Claims:1. A process for the preparation of amorphous Rosuvastatin calcium hydrate with high purity, which process comprises:
a) hydrolysing tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate in presence of aq. HCl in acetonitrile to obtain Rosuvastatin tert-butyl ester;
b) subjecting the Rosuvastatin tert-butyl ester in situ to ester saponification by treatment with sodium hydroxide followed by adjusting the pH of the reaction mass with a mineral acid between 3 to 4 at a temperature of -5 to -80C to obtain Rosuvastatin acid;
c) converting the Rosuvastatin acid in situ into ter. butylamine salt by treating with ter. butylamine to isolate Rosuvastatin Tert-Butyl Amine Salt;
d) treating the Rosuvastatin Tert-Butyl Amine Salt with calcium chloride solution in presence of sodium hydroxide to isolate amorphous Rosuvastatin calcium hydrate with high purity.
2. The process for the preparation of amorphous Rosuvastatin calcium hydrate according to claim 1, wherein, the hydrolysis of the tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate is conducted at a temperature of 20-400C.
3. The process for the preparation of amorphous Rosuvastatin calcium hydrate according to claim 1, wherein, the conversion of Rosuvastatin acid into ter.butylamine salt is carried out at a temperature range of 20-300C.
4. The process for the preparation of amorphous Rosuvastatin calcium hydrate according to claim 1, wherein, the mineral acid used in step b) is hydrochloric acid.
5. The process for the preparation of amorphous Rosuvastatin calcium hydrate according to claim 1, wherein, the Rosuvastatin Tert-Butyl Amine Salt is optionally subjected to purification process which comprises:
a) treating the Rosuvastatin Tert-Butyl Amine Salt with ethyl acetate and methanol in 2:1 ratio at a temperature of 60-800C under stirring to achieve clear solution followed by distillation of the solvent mixture at the same temperature;
b) Stripping the reaction mass with additional ethyl acetate at the same temperature followed by cooling the reaction mass to 25-300C under stirring to isolate the Rosuvastatin Tert-Butyl Amine Salt with HPLC purity more than 99.80 %.
6. A process for the preparation of Rosuvastatin Tert-Butyl Amine Salt with high purity, which process comprises:
a) hydrolysing tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate by aq. HCl in presence of acetonitrile to obtain Rosuvastatin tert-butyl ester;
b) subjecting the Rosuvastatin tert-butyl ester in situ to ester saponification by treatment with sodium hydroxide followed by adjusting the pH of the reaction mass with a mineral acid between 3 to 4 at a temperature of -5 to -80C to obtain Rosuvastatin acid;
c) converting the Rosuvastatin acid in situ into ter. butyl amine salt by treating with ter. butyl amine to isolate Rosuvastatin Tert-Butyl Amine Salt; and
d) Optionally purifying the Rosuvastatin Tert-Butyl Amine Salt from ethyl acetate and methanol.
7. The process for the preparation of Rosuvastatin Tert-Butyl Amine Salt according to claim 6, wherein, the hydrolysis of the tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate is conducted at a temperature of 20-350C.
8. The process for the preparation of Rosuvastatin Tert-Butyl Amine Salt according to claim 6, wherein, the conversion of Rosuvastatin acid into ter.butylamine salt is carried out at a temperature range of 20-300C.
9. The process for the preparation of Rosuvastatin Tert-Butyl Amine Salt according to claim 6, wherein, the mineral acid used in step b) is hydrochloric acid.
10. The process for the preparation of Rosuvastatin Tert-Butyl Amine Salt according to claim 6, wherein, the Rosuvastatin Tert-Butyl Amine Salt isolated with HPLC purity more than 99.80 %.
, Description:Field of Invention:
The present invention relates to a novel process for the manufacture of amorphous Rosuvastatin Calcium. More particularly, it relates to the process for preparation of pure amorphous Rosuvastatin calcium hydrate.

Background of invention:
Rosuvastatin calcium is chemically described as (3R,5S,6E)-7-[4-(4-fluorophenyl)-6-(l- methylethyl)-2-[methyl(methylsulfonyl)amino]-5-pyrimidinyl]-3,5-dihydroxy-6-heptenoic acid, calcium salt (2:1), having the structural Formula I. Rosuvastatin calcium is an antihypercholesterolemic drug used in the treatment of atherosclerosis.

US RE 37314 discloses Rosuvastatin in the generic formula and its various alkali metal salts such as lithium, sodium, potassium, and cesium, as well as alkaline earth metal salts such as beryllium, magnesium, and calcium. RE '314 patent also discloses an amorphous (powder) form of the calcium salt of Rosuvastatin, which is prepared by isolating from its precursor sodium salt.

There is ample literature available on the preparation methods of amorphous rosuvastatin calcium, as detailed below.
EP2508514 discloses a process of preparing pure amorphous form of rosuvastatin calcium which comprises hydrolysis of C1-C5 alkyl esters of rosuvastatin, preferably tert-butyl ester of rosuvastatin, with an organic nitrogen base, tert-butylamine, in the presence of water, optionally containing aprotic solvent, followed by the conversion of rosuvastatin salt with a source of calcium to obtain rosuvastatin calcium, which is then isolated.

WO2006136408 discloses a process for preparing pure amorphous rosuvastatin calcium, which comprises hydrolysing a C1 to C5 alkyl ester of rosuvastatin, with an inorganic base, e.g. sodium hydroxide, in the presence of an aprotic solvent, or in the presence of a mixture of an aprotic solvent and water, to obtain a solution of rosuvastatin salt, which may be converted to rosuvastatin calcium salt using calcium cation to obtain rosuvastatin calcium.

WO 2005/023778 discloses a process for the preparation of rosuvastatin calcium by conversion of C1 to C4 alkyl ester of rosuvastatin, preferably ter-butyl ester of rosuvastatin with a base, preferably sodium hydroxide, in the presence of a C1 to C4 alcohol, preferably ethanol, to obtain a solution of rosuvastatin sodium salt and converted sodium salt into rosuvastatin calcium by adding a source of calcium to said solution.

US9150518 discloses another process for producing amorphous rosuvastatin calcium which comprises: a) hydrolysis of one or more C1 to C5 alkyl esters of rosuvastatin or rosuvastatin lactone with an organic nitrogen base in the presence of a mixture consisting essentially of water and an aprotic solvent to produce a rosuvastatin salt of the base; b) converting the rosuvastatin salt of organic nitrogen base with a source of calcium to obtain a reaction product mixture containing rosuvastatin calcium; and c) isolating pure amorphous rosuvastatin calcium, substantially free from any traces of alkali metal salt impurities, from the reaction product mixture, wherein the process avoids the use of alkali metal hydroxides.
Indian patent IN260931 describes a one pot process of manufacturing of amorphous Rosuvastatin Calcium which comprises: (a) hydrolysis of the protected diol, (tertiary-butyl [(4S,6R)-6-((E)-2-{4-(4- fluorophenyl)-6-isopropyl-2-[methyl(methylsulfonyl)amino]-5- pyrimidinyl}ethenyl)-2)2-dimethyl-l)3-dioxan-4-yl]acetate) with hydrochloric acid in aqueous methanol; (b) conversion of the diol ((E)-7-[4-(4-fluorophenyl)-6-isopropyl-2- [methyl(methylsulfonyl) amino]pyrimidin-5-yl] (3R,5S)-3,5-dihydroxyhept-6- enoic acid) to corresponding sodium salt with suitable base in suitable solvent combination; (c) treatment of the solution of sodium salt with calcium chloride solution to obtain the amorphous form of Rosuvastatin Calcium salt.

The prior art methods are not suitable for commercial scale up because the amorphous product thus obtained is difficult to isolate with high purity, thereby making the prior art methods commercially difficult to implement on larger scale.
Therefore, the objective of the present invention is to provide an improved process for the manufacture of amorphous Rosuvastatin calcium hydrate with high purity, for which the protection is sought in the present invention.

Summary of the invention:
In line with the above objective, the present invention provides a process for the preparation of amorphous Rosuvastatin calcium hydrate with high purity, which process comprises:
a) hydrolysing tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate in presence of aq. HCl in acetonitrile to obtain Rosuvastatin tert-butyl ester;
b) subjecting the Rosuvastatin tert-butyl ester to in situ ester saponification by treatment with sodium hydroxide followed by adjusting the pH of the reaction mass with a mineral acid between 3 to 4 at a temperature of -5 to -80C to obtain Rosuvastatin acid;
c) converting the Rosuvastatin acid in situ into ter. butylamine salt by treating with ter. butylamine to isolate Rosuvastatin Tert-Butyl Amine Salt;
d) optionally purifying the Rosuvastatin Tert-Butyl Amine Salt and
e) Treating the Rosuvastatin Tert-Butyl Amine Salt with calcium chloride solution in presence of sodium hydroxide to isolate amorphous Rosuvastatin calcium hydrate with high purity.

The hydrolysis reaction of the tert-butyl 2-((4R, 6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl) vinyl)-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate can be conducted at a temperature of 20-350C; more preferably at 25-300C.

The conversion of Rosuvastatin acid into tert butyl amine salt is carried out at a temperature range of 20-300C; more preferably at 20-250C.
In another aspect, Rosuvastatin Tert-Butyl Amine Salt thus obtained is optionally subjected to purification process which comprises:
a) treating the Rosuvastatin Tert-Butyl Amine Salt with ethyl acetate and methanol in 2:1 ratio at a temperature of 60-800C under stirring to achieve clear solution followed by distillation of the solvent mixture at the same temperature;
b) Stripping the reaction mass with additional ethyl acetate at the same temperature followed by cooling the reaction mass to 25-300C under stirring to isolate the Rosuvastatin Tert-Butyl Amine Salt with HPLC purity more than 99.80 %.

Detailed description of the invention:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more fully understood and appreciated.
Accordingly, in an embodiment, the present invention provides a process for the preparation of amorphous Rosuvastatin calcium hydrate with high purity, which process comprises:
a) hydrolysing tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate in presence of aq. HCl in acetonitrile to obtain Rosuvastatin tert-butyl ester;
b) subjecting the Rosuvastatin tert-butyl ester to in situ ester saponification by treatment with sodium hydroxide followed by adjusting the pH of the reaction mass with a mineral acid between 3 to 4 at a temperature of -5 to -80C to obtain Rosuvastatin acid;
c) converting the Rosuvastatin acid in situ into ter. butylamine salt by treating with ter. butylamine to isolate Rosuvastatin Tert-Butyl Amine Salt;
d) optionally purifying the Rosuvastatin Tert-Butyl Amine Salt and
e) Treating the Rosuvastatin Tert-Butyl Amine Salt with calcium chloride solution in presence of sodium hydroxide to isolate amorphous Rosuvastatin calcium hydrate with high purity.

The process of the present invention is represented below in scheme I.
Scheme I

Accordingly, hydrolysis/deprotection of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate is carried out in presence hydrochloric acid in acetonitrile to obtain the rosuvastatin ester which is saponified in situ with sodium hydroxide followed by pH adjustment between 3 to 4 at a temperature of -5 to -80C to obtain Rosuvastatin acid. Rosuvastatin acid thus obtained is further reacted in situ with tert. Butyl amine to obtain tert. Butyl amine salt of Rosuvastatin, i.e., 2-methylpropan-2-amine (3R, 5S, E)-7-(4-(4-fluorophenyl)-6-isopropyl-2- (N-methyl methyl sulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate.

The tert. butylamine salt of Rosuvastatin, i.e., 2-methylpropan-2-amine (3R,5S,E)-7-(4- (4-fluorophenyl)-6-isopropyl-2- (N-methyl methyl sulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate salt thus obtained is directly converted into Rosuvastatin calcium salt by treatment with calcium chloride in purified water in presence of Sodium hydroxide to obtain amorphous Rosuvastatin calcium hydrate.
In another embodiment, Rosuvastatin Tert-Butyl Amine Salt thus obtained is optionally subjected to purification process which comprises:
a) treating the Rosuvastatin Tert-Butyl Amine Salt with ethyl acetate and methanol in 2:1 ratio at a temperature of 60-800C under stirring to achieve clear solution followed by distillation of the solvent mixture at the same temperature;
b) Stripping the reaction mass with additional ethyl acetate at the same temperature followed by cooling the reaction mass to 25-300C under stirring to isolate the Rosuvastatin Tert-Butyl Amine Salt with HPLC purity more than 99.80 %.

According to this embodiment, the tert. Butyl amine salt of Rosuvastatin is subjected to purification, wherein, tert. Butyl amine salt of Rosuvastatin is dissolved in ethyl acetate and methanol at 25-300C and the reaction mass is stirred at a temperature of 65-700C to get clear solution. The ethyl acetate and methanol mixture is distilled atmospherically at 65-700C, followed by stripping the reaction mass with ethyl acetate. The reaction mass is cooled to 25-300C, stirred and filtered the solid & washed with ethyl acetate and dried the product at 40-450C for 5-6 hrs. till water content is below 1.00%.

The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.

Examples
Example 1
Preparation of Rosuvastatin Tert-Butyl Amine Salt
Charged tert-butyl 2-((4R, 6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl) vinyl)-2, 2-dimethyl-1, 3-dioxan-4-yl) acetate (100.00 gm.) in acetonitrile (1000.00 ml) at 25-300C and stirred the reaction mass for 10 min. at 25-300C. Slowly charged previously prepared hydrochloric acid solution in 45-60 min (0.02M, 200.0 ML) at 25-300C. At this temperature, the reaction mass will get clear. Cooled reaction mass to 22-270C, stirred and maintained the reaction mass until the completion of the reaction, (tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-1, 3-dioxan-4-yl)acetate NMT: 1.00 % by HPLC), slowly added sodium hydroxide solution (1.125M, 200.0ml) to reaction mass at 20-250C; maintained the reaction mass at 20-250C. until the completion of reaction, ((3R,5S,E)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate ester content NMT: 1.00 % by HPLC), chilled the reaction mass to -5 to -80C, slowly added the hydrochloric acid solution to adjust the pH 3.5 - 4.0 at the same temperature. Stirred the reaction mass for 15 min at -5 to -80C; charged Sodium Chloride 50.00 gm at -5 to -80C; stirred the reaction mass for 15 min at -5 to -80C. The reaction mass was allowed to settle for 15-20 min at -5 to 00C. Layers were separated and charged organic layer in a separate flask; slowly added Tert. Butyl amine (20.00 gm) at 5 to 150C. After the addition, the temperature of the reaction mass was raised to 20-250C; stirred & maintained reaction mass for 60 min at 20-250C. The temperature of the reaction mass was raised to 30-350C and distilled out acetonitrile completely under vacuum below 450C; degassed the reaction mass under vacuum below 450C. Charged mixture of acetonitrile 450.00 ml, Ethyl acetate 40.0 ml and Methanol 10.0 ml to the degassed reaction mass below 450C; raised the temperature of reaction mass to 55-600C; stirred the reaction mass for 30 min at 55-600C; cooled the reaction mass at 25-300C; stirred the reaction mass for 60 min at 25-300C; filtered the solid & washed with acetonitrile 100.0 ml at 25-300C to obtain wet material of Rosuvastatin Tert-Butyl Amine Salt i.e., (2-methylpropan-2-amine (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3,5-dihydroxy hept-6-enoate).
Yield: 65-70 gm. (78%)
HPLC purity: 99.65%.
Example 2
Purification of Rosuvastatin Tert-Butyl Amine Salt
Charged wet material of Rosuvastatin Ter. butyl amine salt to ethyl acetate (600.0 ml) in RBF at 25-300C; charged Methanol (300.0 ml) at 25 to 300C. The reaction temperature was raised to 65-700C; stirred the reaction mass for 5 min and checked clarity of reaction mass at 65-700C. Distilled out the ethyl acetate and methanol mixture atmospherically at 65-700C (Approx. 3.00 to 3.25Times of batch size to be distilled). Added ethyl acetate 300.0 ml to the reaction mass for stripping and again distilled out Ethyl acetate and methanol mixture atmospherically at 65-700C (Approx. 1.50 to 2.00Times of batch size to be distilled). Total distillation was about 450.0-500.0 ml. Heating was removed and allowed to cool reaction mass to 25-300C. Stirred the reaction mass for 1 hr at 25-300C; filtered the solid & washed with Ethyl acetate 100.0 ml at 25-300C. Dried the product under vacuum at 40-450C for 5-6 hrs. till water content is below 1.00%. Dry wt of Rosuvastatin Tert-Butyl Amine Salt or 2-methylpropan-2-amine (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate 65-70 gm. (Yield 72.0% w/w) and purity by HPLC 99.80%.

Example 3
Preparation of Rosuvastatin calcium hydrate amorphous
Charged Purified Water 455.0 ml in RBF at 25-30°C. Charged Rosuvastatin Tert-Butyl Amine Salt or 2-methylpropan-2-amine (3R, 5S, E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (65.00 mgs) under stirring at 25-30°C. Stirred the reaction mass for 5-10 min at 25-30°C; charged slowly sodium hydroxide solution (9.5%w/w aqueous solution 52.00 ml) at 25-30°C, stirred and maintained until clear reaction mass achieved. The reaction mass concentrated under vacuum at 35-40°C for removal of the traces of Tert. Butyl amine.

Meanwhile prepared CaCl2.2H2O solution by dissolving 16.0 gms Calcium Chloride Dihydrate in 65.00 ml purified water. Filtered the solution through hyflow bed & then 0.4 µ filter; washed the bed with purified water 65.00 ml. After distillation, charged purified water 162.50 ml in reaction mass for volume make up at 35-40°C. The reaction mass was filtered through hyflow bed and then 0.4 µ filters and washed the bed with purified water 130.0 ml at 25-30°C.

Slowly added above prepared Calcium Chloride Dihydrate solution to the reaction mass in 20-25 min at 25-30°C; stirred and maintained reaction mass for 90-120 min at 25-30°C. Filtered the reaction mass at 25-30°C. Prepared slurry in purified water 162.50 ml x 2 times at 25-30°C and filtered and dried the material obtained at 40-45°C till Moisture content below 6.00 %.
Dry wt of Rosuvastatin Calcium hydrate 50-52.0 gm (Yield 80.0% w/w) and HPLC purity 99.80%.

Rosuvastatin Calcium hydrate thus obtained was subjected to XRD and found that it is in amorphous form.