FIELD OF THE INVENTION

This invention, in general relates to a process for producing (7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid (Rosuvastatin) or pharmaceutically acceptable salts thereof. More particularly the present invention provides a crystalline form of methyl 7-[4-(4-flourophenyI)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate, process for producing the same and employing the same for producing rosuvastatin or pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION

Rosuvastatin calcium chemically known as 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid calcium salt is an HMG-CoA reductase inhibitor, developed by Shionogi for the treatment of hyperlipidaemia as a once daily oral dosage form (Ann Rep, Shionogi, 1996; Direct communications, Shionogi, 8 Feb 1999 & 25 Feb 2000). The chemical structure of the rosuvastatin calcium is as given in formula (I)

Rosuvastatin calcium is marketed as "CRESTOR" for the treatment of hyperlipidaemia and acts by inhibiting HMG-CoA reductase enzymes in mammals. The daily dose of rosuvastatin is between 5mg to 40mg orally for reducing the LDL cholesterol level in the mammals.

According to the prior art methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate, herein after referred to as "Compound-A" is a key intermediate for producing Rosuvastatin Calcium.
US Patent Number US RE37314 E discloses that the key intermediate "Compound-A" is obtained as "syrup" [example l-(4)]. Furthermore, the WO03/097614 describes the intermediate Compound-A as "thick oil" (example 2, step b).

Existing prior art produce "Compound-A" as an oil or syrup thereby making it difficult to handle during industrial scale production of rosuvastatin.

Therefore, it is desirable to develop an alternative method to obtain Compound-A in a solid form which is easier to handle. Furthermore the compound A so produced is easily converted to rosuvastatin or its pharmaceutically acceptable salts with high purity and yield.

SUMMARY OF THE INVENTION

It is an aspect of the present invention to provide a crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate (Compound-A) for producing 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid.

It is another aspect of the present invention to provide an improved process for large
scale production of 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid (rosuvastatin) employing the crystalline form of intermediate methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy- 5 -oxo-(E)-6-heptenate.

In accordance with one preferred embodiment of the present invention, there is provided a crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate (rosuvastatin intermediate) characterized by PXRD having peaks at 9.7,16.2,18.01, 18.9, 19.3,21.2,22.5 and 24.5 (±) 0.2 degree two theta.

In accordance with another preferred embodiment of the present invention, there is provided a process for producing the crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate, comprising crystallizing the methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate from a solution including at least one organic solvent.

In accordance with still another preferred embodiment of the present invention, there is provided a process for producing crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate comprising deprotecting the silyl group of compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate and treating with an organic solvent.

In accordance with yet another preferred embodiment of the present invention, there is provided an improved process for producing 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid or its pharmaceutically acceptable salts by converting the methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate into the 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-

N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenoic acid or its pharmaceutically acceptable salts.

BRIEF DESCRIPTION OF THE DRAWINGS

Further objects of the present invention together with additional features contributing thereto and advantages accruing there from will be apparent from the following description of preferred embodiments of the invention which are shown in the accompanying drawing figures wherein :

Figure 1: illustrates characteristic X-ray powder diffraction pattern for the crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate.

DETAILED DESCRIPTION OF THE INVENTION

While this specification concludes with claims particularly pointing out and distinctly claiming that, which is regarded as the invention, it is anticipated that the invention can be more readily understood through reading the following detailed description of the invention and study of the included examples.

The present invention relates to a crystalline form of 7-[4-(4-fluorophenyl)-6-isopropyl-
2-(N-methyl-N-methylsulfonylamino) pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-
heptenoic acid intermediate methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate (Compound-A/rosuvastatin intermediate) and a novel process for the preparation thereof. Also, the present invention discloses an improved process for the preparation of pharmaceutical acceptable salts of rosuvastatin using the crystalline form of rosuvastatin intermediate.

Powder X-ray Diffraction (PXRD)

The polymorphs of the present invention are characterized by their X-ray powder
diffraction pattern. Thus, the X-ray diffraction patterns of the polymorphs of the

invention were measured on PANalytical, X'Pert PRO powder diffractometer equipped with goniometer of 0/9 configuration and X'Celerator detector. The Cu-anode X-ray tube was operated at 40kV and 30mA. The experiments were conducted over the 20 range of 2.0°-50.0°, 0.030° step size and 50 seconds step time.

According to the present invention the crystalline form of rosuvastatin intermediate Compound-A is characterized by PXRD having peaks at about 9.7, 16.2, 18.01, 18.9, 19.3, 21.2, 22.5 and 24.5 (±) 0.2 20 values as depicted in figure 1.

According to the embodiments of the present invention, the crystalline rosuvastatin intermediate "Compound-A" is characterized by analytical techniques including, but are not limited to X-ray powder diffraction pattern, moisture content and/or melting point.
Another embodiment of the present invention is to provide a process for the preparation of the crystalline form of rosuvastatin intermediate Compound-A, wherein the process comprises of deprotecting the silyl group of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate and crystallizing with an organic solvent.

In one embodiment of the present invention, deprotection is carried out by the conventional methods, for example as disclosed in EP 0521471 and WO 03/097614.
In another embodiment of the present invention, deprotection is carried out by using copper (II) halide or its hydrates such as copper (II) chloride dihydrate.

In another embodiment of the present invention, the residue obtained after deprotecting
the methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-
pyrimidin-5-yl] -(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate, is crystallized with an organic solvent to obtain the crystalline form of rosuvastatin intermediate Compound-A, wherein the solvent is selected from C1-C5 alcohols preferably isopropyl alcohol.

According to the process of present invention the crystallization is performed by heating a reaction mixture of the crystalline intermediate in the solvent to obtain a solution, followed by cooling, wherein heating is carried out to a temperature of about 40 °C to about 100 °C more preferably at a temperature of 40 °C to 60 °C and wherein cooling is carried out at a temperature of 0 °C to 20 °C more preferably 10 °C to 15 °C.

In accordance with a specific embodiment of the present invention provides a process for preparing the crystalline form of rosuvastatin intermediate "Compound-A" comprises of deprotecting the compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] -(3 R)-3 -(tert-butyldimethylsilyloxy)- 5 -oxo-(E)-6-heptenate and further purifying in an organic solvent such as C1-C5 alcohols.

Another embodiment of the present invention is to provide an improved process for the preparation of rosuvastatin or its pharmaceutically acceptable salts thereof, wherein, the said process comprises of converting the crystalline form of rosuvastatin intermediate Compound-A to rosuvastatin or its pharmaceutically acceptable salts thereof as depicted in Scheme I.

In another embodiment of the present invention rosuvastatin salt is selected from calcium, magnesium and sodium.

Compound-A is reduced to Compound-C by following conventional methods, for example as disclosed in EP 0521471B1, US 20050159615 and WO 03/097614 and Compound-C is further converted to rosuvastatin pharmaceutically acceptable salts by following conventional methods, for example as disclosed in EP 0521471B 1, EP 1816126 Al and EP 1585736 A2.

The following examples are provided to illustrate the process of the present invention. They, are however, not intended to limiting the scope of the present invention in any way and several variants of these examples would be evident to person ordinarily skilled in the art.

Example-1

Preparation of methyl 7-[4-(4-flourophenvl)-6-isopropvl-2-(N-methvl-N-methvlsulfonvl amino Vpvrimidin-5-vl1-(3R)-3-(tert-butvldimethvlsilvloxvV5-oxo-(E)-6-heptenate (Compound-B) Compound-B

Compound 4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5-pyrimidine carbaldehyde (100 g) and (3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-6-triphenylphosphoranylidene (183 g) were taken in acetonitrile (1500 ml) and refluxed for 14 hours. After completion of the reaction, the reaction mass was concentrated. Cyclohexane was added to the reaction mass and solid was filtered. Filtrate was concentrated to yield compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate as a thick syrup.

Example-2

Preparation of methyl 7-[4-(4-flourophenvl)-6-isopropyl-2-(N-methyl-N-methylsulfonvl amino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate(Compound-A)

Compound A methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate (100 g) was taken in acetonitrile (1000 ml). To this a solution of hydrogen fluoride (150 g of 40 % HF in 500 ml acetonitrile) was added slowly at a temperature 0-5°C, and the mixture was brought to room temperature and stirred for two hours. After completion of the reaction dichloromethane was added and washed with water followed by concentration. The obtained residue was taken in isopropyl alcohol and heated to 40-45 °C followed by cooling to 10-15 °C. The obtained solid was filtered and washed with diisopropyl ether. The filtered solid was dried to yield methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate. XRD of the dried sample showed it to be crystalline.

Example-3

Preparation of methyl 7-[4-(4-flourophenylV6-isopropvl-2-(N-methyl-N-methvlsulfonvl amino)-pvrimidin-5-vn-(3R)-3hvdroxy-5-oxo-(E)-6-heptenate(Compound-A)
Compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonyl amino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate (15 g) was taken in a mixture of acetone (150 ml) and water (7.5 ml). To this Copper (II) chloride dihydrate (0.75 g) was added and refluxed for 7-8 hours. After completion of the reaction the reaction mass was cooled to room temperature and dichloromethane was added followed by concentration. The obtained residue was taken in isopropyl alcohol and heated to 40-45 °C followed by cooling to 10-15 °C. The obtained solid was filtered and washed with diisopropyl ether. The filtered solid was dried to yield methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5 -yl] -(3 R)-3 -hydroxy-5-oxo-(E)-6-heptenate. XRD of the dried sample showed it to be crystalline.

Example-4

Preparation of methyl 7- r4-(4-flourophenyl)-6-isopropyl-2-(S-methyl-N-methylsulfonvl amino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate (Compound-C)

Compound-C

Tetrahydrofuran (1800 ml) was taken in a flask and cooled to -90 °C. To this sodiumborohydride (10 g) and diethyl methoxyborane (1.0 M solution in THF) was added and maintained for 30 minutes. To this reaction mixture, solution of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R) -3-hydroxy-5-oxo-(E)-6-heptenate (Compound A) (100.0 g Compound A dissolved in 700 ml THF and 700 ml methanol) was slowly added and maintained at a temperature -90 °C for 2-3 hours. Acetic acid was added to the reaction mass and the temperature was raised to room temperature. To this reaction mass, a mixture of ethyl acetate and water was added. Organic layer was washed with brine solution and dried over sodium sulfate. Methanol was added to the residue and evaporated to yield methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R,5S)-dihydroxy-(E)-6-heptenate.

Example-5

Preparation of Rosuvastatin Sodium

Methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-
pyrimidin-5-yl]-(3R,5S)-dihydroxy -(E)-6-heptenate (100 g ) was added to ethyl alcohol (900 ml). To this aqueous sodium hydroxide (8.0 g sodium hydroxide dissolved in 500 ml of water) was added at a temperature of 0-5 °C. The reaction mixture was heated to room temperature and maintained for 1-2 hours. After completion of the reaction, the reaction mass was concentrated and ethyl alcohol was added and the reaction mass was distilled off azeotropically. To the obtained residue diisopropyl ether was added and stirred for 1hour and filtered. The filtered solid was dried to yield Rosuvastatin sodium.

Example-6

Preparation of Rosuvastatin Calcium

Rosuvastatin Sodium (100 g) was dissolved in water (1000 ml) and stirred at room temperature for 15 minutes. To this solution, calcium chloride solution (29.2 g of calcium chloride dehydrate dissolved in 500 ml of water) was added drop wise for about 90 minutes and stirred for 2 hours. The obtained solid was filtered and washed with water and dried to yield Rosuvastatin Calcium.

While this invention has been described in detail with reference to certain preferred embodiments, it should be appreciated that the present invention is not limited to those precise embodiments. Rather, in view of the present disclosure, which describes the current best mode for practicing the invention, many modifications and variations would present themselves to those skilled in the art without departing from the scope and spirit of this invention.

We Claim:

1. A crystalline form of methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-hydroxy-5-oxo-(E)-6-heptenate (rosuvastatin intermediate) is characterized by having X-ray Diffraction pattern with peaks at about 9.7, 16.2, 18.01,18.9,19.3,21.2,22.5 and 24.5 (±) 0.2 degrees two theta.

2. The intermediate according to claim 1, wherein the crystalline form of rosuvastatin intermediate is characterized by X-ray Diffraction pattern as depicted in figure 1.

3. A process for preparing the crystalline form of rosuvastatin intermediate of claim 1, comprising crystallizing rosuvastatin intermediate from a solution having at least one organic solvent.

4. The process according to claim 3, wherein the organic solvent is selected from C1-C5 alcohols.

5. The process according to claim 3, wherein the crystallization is performed by heating a reaction mixture of the rosuvastatin intermediate in a solvent to obtain a solution, followed by cooling.

6. The process according to claim 5, wherein heating is carried out to a temperature of about 40 °C to about 100 °C.

7. The process according to claim 5, wherein cooling is carried out to a temperature of about 0 °C to 20 °C.

8. The process according to any of claims 3-7, further comprising converting the crystalline form of methyl 7-[4-(4- flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] -(3R)-3-hydroxy-5-oxo-(E)-6-heptenate into rosuvastatin or pharmaceutically acceptable salts thereof.

9. A process for preparing crystalline form of methyl 7-[4-(4- flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] -(3R)-3-hydroxy-5-oxo-(E)-6-heptenate comprising deprotecting the silyl group of compound methyl 7-[4-(4-flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate by using copper (II) halide or its hydrates followed by crystallization in an organic solvent.

10. The process according to claim 9, wherein the copper (II) halide or its hydrates is copper (II) chloride dihydrate.

11. The process according to claim 9, further comprising converting the crystalline form of methyl 7-[4-(4- flourophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-pyrimidin-5-yl] -(3R)-3-hydroxy-5-oxo-(E)-6-heptenate into rosuvastatin or pharmaceutically acceptable salts thereof.