FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
THE PATENTS RULE, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
Title of the invention
"A novel processes for the preparation of rosuvastatin calcium"
Enaltcc Labs Pvt Ltd. an Indian Company, having its Registered Office at 17th floor, Kesar Solitaire, PlotNo.5 Sector-19, Sanpada, Navi Mumbai Maharashtra, Pin Code: 400705 India.
1. The following complete specification particularly describes and ascertains the nature of this invention and the manner in which it is to be performed.

A novel processes for the preparation of rosuvastatin calcium
Field of the invention
The present invention relates to novel processes for the preparation of HMG-CoA reductase inhibitors such as atorvastatin; cerivastatin; fluvastatin; pravastatin and rosuvastatin. The processes comprises the converting a compound of structural formula I into a compound of structural formula II.

Wherein denotes single or double bond and R1 is a residue of an HMG-CoA reductase inhibitor selected from any one of the compound of structural formula-a to structural formula-e,

and R2 is a residue of an HMG-CoA reductase inhibitor selected from any one of the compound of structural formula-f to structural formula-j.


Wherein P1 and P2 are H or alcohol protecting groups or P1 and P2 taken together to form a 1, 3-diol protecting group.
Wherein M is H or carboxylic protecting group or metal atoms like Na+, K+, Mg+2 or Ca+2.
Wherein X is a nitro group or a group which is capable of converting into fluorine atom.
Background of the invention
The HMG-CoA reductase inhibitors are a class of drug used to lower plasma cholesterol level. They lower cholesterol by inhibiting the enzyme HMG-CoA reductase, which is the rate-limiting enzyme of the mevalonate pathway of cholesterol synthesis. Inhibition of this enzyme in the liver results in decreased cholesterol synthesis as well as increased synthesis of LDL receptors, resulting in an increased clearance of low-density lipoprotein (LDL) from the bloodstream. Examples of such HMG-CoA reductase inhibitors include atorvastatin; cerivastatin; fluvastatin; pitavastatm and rosuvastatin.
The chemical name of atorvastatin is [R-(R*, R*)]-2-(4-fluorophenyl)-p, 5-dihydroxy-5-(l-methylethyl)-3-phenyl-4-[(phenylamino)carbonyl]-lH-pyrrole-l-heptanoic acid, calcium salt (2:1) trihydrate and is known form U.S. Patent No. 5,273,995 and is represented by structural formula III.


The chemical name of cerivastatin is sodium [S-[R*, S*-(E)]]-7-[4-(4-fluorophenyl)-5-methoxymethyl)-2, 6 bis (l-methylefhyl)-3-pyridinyl]-3, 5-dihydroxy-6-heptenoate and is known form U.S. Patent No. 5,177,080 and is represented by structural formula IV.

The chemical name of pitavastatin is (+) monocalcium bis {(3R, 5S, 6E)-7-[2-cyclopropyl-4-(4-fluorophenyl)-3-quinolyl]-3, 5-dihydroxy-6-heptenoate} and is known form U.S. Patent No. 5,856,336 and is represented by structural formula V.

The chemical name of fluvastatin is [R*, S*-(E)]-(±)-7-[3-(4-fluorophenyl)-l-(l-methylethyl)-lH-indol-2-yl]-3, 5-dihydroxy-6-heptenoic acid monosodium salt and is known form U.S. Patent No. 5,354,772 and is represented by structural formula VI.


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 VII.

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-methyI- 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 VIII, wherein compound of structural formula VIII is being obtained by reaction of diphenyl [4-(4-fluorophenyl)-6-isopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5-yI methyl] phosphine oxide of structural formula IX with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate of structural formula X in the presence of a strong base.

Summary of the invention
A first aspect of the present invention is to provide a process for the preparation of HMG-CoA reductase inhibitors such as atorvastatin; cerivastatin; fluvastatin; pitavastatin and rosuvastatin comprising the use of a compound of structural formula I.

Wherein R1, P1, P2 and M are as defined above.
A second aspect of the present invention is to provide a compound of structural formula I.
A third aspect of the present invention is to provide processes for preparing a compound of structural formula I.
A fourth aspect of the present invention is to provide processes for preparing rosuvastatin calcium comprising the use of a compound of structural formula XI.


A fifth aspect of the present invention is to provide a compound of formula XII and the processes for preparing rosuvastatin calcium comprising the use of a compound of structural formula XII.

Wherein P1, P2, M and X are as defined above.
A sixth aspect of the present invention is to provide processes for the preparation of a compound
of structural formula XII.
A seventh aspect of the present invention is to provide a novel intermediate compounds of structural formula XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX and their uses in a process of preparing rosuvastatin calcium compound of structural formula VII.

A eighth aspect of the present invention is to provide processes for preparing novel intermediate compounds of structural formula XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX.
A further aspect of the present invention is to provide a novel intermediates of structural formula XXI and XXII and their uses in the processes of preparing rosuvastatin calcium compound of structural formula VII.

Wherein R is the same or different and may be an alkyl group of I to 10 carbon atoms, aryl or an arylalkyl; Y is a halogen and X is a nitro group or a group capable of converting into a fluorine atom.
A further aspect of the present invention is to provide novel intermediates of structural formula XXIV, XXV, XXVI, XXVII, XXVIII, XXIX and XXX and processes of their preparation and

the uses of said intermediates in the processes of preparing rosuvastatin calcium compound of structural formula VII.

Wherein R, P1 and P2 are as defined above and P3 is an alcohol protecting group.
A further aspect of the present invention is to provide novel intermediates of structural formula XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI and XXXVII and processes of their preparation and the use of said intermediates in processes of preparing rosuvastatin calcium compound of structural formula VII.


Wherein X, R, Pi, P2 and P3 are as defined above.
A further aspect of the present invention is to provide novel intermediates of structural formula XXXVIII, XXXIX, XXXX, XXXXI and XXXXII and their uses in processes of preparing rosuvastatin calcium compound of structural formula VII.


Wherein Z is a group, which can be transformed into N-methyl (methylsulfonyl) amino group. X, R, P1, P2 and Y as defined above.
A further aspect of the present invention is to provide a process for the preparation of rosuvastatin calcium comprising the steps of:
a. converting a compound of formula XXXXV into a compound of formula XXXXVI
and

Formula XXXXV Formula XXXVI
b. converting a compound of formula XXXXVI into rosuvastatin calcium compound of formula VII.

wherein N is H, alkyl group of 1 to 10 carbon atoms, aryl or an arylaikyl or carboxylic protecting group or metal atoms like Na+, K+ or Mg+2.
Detailed description of the invention
The compound of structural formula XI may be prepared by the use of following intermediate compounds of structural formula XIII, XIV, XV, XVI, XVII, XVIII, XIX and XX.


The compound of formula XIII may be prepared by reacting isobutyrylacetate ester having structural formula XXIII with 4-nitrobenzaldehyde and urea in the presence of a protonic compound and a metal salt.

Wherein R is as defined above.
Examples of protonic compound include inorganic acid or its salts, organic acid or mixture(s) thereof.
Examples of inorganic acid include hydrochloric acid, sulfuric acid, nitric acid, phosphoric acid or mixture(s) thereof.
Examples of inorganic acid salts include potassium hydrogensulfate, sodium hydrogen sulfate or mixture(s) thereof.

Examples of organic acid include methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, p-bromobenzenesulfonic acid, acetic acid, propionic acid, butyric acid, benzoic acid or mixture(s) thereof.
The protonic compounds may be employed singly or in combination.
The protonic compound can be employed in an amount of, preferably, 0.01 to 5 moles per one mole of the isobutyrylacetate ester.
The metal salt employed in the reaction may be copper(I) chloride, copper(ll) chloride, copper(II) acetate, iron(ll) chloride, iron(III) chloride, aluminum chloride, nickel(II) bromide, tin(IV) chloride, titanium tetrachloride, or magnesium bromide.
The metal salts may contain water of crystallization. The metal salts can be employed singly or in combination.
The metal salt can be employed in an amount of, preferably, 0.001 to 6 moles, per one mol. of the isobutyrylacetate ester.
The 4-nitrobenzaldehyde can be employed in an amount of, 0.5 to 12 moles, per one mol. of the isobutyrylacetate ester.
The urea can be employed in an amount of, preferably, 0.5 to 12 moles, per one mole of the isobutyrylacetate ester compound having structural formula XXIII.
The reaction may be performed in the presence or absence of a solvent.
Examples of the employable solvents include alcohols such as methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butyl alcohol, isobutyl alcohol, sec-butyl alcohol, and t-butyl alcohol; ethers such as diethyl ether, diisopropyl ether, tetrahydrofuran, and dimethoxyethane; nitriles such as acetonitrile, propionitrile, butyronitrile, and isobutyronitrile; halogenated aliphatic hydrocarbons such as dichloromethane, dichloroethane, chloroform, and carbon tetrachloride; aromatic hydrocarbons such as benzene, toluene, and xylene; halogenated aromatic hydrocarbons such as chlorobenzene; and nitrated aromatic hydrocarbons such as nitrobenzene.

The solvents may be employed singly or in combination.
The solvent may be employed in an amount of, preferably 0.1 to 15 liters, per one mole of the isobutyryl acetate ester compound having structural formula XXIII.
The reaction may be conducted by reacting the isobutyryl acetate ester, 4-nitrobenzaldehyde, and urea, in a solvent in the presence of a protonic compound and a metal salt under inert gas atmosphere.
The reaction may be carried out at a temperature in the range of-10°C to 100°C for about 30 minutes to 18 hours.
The resulting product of the reaction, that is, a dihydropyrimidinone compound of the structural formula XIII, may be isolated and purified according to the conventional procedures such as distillation, crystallization, recrystalization, and column chromatography.
The compound of structural formula XIV may be prepared by the oxidation of dihydropyrimidinone compound of structural formula XIII,
The oxidation of dihydropyrimidinone compound of structural formula XIII may be carried out by utilizing nitric acid.
The nitric acid may be employed in an amount of, preferably 1 to 20 mol., per one mole of the dihydropyrimidinone compound of structural formula XIII.
The nitric acid of a concentration of, preferably 40 to 80% may be preferably employed.
The oxidation can be performed in the presence or absence of a solvent. There are no specific limitations with respect to the solvent employed, so far as the solvent does not disturb the desired reaction. Examples of the preferred solvents include carboxylic acids such as acetic acid, propionic acid, and butyric acid. The solvents can be employed singly or in combination.
The solvent can be employed in an amount of, preferably 0.1 to 9 ml, per 1 gm of the dihydropyrimidinone compound of structural formula XIII. The amount may vary depending on

homogeneity and dispersability of the reaction mixture.
The oxidation may be conducted by reacting dihydropyrimidinone compound of structural formula XIII and nitric acid in a solvent under inert gas atmosphere. The oxidation may be carried out at a temperature in the range of-10 to 120°C.
A reaction initiator such as sodium nitrite may be incorporated into the reaction system to accelerate the oxidation rate.
The resulting product of the reaction, that is, the hydroxypyrimidine compound of structural formula XIV may be isolated and purified according to the conventional procedure such as distillation, crystallization, recrystallization, and column chromatography.
The compound of structural formula XVI may be prepared by the protection of alcoholic group of compound of formula XIV by p-toluenesulfonyl chloride in an organic solvent and then reacting resulting reaction product of structural formula XV with N-methyl-N-methane sulfonamide.
The protection of alcoholic group of compound of formula XIV may be carried out in the presence of base.
Examples of base may include but not limited to alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium t-butoxide, potassium t-butoxide, and sodium t-pentoxide; and tertiary amines such as triethylamine, triisopropylamine, diisopropylethylamine, and pyridine. The bases may be employed singly or in combination.
Examples of organic solvents may include but not limited to ketones such as acetone, methyl ethyl ketone, and diethyl ketone; ethers such as diethyl ether and tetrahydrofuran; esters such as ethyl acetate, propyl acetate, and butyl acetate; nitrites such as acetonitrile and propionitrile; amides such as N,N-dimethyIformamide and N-methylpyrrolidone; sulfoxides such as dimethylsulfoxide; ureas such as N,N'-dimethylimidazoIinone. The solvents can be employed

singly or in combination.
The compound of structural formula XVI may be isolated and purified according to the conventional procedures such as distillation, crystallization, recrystallization, and column chromatography.
The compound of structural formula XVII may be obtained by carrying out the reduction of an ester group of structural formula XVI by reducing agent in an organic solvent.
Examples of reducing agent may include diisobutyl aluminum hydride (DIBAL), vitride, sodium borohydride and tetrabutyl ammonium borohydride.
Examples of organic solvent may include but not limited to hexane, toluene, cyclohexane and tetrahydrofuran.
The reduction of ester group of structural formula XVI may be carried out at a temperature in the
rangeof-20°C to 25°C.
The compound of structural formula XVIII may be prepared by reacting compound of structural formula XVII with chlorodiphenyl phosphine in the presence of base.
The compound of structural formula XIX may be prepared by reacting compound of structural formula XVIII with tert-butyl 2-[(4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl] acetate in the presence of strong base.
The reaction of compound of structural formula XVIII with tert-butyl 2-[(4R, 6S)-6-formyl-2, 2-dimethyl-1, 3-dioxan-4-yl] acetate may be carried out in organic solvent such as tetrahydrofuran (THF), dimethoxyethane and toluene, or mixtures thereof.
Examples of strong base may include sodium bis (trimethylsilyl) amide, potassium bis (trimethylsilyl) amide, lithium bis (trimethysilyl) amide, and butyl lithium and sodium hydride.
The compound of formula XX may be prepared by reacting compound of formula XIX with acid in an organic solvent.

Example of acid may include hydrochloric acid.
Examples of organic solvent may include tetrahydrofuran and acetonitrile.
The compound of formula XI may be prepared by the hydrolysis of compound of formula XX.
The hydrolysis of compound of formula XX may be carried out by inorganic base in an organic polar solvent.
Examples of inorganic base may include alkali metal carbonates such as sodium carbonate and potassium carbonate; alkali metal hydrogencarbonates such as sodium hydrogencarbonate; alkali metal hydroxides such as lithium hydroxide, sodium hydroxide and potassium hydroxide; alkali metal alkoxides such as sodium methoxide, sodium t-butoxide, potassium t-butoxide, and sodium t-pentoxide.
Examples of organic polar solvent may include alcoholic solvent and acetonitrile.
Example of alcoholic solvent may include methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof.
The hydrolysis of compound of formula XX may be carried out by calcium hydroxide.
The rosuvastatin calcium may be obtained by reacting compound of formula XI with alkali metal fluoride or alkali earth metal fluoride followed by the reaction of resulting product with a source of calcium ion in an organic solvent.
The rosuvastatin acid may be obtained by reacting compound of formula XI with potassium fluoride or sodium fluoride or cesium fluoride in an organic solvent.
The reaction of a compound of formula XI with potassium fluoride or sodium fluoride or cesium fluoride in an organic solvent may be carried out at temperature in the range of 25°C to 80°C for a period of 2 hours to 16 hours.
The rosuvastatin calcium may be obtained by reducing nitro group of a compound of formula XI to obtain a compound of formula XXXXIII, which is converted into rosuvastatin calcium compound of formula VII by the diazotization reaction and reaction with sodium tetrafluoroborate or HBF4 followed by the salt formation with a source of calcium ion in an organic solvent.


The nitro group of compound of formula XI may be reduced by the reaction of sodium dithionite in the presence of base in an organic solvent.
Example of base may include ammonia.
The compound of formula XXXXIII may be converted into rosuvastatin calcium compound of formula VII by diazotization reaction with sodium nitrite and hydrochloric acid followed by the reaction with sodium tetrafluoroborate or HBF4 in an organic solvent at a temperature in the range of 25°C to 80°C to obtain rosuvastatin acid.
The rosuvastatin acid may be converted into rosuvastatin calcium by reacting rosuvastatin acid with a source of calcium ion in an organic solvent.
Example of source of calcium ion is calcium chloride dihydrate; calcium acetate and calcium hydroxide
Example of organic solvent may include alcoholic solvent, chlorinated hydrocarbons solvent, ethereal solvent.
Examples of alcoholic solvents may include methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof
Examples of ethereal solvents may include tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, methyl ethyl ether or mixture(s) thereof.

Examples of chlorinated hydrocarbons solvent may include dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof.
The rosuvastatin calcium may be isolated by centrifugation, washing, drying or combination thereof. The rosuvastatin calcium obtained by the present invention may be dried under reduced pressure at a temperature in the range of 50°C for 10 hours. The rosuvastatin calcium obtained by the present invention may be amorphous or crystalline in nature.
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 ROSUVASTATIN CALCIUM
Step A: Preparation of methyl 4-isopropyl-6-(4-nitrophenyI)-2-oxo-2, 5-dihydropyrimidine-5-
carboxylate
A solution of methyl isobutyrylacetate (250.3 gm), 4-nitrobenzaldehyde (250 gm), urea (175
gm), copper chloride (2.5 mg) and sulfuric acid (25 ml) in methanol (1500 ml) was stirred at 60-
65°C for 17 hours and then reaction mixture was cooled to 0-5°C, agitated for 2 hours and
resulting solids were filtered and washed with chilled methanol (15 ml) and wash with water (60
ml) to get title compound.
Yield: 187 gm; Purity: 98.89% (By HPLC)
Step B: Preparation of methyl 2-hydroxy-4-isopropyl-6-(4-nitrophenyl) pyrimidine-5-
carboxylate
The step a product (70 gm) was added lot wise into a pre cooled solution of nitric acid (185 ml)
and water (20 ml).The resulting reaction mixture was agitated for 3 hours at 25-30°C. Then
water (495 ml) was added into the reaction mixture at room temperature in 30 minutes and the
pH of resulting solution was adjusted to 6.5 to 7.0 with 25% sodium hydroxide solution and
resulting solution was agitated I hour at 25°C and resulting solids were filtered and washed with
water (350 ml) to get title compound.
Yield: 62 gm; Purity: 98.96 % (By HPLC)
Step C: Preparation of methyl 4-isopropyl-6-(4-nitrophenyl)-2-(tosyloxy) pyrimidine-5-
carboxylate
The solution of step b product (60 gm) in acetone (1200 ml) was added potassium carbonate
(65.25 gm) and then para toluene sulfonyl chloride (43.16 gm) was added lot wise in 20 minutes

at 20-25°C. The resulting reaction mixtures was stirred at 55°C for 3 hours and resulting solids
were filtered and filtrate was concentrated under reduced pressure to get a residue. The residue
was dissolved in dichloromethane, washed with water (2x300ml) and concentrated under
reduced pressure to get a title compound
Yield: 79 gm; Purity: 99.25 % (By HPLC)
Step D: Preparation of methyl 4-isopropyl-2-(N-methylmethylsulfonamido)-6-(4-nitrophenyl)
pyrimidine-5-carboxylate
The solution of step c product (79 gm) in toluene (790 ml) was added N-methyl methane
sulfonamide (44.8 gm) at 30°C and resulting solution was refluxed for 2 hours. The reaction
mixture was cooled to 25°C and then diluted with water (400ml) and stirred for 15 minutes at 25-
30°C. The organic layer was separated and concentrated under reduced pressure to get a residue,
which was recrystallized in 2-propanol to get a title compound.
Yield: 52 gm; Purity: 99.57 % (By HPLC)
Step E: Preparation of N-(5-(hydroxymethyl)-4-isopropyl-6-(4-nitrophenyl) pyrimidin-2-yl)-N-
methylmethanesulfonamide
The solution of step d product (50 gm) in toluene (500 ml) was added diisobutylaluminium
hydride (20% weight in toluene, 260 ml) in 30 minutes at -10°C to -15°C and then the resulting
reaction mixture was stirred at -10°C to -15°C for 15 minutes. The reaction mixture was
quenched with dilute hydrochloric acid (500 ml) and extracted with ethyl acetate (500 ml). The
organic layer was concentrated under reduced pressure to get a title compound.
Yield: 38 gm; Purity: 94.89% (By HPLC)
Step F: Preparation of N-(5-((diphenylphosphoryi) methyl)-4-isopropyl-6-(4-nitrophenyl)
pyrimidin-2-yl)-N-methylmethanesulfonamide
The solution of step e product (40 gm) in toluene (640 ml) was added sodium hydride (60%, 6.35
gm) at 10-15°C and resulting reaction mixture was agitated for 60 minutes at 25-30°C and then
chlorodiphenyl phosphine (26 gm) and sodium iodide (4.4 gm) was added into the reaction
mixture and resulting reaction mixture was agitated at 110°C for 16 hours. The reaction mixture
was quenched with sodium meta bisulphate (30%, 800 ml) and extracted with ethyl acetate (750
ml) and concentrated under reduced pressure to get a residue of title compound.
Yield: 50 gm; Purity: 97.89% (By HPLC)
Step G: Preparation of tert-butyl 2-((4R, 6S)-6-((E)-2-(4-isopropyl-2-(N-methyImethyl
sulfonamido)-6-(4-nitrophenyl) pyrimidin-5-yl) vinyl)-2, 2-dimethyl-l, 3-dioxan-4-yl) acetate

The solution of step f product (50 gm) in dimethyl sulfoxide ( 175 ml) was added tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate (20 gm) and potassium carbonate (16 gm) at 25-30°C and then resulting reaction mixture was agitated for 4 hours at 70°C. The insoluble materials were filtered and filtrate was diluted with toluene (200 ml) and then organic layer was separated and concentrated under reduced pressure to get a residue compound, which was crystallized in methanol (50 ml) and diethyl ether (150 ml) to get a title compound. Yield: 50 gm; Purity: 98,89% (By HPLC) Step H: Preparation of calcium salt of rosuvastatin
The solution of step g product (50 gm) in acetonitrile (500 ml) was added concentrated hydrochloric acid (7 ml in 70 ml water) at 25-30°C and resulting reaction mixture was stirred for 4 hours and then sodium hydroxide solution (5gm dissolved in 50 ml water) was added and resulting reaction mixture was stirred at 30-35°C for 2 hours and then reaction mixture was cooled to 5°C and sodium chloride (20 gm) was added into the reaction mixture. The organic layer was separated and then dimethyl formamide (200 ml) and cesium fluoride (9.6 gm) was added and resulting reaction mixture was stirred for 5 hours at 55-60°C. The reaction mixture was diluted with water, agitated for 30 minutes and then calcium chloride solution (8.5 gm in 100 ml water) was added and resulting reaction mixture was stirred 30 minutes at 40-45°C and then resulting solids were filtered, washed with water and dried under reduced pressure at 45°C Yield: 40 gm; Purity: 99.96% (By HPLC).

WE CLAIM:
1. A process for the preparation of HMG-CoA reductase inhibitors such as atorvastatin; cerivastatin; fluvastatin; pitavastatin and rosuvastatin comprises the converting a compound of structural formula I into a compound of structural formula II.

wherein denotes single or double bond and R1 is a residue of an HMG-CoA reductase inhibitor selected from any one of the compound of structural formula-a to structural formula-e,

and R2 is a residue of an HMG-CoA reductase inhibitor selected from any one of the compound of structural formula-f to structural formula-j.


wherein P1, and P2 are H or alcohol protecting groups or P1 and P2 taken together to form a 1, 3-diol protecting group; M is H or carboxylic protecting group or metal atoms like Na+, K+, Mg+2 or Ca+2 and X is a nitro group or a group which is capable of converting into fluorine atom.
2. A compound of formula 1

wherein R1, P1, P2 and M are as defined above.
3. A novel intermediate compounds of structural formula XII, XHI, XIV, XV, XVI, XVII, XVIII, XIX, XX, XXI, XXII, XXIV, XXV, XXVI, XXVII, XXVIII, XXIX, XXX, XXXI, XXXII, XXXIII, XXXIV, XXXV, XXXVI, XXXVII, XXXVIII, XXXIX, XXXX, XXXXI and XXXXII and their uses in the processes of preparing rosuvastatin calcium.

wherein X, R, P1 and P2 are as defined above and P3 is an alcohol protecting group; Z is a group, which can be transformed into N-methyl (methylsulfonyl) amino group; M is H or carboxylic

protecting group or metal atoms like Na+, K+, Mg+2 or Ca+2; R is the same or different and may be an alkyl group of 1 to 10 carbon atoms, aryl or an arylalkyl and Y is a halogen.
4. A process for the preparation of a compound of formula I

Formula I wherein R1, P1, P2 and M are as defined above.
comprising the steps of:
a. reacting a compound of formula XXXX OR XXXXI with a compound of formula XXXXIV to obtain a compound of formula XXXIX and

b. converting a compound of formula XXXIX into a compound of formula I. wherein R, Rl, Z, Y, Z, P1, P2 and M are as defined above.

5. A process for the preparation of rosuvastatin calcium comprising the steps of:
a. converting a compound of formula XXXXV into a compound of formula XXXXVI and

Formula XXXXV Formula XXXXVI
b. converting a compound of formula XXXXVI into rosuvastatin calcium compound of formula VII.

wherein N is H, alkyl group of 1 to 10 carbon atoms, aryl or an arylalkyl or carboxylic protecting group or metal atoms like Na+, K+ or Mg+2.
6. The process according to claim 5, wherein a compound of formula XXXXV is converted into a compound of formula XXXXVI by the reaction of alkali metal fluoride such as potassium fluoride, sodium fluoride, cesium fluoride or alkali earth metal fluoride such as calcium fluoride, magnesium fluoride in an organic solvent.
7. The process according to claim 5, wherein a compound of formula XXXXV is converted into a compound of formula XXXXVI by the reduction of nitro group of compound of formula XXXXV with sodium dithionite followed by diazotization reaction with sodium nitrite and hydrochloric acid followed by the reaction with sodium tetrafluoroborate in an organic solvent.

8. The process according to claim 5, wherein a compound of formula XXXXVI, wherein N is alkyl group of 1 to 10 carbon atoms, aryl or an arylalkyl or carboxylic protecting group is converted into rosuvastatin calcium compound of formula VII by the reaction of alkali metal hydroxide such as sodium hydroxide followed by the reaction of resulting compound with a source of calcium ion such as calcium chloride dihydrate; calcium acetate or calcium hydroxide in an organic solvent,
9. The process according to claims 6, 7 or 8 wherein organic solvent is selected from the group comprising of alcoholic solvent such as methanol, ethanol, n-propanol, isopropanol, butanol, isobutanol, pentanol or mixture(s) thereof, chlorinated hydrocarbons solvent such as dichloromethane, dichloroethane, carbon tetrachloride, chloroform or mixture(s) thereof, ethereal solvent such as tetrahydrofuran, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, methyl ethyl ether or mixture(s) thereof.
10. The process for the preparation of rosuvastatin calcium as hereinbefore described in example
and specification.