FORM 2
THE PATENT ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"NOVEL 4-CHLOROBENZHYDRYLAMrNE SALT OF ROSUVASTATIN AND PROCESS FOR THE PREPARATION OF SAME"
Enaltee Labs Pvt Ltd. an Indian Company, having its Registered Office at 17 Floor, Kesar Solitaire, Plot No.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, India. Pin Code: 400705
1. The following specification particularly describes the invention and the manner in which it is to be performed.

NOVEL 4-CHLOROBENZHYDRYLAMINE SALT OF ROSUVASTATIN AND PROCESS FOR THE PREPARATION OF SAME
FIELD OF THE INVENTION
The present invention relates to novel 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I as well as processes for their manufacture.

Formula 1
BACKGROUND OF THE INVENTION
Chemically rosuvastatin calcium is bis [(E)-7-[4(4-fluorophenyl)-6-isopropyl-2-[N-methyl (methylsulfonyl) amino] pyrimidin-5-yl] (3R, 5S) -3, 5- dihydroxyhept-6-enoic acid] calcium salt and is known from U.S. Patent No. 5,260,440 and is represented by compound of structural formula II.


Rosuvastatin calcium is commercially available under the brand name of CRESTOR in USA and is marketed by Astrazeneca.
Rosuvastatin calcium is indicated and usage for hyperlipidemia; mixed dyslipidemia; hypertriglyceridemia; primary dysbetaJipoproteinemia (type III hyperlipoproteinema); homozygous familial hypercholesterolemia; slowing of the progression of atherosclerosis and primary prevention of cardiovascular disease.
U.S. Patent No. 6,841,554 ("the '554 patent") discloses pharmaceutical composition comprising a crystalline salt of the compound (E)-7-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl(methyfsulfonyl)ammo]pyrim idin-5-yl]-(3R,5S)-3,5-dihydroxyhept-6-enoic acid, wherein the salt is an ammonium, methylammonium, ethyl ammonium, diethanolammonium, tris(hydroxymethyl)methylammonium, benzylammonium, 4-methoxybenzylammonium, lithium or magnesium salt.
PCT Publication No. 2005/077916 discloses amine salts of rosuvastatin compound of structural formula III, which can be useful as intermediates in the preparation of pharmacologically acceptable salts of rosuvastatin such as rosuvastatin calcium or rosuvastatin magnesium.


Wherein independently R1, R2 and R3 are H, straight or branched chain C1-15 alkyl or
hydroxyalkyl, C3-10 single or fused ring optionally substituted cycloalkyl, optionally
substituted aryl, optionally substituted aralkyl, alkyl cycloalkyl, or independently R1, R2
and R3 can combine with each other to form a C3-7 membered cycloalkyl ring or
heterocyclic residue containing one or more heteroatoms (selected from S, N or 0), with
the proviso that the amine is not selected from ammonia, methylamine, ethylamine,
diethanol amine, tri(hydroxymethyl)-methylamine, benzylamine, or 4-
methoxybenzylamine. Rosuvastatin cyclohexyl ammonium, rosuvastatin diisopropyl ammonium, rosuvastatin isopropyl ammonium, rosuvastatin dicyclohexyl ammonium and rosuvastatin (S)-(+)-methylbenzyl ammonium salts are being specifically prepared.
The rosuvastatin calcium exist in crystalline as well as in amorphous form and amorphous form of rosuvastatin calcium intended for pharmaceutical use may give rise to manufacturing problems and there is therefore a need to identify alternative salts of rosuvastatin acid compound of structural formula I, which are crystalline, such crystalline salts can generally be purified more easily than an amorphous form and may possess other advantageous properties, for example in relation to their particular crystalline form and/or their solubility characteristics and/or their lack of hygroscopicity and/or their stability characteristics including their thermal stability properties and/or their ability to undergo oxidative degradation.

SUMMARY OF THE INVENTION
A first aspect of the present invention is to provide 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I.

A second aspect of the present invention is to provide a process for preparing substantially pure rosuvastatin calcium compound of structural formula II which comprises the steps of:
a. reacting crude rosuvastatin acid with 4-chlorobenzhydrylamine base to form a 4-
chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula 1
and
b. converting 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of
structural formula I into substantially pure rosuvastatin calcium compound of
structural formula II.
A third aspect of the present invention is to provide a pharmaceutical composition comprising 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I in admixture with a pharmaceutically acceptable diluent or carrier.

A fourth aspect of the present invention is to provide a methods for treating
hyperlipidemia; mixed dyslipidemia; hypertriglyceridemia; primary
dysbetalipoproteinemia (type III hyperlipoproteinema); homozygous familial hypercholesterolemia; slowing of the progression of atherosclerosis and primary prevention of cardiovascular disease comprising administering to a subject in need of treatment thereof a therapeutically effective amount of a 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I.
DETAILED DESCRIPTION OF THE INVENTION
Rosuvastatin acid may be prepared by any methods known in the art including U.S.Patent Nos. 5,260,440; 6,784,171; 6,875,867; 7,312,329; 7,582,759; 7,566,782; 7,179,916 and 7,232,920 which are incorporated herein by reference only.
Crude rosuvastatin acid compound may contain up to 8% w/w of rosuvastatin lactone compound of structural formula IV

The crude rosuvastatin acid may be reacted with 4-chlorobenzhydrylamine base in an organic solvent.
The examples of organic solvents include solvents such as ketones, alcohols, chlorinated hydrocarbons, ethers, alkyl acetate solvents or polar aprotic solvents.
The examples of ketone solvents may include but not limited to acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone or mixture(s) thereof.

The examples of alcohol solvents may include but not limited to methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol or mixture(s) thereof.
The examples of chlorinated hydrocarbon solvents may include but not limited to methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform or mixture(s) thereof.
The examples of ether solvents may include but not limited to diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether or mixture(s) thereof.
The examples of alkyl acetate solvents may include but not limited to methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or mixture(s) thereof.
The examples of polar aprotic solvents may include but not limited to acetonitrile, dimethyl formamide, dimethyl sulfoxide or mixture(s) thereof.
The crude rosuvastatin acid may be reacted with 4-chlorobenzhydrylamine base at a temperature in the range of 0°C to 80°C for a period of 1 hour to 12 hours to get a 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I.
The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I may be isolated by the addition of nonpolar organic solvent at a temperature in the range of 0°C to 25°C.
The examples of nonpolar organic solvent may include hexane, heptane, pentane, octane or mixture(s) thereof.

The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I may be isolated by the steps of centrifugation, filtration, washing, drying or combination thereof.
The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula 1 may be reacted with calcium hydroxide to get substantially pure rosuvastatin calcium compound of structural formula II in one step.
The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I may be reacted with an acid to get substantially pure rosuvastatin acid compound of structural formula I, which may be further reacted with a source of calcium to get substantially pure rosuvastatin calcium compound of structural formula II.
Examples of an acid may include hydrochloric acid, hydrobromic acid or acetic acid.
Examples of source of calcium may include calcium chloride, calcium carbonate or calcium hydroxide.
The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I may be reacted with calcium hydroxide at a temperature in the range of 10°C to 50°C in an organic solvent selected from the group comprising of ketones, alcohols or alkyl acetate solvents.
The examples of ketones, alcohols or alkyl acetate solvents are described above.
The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I may be reacted with calcium hydroxide for a period of 30 minutes to 6 hours.
The 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I may be reacted with an acid at a temperature in the range of 0°C to 30°for a period of 30 minutes to 2 hours.

The word " substantially pure rosuvastatin calcium compound of structural formula II" refers to rosuvastatin calcium compound contain less than 0.50% weight/weight of rosuvastatin lactone compound of structural formula IV.
The word "substantially pure rosuvastatin acid compound of structural formula I" refers to rosuvastatin acid compound contain less than 0.50% weight/weight of rosuvastatin lactone compound of structural formula IV.
The substantially pure rosuvastatin calcium compound of structural formula II may be isolated by the steps of centrifugation, filtration, washing, drying or combination thereof.
The substantially pure rosuvastatin calcium compound of structural formula II may be crystalline or amorphous in nature.
The substantially pure rosuvastatin calcium compound of structural formula II may be dried at a temperature in the range of 45°C to 80°C under reduced pressure.
The substantially pure rosuvastatin calcium compound of structural formula II may be dried for a period of 12 hours to 18 hours.
The substantially pure rosuvastatin calcium compound of structural formula II may contain moisture content in the range of 0.25% weight/ weight to 5% weight/ weight.
In the following example, the preferred aspects of the present invention are described only by way of illustrating the process of the invention. However, these are not intended to limit the scope of the present invention in any way.

EXAMPLE 1: PRPARATION OF SUBSTANTIALLY PURE ROSUVASTATIN CALCIUM COMPOUND OF STRUCTURAL FORMULA II
Step 1; Preparation of 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I.
A solution of crude rosuvastatin acid (10 gm) in acetonitrile (100 ml) was added a solution of 4-chlorobenzhydrylamine (5 gm) in acetonitrile (15ml) in 1 hour at 0-5°C and then resulting reaction mixture was agitated for 2 hours at 55-60°C. The reaction mixture was cooled to 0°C and then n-hexane (175 ml) was added and then resulting reaction mixture was agitated for 6 hours at 0-5°C and then resulting solids were filtered, washed with acetonitrile (10 ml) and dried at 50°C under reduced pressure to get title compound. Yield: 13 gm; Purity: 99.97% (By HPLC)
Step 2: Conversion of 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I into substantially pure rosuvastatin calcium compound of structural formula II.
A solution of 4-chlorobenzhydrylamine salt of rosuvastatin acid compound of structural formula I (10gm) in ethanol (65 ml) was treated with an aqueous solution of calcium hydroxide (3 gm dissolved in 25 ml water) at 30°C for 5 hours and then resulting solids were filtered and dried at 60°C under reduced pressure to get title compound. Yield: 12 gm; Purity: 99.89% (By HPLC) Rosuvastatin lactone compound of structural formula IV: 0.06% weight/weight

WE CLAIM:
1. A process for preparing substantially pure rosuvastatin calcium which comprises the
steps of:
a. reacting crude rosuvastatin acid with 4-chlorobenzhydrylamine base to form a 4-
chlorobenzhydrylamine salt of rosuvastatin acid and
b. converting 4-chlorobenzhydrylamine salt of rosuvastatin acid into substantially
pure rosuvastatin calcium.
2. The process according to claim 1, wherein crude rosuvastatin acid contain up to 8%
w/w of rosuvastatin lactone compound of structural formula IV

3. The process according to claim 1, wherein crude rosuvastatin acid is reacted with 4-chlorobenzhydrylamine base in an organic solvent selected from the group comprising of such as ketones, alcohols, chlorinated hydrocarbons, ethers, alkyl acetate solvents or polar aprotic solvents.
4. The process according to claim 1, wherein ketone solvents include acetone, methyl ethyl ketone, methyl isobutyl ketone, diethyl ketone, dipropyl ketone or mixture(s) thereof; alcohol solvents include methanol, ethanol, n-propanol, isopropanol, n-butanol. isobutanol or mixture(s) thereof; chlorinated hydrocarbon solvents include methylene chloride, ethylene dichloride, carbon tetrachloride, chloroform or mixture(s) thereof; ether solvents include diethyl ether, methyl tertiary butyl ether, dioxane, tetrahydrofuran, 2-methyl tetrahydrofuran, diisopropyl ether or mixture(s) thereof; alkyl acetate solvents include methyl acetate, ethyl acetate, propyl acetate, butyl acetate, isobutyl acetate or

mixture(s) thereof and polar aprotic solvents include acetonitrile, dimethyl formamide. dimethyl sulfoxide or mixture(s) thereof.
5. The process according to claim ls wherein crude rosuvastatin acid is reacted with 4-chlorobenzhydrylamine base at a temperature in the range of 0° to 80°C for a period of 1 hour to 12 hours to get a 4-chlorobenzhydrylamine salt of rosuvastatin acid.
6. The process according to claim 1, wherein 4-chlorobenzhydrylamine salt of rosuvastatin acid is isolated by the addition of nonpolar organic solvent at a temperature in the range of 0°C to 25°C.
7. The process according to claim 6, wherein nonpolar organic solvent is selected from the group comprising of hexane, heptane, pentane, octane or mixture(s) thereof.
8. The process according to claim 1. wherein 4-chlorobenzhydrylamine salt of rosuvastatin acid is reacted with calcium hydroxide to get substantially pure rosuvastatin calcium.
9. The process according to claim 8, wherein substantially pure rosuvastatin calcium contain less than 0.50% weight/weight of rosuvastatin lactone compound of structural
formula IV.
10. A process for the preparation of substantially pure rosuvastatin calcium as herein
described in specification and example.