FIELD OF THE INVENTION
The present invention relates to a process for preparation of rosuvastatin and its pharmaceutically acceptable salts thereof. The present invention also relates to a novel intermediate of rosuvastatin and its pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Rosuvastatin calcium, (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-(1-methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydoxy-6-heptenoic acid hemicalcium salt having the chemical formula

Rosuvastatin in the form of its calcium salt for the pharmaceutical products, marketed under the name Crestor®. It is a synthetic lipid-lowering agent.

U.S. Pat. No. 5,260,440 describes rosuvastatin and pharmaceutically acceptable salts thereof. The process for the preparation of rosuvastatin comprises condensing the intermediate of Formula II with methyl (3R)-3-(tert-butylidimethylsilyloxy)-5-oxo-6-triphenyl phosphoranylidenehexanate followed by desilylation of the resultant compound and further reduction of the obtained compound with sodium borohydride gives rosuvastatin, which is further converted into the calcium salt. This process is not industrially feasible and also economically expensive.

US Pat. No. 7,556,782 describes a process for the preparation of rosuvastatin and its pharmaceutically acceptable salts thereof. The process emphasizes on the use of cyano triphenylphosphororanylidene derivative and further reduction and hydrolysis of the intermediate gives the desired product. The process incorporates the fatal reagents and lengthy towards the commercial scale up.

Further, patent application No. WO03/097614A2 describes a process for preparation of rosuvastatin and its pharmaceutically acceptable salts thereof. The process uses the hazardous and expensive chemicals.

The processes described in these publications for preparation of rosuvastatin calcium are of general nature. There is a need in the art for processes that allow for preparation of highly pure rosuvastatin calcium in a facile manner on an industrial scale.

OBJECT OF THE INVENTION
The object of the present invention is to provide a process for preparation of the rosuvastatin calcium.

Another object of the invention is to provide a novel intermediate of rosuvastatin calcium i.e. diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl –methylsulfonamido)pyrimidin-5-yl)methyl)phosphonate.

One more object of the invention is to provide use of the novel intermediate diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfona -mido)pyrimidin-5-yl)methyl)phosphonate in preparation of rosuvastatin calcium.

One more object of the invention is to provide the process for preparation of novel intermediate diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl -sulfonamido)pyrimidin-5-yl)methyl)phosphonate.

One more object of the present invention is to provide an industrially applicable, cost effective process for preparation of rosuvastatin calcium.

A further object of the present invention is to provide a process for preparation of rosuvastatin calcium which results in high yield and purity.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of rosuvastatin calcium

comprising reacting the alcohol of pyrimidine derivative of formula (I)

with phosphorus halide in an aromatic solvent and converting into the compound of formula (II) i.e.

the compound of formula (II) reacting with triethyl phosphite in the presence of an aromatic solvent to get the compound of formula (III).

The compound of formula (III) is reacting with tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate (BFA) to get the compound of formula (IV).

Further, treating with acid and base the resultant solution reacting with an amine resulting to get the compound of formula (IV).

And finally the compound of formula (V) is converting in to rosuvastatin calcium using calcium source.

This invention also relates to the novel intermediate i.e. compound of formula (III) and process of preparation thereof.

The process provides benefits with respect to economics and convenience to operate on a commercial scale.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the preparation of rosuvastatin calcium comprising
a. reacting the N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (compound of formula (II)) with triethyl phosphite;
b. isolating diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfon -amido)-pyrimidin-5-yl)methyl)phosphonate (compound of formula (III));
c. condensing the diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methyl –sulfonamido)pyrimidin-5-yl)methyl)phosphonate (compound of formula (III)) with tertiary butyl 2-(6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate (BFA) in presence of base and further converting into the rosuvastatin amine salt (compound of formula (V)) using an amine;
d. reacting said the rosuvastatin amine salt (compound of formula (V)) with a calcium source to get the solid;
e. isolating the solid as rosuvastatin calcium.

The synthetic scheme for preparation of the rosuvastatin calcium is depicted as in following manner by reaction of alcohol of pyrimidine derivative of formula (I)

with phosphorus halide in an aromatic solvent. The suitable reagent for halogenation is phosphorus trichloride, phosphorus tribromide and phosphorus triiodide. The solvent used to perform this step is toluene or xylene to get the desired compound of formula (II) i.e.

Further, the compound of formula (II) is converted into the compound of formula (III) using triethyl phosphite in the presence of an aromatic solvent. The preferred solvent used is toluene, and xylene.

The compound of formula (III) is cost effective and good yield with superior quality.

The condensation step involves the reaction of compound of formula (III) with the tertiary butyl-2-[(4R,6S)-6-formyl-2,2-dimethyl-1,3-dioxan-4-yl] acetate (BFA). This reaction is carried out in the presence of lithium bis(trimethylsilyl) -amide as a base.

Further, the compound of formula (IV) is deprotected using acid and base. The preferred acid is hydrochloric acid and sulphuric acid. The preferred base used is sodium hydroxide or potassium hydroxide.

The hydrolyzed product i.e. compound of formula (IV) is further reacted with an amine to produce a rosuvastatin amine salt. i.e. the compound of formula (V). The amine used for the rosuvastatin amine salt is tertiary butyl amine, phenylethylamine, 4-methoxy phenylethylamine, cinchonine, cinchonidine, ephedrine, quinine, and quinidine. The preferred amine is tertiary butyl amine.

The compound of formula (IV) is further converted into rosuvastatin calcium using calcium source. The calcium source used for preparation of rosuvastatin calcium salt is calcium chloride, calcium hydroxide, and calcium acetate. The preferable calcium source is calcium hydroxide.

This process of invention provides significantly improved yield and quality of product by comparison to the existing processes.

The illustrated reactions have been set forth only for the purposes of example and should not be taken as limiting the invention. Therefore, it should be understood that, within the scope of the appended claims, the invention may be practiced other than specifically described herein.

EXAMPLES

Step-I: Preparation of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide
1 Ltr flask was charged with 400ml toluene, 200 ml acetonitrile and 50 gm of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-methyl -methanesulfonamide and cooled to 10 to 15° C. The 23 gm of phosphorus tribromide was added slowly to this. The reaction mass was stirred for 1 to 2 hrs at 20 to 25° C. After completion of reaction, 500 ml of water was charged in reaction mass and it was stirred for 15 to 30 mins. The layers were separated. The organic layer was washed with 8% sodium bicarbonate solution and then 250 ml water. The organic layer was separated and distilled off under vacuum. The dry mass was charged with 250 ml cyclohexane. The reaction content was stirred for half an hour at 45 to 60° C. Further, it was cooled 20 to 25° C and stirred for 1 to 2 hrs. The solid was filtered and washed with 50 ml of cyclohexane. The solid was dried well. The 52 gm of title compound was obtained.

Step-II: Preparation of diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl -methylsulfonamido)pyrimidin-5-yl)methyl)phosphonate
In a clean 150ml flask, 50 ml of toluene, 5 gm of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide, and 2.4 gm of triethyl phosphite was charged. The reaction mass was diluted with 200 ml water and heated at 95 to 100° C for 6 to 8 hrs. The reaction mixture was heated for 1 to 2 hrs at 110 to 120° C. After completion of reaction, the solvent was distilled out from reaction mass. The reaction mass was stripped out with tetrahydrofuran. The 5.5 gm of the oily mass was obtained.

Step-III: Preparation of Rosuvastatin tertiary butyl amine salt

In a clean 150 ml flask, 60 ml of tetrahydrofuran, 2.8 gm of oily mass of step-II was charged and cooled to -65 to -70° C. The reaction mass was charged with 21 ml of Li-HMDS gradually and the resultant reaction mass was stirred for ah hour. The 5.4 gm of tertiary butyl 2-(6-formyl-2, 2-dimethyl-1,3-dioxan-4-yl) acetate (BFA) was dissolved in 20 ml of tetrahydrofuran and charged to reaction mass. The reaction mass was stirred for 2 hrs at 25 to 30° C. After completion of reaction, the reaction mass was diluted with 2ml of acetic acid. The solvent was distilled off under vacuum at 40 to 45° C. The reaction mass was diluted with 20 ml of dichloromethane and 20ml of water. The reaction mass was stirred, settled and layers were separated. The organic layer was washed with water and brine solution subsequently. The organic layer was distilled off under vacuum completely. The crude product was purified by column chromatography using hexane and ethyl acetate. The purified compound was diluted with 10 ml of acetonitrile and stirred to 35 to 40° C. The reaction mass was acidified with 1.6ml of hydrochloric acid and stirred for 3 hrs at 35 to 40° C. After completion of reaction, the reaction mass was neutralized with 5 ml of sodium hydroxide solution. The acetonitrile was distilled off from reaction mass. The resultant solid was charged with 10 ml of water and 20ml of dichloromethane and cooled to 0 to 5° C. The pH was adjusted to 3.5 to 4 with 1:1 hydrochloric acid solution. The layers were separated. The organic layer was mixed with 0.2 gm of tertiary butyl amine. The reaction mass was stirred and further dichloromethane was distilled out under vacuum. The titled compound was recrystalized by acetone. The 1gm of title compound was isolated.

Step-IV: Preparation of Rosuvastatin Calcium salt
In a clean 150 ml flask, 5 ml of water and 1gm of compound of step-III was charged. The 20 ml sodium hydroxide solution (0.072 gm of sodium hydroxide was diluted with 20 ml of water) was charged gradually under nitrogen atmosphere. The reaction mass was stirred for 1 to 2 hrs at 25 to 30° C. The resultant reaction mass was diluted with 5ml of calcium chloride solution (0.26 gm of calcium chloride dihydrate was diluted with 5 ml of water). The reaction mass was stirred for half an hour at 25 to 30° C. The solid was filtered and washed with 1 ml of water. Dried and the solid was unloaded. The 0.5 gm of rosuvastatin calcium salt was obtained.

We Claim:

1. A process for preparation of rosuvastatin calcium, comprising the steps of:
a. condensing the diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methyl –sulfonamido)pyrimidin-5-yl)methyl)phosphonate (compound of formula (III)) with tertiary butyl 2-(6-formyl-2,2-dimethyl-1,3-dioxan-4-yl) acetate (BFA) in presence of base and further converting into the compound of formula (V) using an amine;
b. reacting said compound of formula (V) with a calcium source to get the solid;
c. isolating the solid as rosuvastatin calcium.

2. A process as claimed in claim 1 wherein step (a) said base is lithium -bis(trimethylsilyl)amide.

3. A process as claimed in claim 1 wherein step (a), said an amine is selected from the group consisting of tertiary butyl amine, phenylethylamine, 4-methoxy phenylethylamine, cinchonine, cinchonidine, ephedrine, quinine and quinidine. The preferable amine is tertiary butyl amine.

4. A process as claimed in claim 3 wherein an amine is tertiary butyl amine.

5. A process as claimed in claim 1 wherein the calcium source in step (b), is selected from group consisting of calcium chloride, calcium hydroxide and calcium acetate.

6. A process as claimed in claim 5 wherein a calcium source is calcium chloride.

7. Diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methylsulfonamido) -pyrimidin-5-yl)methyl)phosphonate.

8. Diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methylsulfona -mido)pyrimidin-5-yl)methyl)phosphonate adapted for use in the preparation of rosuvastatin calcium.
9. A process for preparation of diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methylsulfonamido)pyrimidin-5-yl)methyl)phosphonate, comprising the steps of:
a. reacting the N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide with triethyl phosphite;
b. isolating diethyl ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-methylsulfona -mido) pyrimidin-5-yl)methyl)phosphonate.

The present invention relates to a process for preparation of rosuvastatin and its pharmaceutically acceptable salts thereof. The invention also provides a novel intermediate and its use in preparation of rosuvastatin and its pharmaceutically acceptable salts thereof.