its corresponding alkali salt by treating with an 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 in a suitable solvent to give free flow calcium salt compound of formula (1). Wherein M is Ca+2 Advantageous of the present invention • The present invention is more economical process on commercial scale because of the use of inexpensive raw materials, such as triphenyl phosphine and alkali/alkaline earth metal bases like carbonate bases. • Easier and more economical production because of the reaction conditions are simple, like normal temperatures, and using a Wittig reagent instead of Wittig- Horner type reagent. • The present invention provides highest yields and highest purity of Pitavastatin and its intermediates • The present invention provides free flow salt of Pitavastatin calcium Detailed description of the Invention In accordance with the present invention, a novel process is provided for the preparation of quinoline derivatives such as Pitavastatin, useful as HMG-CoA inhibitor, more specifically, the present invention provides a novel process for the preparation of Pitavastatin using Wittig reagents. The first aspect of the present invention is to provide a Novel process for the preparation of Pitavastatin and its pharmaceutically acceptable salt compound of formula (1), preferably Calcium salt, in accordance with the present invention, a novel process is provided for preparing pitavastatin and its pharmaceutically acceptable salt compound of general formula (1) Wherein M is H, Na+,K+,Mg+2,Ca+2. A Novel process is provided for the preparation of pitavastatin and its acceptable salt compound of formula (1) via Wittig reaction, which comprises of the following steps a) Reacting 3-(bromomethyl)2-(l-cylcopropyl)-4(4’-fluorophenyl) quinoline compound of formula (2), With Wittig reagent like triphenyl phosphine, tributyl phosphine, preferably Triphenyl Phosphine in a suitable solvent selected from non-polar solvents like toluene, o-xylene, chlorobenzene preferably toluene at a temperature ranging from 80 to 140°C preferably at 110°C to provide Triphenyl[-2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-ylmethyl)-phosphonium bromide salt compound of formula (3). b) Reacting the TriphenyI[-2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3- ylmethyl)-phosphonium] bromide salt compound of formula (3) with an aldehyde compound of formula (4) In presence of an alkali or alkaline earth metal bases such as sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, lithium carbonate, and cesium carbonate preferably potassium carbonate in a suitable polar aprotic solvent like dimethyl formamide, dimethyl sulfoxide, dimethylacetamide or mixtures thereof, preferably dimethylsulfoxide at a temperature ranging from 40-80°C preferably at 70°C to provide (4R,6S)-(E)-(+)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl]-2,2-dimethyl-[l,3]-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula (5). c) (4R, 6S)-(E)-(+)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl]- 2,2-dimethyl-[l53]-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula (5) may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting (4R,6S)-(E)-(+)»6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl]-2,2-dimethy!-[l,3]-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula (5) 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 methyl amine to form corresponding organic amine salt compound of formula (6). d) Converting the organic amine salt compound of formula (6) into its pharmaceutically acceptable salt compound of general formula (1) by treating the organic amine compound of general formula (6) with an alkali base followed by treating with corresponding alkali or alkaline earth metal salts in a suitable solvent. Wherein M is H, Na+,K+,Mg+2,Ca+2. The second aspect of the invention is to provide a novel process for the preparation of calcium salt of Pitavastatin, which comprises of the following steps. (a) Converting the organic amine salt compound of general formula (6) 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 or acetic acid to set the pH of the reaction mixture to 8.0 to 9.2, preferably 8.5to 9.2, more preferably 9.0 to 9.2. (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 at a temperature ranging from 25 - 50°C, preferably 35-45°C, more preferable 40-45°C to give free flow calcium salt compound of formula (1). Wherein M is Ca+2 Following three options useful to remove the organic amine and to set the pH of the reaction mixture. • Setting the reaction mixture pH 8.0 to 9.2 by expelling the reaction mixture to remove the traces of organic amine and finally extracting the reaction mixture with suitable solvent to remove the final traces of organic amine • Or simply extracting the reaction mixture with suitable solvent to remove the complete traces of organic amine and to set the pH of the reaction mixture 8.0 to 9.2. • Or by adding an acid like acetic acid, hydrochloric acid to the reaction mixture to set the pH 8.0 to 9.2 The addition is carried out at a temperature of between 25 and approximately 50°C, preferably 35-43°C, more preferably between 35 and 45°C, and most preferably at 45°C. The aqueous phase of the reaction mixture is added at a temperature of between 40 to 45°C over a period of 15 to 45 minutes, the mixture is held at a temperature of between 40-45°C over period of at least 30 minutes. Particle size of the Pitavastatin calcium salt before micronisation is below 200)4, (90%) and below 50JI (50%), after micronisation the particle size is below 40(i (90%) and below 20p, (50%). The starting material compound of formula (2) process described in US Patents 6627636 and US 5763675. Particle size of Pitavastatin calcium analyzed by laser technique and the MALVERN instrument is used and the method is dry powder. 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. Example 1 : Preparation of Triphenyl[-2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-ylmethyl)-phosphonium] bromide compound of formula (3) 16.1g of Triphenyl phosphine in 50ml of toluene was added slowly to 15 gr of 3-(bromomethyl)2-(l-cylcopropyl)-4(4’-fluorophenyl) quinoline compound of formula (2). The reaction mixture heated slowly to 110°C and stirred for 60 minutes. The mixture is allowed to cool to 25-35°C. Filtered the mass and washed with hexanes to get title compound. Yield: 20gram M.R: 218 - 225°C (decomposed) Example 2 : Preparation of (4R, 6S)-(E)-(+)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl) quinoline-3-yl)-vinyl]~2, 2-dimethyl-[l, 3]-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula (5) 2.7gr of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-(l?3)-dioxan-4-yl) acetate compound of formula (4) in 46ml of dimethylsulfoxide was added to a mixture of 5.0 gr of Triphenyl [-2-cyclopropyl-4-(4-fluorophenyl)-quinoline-3-ylmethyl)-phosphonium] bromide compound of formula (3) and 2.88 gr of potassium carbonate. Heated the reaction mixture to 70°C and stirred the reaction mixture for 3 hours. Quenched the reaction mixture with water and extracted the reaction mixture with toluene. Concentrated the organic phase and isolated the title compound using hexanes. Yield : 13 gram M.R: 105-116°C Example 3 : Preparation of (3R, 5S)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3, 5- dihydroxv -6(E)-heptenoic acid Methyl Amine Salt compound of formula (6a) A solution of 7.2g of (4R,6S)-(E)-(+)-6-[2-(2-cyclopropyl-4-(4-fluorophenyl)quinoline-3-yl)-vinyl]-2,2-dimethyl-[l,3]-dioxane-4-yl] acetic acid tertiary butyl ester compound of formula (5) prepared as per the example 2 and 216ml of acetonitrile, is cooled to 23-28°C. Added 45.36 ml of 4.75% aqueous hydrochloric acid, stirred for 2 hours. Added 21.6 ml of 10% sodium hydroxide solution and stirred for another 2 hours 30 minutes at 25-35°C. Distilled the solvent completely and quenched the reaction mixture with water and passed the reaction mixture through celite (hyflow). Washed the reaction mixture with tertiary butyl acetate and expelled the aqueous phase. Added sodium chloride solution and acetonitrile and cooled to 0-10°C. Adjusted the pH of the reaction mixture to 4.5 with 10% hydrochloric acid solution. Stirred for 1 hour and separated the organic phase and cooled to 0-10°C. Added 2.38ml of methyl amine solution. Stirred for 30 minutes at 25-35°C. Distilled the solvent completely and isolated the title compound using acetonitrile as a solvent. Yield: 2.5gram M.R: 136-143°C Example 4 : Preparation of Calcium Salt of (3R, 5S)-7-[2-cyclopropyl-4-(4-fluorophenyl)quinolin-3-yl]-3,5-dihydroxy-6(E)-heptenoic acid compound of formula (1) A solution of 2gram of (3R, 5S)-7-[2-cyclopropyl-4-(4-fluorophenyl) quinolin-3-yl]-3, 5-dihydroxy-6(E)-heptenoic acid Methyl Amine Salt compound of formula (6) as obtained by example 3 and 12 ml of water, is cooled to 25-30°C. Added 2.0 ml of 8.0% aqueous sodium hydroxide solution. Stirred for 1 hour. Washed the reaction mixture with tertiary butyl acetate and expelled the solvent completely under nitrogen atmosphere and pass the reaction mixture through filter paper. The aqueous phase of the reaction mixture was added in 15 minutes to a solution of 0.4g of calcium chloride dihydrate and 2 ml of water at a temperature of 45°C. Stirred for 30 minutes. The obtained precipitate filtered and washed with water to get title compound. Yield: 2.5gram

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