NOVEL PROCESSES FOR PREPARING ROSUVASTATIN CALCIUM

The instant patent application claims priority to our earlier provisional patent application IN 4347/CHE/2013 filed on September 25, 2013.

FIELD OF THE INVENTION

The present invention relates to a novel processes for preparing Rosuvastatin Calcium. The present invention is also relates to commercial viable process.

BACKGROUND OF THE INVENTION

Rosuvastatin is a synthetic lipid lowering agent for oral administration. Rosuvastatin is a competitive inhibitor of the enzyme HMG-CoA reductase, having a mechanism of action similar to that of other statins. Rosuvastatin is approved for the treatment of high LDL cholesterol (dyslipidemia), total cholesterol (hypercholesterolemia), and/or triglycerides (hypertriglyceridemia).

Chemically, Rosuvastatin calcium is bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2 [methyl(methylsulfonyl)amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6-enoicacid]calcium salt of formula (I). The empirical formula is (C22H27FN306S)2 Ca. Its molecular weight is 1001.14, and its chemical structure is represented below:
Rosuvastatin is marketed by Astra Zeneca under the trade name of Crestor . The primary use of Rosuvastatin is for the treatment of dyslipidemia.
US 5,260,440, first discloses Rosuvastatin calcium and its process for preparing by reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5 - pyrimidine carbaldeh yde with (3i?)-3-(terr-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate in acetonitrile under reflux. The silyl group is cleaved with hydrogen fluoride, followed by reduction with NaBH4 to obtain a methyl ester of Rosuvastatin. The ester is hydrolysed with sodium hydroxide in ethanol at room temperature to obtain the sodium salt of Rosuvastatin. followed by addition of water and calcium chloride to result Rosuvastatin calcium salt.

The process is as shown in Scheme-I below:
US 6,844,437 discloses a process for preparing ter/-butyl (£)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl]vinyl}-(4i?,65)-2,2-dimethyl [l,3]dioxan-4-yl)acetate by reaction of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl)amino]pyrimidin-5-ylmethyl]phosphine oxide with tert-buXy\ 2-[(4i?,6S)-6-formyl-2,2-dimethyl[l,3]dioxan-4-yl]acetate in presence of a strong base such as sodium hexamethyldisilazane (HMDS).

The main drawback of the process disclosed in US '437 is the preparation of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino] pyrimidin-5-ylmethyl]phosphine oxide and use of this intermediate which are not industrial friendly since condensation of this intermediate with aldehyde is carried out at -75°C. Further, the use of strong base like sodium HMDS that are highly moisture sensitive and not easily available on commercial scale makes it difficult to handle it in scale-up operations.

WO 2006/100689 discloses a process for preparing Rosuvastatin calcium by early introduction of Rosuvastatin side chain to N-(4-(4-fluorophenyl)-6-isopropyl-5- methylpyrimidin-2-yl)-N-methylmethanesulfonamide followed by regioselective chain extensions.

The process is as shown in Scheme-H below:
Scheme-II

The disadvantage of the invention covered under WO '689 is that it is cumbersome /lengthy process, which will reduce the industrial productivity and make the process costly.

WO 2007/074391 relates to a process for preparing methyl 4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-pyrimidine-5-carboxylate (ester intermediate) from methyl 4-(4-fluorophenyl)-6-isopropyl-2-(methylsulfonyl)pyrimidine-5-carboxylate using N-methyl methane sulfonamide or its salt and a base.

It further provides a process for preparing N-[4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl]-N-methyl methane sulfonamide (i.e. aromatic aldehyde derivative of Rosuvastatin), an intermediate used in the preparation of Rosuvastatin calcium from the ester intermediate, that is reduced to its corresponding primary alcohol derivative, followed by oxidation using calcium hypochlorite with (2,2,6,6-tetramethylpiperidin-l-yl)oxy (TEMPO) as catalyst to give the aromatic aldehyde derivative of Rosuvastatin. The intermediate, methyl (3i?)-3-(te^butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene hexanate is not stable at ambient temperature and not economical as it requires a number of purification steps to prepare Rosuvastatin and is difficult to use on industrial scale.

WO 2008038132 relates to process for preparation of Rosuvastatin diamine salts from Rosuvastatin acid or Rosuvastatin sodium which is reacted with diamine derivative or its salt and its conversion to Rosuvastatin diamine salt. It also describes the process for preparation of Rosuvastatin calcium from Rosuvastatin diamine salt. The drawbacks of using diamine salt in the preparation of Rosuvastatin calcium is the presence of the anti isomer content, which may affect the quality of Rosuvastatin calcium.

WO 2012073055 covers method for preparation of Rosuvastatin te/t-butylamine salt by reacting Rosuvastatin ester (methyl, ethyl or tert-butyl) with tert-butylamine in aqueous solution in presence of a polar solvent. It also covers polymorphic forms of Rosuvastatin ester and Rosuvastatin TBA salt as well as their preparations.

The preparation of Rosuvastatin tertiary butyl amine salt is carried out at under tedious reaction conditions, which may give low yields of Rosuvastatin calcium.

The inventors of the present invention have developed improved processes for preparing Rosuvastatin calcium. The inventors have worked towards developing a cost-effective process for preparing Rosuvastatin calcium in good yield.

SUMMARY OF THE INVENTION

The present invention provides an improved process for the preparation of Rosuvastatin calcium of formula (I) comprising
i) reducing the compound of formula (II) in an organic solvent using reducing agent at room temperature to give a compound of formula (III);
wherein, R=H or S02CH3 ii) bromination of compound of formula (III) using concentrated hydrobromic acid at ambient temperature to produce compound of formula (IV) followed by
a) triphenylphosphine in organic solvent to produce compound of formula (V)
(or) b) trimethylphosphite in organic solvent to produce compound of formula (VI)

iii) a) the compound of formula (V) condensed with tert-butyl 2-((2R, 45)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (VII) in presence of polar solvent and a base to provide the compound of formula (VIII)
or iii) b) the compound of formula (VI) in «-butyl lithium in hexane is condensed with the compound of formula VII in polar solvent to produce compound of formula (VIII);
iv) sulfonating the compound of formula VIII (wherein, R=H) in a polar solvent in with p-toluene sulfonyl chloride in presence of tertiary amine to produce compound of formula IX,
(wherein X=tosyloxy) v) N-methylating the compound of formula VIII (wherein, R=S03H) or compound of formula IX using N-methylating agent in an organic solvent in presence of a base to provide the compound of formula X

vi) hydrolysis of the compound of formula (X) using organic acid in presence of polar solvent to produce compound of formula XI.
vii) deprotection of the compound of formula XI with a base in presence of polar solvent to produce Rosuvastatin acid (XII), which is in-situ reaction with dicyclohexylamine will produce the amine salt compound of formula XIII.
viii) hydrolysis of compound of formula (XIII) with a base in polar solvent, followed by reaction with calcium acetate solution to produce Rosuvastatin calcium of formula I.

In another aspect, the present invention provides an alternate process for the preparation of compound of formula (I) which comprising condensing dimethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)phosphonate (XIV) with compound of formula VII in n-butyl lithium in hexane and lithium chloride in presence of polar solvent to provide compound of formula (X).

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides an improved, novel and cost-effective processes for the preparation of Rosuvastatin calcium in a good yield.
In one embodiment, the present invention provides a process for the preparation of Rosuvastatin calcium, which comprises
i) reduction of compound of formula II reducing agent in an organic solvent at room temperature to produce the compound of formula III
The organic solvent can be selected from the group comprising of hexane, toluene and the like, preferably toluene.
The reducing agent can be selected from sodium borohydride, lithium aluminum hydride, diisobutylaluminium hydride (DIBAL-H), preferably DIBAL-H. ii) bromination of compound of formula (III) using concentrated hydrobromic acid at ambient temperature to produce compound of formula (IV) followed by
a) triphenylphosphine in organic solvent to produce compound of formula (V)
(or)
b) trimethylphosphite in organic solvent to produce compound of formula (VI)

The organic solvent in this reactions can be selected from hexane, toluene and the like, preferably toluene, iii) a) the compound of formula (V) condensed with tert-butyl 2-((2R, 45)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (VII) in presence of polar solvent and a base to provide the compound of formula (VIII)

The polar solvent can be selected from the group comprising of tetrahydrofuran, dimethyl sulfoxide, dimethyl formamide, acetonitrile, ethyl acetate and the like, preferably dimethyl sulfoxide.

The base can be selected from inorganic bases such as alkali metal carbonates. The alkali metal carbonates can be selected from sodium carbonate, potassium carbonate, preferably potassium carbonate.

The reaction is performed at temperature range of temperature range of 50-120°C, preferably 80-85 °C; or iii) b) the compound of formula (VI) in «-butyl lithium in hexane is condensed with the compound of formula VII in polar solvent to produce compound of formula (VIII);

The above reaction is carried out in a polar solvent selected from dichloromethane, tetrahydrofuran and the like, preferably dry tetrahydrofuran at a temperature range of -20 to 30°C, preferably -5 to -10 °C.
iv) sulfonating the compound of formula VIII (wherein, R=H) in a polar solvent in presence of/>-toluene sulfonyl chloride and a tertiary amine base at room temperature produce compound of formula IX,
(wherein X=tosyloxy)

Tertiary amine is selected the group comprising of triethylamine, diisopropyl ethylamine and the like, preferably triethylamine. v) N-methylating the compound of formula VIII (wherein, R=S03H) or compound of formula IX using N-methylating agent in an organic solvent in presence of a base to provide the compound of formula X

wherein, an organic solvent is selected from the group comprising of esters such as ethyl acetate, propyl acetate, n-butyl acetate, preferably n-butyl acetate, a base is selected from the group comprising of inorganic bases such as alkali metal carbonates, alkali metal carbonates such as sodium carbonate, potassium carbonate, preferably potassium carbonate.

A methylating reagent is selected from the comprising such as N-methyl methane sulfonamide and the like at a temperature range of 60-120°C. vi) hydrolysis of the compound of formula (X) using organic acid in presence of polar solvent to produce compound of formula XI.

The organic acid is selected from the group comprising of C1-C4 carboxylic acids such as acetic acid, formic acid and the like at temperature range of 25-80°C. The polar solvent can be selected from water, acetonitrile and the like, preferably water, vii) deprotection of the compound of formula XI with a base in presence of polar solvent to produce Rosuvastatin acid (XII), which is in-situ reaction with dicyclohexylamine will produce the amine salt compound of formula XIII.

wherein, the base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxides and the like, preferably sodium hydroxide. The polar solvents are selected from methanol, ethanol, water, ethyl acetate or a mixture thereof, preferably methanol and water, viii) hydrolysis of compound of formula (XIII) with a base in polar solvent, followed by reaction with calcium acetate solution at room temperature to produce Rosuvastatin
13

The base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxides and the like, preferably sodium hydroxide. The polar solvents are selected from methanol, ethanol, water, ethyl acetate or a mixture thereof, preferably water.

A novel process for the preparation of Rosuvastatin calcium (I) is illustrated in scheme III:
In an another embodiment, the present invention provides an alternate process for the preparation of compound of formula (X) which comprising condensing dimethyl ((4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonamido) pyrimidin-5- yl)methyl)phosphonate (XIV) with compound of formula (VII) in presence of in n-butyl lithium in hexane and lithium chloride in polar solvent. wherein, polar solvent selected from dichloromethane, tetrahydrofuran and the like, preferably dry tetrahydrofuran at a temperature range of 30 to -20°C, preferably -5 to -10 °C.

The alternate process for preparation of Rosuvastatin calcium is illustrated in scheme-IV:

The present invention has certain advantages by using novel intermediate, cyclohexane protecting intermediate, which increases the selectivity for obtaining the desired trans isomer of Rosuvastatin calcium in good yield.

While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention. The invention is illustrated below with reference to inventive and comparative examples and should not be construed to limit the scope of the invention.

EXAMPLES

Example-1: Preparation of methyl 4-(4-fluorophenyi)-2-methanesuIfonyloxy-6- isopropyl-2,5-dihydropyrimidine-5-carboxylate (II) (where R= SO2CH3) Methyl 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-2,5-dihydropyrimidine-5-carboxylate (29 g, 0.1 moles) was added to dichloromethane (300 ml) and triethyl amine (30 .3 g) under nitrogen atm. Methane sulphonyl chloride (17 g, 0.15 moles) was added to the reaction mixture at 0-5°C and resultant reaction mixture was stirred for 2-4 h. Water (150 ml) was added to the reaction mixture and dichloromethane layer was separated. The dichloromethane layer was washed with 4.0 N hydrochloric acid solution (100 ml), followed by water (100 ml) and dichloromethane was distilled out completely under reduced pressure to get pale yellow colored solid (34.2 g, 93%).

Example-2: Preparation of methanesulfonic acid 4-(4-fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl ester (III) (R= SO2CH3) Methyl 4-(4-fluorophenyl)-2-methanesulfonyloxy-6-isopropyl-2,5-dihydropyrimidine-5- carboxylate (36.8 g, 0.1 moles) was added to toluene (200 ml) under nitrogen atm. Diisobutyl aluminum hydride (DIBAL-H) (140 ml) was added to the reaction mass drop wise and the temperature was maintained at 25-30° C for 60 min. Acetic acid (15 ml) was added drop wise to quench the reaction mass and stirred for 15 min. Methanol (10 ml) was added to the reaction mass, stirred for 15 min, ethyl acetate (150 ml) was added to it, followed by addition of IN HC1 (100 ml) and stirred for 30 min at 25-30°C. The contents were filtered through hi-flo bed and washed with ethyl acetate (50 ml). The combined organic layers were washed with IN HC1 solution (100 ml), the layers were separated and washed with 10% NaCl solution. The organic layer was dried over sodium sulphate and distilled under reduced pressure at below 50°C to give a crude product. Isopropyl ether (100 ml) was added to the obtained crude product, cooled to 10-15°C, stirred for 15-20 min and filtered to yield the title compound (32.3 g, 95%).

Example-3: Preparation of [4-(4-Fluoro-phenyi)-6-isopropyl-2-methanesulfonyloxy-pyrimidin-5-ylmethyl]-triphenyl-phosphonium bromide (IV) (R= S02CH3)
Methanesulfonic acid 4-(4-fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl ester (34 g, 0.1 moles) was added to toluene (150 ml) at ambient temperature, cone, hydrobromic acid (25 ml) was added to it and heated to azeotropic reflux and water was collected. After completion of the reaction, the reaction mixture was cooled to ambient temperature; water (100 ml) was added to it and stirred for 10 min. The organic layer was separated, washed with 10% sodium carbonate solution (50 ml) and water (50 ml). The organic layer was dried over sodium sulphate and to the clear solution; triphenylphosphine (28.8 g, 0.11 moles) in toluene (50 ml) was added in 10-15 min at 25-30°C. The thick solid obtained was stirred for 60 min, filtered, washed with toluene (50 ml) and dried at 60-65°C to yield the title compound. Weight: 58.5 g (88%)

Example-4: Preparation of Methanesulfonic acid 5-(dimethoxy-phosphorylmethyl)-4-(4-fluoro-phenyI)-6-isopropyl-pyrimidin-2-yl ester (VI) (R= SO2CH3) To the methanesulfonic acid 5-bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl ester (40.3 g, 0.10 moles ) in toluene (300 ml), trimethyl phospite (24.8 g, 0.20 moles) was added and the resultant reaction mixture was refluxed and maintained for 8-12 h . After completion of the reaction, the solvent was distilled out at atmospheric pressure. Traces of the solvent were removed under reduced pressure completely to obtain the crude residue. Toluene (150 ml) was added to the crude residue, stirred for 1 h at 25-30°C, filtered the solid obtained and washed with toluene (50 ml) to furnish the title product (38 g, 88%).

Example-5: Preparation of (4-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2- methanesulfonyloxy-pyrimidin-5-yl]-vinyl}-l,5-dioxa-spiro[5.5]undec-2-yl)-acetic acid tert-butyl ester (VIII) (R= SO2CH3)To a suspension of [4-(4-fluoro-phenyl)-6-isopropyl-2-methanesulfonyloxy-pyrimidin-5-ylmethyl]-triphenyl-phosphonium bromide (66.5. g, 0.1 moles) and tert-butyl 2-((2i?,4S)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (32.8 g, 0.11 moles) in dimethyl sulfoxide (300 ml), was added anhydrous potassium carbonate (34.5 g, 0.25 moles), heated to 80-85°C and maintained for 1-2 hours. After completion of the reaction, the reaction mixture was cooled to 10-15°C, toluene (350 ml) was added to it, followed by water (200 ml), the layers were separated and the aqueous layer was extracted with toluene (3 xl25 ml). The combined organic layers were washed with water (3x150 ml). Toluene was distilled under reduced pressure at 60-65°C, followed by addition of methanol (130 ml) and again distilled out to give a crude product. To the obtained crude product, methanol (160 ml) was added, refluxed, cooled to 20-30°C and stirred for 60 min. The solid material was filtered, washed with methanol (2 x 30 ml) and dried the solid at 60-65°C for 6-8 h to yield the title compound as a white solid. Weight: 49.5 g (82%)

Example-6: Alternate Preparation of (4-{2-[4-(4-fluoro-phenyl)-6-isopropyl-2-methanesulfonyloxy-pyrimidin-5-yl]-vinyl}-l,5-dioxa-spiro[5.5]undec-2-yl)-acetic acid tert-butyl ester (VIII) (R= S02CH3) 68 ml of 1.6M «-butyl lithium in n-hexane was added drop wise to a suspension of methanesulfonic acid 5-(dimethoxy-phosphorylmethyl)-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl ester (44.1, 0.1 mol) in dry THF (250 ml) over a period of 20-25 min at -5 to -10°C and further stirred for 30-40 min at the same temperature. A solution of tert-butyl 2-((2i?,45)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (33 g, 0.11 mol) in dry THF (50 ml) was added to the reaction mixture over a period of 25-35 min at -5 to -10°C. The resultant reaction mixture was stirred for 1 h, the reaction temperature was raised to 20-25°C and stirred for 24 h at same temperature. The reaction mixture was cooled to 10°C and ammonium chloride solution (600 ml) was added to it to give a residue. The residue obtained was extracted with toluene (3x 120 ml), washed with water (3x 120 ml), toluene was distilled out completely under reduced pressure at below 60°C to get the crude product, which was crystallised from methanol (200 ml) to obtained pure titled compound (45.9 g, 76%).

Example-7: Preparation of tert-butyl 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyI)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-l,5-dioxaspiro[5.5] undecan-2-yl)acetate (X) (R= SO2CH3) To (4-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-methanesulfonyloxy-pyrimidin-5-yl]-vinyl}-l,5-dioxa-spiro[5.5]undec-2-yl)-acetic acid ter/-butyl ester (60.4 g, 0.1 moles) in n-butyl acetate (500 ml), potassium carbonate (27.6 g, 0.2 moles) was added and stirred for 10-15 min at 25-30°C. N-methyl methyl sulfonamide (35 ml) was added to the reaction mixture, refluxed and maintained for 4-5 h. After completion of the reaction, the reaction mixture was cooled to 25-30°C and washed with water. The layers were separated and the obtained organic layer was washed with 1% sodium hydroxide solution and brine. The organic layer was dried over sodium sulphate and the solvent was distilled out completely under vacuum below 50-55°C. The obtained crude product was crystallized from methanol to yield the titled compound. Weight: 53 g (86%)

Example-8: Preparation of 4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-ol (III) (R= H) Methyl 4-(4-fluorophenyl)-2-hydroxy-6-isopropyl-2,5-dihydropyrimidine-5-carboxylate (29 g, 0.1 moles) was added to toluene (150 ml) under nitrogen atm. DIBAL-H (140 ml) was added to it drop wise and the temperature was maintained at 25-30° C for 60 min. Acetic acid (15 ml) was added drop wise to quench the reaction mass and stirred for 15 min. Methanol (10 ml) was added to the reaction mass and stirred for 15 min. Ethyl acetate (150 ml) and IN HC1 (100 ml) were added to the reaction mass and stirred for 30 min at 25-30°C. The contents were filtered through hi-flo and washed with ethyl acetate (50 ml). The combined organic layers were washed with IN HC1 solution (100 ml); the layers were separated and washed with 10% NaCl solution. The organic layer was dried over sodium sulphate and distilled under reduced pressure at below 50°C. Diisopropyl ether (100 ml) was added to the obtained crude product, cooled to 10-15°C, stirred for 15-20 min and filtered to yield the title compound (18.2 g, 69.3%).

ExampIe-9: Preparation of ((4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidin-5-yl) methyl) triphenyl phosphonium bromide (V) (R= H) 4-(4-Fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-ol (26.2 g, 0.1 moles) was added to toluene (100 ml) at ambient temperature, concentrated hydrobromic acid (25 ml) was added to it, heated to azeotropic reflux and water was collected. After completion of the reaction, the reaction mass was cooled to ambient temperature, water (75 ml) was added to it and stirred for 10 min. The organic layer was separated and washed with 10% sodium carbonate solution (50 ml) and water (30 ml). The organic layer was dried over sodium sulphate arid to the clear solution, triphenylphosphine (28.8 g, 0.11 moles) in toluene (50 ml) was added in 10-15 min at 25-30°C. The resultant thick solid was further stirred for 60 min, filtered, washed with toluene (50 ml) and dried at 60-65 °C to yield the title compound. Weight: 58.5 g (88%)

Example-10: Preparation of tert-butyl 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidin-5'yl)vinyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (VIII) (R=H) To a suspension of ((4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidin-5-yl)methyl)triphenyl phosphonium bromide (58.7 g, 0.1 moles) and tert-butyl 2-((2R,4S)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (32.8 g, 0.11 moles) in dimethyl sulfoxide (200 ml), was added anhydrous potassium carbonate (34.5 g, 0.25 moles), heated to 80-85°C and maintained for 1-2 hours. After completion of the reaction, the reaction mass was cooled to 10-15°C, toluene (250 ml) was added to it, followed by water (200 ml). The layers were separated and the aqueous layer was extracted with Toluene (3x100ml). The combined organic layers were washed with water (3x100ml). Toluene was distilled under reduced pressure at 60-65°C, followed by addition of methanol (100 ml) and further distillation was done. To the obtained crude product, methanol (150 ml) was added, refluxed, cooled to 20-30°C and stirred for 60 min. The solid material obtained was filtered, washed with methanol (2x25 ml) and dried the solid at 60-65°C for 6-8 h to yield the title compound as a white solid. Weight: 44 g (84.2%)

Example-11: Preparation of [4-(4-fluoro-phenyl)-2-hydroxy-6-isopropyI-pyrimidin-5-ylmethyl]-phosphonic acid dimethyl ester (V) (R=H) To 5-bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-ol (32.5 g , 0.10 moles) in toluene (300 ml), trimethyl phospite (24.8 g, 0.20 moles) was added and the resultant reaction mixture was refluxed and maintained for 8-12 h . After completion of the reaction, toluene was distilled out at atmospheric pressure. Traces of toluene were removed under reduced pressure completely to obtain the crude product. Toluene (150 ml) was added to the crude product, stirred for 1 h at 25-30°C, filtered the solid obtained and washed with toluene (50 ml) to furnish title product (38.1 g, 87.5%).

Example-12: Alternate preparation of tert-butyl 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-2-hydroxy-6-isopropylpy rimidin-5-yl)vinyl)-l ,5-dioxaspiro [5.5] undecan-2-yl)acetate (VIII) (R= H) 68 ml of 1.6 M n-butyl lithium in «-hexane was added drop wise to a suspension of dimethyl ((4-(4-fluorophenyl)-6-isopropyl-2-hydroxy pyrimidin-5-yl)methyl) phosphonate (35.7g, 0.1 mol) in dry THF (200 ml) over a period of 20-25 min at -5 to -10°C. The resultant reaction mixture was stirred for 30-40 min at the same temperature. A solution of tert-butyl 2-((2i?,4S)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl) acetate (33 g,0.11 mol) in dry THF (50 ml) was added to the reaction mixture over a period of 25-35 min at -5 to -10°C. The resultant reaction mixture was stirred for 1 h while the reaction temperature was raised to 20-2 5 °C and stirred for 24 h at the same temperature. The reaction mixture was cooled to 10°C and ammonium chloride solution (500 ml) was added to it. The reaction mixture was extracted with toluene (3x100 ml), washed the toluene layer with water (3x 100 ml), distilled out toluene completely under reduced pressure at below 60°C to get the crude product. The residual solid was crystallized from methanol (200 ml) to obtain the pure titled compound (40 g, 84.5%).

Example-13: Preparation of tert-butyl 2-((2i?,45)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(tosyIoxy)pyrimidin-5-yI)vinyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (IX) To a solution of tert-butyl 2-((2i?,45)-4-((E)-2-(4-(4-fluorophenyl)-2-hydroxy-6-isopropylpyrimidin-5-yl)vinyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (52.6 g, 0.1 moles) in dichloromethane (500 ml) was added triethylamine (20.2 g, 0.2 moles) and stirred for 10-15 min at 25-30°C. Para toluenesulfonyl chloride (28.5 g, 0.15 moles) was added to the reaction mixture at 25-30°C and stirred overnight at ambient temperature. After completion of the reaction, water (500 ml) was added and stirred for 10 min at 25-30°C. The organic layer was separated, dried over sodium sulphate and concentrated under reduced pressure to yield the title compound. Weight: 64.3 g (94.6%)

Example-14: Preparation of tert-butyl 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-l,5-dioxaspiro[5.5] undecan-2-yl)acetate (X) To tert-butyl 2-((2R,4S)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(tosyloxy)pyrimidin-5-yl)vinyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (67.9 g, 0.1 moles) in n-butyl acetate (500 ml), was added potassium carbonate (27.6 g, 0.2 moles) and stirred for 10-15 min at 25-30°C. N-methyl methyl sulfonamide (35 ml) was added to the reaction mixture, refluxed and maintained for 4-5 h. After completion of the reaction, the reaction mixture was cooled to 25-30°C and washed with water. The layers were separated and the obtained organic layer was washed with 1% sodium hydroxide solution followed by saturated brine solution. The organic layer was dried over sodium sulphate and distilled the solvent completely under vacuum below 50-55°C. The obtained crude product was crystallized from methanol to yield the titled compound. Weight: 50.9 g (83%)

Example -15: Alternative Preparation of tert-butyl 2-((2R, 4S)-4-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl) vinyl)-1,5-dioxaspiro[5.5]undecan-2-yl)acetate(X) 68 ml of 1.6M n-butyl lithium in n-hexane was added drop wise to a suspension of 44.5 g of dimethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5- yl)methyl)phosphonate (Commercially available) and lithium chloride (2.0 g) in dry THF (200 ml) over a period of 20-25 min at -5 to -10°C. The resultant reaction mixture was stirred for 30-40 min at the same temperature. A solution of tert-butyl 2-((2i?,45)-4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (33 g,0.11 mol) in dry THF (50ml) was added to the reaction mixture for a period of 25-35 min at -5 to -10°C. The resultant reaction mixture was stirred for 1 h while the reaction temperature was raised to 20-25 °C and stirred for 24 h at same temperature. The reaction mixture was cooled to 10°C and ammonium chloride solution (500 ml) was added to it. The reaction mixture was extracted with toluene (3x 100 ml), washed the toluene layer with water (3x 100 ml), distilled out toluene completely under reduced pressure at below 60°C to get the crude product. The residual solid was crystallised from methanol (200 ml) to yield pure titled compound 47.4 g (77%).

Example- 16: Preparation of (3/?, 5S, £)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate(XI) To tert-butyl 2-((2i?,4S)-4-((£)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methyl sulfonamido)pyrimidin-5-yl)vinyl)-l,5-dioxaspiro[5.5]undecan-2-yl)acetate (61.7 g, 0.10 mol), acetic acid (200 ml) and water (100 ml) were added and refluxed for 4-6 h. After completion of the reaction, the reaction mixture was cooled to 25-35°C; water (500 ml) was added, followed by addition of dichloromethane (200 ml). The reaction mixture was stirred for 10 min and the organic layer was separated. The aqueous layer was extracted with dichloromethane (2x200 ml). The combined organic layer was washed with water (3x100 ml) and concentrated at atmospheric pressure to get the title compound. Weight: 45.9 g (88.1%)

Example-17: Preparation of dicyclohexylamine (3R,5S,E)-7-(4-(4-fluorophenyl)-6- isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate
(XIII)
To a suspension of (3R, 5S, E)-tert-butyl 7-(4-(4-fruorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (52.1 g,0.1 mol) in methanol (250 ml) and water (500 ml), sodium hydroxide solution (5 g in 10 ml water) was added at 25-30°C and stirred for 2-4 h at 25-30°C. After completion of the reaction, methanol was removed under reduced pressure at below 40°C to obtain a clear solution. Ethyl acetate (250 ml) was added to the solution and acidified to pH 3-4 with 1 N hydrochloric acid solution at 5-10°C. The layers were separated and the aqueous layer was extracted with ethyl acetate (100 ml). The combined organic layer was washed with brine solution (200 ml) and dried the organic laver over sodium sulphate. Dicyclohexyl amine (36 g) was added to the ethyl acetate layer at 25-30°C, stirred the slurry for 1 h at 25-30°C, filtered the solid obtained, washed with ethyl acetate (100ml) and dried the solid at 50-55°C till constant weight. Weight: 48.9 g (79.3%)

Example-18: Preparation of Rosuvastatin calcium (I) To a suspension of dicyclohexylamine (3R, 5S, £)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (66.3 g , 0.1 mol) in water ( 700 ml), sodium hydroxide solution ( 5 g in 10 ml water) was added at 25-35°C . The resultant reaction mixture was heated to 50-55°C to get a clear colourless solution. The solution obtained was washed with methyl tert butyl ether (2x100 ml). The aqueous layer was concentrated to about half of its volume under reduced pressure at below 50°C, cooled to 20-25°C and filtered through suitable filtration aid to make the solution particle free. The clear filtrate obtained was cooled to 5-10°C and calcium acetate solution (18.7 g in 150 ml water) was added to it in 10-15 min. The slurry obtained was stirred for 10-15min, filtered and the solid obtained was dried under vacuum at 50°C till moisture content < 6%.
Dried wt = 37.5 g (75%)

We claimed;

1. A process for the preparation of Rosuvastatin calcium of formula (I), which comprising the steps of: i) reducing the compound of formula (II) using a reducing agent in an organic solvent to produce compound of formula (III);
ii) bromination of compound of formula (III) using concentrated hydrobromic acid
at to produce compound of formula (IV) followed by reaction with: a) triphenylphosphine in organic solvent to produce compound of formula (V)
(or) b) trimethylphosphite in organic solvent to produce compound of formula (VI)

iii) a) the compound of formula (V) condensed with tert-butyl 2-((2R, 4S>4-formyl-l,5-dioxaspiro[5.5]undecan-2-yl)acetate of formula (VII) in presence of polar solvent and abase to provide the compound of formula (Vffi.)
iii) b) the compound of formula (VI) in rc-butyl lithium in hexane is condensed with the compound of formula VII in polar solvent to produce compound of formula (VIII);
iv) sulfonating the compound of formula VIII (wherein, R=H) in a polar solvent in presence of p-toluene sulfonyl chloride and a tertiary amine base produce compound of formula IX,
(wherein X=tosyloxy) v) N-methylating the compound of formula VIII (wherein, R=SC>3H) or compound of formula IX using N-methylating agent in an organic solvent in presence of a base to provide the compound of formula X

viii) hydrolysis of compound of formula (XIII) with a base in polar solvent, followed by reaction with calcium acetate solution to produce Rosuvastatin calcium of formula I.

2. The process according to claim 1, in step-i), the reducing agent selected from the comprising of sodium borohydride, lithium aluminium hydride, DIBAL-H, preferably DIBAL-H; an organic solvent is selected from the group comprising of hexane, toluene and the like, preferably toluene.

3. The process according to claim 1, in step-ii), the organic solvent in this reactions can be selected from hexane, toluene and the like, preferably toluene.

4. The process according to claim 1, in step-iii), the polar solvent can be selected from the group comprising of THF, DMSO, DMF, CH3CN, ethyl acetate, CH2C12 preferably DMSO; the base is alkali metal carbonates.

5. The process according to claim 1, in step-iv), the base is tertiary amine is selected the group comprising of triethylamine, diisopropyl ethylamine and the like, preferably triethylamine.

6. The process according to claim 1, in step-v), an organic solvent is selected from the group comprising of esters such as ethyl acetate, propyl acetate, n-butyl acetate, preferably n-butyl acetate; a base is selected from the group comprising of inorganic bases such as alkali metal carbonates, alkali metal carbonates such as sodium carbonate, potassium carbonate, preferably potassium carbonate.

7. The process according to claim 1, in step-vi), the organic acid is selected from the group comprising of C1-C4 carboxylic acids such as acetic acid, formic acid and the like at temperature range of 25-80°C. The polar solvent can be selected from water, acetonitrile and the like, preferably water.

8. The process according to claim 1, in step-vii), the base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxides and the like, preferably sodium hydroxide; the polar solvents are selected from methanol, ethanol, water, ethyl acetate or a mixture thereof, preferably methanol and water.

9. The process according to claim 1, in step-viii), the base is selected from alkali metal hydroxides such as sodium hydroxide, potassium hydroxides and the like, preferably sodium hydroxide; the polar solvents are selected from methanol, ethanol, water, ethyl acetate or a mixture thereof, preferably water.

10. A process for the preparation of compound of formula (X) which comprising condensing dimethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl methylsulfonamido) pyrimidin-5-yl)methyl)phosphonate (XIV) with compound of formula (VII) in presence of in n-butyl lithium in hexane and lithium chloride in polar solvent.