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
"A PROCESS FOR THE PREPARATION OF ROSUVASTATIN CALCIUM"
Ennltcc Labs Pvt. Ltd. an Indian Company, having it.s Registered Office at 17lhFloor, 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.

A PROCESS FOR THE PREPARATION OF ROSUVASTATIN CALCIUM FIELD OF THE INVENTION:
The present invention provides a process for the preparation of rosuvastatin calcium comprising reacting compound of structural formula V with a compound of structural formula III to get a compound of structural formula IV and then converting a compound of structural formula IV into rosuvastatin calcium compound of structural formula I.
BACKGROUND OF THE INVENTION:
The chemical name of 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 structural formula I.

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 dysbetalipoproteinemia (type III hyperlipoproteinema); homozygous familial hypercholesterolemia; slowing of the progression of atherosclerosis and primary prevention of cardiovascular disease.
U.S. Patent No. 5,260,440 discloses a process for the preparation of rosuvastatin calcium by
condensation of methyl (3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-6-
triphenylphosphoranylidene hexanoate with 4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl- N-methylsulfonylamino)- 5-pyrimidinecarboxaldehyde, followed by deprotection of the 3-hydroxy group, asymmetric reduction of the 5-oxo group; hydrolysis and salt formation with calcium chloride in aqueous solvent.
U.S. Patent No. 6,784,171 discloses a process for the preparation of rosuvastatin calcium via the manufacture of tert-butyl (E)-(6-{2-[4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl] vinyl) (4R, 6S)-2, 2-dimethyl [1, 3] dioxan-4-yl) acetate of structural formula VII, wherein compound of structural formula VII is being obtained by reaction of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yl methyl] phosphine oxide of structural formula V with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-1.3-dioxan-4-yl] acetate of structural formula VI in the presence of a strong base.

U.S. Patent No. 7, 312, 329 discloses a process for the preparation of pyrimidine derivatives comprising reacting Wittig reagent of the general formula VIII


wherein R is an alkyl of from 1 to 10 carbon atoms, aryl or arylalkyl, R1 is a substituted or unsubstituted hydrocarbon group, R2 and R3 are the same or different and are hydrogen or a substituted or unsubstituted hydrocarbon group; Z is sulfur, oxygen, sulfonyl, or imino which may be substituted by formyl, acetyl, propionyl, butyryi, isobutyryl, valeryl, isovaleryl, amino substituted by sulfonyl or alkylsulfonyl, and sulfonyl substituted by alkyl, amino or alkylamino and X is a halogen; with an aldehyde compound of the structural formula IX

wherein R4 is hydrogen, a lower alkyl or a cation capable of forming a non-toxic pharmaceutically acceptable salt and each R5 are the same or different and are hydrogen or a hydrolyzable protecting group, or each R , together with the oxygen atom to which each is bonded, form a hydrolyzable cyclic protecting group, or each R5 is bonded to the same substituent which is bonded to each oxygen atom to form a hydrolyzable protecting group; in the presence of a base to provide a pyrimidine derivative of structural formula X

wherein R, R1, R2, R3, R4, R5 X and Z have the afore stated meanings or a racemic mixture, an enantiomer, a diastereoisomer or a mixture thereof.

The disadvantages of the prior art methods for preparing rosuvastatin calcium include multiple steps resulting in difficult preparations, the use of expensive reagents, reagents that are difficult to use on a commercial scale, the use of low temperatures that make the process more difficult to perform, and time consuming and expensive techniques for purification.
Accordingly, there remains a need for a new process for the preparation of rosuvastatin calcium that eliminates and reduces the problems of the prior art on a commercial scale in a convenient and cost efficient manner,
SUMMARY OF THE INVENTION:
A first aspect of the present invention is to provide a process for preparing rosuvastatin calcium compound of structural formula 1 comprising the steps of:
a. reacting compound of structural formula V with a compound of structural formula III to get a compound of structural formula IV and

wherein P1 is an ester protecting group b. converting a compound of structural formula IV into rosuvastatin calcium compound of structural formula I.


A second aspect of the present invention is to provide a process for preparing compound of structural formula V comprising the steps of:
a. reacting compound of structural formula II with reducing agent to get a compound of structural formula XI;

wherein P2 is an aryl or an arylalkyl group b. reacting compound of structural formula XI with a halogenating agent to get a compound of structural formula XII and


wherein X is a halogen atom c. reacting a compound of structural formula XII with an alkyldiarylphosphinite to get a compound of structural formula V
A third aspect of the present invention is to provide a process for preparing rosuvastatin calcium compound of structural formula I comprising the steps of:
a. reacting compound of structural formula XIII with a compound of structural formula III to get a compound of structural formula IV and

wherein R is an alkyl, aryl or arylalkyl group and P1 is an ester protecting group b. converting a compound of structural formula IV into rosuvastatin calcium compound of structural formula I.


DETAIL DESCRIPTION OF THE INVENTION:
The carboxylate group of the compound of structural formula II is converted into the alcohol group of compound of structural formula XI by reduction in an appropriate inactive solvent such as tetrahydrofuran, diethyl ether or toluene in the presence of reductant sodium borohydride. sodium triacetoxyborohydride, lithium aluminiumhydride or diisobutylaluminium hydride (DIBAL-H). The reaction is performed at -50°C to 60°C for a period of 30 minutes to 8 hours.
The example of compound of structural formula II may include benzyl 4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonarnido) pyrimidine-5-carboxylate compound of structural formula XV.

The compound of structural formula XI is isolated by quenching the reaction mixture with acetic acid and then resulting reaction mixture is extracted with ether solvent. The organic layer is washed with sodium bicarbonate solution and water and then it is concentrated under reduced pressure at 25-50°C to get compound of structural formula XI.
The examples of ether solvents may include but not limited to diethyl ether, diisopropyl ether, dibutyl ether, methyl tertiary butyl ether or methyl ethyl ether.
The halogenations of the compound of structural formula XI may be carried out by treating compound of structural formula XI with halogenating agent in an inert, preferably halogenated.

solvent, e.g. carbon tetrachloride, chloroform, dichloromethane, chlorobenzene or dichlorobenzene, or also HMPT at a temperature in the range of -5°C to 25°C to get compound of structural formula XII.
The example of halogenating agent may include but not limited to SOCI2, PCI5, PCI3, or PBr3.
The example of compound of structural formula XII may include N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpynmidin-2-yl)-N-methylmethanesulfonamide compound of structural formula XVI.

The reaction of compound of structural formula XII with an alkyldiarylphosphinite can be carried out by methods generally customary for the preparation of compounds substituted by phosphorus derivatives in an inert, preferably hydrocarbon-containing, solvent such as toluene or in a halogenated solvent such as carbon tetrachloride, chloroform, chlorobenzene or dichlorobenzene. The reaction with the alkyldiarylphosphinite is generally carried out at a temperature in the range from 20°C to 100°C (in the case of ethyl diphenyl phosphinite in the range from 40°C to 80°C) to get compound of structural formula V.
The alkyldiarylphosphinite preferably used in the above reaction are, for example, a C1-C6 alkyl diphenyl phosphinite, e.g. methyl diphenyl phosphinite, ethyl diphenyl phosphinite, propyl diphenyl phosphinite, butyl diphenyl phosphinite, pentyl diphenyl phosphinite or hexyl diphenyl phosphinite.

The reaction of a compound of structural formula V with a compound of structural formula III may be carried out in the presence of inorganic base in an aprotic solvent at a temperature in the range of -30°C to 80°C for a period of 30 minutes to 5 hours to get a compound of structural formula IV.
The example of compound of structural formula III may include (3R, 5S)-tert-butyl 3. 5-dihydroxy-6-oxohexanoate compound of structural formula XVII.

The examples of an inorganic base may include but not limited to sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide or lithium carbonate.
The examples of aprotic solvents may include but not limited to dimethylsulfoxide, dimethylformamide, dimethylacetamide or mixture(s) thereof.
The compound of structural formula IV may be isolated by diluting the reaction mixture with an aromatic hydrocarbon solvent, followed by the washing of an organic layer with water and concentrating under reduced pressure to get compound of structural formula IV.
The examples of aromatic hydrocarbon solvents may include but not limited to toluene, xylene, cresol or mixture(s) thereof.
The example of compound of structural formula IV may include (3R, 5S, E)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3, 5-dihydroxyhept-6-enoate compound of structural formula XIV


The compound of structural formula IV may be converted into rosuvastatin calcium compound of structural formula I by methods known in the art such as those described in U.S Patent nos. 6,784,171; 6,875,867; 7,232,920 or 7,312,329 and U.S Patent publication no 20070155765; 20070255060; 2008207903 or 2010056783, which are incorporated herein by reference only.
The compound of structural formula XIII is prepared by following the teaching described in PCT publication no. 2004/103977. which is incorporated herein by reference only.
The compound of structural formula IV is also prepared by reacting compound of structural formula XIII with a compound of structural formula III.
The reaction of a compound of structural formula X1I1 with a compound of structural formula III may be carried out in the presence of inorganic base in an aprotic solvent at a temperature in the range of -30°C to 80°C for a period of 30 minutes to 5 hours to get a compound of structural formula IV.

EXAMPLE:
In the following example, the preferred embodiments 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: Preparation of (3R, 5S, E)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido) pyrimidin-5-yl)-3, 5-dihydroxyhept-6-enoate compound of structural formula XIV.
Stage 1: Preparation of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-
mefhylmethanesulfonamide compound of structural formula XI.
A solution of benzyl 4-(4-f]uorophenyl)-6-isopropy]-2-(N-methylmethylsulfonamido)
pyrimidine-5-carboxylate compound of structural formula XV (50gm) in toluene (750ml) was
added dropwise at -10°C a solution of DIBAL-H (1M in toluene, 500ml) and the resulting
reaction mixture was stirred for 1 hour. The reaction mixture was quenched with acetic acid (5%.
50ml) and the resulting reaction mixture was extract with diethyl ether (500ml) and washed with
sodium bicarbonate solution (5%, 50ml) and then with water (50ml). The resulting organic layer
was concentrated under reduced pressure at 40-45°C to get title compound.
Yield: 38.6gm
Purity: 99.8% (By HPLC)
Stage 2: Preparation of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-
methylmethanesulfonamide compound of structural formula XVI.
A solution of N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-
methylmethanesulfonamide compound of structural formula XI (30gm) in dichloromethane
(350ml) was added phosphorus tribromide (11.8gm) and the resulting reaction mixture was
stirred for 1 hour at room temperature. The reaction mixture was then added water 300ml and the
organic layer was separated and dried over sodium sulfate (15gm). The salt mixture was filtered
and filtrate was concentrated under reduced pressure to get title compound.
Yield: 35.3gm
Purity: 99.7% (By HPLC)

Stage 3: Preparation of N-(5-((diphenylphosphoryl) methyl)-4-(4-fluorophenyl)-6-
isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide compound of structural formula V.
A solution of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-
methylmethanesulfonamide compound of structural formula XVI (30gm) in toluene (700ml) was
added ethyl diphenyl phosphinite (24.5gm) and the reaction mixture was stirred at 60°C for 3
hours and then concentrated to get residue. The residue was dissolved in toluene (60ml) and
hexane (60ml) are added, the product precipitating out in the form of colorless powder, which
was filtered off.
Yield: 38.7gm
Purity: 99.9% (By HPLC)
Stage 4: Preparation of (3R, 5S, E)-tert-butyl 7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-
methylmet'hylsulfonamido) pyrimidin-5-yl)-3, 5-dihydroxyhept-6-enoate compound of structural
formula XIV.
A solution of N-(5-((diphenylphosphoryl) methyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-
yl)-N-methylmethanesulfonamide compound of structural formula V (25gm) in dimethyl
sulfoxide (250ml) was added potassium carbonate (15gm), and (3R,5S)-tert-butyl 3,5-dihydroxy-
6-oxohexanoate compound of structural formula XVII (10.5gm) at 30°C under stirring. The
resulting reaction mixture was agitated at 70°C to 75°C for 2 hours and then reaction mixture
was cooled to 25°C and diluted with toluene (300ml). The resulting reaction mixture was filtered
and filtrate was washed with water (200ml), concentrated under reduced pressure to get title
compound.
Yield: 24.5gm
Purity: 99.8% (By HPLC)

WE CLAIM:
1. A process for preparing rosuvastatin calcium compound of structural formula I comprising the steps of:
a. reacting compound of structural formula V with a compound of structural formula III to get a compound of structural formula IV and

wherein P is an ester protecting group b. converting a compound of structural formula IV into rosuvastatin calcium compound of structural formula 1.

2. A process for preparing compound of structural formula V comprising the steps of:
a. reacting compound of structural formula II with reducing agent to get a compound of structural formula XI;


wherein P2 is an aryl or an arylalkyl group b. reacting compound of structural formula XI with a halogenating agent to get a compound of structural formula XII and

wherein X is a halogen atom c. reacting a compound of structural formula XII with an alkyldiarylphosphinite to get a compound of structural formula V
3. A process for preparing rosuvastatin calcium compound of structural formula I comprising the steps of.
a. reacting compound of structural formula XIII with a compound of structural formula III to get a compound of structural formula IV and


wherein R6 is an alkyl, aryl or arylalkyl group and P1 is an ester protecting group b. converting a compound of structural formula IV into rosuvastatin calcium compound of structural formula I.

4. The process according to claim no. 1, wherein reaction of a compound of structural formula V with a compound of structural formula III is carried out in the presence of inorganic base in an aprotic solvent at a temperature in the range of -30°C to 80°C for a period of 30 minutes to 5 hours to get a compound of structural formula IV.
5. The process according to claim no. 4, wherein aprotic solvents is selected from the group comprising of dimethylsulfoxide, dimethylformamide, dimethylacetamide or mixture(s) thereof.

6. The process according to claim no. 2. wherein reducing agent is selected from the group comprising of sodium borohydride, sodium triacetoxyborohydride, lithium aiuminiumhydride or diisobutylaluminium hydride (DIBAL-H).
7. The process according to claim no. 2, wherein halogenating agent is selected from the group comprising of SOCI2, PC1S, PC13, or PBr3.
8. The process according to claim no. 2, wherein alkyldiarylphosphinite is selected from the group comprising of methyl diphenyl phosphinite. ethyl diphenyl phosphinite, propyl diphenyl phosphinite, butyl diphenyl phosphinite, pentyl diphenyl phosphinite or hexyl diphenyl phosphinite.
9. The process according to claim no. 3 wherein reaction of a compound of structural formula XIII with a compound of structural formula III is carried out in the presence of inorganic base in an aprotic solvent at a temperature in the range of -30°C to 80°C for a period of 30 minutes to 5 hours to get a compound of structural formula IV.
10. The process according to claim nos. 4 and 9, wherein examples of an inorganic base is
selected from the group comprising of sodium carbonate, potassium carbonate, sodium
hydroxide, potassium hydroxide, sodium bicarbonate, potassium bicarbonate, lithium hydroxide
or lithium carbonate.