PROCESS FOR THE PREPARATION OF ROSUVASTATIN CALCIUM

FIELD OF THE INVENTION

The present invention relates to a novel process and intermediates for the preparation of bis[(E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S) -3,5-dihydroxyhept-6-enoic acid] calcium salt, commonly known as Rosuvastatin calcium of formula I.

BACKGROUND OF THE INVENTION

Chemically Rosuvastatin is (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]3,5-dihydroxy-6(E)-heptenoic acid calcium salt (2:1) of formula I. Rosuvastatin is one of HMG-CoA reductase inhibitors, administered as its calcium salt. HMG CoA reductase inhibitors (also called statins) are optically active molecules containing chiral (3R,5S)-hept-6-enoic or heptanoic acid moiety. They are used for manufecturing medicaments to treat hypercholesterolemia. HMG-CoA reductase inhibitors are also simvastatin, pravastatin, lovastatin, atorvastatin and fluvastatin.

Rosuvastatin and a process for its preparation is disclosed in US Patent No. US5260440. The process disclosed therein involves four distinct chemical steps: (1) condensation of methyl (3R)-3-[(tert-butyldimethylsilyI)oxy]-5-oxo-6-triphenylphosphoranylidene hexanoate with 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)-5-pyrimidine-carboxaldehyde;

(2) deprotection of the 3-hydroxyl group to give the keto alcohol; (3) reduction of 5-oxo to get the chiral dihydroxy heptenoate; and (4) hydrolysis of the dihydroxy heptenoate.

The generation of the phosphorane side chain requires eight synthetic steps and involves expensive reagents. The process is both uneconomical and time consuming, hence not suitable for commercial production.

WO2005/054207 describes a process for the preparation of Rosuvastatin calcium as depicted in below scheme:

The disadvantages of the prior arts include multiple steps, which result in the preparation difficulties, use of expensive reagents, and use of reagents that are difficult to use on an industrial scale.

Therefore, there is a continued need to develop an improved process for the manufacture of Rosuvastatin, which provides a better conversion, and which is easy and economical on industrial scale. The present inventors developed a novel process having novel intermediates which overcomes the most of the drawbacks available in prior art and provides a simple and cost effective process.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of calcium salt of (+)-(3R,5S)-7-[4-(4-Fluorophenyl)-6-isopropyl-2-(N-methyl-N-methanesulfonylamino)pyrimidin-5-yl]3,5-dihydroxy-6(E)-heptenoic acid generically known as Rosuvastatin calcium comprising:
in the presence of dichloromethane (MDC) and diisopropylethyl amine, trifilic anhydride to give a compound of formula 4;

b) oxidation of compound of formula 4 to give compound of formula 5 in the presence of a solvent, ammonium molebdate in hydrogen peroxide and tertiary butyl ammonium bromide;

c) methylation of compound of formula S to give compound of formula 6 in the presence of a solvent acetone, dimethyl sulphate and a base potassium carbonate;

d) condensation of compound of formula 6 and a compound of formula 7 in the presence of tetrahydrofliran, sodium hexamethyl disilazine (NaHMDS), hydrochloric acid and sodium hydroxide to give a compound of formula 8;

e) converting compound of formula 8 to its amine salt of fonnula 9 in presence of a solvent and tertiary butylamine; and

f) hydrolysis of compound 9 in the presence of v/ater, sodium hydroxide and a calcium source to give Rosuvastatin calcium of formula 1.

The above process is illustrated in below scheme :

DETAILED DESCRIRTION Of THE INVENTION
Accordingly in an embodiment of the invention, the condensation of 4(R-cis)6-hydroxy methyl-2,2-dimethyl-l,3-dioxane-acetic acid-1,1-dimethyl ethyl ester of formula 2 and Difluoro methoxy-2-mercapto benzimidazole of formula 3 is carried out in presence of a suitable re¬agent, such as trifilic anhydride, paratoluene sulfonyl chloride , methane sulfonyl chloride and the like, preferably triflic anhydride; and a suitable organic solvent selected from the group con¬sisting of acetonitrile, toluene, dimethylformamide, dichloromethane, dichloroethane, chloro¬form, preferably dichloromethane and a suitable organic base selected from the group consisting of pyridine, triethylamine, tertiary butyl amine, diisopropyl ethyl amine, preferably diisopropyl ethyl amine.

In another embodiment of the invention, the oxidation of Tert-butyl 2-[6-({[5-(difluoro-methoxy)-1H-1,3-benzodiazol-2-yl]sulfanyl}methyl)-2,2-dimethyl-1,3-dioxan-4-yl]acetate of formula 4 is carried out in presence of a suitable oxidizing reagent selected from the group con¬sisting of hydrogen peroxide, potassium permanganate, chromium oxide, preferably hydrogen peroxide most preferably ammonium molebdate in hydrogen peroxide; in presence of a suitable solvent selected from the group consisting of chlorinated solvent such as dichloromethane, di-chloroethane, chloroform, ether solvents such as diethyl ether, tetrahydroftiran, diisopropyl eth¬er and toluene, preferably dichloromethane and a catalyst tetrabutyl ammonium bromide (TBAB).

In further embodiment of the invention, the methylation of Tert-butyl 2-(6-{[5-(di-fluoromethoxy)-1H-1,3-benzodiazole-2-sulfonyl]methyl} -2,2-dimethyl-1,3-dioxan-4-yl)acetate of formula S is carried out in presence of a suitable methylating {^ent selected from the group consisting of iodometiiane, dimethyl sulphate and dimethyl carbonate preferably dimetiiyl sulphate; a suitable solvent selected from the group consisting of acetone, dimethyl formamide and the like; preferably acetone and a base selected from group consisting of potassium car¬bonate, sodium carbonate, sodium hydroxide, potassium hydroxide and the like; preferably po¬tassium carbonate.

In yet another embodiment of the mvention, condensation of the Tert-butyl 2-(6-{[5-(difluoromethoxy)-1 -methyl-1H-1,3-benzodiazole-2-sulfonyl]methyl} -2,2-dimethyl-1,3-dioxan-4-yl)acetate of formula 6 and the 4-(4-Fluorophenyl)-6-isopropyl-2-[(N-methyl-n-methylsulf-onyl)amino3pyrimidine-5-yl-formyl of formula 7 is carried out in the presence of a solvent se-lecsted from the group consisting of dimethylformamide, tetrahydroftiran, diethyl ether, di-methylsulfoxide, toluene and the like; preferably tetrahydroftiran and a base selected from the group consisting of n-butyl lithium (n-BuLi), lithium hexamethyldisilazine (LHMDS), sodium hexamethyldisilazine (NaHMDS), potassium hexamethyldisilazine (PHMDS), lithium diisopropyl amine (LDA) and the like; preferably sodium hexamethyldisilazine.

In yet another embodiment of the invention, Rosuvastatin acid of formula 8 is converted into its tertiary butylamine salt in a suitable solvent, selected from the group consisting of an alcoholic solvent like methanol, ethanol, isopropanol; a chlorinated solvent like dichloromethane, dichloroethane, chloroform; and other solvents like toluene, acetonitrile; preferably in acetoni- trile and a base preferably an organic base selected from the group consisting of tertiary butylamine, isopropyl amine, most preferably tertiary butylamine.

In yet another embodiment of the invention, Rosuvastatin amine salt is hydrolysed in a suitable solvents like water, methanol, ethanol and the like; preferably DM water and a base selected from group consisting of sodium hydroxide, cesium hydroxide, lithium hydroxide and the like; preferably sodium hydroxide; and a calcium source like calcium chloride, calcium hydroxide, calcium carbonate and the like; preferably calcium chloride.

The examples are provided below is only for the illustrationand should not be constru to limit the scope of the invention as defined by the claims.

EXAMPLES:
Exampkl: preparation of Tert-butvl 2-[6-r{[S-rdiflMoromethorV1 H-1 J-benzodiazol-l-
vl]sulfanvnmethvn-2.2-diinethvl-l J-dioMn-4-vl]acetate fcompound 4
4(R-cis)6-hydroxy methyl-2,2-dimethyl-l,3-dioxane-acetic acid-1,1-dimethyl ethyl ester (10.0 g) was dissolved in methylene chloride and diisopropyl ethylamine (14.8 mL) was into it under nitogen atmosphere at 25-30°C. The content was cooled to -35 to -30''C and triflicanhydride was added slowly and maintained for 1-2 hours. The temperature was raised to 25-30°C and 5-Difluoro methoxy-2-mercapto benzimidazoles (8.3g) was added into the reaction mass and maintained for 12 hours. The product was filtered and removed the undissolved compounds.

Water (50 mL) was added to the filterate and extracted with methylene chloride. The organic layer was washed with 5.0% sodium bicarbonate solution (50.0 ml) and water (50.0 ml), dried with sodium sulphate (2.0 g)and the solvent distilled off completely.

Yeild : 25.Og (residue wt.)
Example 2; Preparation of Tert-butvl 2-f6-{f 5-(difluoromethoxvVlH-L3-benzodiazole-2-su!fonyl]metliv»-2.2-dimethvi-l J-dioxan-4-vl>acetate ( comDOund 5).

Tert-butyl 2-[6-({[5-(difluoromethoxy)-lH-l,3-ben2odiazol-2-yl]sulfanyl}methyl)-2,2- dimethyl-l,3-dioxan-4-yl]acetate (25.0 g) obtained above was dissolved in methylene chloride (250.0 ml) and tetra butyl ammonium bromide (1,21 g) at 25-30°C was added to it and cooled to 0-5 "C. Ammonium molibdate (3.1g) was added to the above reaction mixture followed by slow addition of 30% hydrogen peroxide (34.0 ml) at 0-5°C. and maintained for 12 hours at 25-30°C . After the completion of the reaction, water (130.0mL) was added and organic layer was separated and extracted with dichloromethane, the product was dried and the solvents were distilled off completely. Yield 18.7 g.

Example 3; Preparation of Tert-butvl 2-r6-ffS-rdifluoromethoxvVl-methvl-lH-1.3-benzodiazole-2-sulfonvllmethvU-2J-dimethvl-1.3-dioxaH-4-vnacetate (compound 6

Potassium carbonate (3.38g) was added into a solution of Tert-butyl -2-(6-{[5-
(difluoromethoxy)- IH-1,3-benzodiazole-2-suIfonyl]methyl} -2,2-dimethyl- 1,3-dioxan-4- yl)acetate(15.0g) in acetone (105.0 ml) and cooled the contents at 0-5°C.

Dimethyl sulfonate (3.13 mL) was added slowly to the above reaction mixture and maintained for 1 hour. After completion of the reaction undissolved compounds was washed with acetone and water. The solvent was distilled off from the filtrate and the residue was dissolved in methylene chloride (150.0 ml) and washed with 5% potassium carbonate solution (75.0 ml) followed by DM water (75.0 ml). The organic layer was dried with anhydrous sodium sulphate (3.0 g) and solvents were evaporated below 40°C. Yield 14.0 g.

Example 4! Preparing tert.butvlamine salt of Rosuvastatin ( componnd 9
Tert-butyl 2-(6-{[5-(difluoromethoxy)-1 -methyl-1H-1,3-benzodiazole-2-sulfonyl]methyl}-2,2-dimethyl-l,3-dioxan-4-yl)acetate (15.0g) was dissolved in THF (150.0 ml) at 25-30''C under nitrogen atmosphere. 4-(4-Fluorophenyl)-6-isopropyl-2-[(N-methyl-n-methylsulfonyl)amino] pyrimidine-5-yl-formyl (5.22 g) was added into the above solution and cooled to -78 to -70°C.

Na HMDS (36.0 ml) was added to the above reaction mixture slowly and the temperature was raised to -45 to 40 °C. The content was fiirther cooled to -78 to -70"'C and added saturated ammonium chloride solution (75.0 ml) and DM water (75.0 ml) to the reaction mass and the temperature was raised 20-25°C. The compound was extracted in toluene (150.0 ml) and washed the toluene layer with sodium bicarbonate solution (3x75.0 ml) followed by sodium chloride solution (75,0 ml). The toluene layer was evaporated under vacuum at below 40°C. The residue was dissolved in acetonitrile and added 10% aqueous hydrochloric acid (40.0 ml)

and the content was stirred for 1.0-2.0 hrs at 25-30°C, distilled off completely under vaccum below 40°C again dissolved the compound in water (45.0 ml) and washed with methyl tertiary butyl ether (150.0 ml) added methylene chloride (150.0 ml), cooled the contents 5 -10°C and adjusted the reaction mass pH 7.0-6.0 with 10% hydrochloric acid and stir for 15-30 minutes, washed the organic layer with water and evoparated under vaccum below 40°C. Dissolved the above residue in acetonitrile (45.0 ml) and distill off acetonitrile completely and added fresh acetonitrile (75.0 ml) stir for 15 minutes at 25-30°C, cooled the contents 0-5°C and added tert.butylamine and stirred 30 minutes and distilled off acetonitrile below 40 °C , again added acetonitrile (75.0 ml) ,cooled the contents to 0-10°C and stir for 1.0 hr. Filtered the compound and washed with chilled acetonitrile (30.0 ml), dried the compound at 40 °C. weight 11.8 g

Example 5: Preparing calcium salt of Rosuvastatin ( compound 1
Tert.butylamine salt of rosuvastatin was dissolved in water at 25-30°C, cooled the contents 20-25°C and added sodium hydroxide solution under nitrogen atmosphere, stirred for 1 hour at 20-25''C, reaction mass was washed with methyl tertiary butyl ether (2x10.0 ml) and filtered the aqueous layer and distilled off water under below 40°C.

Added purified water and distilled off under below 40°C and repeated this process two times, again cooled the reaction mass 20-25°C added purified water (50.0 ml) and calcium chloride dehydrate (1.32 g) in purified water (10.0 ml)drop wise at 20-25°C and maintained for 1 hour. Filtered the compound and washed with water and dried the compound at 40-45°C under vacuum for 12 hrs. weight 6,7 g.

1. A process for the preparation of Rosuvastatin calcium of formula I comprising:

a) condensation of the compound of formula 2
with compound of formula 3
in the presence of a solvent, a base, and a reagent to give compound of formula 4;

b) oxidation the compound of formula 4 gives compound of formula 5 in the presence of a solvent an oxidizing;

c) methylation of compound of formula 5 to give compound of formula 6 in the presence of a methylating agent;

d) condensation of compound of formula 6 with compound of formula 7. to obtain compound of formula 8 in the presence of a solvent, base and a mineral acid;

e) converting compound of formula 8 to its amine salt of formula 9 in presence of a solvent and tertiary butylamine; and

f) hydrolysis of compound 9 in the presence of a solvent, a base and a calcium source to give Rosuvastatin calcium of formula 1.

2. A process according to claim 1 where in the condensation in step (a) is carried out in presence of a solvent dichloro methane, base diisopropylethyl amine, and a reagent trifilic anhydride.

3. A process according to claim 1 where in the oxidation in step (b) is carried out in presence of solvent dichloromethane, an oxidizing agent ammonium molebdate in hydrogen peroxide and a catalyst tetrabutyl ammonium bromide.

4. A process according to claim 1 where in the methylation in step (c) is carried out in presence of solvent acetone, a methylating agent dimethyl sulfoxide, and a base potassium carbonate.

5. A process according to claim 1 where in the condensation in step (d) is carried out in presence of tetrahydrofuran, sodium hexamethyldisilazine, hydrochloric acid, and potassium carbonate.

6. A process according to claim 1 where calcium source in step (f) is calcium chloride.

7. A compound of the formula 4.

8. A compound of the formula 5.

9. A compound of the formula 6.