Rosuvastatin, is a member of drug class of statins (HMG-CoA reductase inhibitors) and is used for the treatment of high cholesterol and related conditions and to prevent cardiovascular disease.

Rosuvastatin was marketed under trade name as Crestor having rosuvastatin calcium as active ingredient which is chemically known as (E,3R,5S)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid.

US patent number 5,260,440 discloses rosuvastatin and its calcium salt and process of preparation thereof.

US patent number 6,784,171 discloses process for the preparation of rosuvastatin calcium by preparing methyl amine salt of rosuvastatin as disclosed in the scheme below:
Scheme-1:

US 8,536,330 discloses process for the preparation of rosuvastatin calcium by reacting [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate with 2-mercapto-5-methyl-1,3,4-thiadiazole followed by reacting the resulting N-[4-(4-fluorophenyl)-5-{[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide with hydrogen peroxide in presence of phase transfer catalyst. The resulting intermediate is reacted with tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate in presence of reagents like lithium bis(trimethylsilyl)azanide followed by conversion to rosuvastatin and its calcium salt.

Although there are several processes known in the prior published references, however these processes suffers from the drawback of using impure intermediates resulting into preparation of various undesired compounds which are required to be removed to get pure final active ingredient. As per prior known processes, intermediates like N-[4-(4-fluorophenyl)-5-{[(5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethane sulfonamide of Formula II is not purified and are coupled as crude compounds which results into formation of various impurities which are carried forward to the final product and hence ultimately result into loss in the yield of desired pure compounds. Based on aforesaid, the present invention is focused towards the development of an improved process that requires minimum isolation and the intermediates isolated (such as compound of Formula II) are purified before converting to final desired compound in order to increase the quality and yields of the rosuvastatin calcium.

OBJECTIVE OF THE INVENTION

Main object of the present invention is to provide a process for the preparation of rosuvastatin calcium.

Another object of the present invention is to provide pure intermediate of Formula II and use of said intermediate in the preparation of rosuvastatin calcium.

Another object of the present invention is to provide a novel polymorphs of compound of Formula II and process of preparation thereof.

Another object of the present invention is to provide a composition comprising rosuvastatin calcium along with atleast one pharmaceutically acceptable excipient.

SUMMARY OF THE INVENTION

In main aspect, the present invention provides a process for the preparation of rosuvastatin calcium, comprising the steps of:
a) converting tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III to tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V without isolation of hydroxyl intermediate of Formula IV in presence of suitable solvent;
;
b) reacting N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II with the compound of Formula V in presence of suitable solvent,
; and
c) converting compound of Formula VI to rosuvastatin calcium, wherein said compound of Formula V is optionally not isolated.

In another aspect, the present invention provides a process of the preparation of rosuvastatin calcium, comprising the steps of:
a) adding crude N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II to a suitable solvent;
b) optionally heating at a temperature in the range of 25oC-100oC;
c) isolating crystalline compound of Formula II; and
d) converting the crystalline compound of Formula II of step c) to rosuvastatin calcium.

In another aspect, the present invention provides crystalline Form A and Form B of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl) sulfonyl) methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II.

In another aspect, the present invention provides a composition comprising rosuvastatin calcium, wherein said rosuvastatin calcium is prepared by a process comprising the steps of:
a) converting tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III to tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in presence of suitable solvent without isolation of hydroxyl intermediate of Formula IV,
;
b) reacting crystalline N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II with the compound of Formula V in presence of suitable solvent,
;
c) converting compound of Formula VI to rosuvastatin calcium;
wherein said compound of Formula V is optionally not isolated; and wherein said composition further comprises atleast one pharmaceutically acceptable excipient.

In another aspect, the present invention provides crystalline form A of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II characterized by XRPD pattern having 2? value of 7.23, 8.28, 10.09, 10.39, 16.70, 18.00, 20.64, 22.02, and 24.42 ±0.2°?.

In another aspect, the present invention provides crystalline form B of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II characterized by XRD pattern having 2? value of 5.08, 10.27, 11.99, 16.27, 18.55, 20.13, 20.73, and 26.23 ±0.2°?.

DETAILED DISCRIPTION

Drawings:
Fig. 1 represents XRPD graph of crystalline Form A of Formula II.
Fig. 2 represents XRPD graph of crystalline Form B of Formula II.

Definitions:
The term “suitable solvent” as used in the context of the present invention is selected from, but not limited to, the group comprising of alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, polyethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated hydrocarbons such as dichloromethane, 1,2-dichloroethane, trichloroethylene, perchloroethylene, 1,1,1-trichloroethane, 1,1,2-trichloroethane, chloroform, carbon tetrachloride; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketone solvents such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene, cyclohexane and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

The term "excipient" or "pharmaceutically acceptable excipient" means a component of a pharmaceutical product that is not an active ingredient, and includes, but not limited to, filler, diluent, binder, disintegrants, glidants, stabilizers, surface active agents etc. The excipients that are useful in preparing a pharmaceutical composition are generally safe, non-toxic and neither biologically nor otherwise undesirable, and are acceptable for veterinary use as well as human pharmaceutical use. One excipient can perform more than one function.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

In one embodiment, the present invention provides a process for the preparation of rosuvastatin calcium, comprising the steps of:
a) converting tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III to tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in presence of suitable solvent without the isolation of hydroxyl intermediate of Formula IV
;
b) reacting N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II with the compound of Formula V in presence of suitable solvent,
; and
c) converting compound of Formula VI to rosuvastatin calcium; and wherein said compound of Formula V is optionally not isolated.

In a preferred embodiment, the present invention provides a process for the preparation of rosuvastatin calcium wherein the intermediate N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl) pyrimidin-2-yl)-N-methylmethane sulfonamide of Formula II is isolated in substantially pure crystalline form and is added to the reaction mixture comprising tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V without isolation of compound of Formula V

In another preferred embodiment, the present invention provides a process for the preparation of rosuvastatin calcium wherein the intermediate N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl) pyrimidin-2-yl)-N-methylmethane sulfonamide of Formula II is isolated in substantially pure crystalline form and reacted with tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V of compound of Formula V.

In another embodiment, the present invention provides a process for the preparation of rosuvastatin calcium, wherein said process comprising the steps of:
a) hydrolysing compound of Formula VI to give tert-butyl (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate of Formula VII in presence of suitable solvent and acid,
b) converting compound of Formula VII to (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate salt of Formula VIII,
c) converting salt of Formula VIII to rosuvastatin calcium in presence of suitable calcium ion source,
wherein said compound of Formula VII & VIII are not isolated;

.

In another embodiment, the B+ in compound of Formula VIII is selected from alkali metal, alkaline earth metal or suitable amine.

In another embodiment, the salts of Formula VIII are selected from but not limited to, sodium, potassium, calcium, magnesium, barium, and the like.

In another embodiment, the salts of Formula VIII is further selected from, but not limited to, amine salts such as methylamine salt, ethylamine salt, cyclohexyl amine, dicyclohexyl amine, tromethamine salt and the like.

In another embodiment, the present invention provides a process for the preparation of rosuvastatin calcium, comprising the steps of:
a) hydrolysing compound of Formula VI to give tert-butyl (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate of Formula VII in presence of suitable solvent and acid;
b) converting compound of Formula VII to (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxy hept-6-enoic acid salt of Formula VIII;
c) converting compound of formula VIII to methyl amine salt in temperature range of -10oC to 10oC; and
d) converting methylamine salt of Formula IX to rosuvastatin calcium in presence of suitable calcium ion source,
wherein said compound of Formula VII & VIII are not isolated;

.

In another embodiment, the present invention provides a process of the preparation of rosuvastatin calcium, comprising the steps of:
a) adding crude N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol -2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II to a suitable solvent;
b) optionally heating at a temperature in the range of 25oC-100oC;
c) isolating crystalline compound of Formula II; and
d) converting the crystalline compound of Formula II of step c) to rosuvastatin calcium.
In another embodiment, the present invention provides a process of the preparation of substantially pure crystalline compound of Formula II, comprising the steps of:
a) adding crude N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II to a suitable solvent;
b) optionally heating at a temperature in the range of 25oC-100oC;
c) isolating substantially pure crystalline compound of Formula II.
In another embodiment, the suitable solvent used for purifying and crystallization of compound of Formula II is selected from, but not limited to, methanol, ethanol, ethylene glycol, isopropyl alcohol, t-butanol, 2-butanol, diethylene glycol, cyclohexane, heptane, toluene, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, methyl t-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, ethyl acetate, propyl acetate, propylene acetate, acetonitrile, water and mixture thereof.

In another embodiment, the present invention provides crystalline Form A of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl) methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II, wherein said crystalline Form A is characterized by XRPD pattern having 2? value of 7.2, 8.2, 10.0, 10.3, 11.9, 12.7, 13.3, 13.9, 14.6, 14.8, 15.5, 16.3, 16.7, 17.1, 17.7,18.0, 18.8, 19.6, 20.0, 20.3, 20.6, 21.2, 21.8, 22.0, 22.7, 23.5, 24.4, 25.0, 25.7, 25.8, 26.4, 26.8, 27.3, 27.89, 28.11, 28.78, 29.3, 29.7, 30.1, 30.2, 30.5, 31.7, 32.1, 32.8, 33.1, 34.2, 34.8, 35.1 and 35.9 ±0.2°?.

In another embodiment, the present invention provides crystalline Form A of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl) methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II, characterized by X-ray powder diffraction pattern substantially similar as shown in Fig 1.

In another embodiment, the present invention provides crystalline Form B of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl) methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II, wherein said crystalline Form B is characterized by XRPD pattern having 2? value of 5.08, 10.27, 11.71, 11.99, 12.54, 12.80, 13.86, 14.06, 15.48, 15.63, 16.27, 17.31, 17.48, 18.55, 19.33, 20.13, 20.53, 20.73, 20.96, 21.64, 21.91, 22.44, 22.82, 23.15, 23.30, 23.74, 24.23, 24.53, 25.44, 26.12, 26.23, 26.61, 26.88, 27.24, 27.68, 28.10, 28.60, 28.91, 29.22, 29.54, 30.15, 30.40, 31.00, 31.09, 31.47, 32.71, 32.97, 33.56, 34.09, and 35.13 ±0.2°?.

In another embodiment, the present invention provides crystalline Form B of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl) methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II, characterized by X-ray powder diffraction pattern substantially similar as shown in Fig 2.

The term “substantially pure crystalline form of compound of Formula II” refers to the crystalline form having purity greater than about 95%, specifically greater than about 97% and more specifically greater than about 99%.

In another embodiment, the present invention provides crystalline form of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl) pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II, having purity of about 99.0% and more.
In another embodiment, the present invention provides a process for the preparation of rosuvastatin calcium comprising the steps of:
a) treating N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methyl methanesulfonamide or pharmaceutically acceptable salt thereof, with suitable reagent to give compound of Formula XI,
;
wherein X is a suitable leaving group;
b) insitu reacting compound of Formula XI with 5-methyl-1,3,4-thiadiazole-2-thiol to give N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)thio)methyl) pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula X,
;
c) oxidizing compound of Formula X in presence of oxidizing agent and suitable solvent to give compound of Formula II;
;
d) adding compound of Formula II to a suitable solvent;
e) optionally heating at a temperature in the range of 25oC-100oC;
f) isolating crystalline compound of Formula II; and
g) converting the crystalline compound of Formula II of step c) to rosuvastatin calcium.

In another embodiment, the present invention provides a composition comprising rosuvastatin calcium and atleast one pharmaceutically acceptable excipient.

In another embodiment, the present invention provides a composition comprising rosuvastatin calcium, wherein said rosuvastatin calcium is prepared by a process comprising the steps of:
a) converting tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III to tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in presence of suitable solvent without isolation of hydroxyl intermediate of Formula IV;
;
b) reacting crystalline N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II with the compound of Formula V in presence of suitable solvent;
;
c) converting compound of Formula VI to rosuvastatin calcium; wherein said compound of Formula V is optionally not isolated; and wherein said composition further comprises atleast one pharmaceutically acceptable excipient.

In another embodiment, the rosuvastatin calcium of the present invention is having purity of about 99.0% and more, preferably about 99.5% and more, and most preferably about 99.9% and more as measured by HPLC.

In another embodiment, the present invention provides rosuvastatin calcium characterized by particle size distribution with d90 in the range of 0.1µm to 200µm.

Now, the present invention will be explained in details through experimentations. However, the examples are provided as one of the possible way to practice the invention and should not be considered as limitation of the scope of the invention.

EXAMPLES

EXAMPLE 1: Preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II

Added phosphorous tribromide to the solution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methyl methanesulfonamide in dichloromethane (DCM) and stirred for 2 hrs. After reaction completion, quenched the reaction mass with water and separated the layers. Washed the organic layer with DM water and to the organic layer 5-methyl-1,3,4-thiadiazole-2-thiol in 5M sodium hydroxide solution was added and stirred for 1-2 hrs at 20-30oC. After completion of reaction, separated the organic layer and distilled the organic layer followed by addition of methanol. Added aqueous solution of hydrogen peroxide, sodium tungstate at 10-40°C and stirred for 20 hours at 40-65°C. After completion of reaction, filtered the mass and dissolved the wet cake so obtained in dichloromethane and added 22% aq. solution of sodium thio sulphate to the reaction mixture at 10-20°C. After completion of reaction, adjusted the pH to not more than 8.0. Separated the organic layer and washed with DM water. Distilled the organic layer and purified the compound in toluene by heating the reaction mass. Cool the reaction mass & filtered to get pure material as a white solid powder with purity of 99.7%.

EXAMPLE 2: Preparation of Form A of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II

Added phosphorous tribromide to the solution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methyl methanesulfonamide in dichloromethane (DCM) and stirred for 2 hrs. After reaction completion, quenched the reaction mass with water and separated the layers. Washed the organic layer with DM water. To the organic layer 5-methyl-1,3,4-thiadiazole-2-thiol in 5M sodium hydroxide solution was added and stirred for 1-2 hrs at 20-30oC. After completion of reaction, separated the organic layer & distilled out. Charged methanol to the residue at 10-40°C followed by addition of aqueous solution of hydrogen peroxide, sodium tungstate. Stirred the reaction mixture for 20 hours at 40-65°C. After reaction completion filtered the reaction mass and obtained wet cake was dissolved in dichloromethane. Added 22% aq. solution of sodium thiosulphate to the reaction mass at 10-20°C, adjusted the pH not more than 8.0. Separated the organic layer and washed with DM water. Concentrated the organic layer and dried to get crude compound. Crude compound was dissolved in toluene at 80-85°C then slowly cooled the reaction mixture up to 25-30°C. Further cooled the reaction mass up to 0-5°C, under stirring, filtered and dry the reaction mass to get substantially pure crystalline Form A of compound of Formula II with purity more than 99.5%.

EXAMPLE 3: Preparation of Form B of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methyl methanesulfonamide of Formula II

Added phosphorous tribromide to the solution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methyl methanesulfonamide in dichloromethane (DCM) and stirred for 2 hrs. After reaction completion, quenched the reaction mass with water and separated the layers. Washed the organic layer with DM water. To the organic layer 5-methyl-1,3,4-thiadiazole-2-thiol in 5M sodium hydroxide solution was added and stirred for 1-2 hrs at 20-30oC. After completion of reaction, separated the organic layer & distilled out. Charged methanol to the residue at 10-40°C followed by addition of aqueous solution of hydrogen peroxide, sodium tungstate. Stirred the reaction mixture for 20 hours at 40-65°C. After reaction completion filtered the reaction mass and obtained wet cake was dissolved in dichloromethane. Aqueous solution of sodium thiosulphate (22%) was added to the reaction mass at 10-20°C, maintaining the pH not more than 8.0. Separated the organic layer and washed with DM water. Concentrated the organic layer and dried to get crude compound. Crude compound was dissolved in toluene at 55-60°C then slowly cooled the reaction mixture up to 25-30°C under stirring, filtered and dry the reaction mass to get substantially pure crystalline Form B of compound of Formula II with purity more than 99%.

EXAMPLE 4: Preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V

Added potassium carbonate to the solution of tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III in methanol and stirred at room temperature till reaction completion. After completion of reaction, filtered the reaction mass to remove inorganic salt and evaporated the solvent under vacuum. Dissolved the residue so obtained in dichloromethane. Washed the organic layer with DM water and adjusted the pH between 7.0 to 8.0 with 5% acetic acid solution to separate the layer. Washed the organic layer with DM water, added a solution of TEMPO and sodium bicarbonate to the dichloromethane layer at 0-10°C under stirring. Added 10% sodium hypochlorite aqueous solution to the reaction mass at 0-10°C and stirred the reaction mass till the completion of reaction. Filtered the reaction mass to remove inorganic salts, washed the organic layer with sodium thiosulphate solution and DM water. Organic layer thus obtained was evaporated under vacuum to get oily mass of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate.

EXAMPLE 5: Preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI

Sodium t-butoxide (30% solution in tetrahydrofuran) was added to the reaction mixture of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate and N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II in tetrahydrofuran, under a nitrogen atmosphere at -45oC to -55°C and stirred the reaction mass for 2 hrs. After the completion of reaction, reaction mass was quenched with water and extracted the desired compound with ethyl acetate. Combined organic layers and washed with a saturated brine solution and evaporated to get crude tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI which was purified in 30% aqueous Isopropyl alcohol to get pure desired compound with purity of 99.9%.

EXAMPLE 6: Preparation of Rosuvastatin calcium

Charged 50gm of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI to 350 ml acetonitrile followed by addition of 0.02M HCl solution. Maintain the reaction mass at temperature 35°C to 40°C. Cooled the reaction mass at 25°C, and then added 1M NaOH solution (95 ml). Stirred and cooled the reaction mass to -5°C. Separated the layers, added 600 ml acetonitrile, 40% aqueous methyl amine solution (11 ml) to acetonitrile layer. Maintain the reaction mass at 0°C to -5°C under stirring for 30 min. After completion of the reaction, filtered the rosuvastatin methyl amine salt of Formula IX. Charged methyl amine salt of Formula IX in 300 ml of water, added 55ml of 8% aqueous sodium hydroxide. Distilled 50% reaction mass and again made up volume with water. Added aqueous calcium chloride (10.3gm of calcium chloride in 60 ml DM water) to the reaction mixture, stirred the reaction mass at 20°C-30°C to obtain the solid. Filtered and dried the solids to get Rosuvastatin calcium as a white solid with HPLC Purity of 99.5%.

EXAMPLE 7: Preparation of Rosuvastatin calcium

Aqueous HCl solution was added to a solution of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula VI in acetonitrile at 25-35°C and stirred the reaction mass for 6 hours. After completion of reaction pH of reaction was adjusted with 1.6% w/v sodium hydroxide solution. Stirred the reaction mass till reaction completion. Solvent was evaporated at 50-55°C to obtain the residue. Obtained residue was dissolved in water and washed with methyl t-butyl ether. Aqueous layer was treated with calcium acetate and stirred for 2 hrs. Filtered the solids to get rosuvastatin calcium as a white solid with HPLC purity of 99.5%.

Claims:WE CLAIM

1. A process for the preparation of rosuvastatin calcium, wherein said process comprising the steps of:
a) converting tert-butyl 2-((4R,6S)-6-(acetoxymethyl)-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula III to tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl)acetate of Formula V in presence of suitable solvent without isolation of hydroxyl intermediate of Formula IV;
;
b) reacting N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol-2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II with the compound of Formula V in presence of suitable solvent,
; and
c) converting compound of Formula VI to rosuvastatin calcium ; wherein said compound of Formula V is optionally not isolated.

2. The process as claimed in claim 1, wherein said process further comprises the steps of:
a) hydrolysing compound of Formula VI to give tert-butyl (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate of Formula VII in presence of suitable solvent and acid ;
b) converting compound of Formula VII to (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxy hept-6-enoate salt of Formula VIII; and
c) converting salt of Formula VIII to rosuvastatin calcium in presence of suitable calcium ion source,
wherein said compound of Formula VII & VIII are optionally not isolated;
.

3. The process as claimed in claim 1, wherein said process further comprises the steps of:
a) hydrolysing compound of Formula VI to give tert-butyl (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate of Formula VII in presence of suitable solvent and acid;
b) converting compound of Formula VII to (3R,5S)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxy hept-6-enoic acid salt of Formula VIII; and
c) converting compound of formula VIII to methyl amine salt in temperature range of -10oC to 10oC; and
d) converting methylamine salt of Formula IX to rosuvastatin calcium in presence of suitable calcium ion source, wherein said compound of Formula VII & VIII is not isolated;

.

4. The process as claimed in claims 2 and 3, wherein said salt of Formula VIII is selected from sodium, potassium, calcium, magnesium, barium, methylamine salt, ethylamine salt, cyclohexylamine, dicyclohexylamine and tromethamine.

5. A process for the preparation of rosuvastatin calcium, wherein said process comprising the steps of:
a) adding crude N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol -2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II to a suitable solvent;
b) optionally heating at a temperature in the range of 25oC-100oC;
c) isolating crystalline compound of Formula II; and
d) converting the crystalline compound of Formula II of step c) to rosuvastatin calcium.

6. The process as claimed in claims 1 and 5, wherein said rosuvastatin calcium is isolated with purity of about 99.0% and more.

7. The process as claimed in claim 5, wherein said suitable solvent is selected from the group comprising of methanol, ethanol, ethylene glycol, isopropyl alcohol, t-butanol, 2-bitanol, diethylene glycol, cyclohexane, heptane, toluene, acetone, methyl ethyl ketone, dichloromethane, dichloroethane, methyl t-butyl ether, tetrahydrofuran, methyl tetrahydrofuran, ethyl acetate, propyl acetate, propylene acetate, acetonitrile, water and mixture thereof.

8. Crystalline form A of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol -2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II characterized by XRPD comprising diffraction peaks at 2? values of 7.23, 8.28, 10.09, 10.39, 16.70, 18.00, 20.64, 22.02, and 24.42 ±0.2°?; and

9. Crystalline Form B of N-(4-(4-fluorophenyl)-6-isopropyl-5-(((5-methyl-1,3,4-thiadiazol -2-yl)sulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula II characterized by XRPD comprising diffraction peaks at 2? values of 5.08, 10.27, 11.99, 16.27, 18.55, 20.13, 20.73 and 26.23 ±0.2°?.

10. The crystalline compound as claimed in claim 8 & 9, is prepared by a process comprising steps of;
a) adding crude compound of Formula II to a suitable solvent;
b) heating the solution at a temperature in the range of 40oC-90oC; and
c) isolating the crystalline compound of formula II.