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)an3ino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-enoic acid] calcium salt, commonly known as Rosuvasiatin 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 manufacturing 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. US 5260440, The process disclosed therein involves four distinct chemical steps; (1) condensation of methyl (3R)-3-[(tert-butyIdiinethyIsiIyi)oxy]-5-oxo-6-triphenyIphosphoranyIidene hexanoate with 4-(4-fluorophenyl)-6-isopropyl-2-(N-niethyl-N-methanesulfonylamino)-5-pyrimidine-carboxaldehyde; (2) deprotection of the 3-hydroxyi 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 1:

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 (+)-(3R,5S)-7-[4-(4-FluorophenyI)-6-isopropyI-2-(N-methyl-N-niethanesulfonylamino)pyrimidin-5-yl]3,5-dihydroxy-6{E)-heptenoic acid generically known as calcium salt Rosuvastatin calcium comprising of;

a) reduction of a compound of formula VII with a suitable reducing agent in the presence of a suitable organic solvent to give a compound of formula VI;

b) bromination of a compound of formula VI with a brominating agent to give a compound of
formula V;

c) reaction of a compound of formula V with tertiary butyl phosphonium' in the presence of a
suitable organic solvent to give a compound of formula IV;

d) condensation of a compound of formula IV with a compound of VIII in the presence of a
suitable organic solvent and a base to give a compound of formula III;

e) reaction of a compound of formula III with n-butyl acetate in the presence of a suitable base and N-methyl, methyl sulfonamide (NMMS) to give a compound of formula II;

f) hydrolysis of a compound of formula II in the presence of a suitable organic solvent and a base with hydrochloric acid and calcium chloride to give a compound of formula I.

The above process is shown in below mentioned Scheme 2:

DETAILED DESCRIPTION OF THE INVENTION

In an embodiment, the present invention, provide a process for the preparation of rosuvastatin calcium reduction of a compound of formula VII is carried out in step (a) with a suitable reducing agent selected from the group consisting of lithium aluminium hydride, diisobutyl aluminium hydride, sodium borohydride and the like; preferably diisobutyl aluminium hydride in the presence of an organic solvent selected from the group consisting of ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; ether solvents such as diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofiiran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures thereof; preferably toluene to give a compound of formula VI.
In an another embodiment of the present invention, bromination of a compound of formula VI is carried out in step (b) with a brominating agent selected from the group consisting of bromine chloride, phosphorus tribromide, aluminium tribromide and the like; preferably phosphorus tribromide to give a compound of formula V.

In an another embodiment of the present invention, reaction of a compound of formula V with tertiary butyl phosphonium is carried out in step (c) in the presence of a suitable organic solvent selected from the group consisting of ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; ether solvents such as diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofiiran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures thereof; preferably toluene to give a compound of formula IV.

In an another embodiment of the present invention, condensation of a compound of formula IV is carried out in step (d) with a compound of formula VIII in the presence of a solvent wherein the suitable solvent is selected from the group consisting ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; hydrocarbon selected from toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures thereof and a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, tri ethyl amine, diisopropyl amine and the like; preferably potassium carbonate to give a compound of formula III.

In an another of the present invention, reaction of a compound of formula III is carried out in step (e) with n-butyl acetate in the presence of a suitable base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, tri ethyl amine, diisopropyl amine and the like; preferably potassium carbonate.

In an another embodiment of the present invention, hydrolysis of a compound of formula II is carried out in step (f) in the presence of a suitable organic solvent selected from the group consisting of ketonic solvents such as acetone, ethylmethyl ketone, methyl isobutyl ketone and the like; ether solvents such as diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofUran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; halogenated solvents such as dichloromethane, chloroform, carbon tetrachloride and the like; aprotic polar solvents such as dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide and the like; or mixtures thereof; preferably acetonitrile and hydrochloric acid to give a compound of formula I.

In another aspect of the invention, compounds of formulae VI, V, IV and III are novel intermediates.

Having thus described the invention with reference to particular preferred embodiments and illustrative examples, those in the art would appreciate modifications to the invention as described and illustrated that do not depart from the spirit and scope of the invention as disclosed in the specification.
The examples are provided to illustrate particular aspects of the disclosure and do not limit the scope of the present invention as defined by the claims.

EXAMPLES:

Example 1: Preparation of 4-(4-fluorophenyI)-5-(hydroxymethyl)-6-(propan-2-yl)pyrimidm-2-yl-4-methylbenzene-1 -sulfonate Compound VII (60.0 g) was added in 300 mL of toluene under nitrogen atmosphere. 280 mL of Diisobutyl aluminium hydride (DIBAL-H) was added to it drop wise and temperature was maintained to 25-30°C for 1 hour under Nitrogen atmosphere. Acetic acid (27 mL) was quenched dropwise into it and stirred for 15 minutes. Methanol (20 mL) was added to it and stirred for 15 minutes. Ethyl acetate (240 mL) was charged into it. IN HCl (240 mL) was added and stirred for 30 minutes. The content was filtered and washed with hyflow bed and bed was washed with Ethyl acetate. Layers were separated and aqueous layer was extracted with Ethyl acetate (120 mL). The organic layer were combined and washed with IN HCl (240 mL). Layers were separated and washed with 10% NaCl solution. The organic layer was dried with Sodium Sulphate 20 g and distilled completely under vacuum below 40°C. The organic layer was cooled to to 30°C and vacuum was released. The obtained crude was dissolved in ethyl acetate (50 mL) and cooled to 0-5**C and extracted with hexane (120 mL) at 0-5°C. The compound was filtered and washed with hexane. The compound was dried at 50-55°C under vacuum 8 hours. The temperature was cooled to 30°C to obtain the title compound of formula (VI).

DryWeight:35.0.0g

Yield: 65.0%

Example 2: Preparation of 5-[(l-bromo-l-tert-butyl-2,2,4,4-tetramethyl-phosphetan-l-yl)methyl]-4-{4-fluorophenyl)-6-(propan-2-yl)pyrimidin-2-yl-4-methylbenzene-l-sulfonate
4-(4-fluorophenyl)-5-(hydroxymethyl)-6-(propan-2-yl)pyriinidin-2-yl-4-methylbenzene-l-sulfonate (50 g) as obtained in above example was added in toluene (300 mL) and acetonitrile (200 mL) under nitrogen atmosphere. The reaction mass was cooled to 0-5°C and PBrj (6.8 mL) was added to it drop wise and temperature was maintained to 25-30°C for 1 hour under Nitrogen atmosphere. Acetic acid (27 mL) was quenched dropwise into it and stirred for 1 hour at 0-5°C. DM water (250 mL) was added to it at 0-5°C reaction mass temperature was raised to 25-30°C and stirred for 10 minutes. Layers were separated and aqueous layer was extracted with toluene (100 mL). The organic Layers ware combined and washed with 5% sodium bicarbonate solution (250 mL). The organic layer was dried with Sodium Sulphate (20 g) and distilled completely under vacuiun below 40°C. The residue 5-(bromomethyl)-4-(4-fluorophenyl)-6-(propan-2-yl)pyrimidin-2-yl-4-methylbenzene-l-sulfonate (Compound-V) was cooled to to 30°C and vacuum was released. The obtained crude was dissolved in toluene (150 mL) and cooled to 20-25^C and tributylphospine 50% solution in ethyl acetate was added slowly and the reaction was maintained 1 hour. The compound was filtered and washed with toluene (10 mL). The compound was dried at 50-55°C under vacuum 12 hours to obtain the title compoimd of formula (IV).

5-[(l-bromo-l-tert-butyl-2,2,4,4-tetramethyl-phosphetan-l-yl)niethyl]-4-(4-fluorophenyl)-6-(propan-2-yl)pyrimidin-2-yI-4-methylbenzene-l-sulfonate (25 g) as obtained in above example was dissolved in DMSO (125 mL) under stirring at 25-30°C and potassium carbonate (15.2 g) was added and reaction mass was stirred for 15 minutes at 25-30°C. Compound-VIII (14.2 g) solution dissolved in toluene was added slowly and heated the reaction mass to 70-75°C and maintained for 6 hours. The reaction mass was cooled to 25-30°C added toluene (125 mL) stirred for 15 minutes at 25-30°C. The contents were filtered and washed with toluene (25 mL). Water was added to filtrate and stirred for 15 minutes at 25-30°C. Layers were separated and organic layer was washed with DM water (125 mL) followed by sodium chloride solution (125 mL). The organic layer was dried with sodium sulphate (10 g) and distilled completely under vacuum below 60°C. The residue was cooled to 30°C and vacuum was released. The obtained residue was purified using column chromatography to get compound of formula (III).

Residue weight: 15.0 g Yield: 64.0%

Compound of formula III (6 g) and n-Butyl acetate (60 mL) was stined for 5 minutes K2CO3 (3.9 g) was added into it at 25-30°C. N-methyl, methyl sulfonamide (3.5 mL) was added into it and heated to 120°C and maintamed for 3-5 hours. After completion of the reaction the content was cooled to 25-3 0°C, washed with water. The layers were separated and obtained organic layer was washed with 1% NaOH solution followed by NaCl solution. The organic layer was dried with Na2S04 (lOg) and distilled the solvent completely under vacuum below 55-60°C. The obtained residue was purified by using column chromatography. Residue weight: 5.0 g % Yield: 92.0% Tert-butyl[E]-(6-{2[4-(fluororphenyl]-6-isopropyl-2 [methyl(methylsulfonyl)amino]pyrimidine-5-yl]vinyl-(4R,6S)-2,2-dimethyl[l,3]dioxan-4-yl)acetate of formula 11 (5 g) was taken in acetonitrile (7 mL) at 25-30°C and stirred. 4N HCl (1.3 mL) was added slowly into it and maintained for 3 hours. After completion of the reaction 10% NaOH solution (3.5 mL) was added into above contents and pH was maintained above 10 for 1 hour. NaCl (1.0 g) was added into the reaction mass and stirred for 10 minutes. Layers were separated and in aqueous layer, CaCb (38 g) solution was added slowly and maintained at 20-25°C for 1 hour. The compound was filtered, washed with water and dried iinder under vacuum 12 hours.

Dry Weight: 0.7g Theoretical: 78.6%

We Claim:

1. A process for the preparation of Rosuvastatin and its pharmaceutically acceptable salts thereof comprising:

a) reduction of compound of formula VII with a reducing agent in the presence of an organic solvent to give a compound of formula VI;
wherein Ts is tosyl group.

b) bromination of a compound of formula VI with a brominating agent to give a compound of
formula V;

c) reaction of a compound of formula V with tertiary butyl phosphonium in the presence of an
organic solvent to give a compound of formula IV;

d) condensation of a compound of formula IV with a compound of VIII in the presence of a
solvent and a base to give a compound of formula III;

e) reacting a compound of formula III with n-butyl acetate in the presence of a base and N-methyl,methyl sulfonamide (NMMS) to give a compound of formula II;

f) hydrolysis of a compound of formula II in the presence of an organic solvent and
hydrochloric acid to give a compound of formula I.

2. A process according to claim 1, wherein the reduction is carried out in step (a), by using a reducing agent selected from the group consisting of lithium aluminium hydride,
diisobutyl aluminium hydride, sodium borohydride; preferably diisobutyl aluminium hydride and the solvent is selected from the group consisting of acetone, ethylmethyl ketone, methyl isobutyl ketone , diethyl ether, dimethyl ether, di-isoopropyl ether, methyltertiarybutyl ether, tetrahydrofuran, 1,4-dioxane, toluene, xylene,acetonitrile, propionitrile, dichloromethane, chloroform, carbon tetrachloride, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide or mixtures thereof; preferably toluene.

3. A process according to claim 1, wherein the salt formation is carried out in step (c), in the presence of a brominating agent selected from the group consisting of bromine chloride, phosphorus tribromide, alumiiuum tribromide; preferably phosphorus tribromide and the solvent is selected from the group consisting of acetone, ethyhnethyl ketone, methyl isobutyl ketone, acetonitrile, propionitrile, toluene, xylene, dichloromethane, chloroform, carbon tetrachloride, dimethylsulfoxide, (DMSO),N,N-dimethylfonnamide (DMF), N,N-dimethylacetamide or mixtures thereof; preferably toluene.

4. A process according to claim 1, wherein the condensation is carried out in step (d), in the presence of a solvent selected from the group consisting of acetone, ethyl methyl ketone, methyl isobutyl ketone, toluene, xylene, acetonitrile, propionitrile, dichloromethane, chloroform, carbon tetrachloride, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide or mixtures thereof and a base selected from the group consisting of
sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, triethylamine, diisopropyl amine preferably potassium carbonate.

5. A process according to claim 1, wherein the reaction is carried out in step (e), in the presence of a base selected from the group consisting of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, potassium bicarbonate, potassium tert-butoxide, tri ethyl amine, diisopropyl amine, preferably potassium carbonate.

6. A process according to claim I, wherein the hydrolysis is carried out in step (f), in the presence of a solvent selected from the group consisting of acetone, ethyl methyl ketone, methyl isobutyl ketone, toluene, xylene, acetonitrile, propionitrile, dichloromethane, chloroform, carbon tetrachloride, dimethylsulfoxide (DMSO), N,N-dimethylformamide (DMF), N,N-dimethylacetamide or mixtures thereof; preferably acetonitrile.

7. A compound of formula VI: wherein Ts is as described in Claim 1.

8. A compound of formula V: wherein Ts is as described in Claim 1.

9. A compound of formula IV: wherein Ts is as described in Claim 1.

10. A compound of formula III: wherein Ts is as described in Claim 1.