FIELD OF INVENTION
The invention describes an elegant process for the preparation of Rosuvastatin Intermediate in the solid state and isolation of substantially pure crystalline form thereof.
BACK GROUND OF INVENTION
Rosuvastatin calcium which is chemically known as Calcium (+)-7-[(4-(4-fluorophenyl)-6-isopropyl-2-(N-acetyl-N-methyl amino) pyrimidin-5-yl)] - (3R,5S)-dihydroxy-6-(E)-Heptenoate, developed by Shinogi is used in the treatment of hypercholesterolemia, hyper-lipoproteinemia and atherosclerosis.Rosuvastatin Calcium has the following Chemical Formula.

Rosuvastatin Calcium

A number of relevant processes for the preparation of Rosuvastatin Calcium, Intermediates and thereof are disclosed .One of the Important intermediates in the preparation of Rosuvastatin Calcium is Compound of formula 2, disclosed in U.S. Patent No.RE37,314E which is chemically named as Methyl-(+)-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methanesulfonylamino) pyrymidine-5-yl) - (3R) -Hydroxy-5-Oxo-6 - (E)-Heptonoate.

1 2

3 Rosuvastatin Calcium

US RE 37314E, describes the preparation of the Compound of formula 2 and WO03/097614 teaches isolation as syrup by column chromatography, WO 03/087112 describes the preparation of tert-butyl ester of the same compound and isolated in the pure form by Column chromatography.
Nevertheless there remains a need of processes for the preparation of Rosuvastatin which is cost effective with simple purification steps. Further the process is suitable for industrial scale preparation.
STATEMENT OF INVENTION
The present invention relates to a crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate which provides at least one of: (i) FTIR spectra of crystalline form of Compound-2 with peaks at 3515, 2969, 1747, 1662, 1604, 1541, 1508, 1443, 1379, 1326, 1269, 1229, 1157, 960, 903, 851, 808, 778, 565, 523, 490 cm-1, (ii) DSC thermogram of crystalline form with endothermic peak at 105.70°C; and/or (iii) an X-ray powder diffraction (XRPD) pattern with 5.917, 7.607,8.193, 8.88, 9.815, 10.11, 11.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651, 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees two theta values and a process for preparing crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate , comprising steps of: a. reacting 3(R)-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester with aqueous hydrogen halides of appropriate concentrations in an aliphatic alcohol as a solvent and isolating crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate by filtration.

DETAILED DESCRIPTION OF INVENTION
The present invention is in relation to a crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate which provides at least one of:
(i) FTIR spectra of crystalline form of Compound-2 with peaks at 3515, 2969, 1747, 1662, 1604, 1541, 1508, 1443, 1379, 1326, 1269, 1229, 1157, 960, 903, 851, 808, 778, 565, 523, 490 cm-1,
(ii) DSC thermogram of crystalline form with endothermic peak at 105.70°C; and/or
(iii) an X-ray powder diffraction (XRPD) pattern with 5.917, 7.607,8.193, 8.88, 9.815, 10.11, 11.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651, 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees two theta values.
In another embodiment of the present invention, the crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate is in isolated form.
In still another embodiment of the present invention, the crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate is in pure form.
In still another embodiment of the present invention, the crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate is in crystalline form.
The present invention is also in relation to a process for preparing crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate , comprising steps of:
a. reacting 3(R)-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester with aqueous hydrogen halides of appropriate concentrations in an aliphatic alcohol as a solvent; and
b. isolating crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate by filtration.
In still another embodiment of the present invention, the hydrogen halides are selected from HCl and HF.
In still another embodiment of the present invention, the solvent is selected from C1- C4 aliphatic alcohols.
In yet another embodiment of the present invention, C1- C4 aliphatic alcohol is selected from a group comprising methanol, ethanol and isopropyl alcohol.
The main objective of the invention is to provide a method for the preparation of the Rosuvastatin Intermediate 7-[4-(4-Fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)- pyrimidin-5-yl]-3(R) - hydroxy-5-oxo-hept-6-enoic acid methyl ester (Compound-2) in solid state with good yield, high purity and ease of operations. The intermediate is further characterized by well established techniques like XRD, DSC and FTIR.

1 2
In one embodiment the present invention provides a method for the preparation of Rosuvastatin intermediate (Compound- 2) using simple process in a substantially pure crystalline form. It involves the deprotection of tert-Butyl dimethyl silyl group (TBDMS) of 3(R)-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl -methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester (Compound-1) using hydrogen halides (HCl, HF) in appropriate concentrations in an aliphatic alcohol as a solvent preferably methanol. Without any additional purification the product is directly isolated from the reaction mixture.
In another embodiment, the present invention provides a crystalline form of Compound- 2 having the X-ray diffraction pattern with peaks at 5.917, 7.607, 8.193, 8.88, 9.815, 10.11, 11.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651, 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees two theta values.
In another embodiment the present invention provides FTIR spectra of crystalline form of Compound-2 with peaks at 3515, 2969, 1747, 1662, 1604, 1541, 1508, 1443, 1379, 1326, 1269, 1229, 1157, 960, 903, 851, 808, 778, 565, 523, 490 cm-1.
In another embodiment the present invention provides DSC thermogram of crystalline form of Compound- 2 with endothermic peak at 105.70°C.
The present invention provides a method for the preparation of Compound-2 comprising the steps of:
a) Reacting compound-1 with aq hydrogen halides (HF, HCl) of appropriate concentrations in an aliphatic alcohol as a solvent.
b) Isolating the Solid Compound-2 by filtration
In a particular preferred embodiment Solvents can be selected from a group consisting of C1- C4 aliphatic alcohols like methanol, ethanol and IPA, most preferably methanol. Solvent is in an amount of 5-20 vol, most preferably 10 vol relative to Compound -1.
In another embodiment, reactions are carried out using hydrogen halides like HF or HCl in suitable concentrations in above mentioned solvent.
Hydrogen halide concentrations in case of HCl may be selected between 1.0 - 10.0 % as an aqueous solution, preferably between 1.0 – 3.0 % and in case of HF may be selected between 5.0 - 20.0 % as an aqueous solution, preferably between 5.0 -10.0 %.
In another aspect of invention, reactions stirring time is selected between 10 - 50 hrs, preferably 25-30 hrs which may vary depending on the reaction conditions. The resulting crystalline solids from the above mentioned aspects is recovered by conventional techniques like filtration. The crystals are then dried. Drying may be carried out at a temperature less than 60°C under vacuum.
The invention encompasses a crystalline form of compound - 2 characterized by powder X-Ray Diffraction pattern having Prominent peaks at 9.815, 16.2, 18.159, 19.513, 19.74, 20.875, 21.345, 21.943, 22.651, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees two theta values. The crystalline form may be further characterized by X-Ray powder diffraction peaks at about 5.917, 7.607,8.193, 8.88, 9.815, 10.11, 11.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651, 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees two theta values.
Crystalline intermediate of the present invention shows main FTIR peaks at 3515, 2969, 1747, 1662, 1604, 1541, 1508, 1443, 1379, 1326, 1269, 1229, 1157, 960, 903, 851, 808, 778, 565, 523, 490 cm-1.
The most intense peaks appear at 3515, 2969, 1747, 1662, 1541, 1508, 1379, 1326, 1229, 1157, 960, 851, 778, 565, 523 cm-1.
DSC thermogram for crystalline Rosuvastatin intermediate of present invention shows an endothermic peak at about 105.70 °C.
In yet another embodiment of the present invention the crystalline form of Compound-2 may be converted into Rosuvastatin and its pharmaceutically acceptable salts by conventional methods.
In the present invention starting material (Compound-1) for the preparation of the said intermediate was prepared according to the known processes in the prior art.
The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.
Characterization
Rosuvastatin intermediate of the present invention (Compound - 2) is characterized by X-Ray powder Diffraction (XRD), DSC analysis, and FTIR spectroscopy.
XRD: XRD Diffractograms were collected on Bruker AXS D-8 advance X- Ray powder diffract meter, Scintillation detector. Scanning Parameters : ScanType - Locked Coupled, Scan Mode -Continuous, Range (2 theta) - 3.0°- 60.0°, Rate - 3.6°/min

FTIR Spectroscopy:
FTIR Spectrum was recorded on Perkin-Elmer spectrum-1spectrometer, Diffuse Reflectance Technique. The sample was finely ground with Potassium Bromide, and the spectrum was recorded using Potassium Bromide background in a Diffused reflectance accessory.
Thermal analysis:
Differential Scaning Calorimetry was performed on Perkin Elmer Diamond. The Crucible was Crimped and punched prior to analysis. Experimental conditions: sample Weight: 2.0 – 3.0 mg, Heating Rate: 10°C/min.
Examples
Example 1: Preparation of Compound- 2 using 1.0% HCl /Methanol
A mixture of 1.0% HCl (8.0ml), Compound - 1(3.0g) and methanol (20ml) was stirred at ambient temperature for about 40--50 hrs. The separated solid was filtered ,washed with water and dried under vacuum for 10 hrs yielding compound - 2 (2.2g) as a pale yellow crystalline solid .
Example 2: Preparation of Compound- 2 using 2.0% HCl /Methanol
A mixture of 2.0% HCl (8.0ml), Compound – 1(3.0g) and methanol (20ml) was stirred at ambient temperature for about 20 - 25 hrs. The separated solid was filtered, washed with water and dried under vacuum for 10 hrs yielding compound - 2 (2.7g) as a pale yellow crystalline solid.
Example 3: Preparation of Compound- 2 using 3.0% HCl /Methanol A mixture of 3.0%HCl (8.0ml), Compound –1(3.0g) and methanol (20ml) was stirred at ambient temperature for about 15 - 20 hrs. The separated solid was filtered, washed with water and dried under vacuum for 10 hrs yielding compound- 2 (1.8g) as a pale yellow crystalline solid .
Example 4: Preparation of Compound- 2 using 5% aq HF / Methanol
A mixture of 5.0% HF (80ml), Compound-1(14.0g) and methanol (100ml) was stirred at ambient temperature for about 40 - 50 hrs. The separated solid was filtered, washed with water and dried under vacuum for 10 hrs yielding compound - 2 (13.0g) as a pale yellow crystalline solid.
Example 5: Preparation of Compound- 2 using 10% aq HF / Methanol
A mixture of 10.0% HF(40ml ), Compound – 1(14.0g) and methanol (100ml ) was stirred at ambient temperature for about 25-30 hrs.The separated solid was filtered ,washed with water and dried under vacuum for 10 hrs yielding compound- 2 (11.5g ) as a pale yellow crystalline solid .

Example 6: Preparation of Compound- 2 using 15% aq HF / Methanol
A mixture of 15.0% HF(36ml ), Compound -1(14.0g) and methanol (100ml) was stirred at ambient temperature for about 25-30 hrs.The separated solid was filtered ,washed with water and dried under vacuum for 10 hrs yielding compound - 2 (14.0g) as a pale yellow crystalline solid.
Example 7: Preparation of Compound- 2 using 20% aq HF / Methanol
A mixture of 20.0% HF(20ml), Compound 1(14.0g) and methanol (100ml) was stirred at ambient temperature for about 25-30 hrs.The separated solid was filtered ,washed with water and dried under vacuum for 10 hrs yielding compound 2 (14.2g) as a pale yellow crystalline solid .

WE CLAIM
1. A crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate which provides at least one of:
(i) FTIR spectra of crystalline form of Compound-2 with peaks at 3515, 2969, 1747, 1662, 1604, 1541, 1508, 1443, 1379, 1326, 1269, 1229, 1157, 960, 903, 851, 808, 778, 565, 523, 490 cm-1,
(ii) DSC thermogram of crystalline form with endothermic peak at 105.70°C; and/or
(iii) an X-ray powder diffraction (XRPD) pattern with 5.917, 7.607,8.193, 8.88, 9.815, 10.11, 11.633, 12.202, 13.729, 14.725, 14.81, 15.193, 15.549, 16.2, 16.411, 16.976, 18.159, 19.024, 19.513, 19.74, 20.311, 20.875, 21.345, 21.943, 22.651, 23.563, 24.082, 24.726, 24.98, 25.2, 25.846, 26.388, 27.367, 27.654, 28.079, 28.698, 29.855, 31.38, 32.635, 33.051, 33.962, 34.753, 35.178, 35.555, 36.292, 36.574, ± 0.2 degrees two theta values.
2. The crystalline form as claimed in claim 1is in isolated form.
3. The crystalline form as claimed in any one of claims 1 to 2 is in pure form.
4. The crystalline form as claimed in any one of claims 1 to 3 is in crystalline form.
5. A process for preparing crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate , comprising steps of:
a. reacting 3(R)-(tert-Butyl-dimethyl-silanyloxy)-7-[4-(4-fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-5-oxo-hept-6-enoic acid methyl ester with aqueous hydrogen halides of appropriate concentrations in an aliphatic alcohol as a solvent; and
b. isolating crystalline form of Methyl-7-(4-(4-Fluorophenyl) - 6-Isopropyl-2-(N-methane sulfonylamino) pyrymidine-5-yl)-Hydroxy-5-Oxo-6-Heptonoate by filtration.
6. The process as claimed in claim 5, wherein the hydrogen halides are selected from HCl and HF.
7. The process as claimed in claim 5, wherein the solvent is selected from C1- C4 aliphatic alcohols.
8. The process as claimed in claim 7, wherein C1- C4 aliphatic alcohol is selected from a group comprising methanol, ethanol and isopropyl alcohol.