DESC:FIELD OF INVENTION
The present invention relates to an improved process for the preparation of Rosuvastatin or its pharmaceutical acceptable salt thereof.

The present invention further relates to an improved process for the preparation of Rosuvastatin or its pharmaceutical acceptable salt by using compound of Formula I or compound of Formula III.

X-= halogen
Formula I Formula III

BACKGROUND OF THE INVENTION
Rosuvastatin, is a member of drug class of statins (HMG-CoA reductase inhibitors) and is used for the treatment of high cholesterol and related conditions and to prevent cardiovascular disease.

Rosuvastatin is marketed under trade name as Crestor having Rosuvastatin Calcium as active ingredient which is chemically known as (E,3R,5S)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid and is represented by chemical structure of Formula II below.

Formula II
US 5260440 describes Rosuvastatin Calcium and process for preparation thereof.

US 6,784,171 discloses process for the preparation of Rosuvastatin Calcium by preparing methyl amine salt of Rosuvastatin as disclosed in the scheme below:
Scheme-1:

US 8,536,330 discloses process for the preparation of Rosuvastatin Calcium by reacting [4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-(propan-2-yl)pyrimidin-5-yl]methyl diphenyl phosphate with 2-mercapto-5-methyl-1,3,4-thiadiazole followed by reacting the resulting N-[4-(4-fluorophenyl)-5-{[(5-methyl-1,3,4-thiadiazol-2-yl)sulfanyl]methyl}-6-(propan-2-yl)pyrimidin-2-yl]-N-methylmethanesulfonamide with hydrogen peroxide in presence of phase transfer catalyst. The resulting intermediate is reacted with tert-butyl 3,5-dideoxy-2,4-O-(1-methylethylidene)-L-erythro-hexuronate in presence of reagents like lithium bis(trimethylsilyl)azanide followed by conversion to Rosuvastatin and its Calcium salt.

CN 104,230,990 discloses process for the preparation of Rosuvastatin Calcium by reacting N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide with triphenyl phosphine sidechain and further deprotecting the resulting intermediate to obtain Rosuvastatin Calcium as disclosed in the scheme below:
Scheme-2:

KR20120092788 discloses process of preparing Rosuvstatin Calcium salt by reacting N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide with compound of Formula IX as disclosed in the scheme below:
Scheme III:
The major drawback of this process is use of compound of Formula IX which involve an extra step and increases the cost of overall process. Further above processes results in impurities making the process uneconomical.

Although there are currently many methods reported in literature for the preparation of statins, specifically Rosuvastatin and its salts, still there is a continuing need to develop alternative processes for the preparation of Rosuvastatin by employing intermediates which are produced through an economical process and is reproducible during scale up for achieving purity and meeting cost concerns. Present invention focused to reduce the number of steps and to reduce overall cost of the process.

The present invention focusses on the development of intermediates which are easy to scale up and are prepared through a cost effective process which is found to be more convenient to use, provides product in a better yield, when compared to previously known processes.

OBJECTIVE OF THE INVENTION
Main object of the present invention is to develop a process for the preparation of Rosuvastatin and its pharmaceutical acceptable salts by using compound of Formula I or compound of Formula III.

X-= halogen
Formula I Formula III

Another object of the present invention is to develop a process for the preparation of intermediates of Formula I.

Another object of the present invention is to develop a process for the preparation of intermediates of Formula III.

SUMMARY OF THE INVENTION
The present invention provides a process for the preparation of Rosuvastatin and its pharmaceutical acceptable salts by using compound of Formula I or compound of Formula III.

X-= halogen
Formula I Formula III

The present invention further provides a process of preparation of Rosuvastatin or its pharmaceutical acceptable salts by employing compounds of Formula I, wherein said process comprises the steps of:
a) reacting compound of Formula I with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethane sulphonamide to give compound of Formula IV;

Formula I Formula IV
b) converting compound of Formula IV into Rosuvastatin or its pharmaceutical acceptable salts thereof.

The present invention further provides a process of preparation of Rosuvastatin or its pharmaceutical acceptable salts, wherein said process comprises the steps of:
a) reacting compound of Formula III with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide to give compound of Formula IV;

Formula III Formula IV
X-= halogen
b) converting compound of Formula IV into Rosuvastatin or its pharmaceutical acceptable salts.

The present invention further provides a process of preparation of compound of Formula I.

The present invention further provides a process of preparation of compound of Formula III.

DETAILED DESCRIPTION OF THE INVENTION
Definitions:
The terms “pharmaceutically acceptable salt” or “salt” are used interchangeably in the context of the present invention. “Pharmaceutically acceptable salts” or “salts” as used in the context of the present invention refers to inorganic acids such as hydrochloric acid, hydrobromic acid, sulphuric acid, phosphoric acid salt, carbonate salts; organic acids such as succinic acid, formic acids, acetic acid, diphenyl acetic acid, palmoic acid, triphenylacetic acid, caprylic acid, dichloroacetic acid, trifluoro acetic acid, propionic acid, butyric acid, lactic acid, citric acid, gluconic acid, mandelic acid, tartaric acid, malic acid, adipic acid, aspartic acid, fumaric acid, glutamic acid, maleic acid, malonic acid, benzoic acid, p-chlorobenzoic acid, dibenzoyl tartaric acid, oxalic acid, nicotinic acid, o-hydroxybenzoic acid, p-hydroxybenzoic acid, 1-hydroxy-naphthalene-2-carboxylic acid, hydroxynaphthalene-2-carboxylic acid, ethanesulfonic acid, ethane-1,2-disulfonic acid, 2-hydroxyethane sulfonic acid, methanesulfonic acid, (+)-camphor-10-sulfonic acid, benzenesulfonic acid, naphthalene-2-sulfonic acid, p-toluenesulfonic acid and the like. The inorganic salts may further includes alkali metal and alkaline earth metal salts such as sodium, potassium, barium, lithium, calcium, magnesium, rhodium, zinc, cesium, selenium, and the like or, benethamine, benzathine, diethanolamine, ethanolamine, 4-(2-hydroxy-ethyl) morpholine, 1-(2-hydroxyethyl)pyrrolidine, N-methyl glucamine, piperazine, triethanol amine or tromethamine and the like.

The present invention will now be explained in details. While the invention is susceptible to various modifications and alternative forms, specific embodiment thereof will be described in detail below. It should be understood, however that it is not intended to limit the invention to the particular forms disclosed, but on the contrary, the invention is to cover all modifications, equivalents, and alternative falling within the scope of the invention as defined by the appended claims.

The steps of a method may be providing more details that are pertinent to understanding the embodiments of the present invention and so as not to obscure the disclosure with details that will be readily apparent to those of ordinary skill in the art having benefit of the description herein.

Further characteristics and advantages of the process according to the invention will result from the description herein below of preferred exemplary embodiments, which are given as indicative and non-limiting examples.

In one embodiment, the present invention provides process of preparation of Rosuvastatin or its pharmaceutical acceptable salts thereof comprising:
a) reacting compound of Formula I with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide to give compound of Formula IV;

Formula I Formula IV
b) converting compound of Formula IV into Rosuvastatin or its pharmaceutical acceptable salts thereof.

In another embodiment, the present invention provides process of preparation of Rosuvastatin or its pharmaceutical acceptable salt comprising:
a) reacting compound of Formula III with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide to give compound of Formula IV;

Formula III Formula IV
X-= halogen
b) converting compound of Formula IV into Rosuvastatin or its pharmaceutical acceptable salts.

In another embodiment, the present invention provides process of preparation of Rosuvastatin calcium comprising:
a) reacting compound of Formula, I or compound of formula III
, ,
wherein, X- is halide selected from chloride, bromide, iodide or fluoride,
with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

to give compound of Formula IV;

b) deprotecting compound of Formula IV to give compound of formula VI;

wherein compounds of formulae VI is formed in-situ;
c) reacting compound of Formula VI with suitable source of alkali metal or alkaline earth metal to give compound of formula VII;

wherein B+ is selected from alkali metal or alkaline earth metal,
wherein compounds of formula VII is formed in-situ;
d) converting the compound of formula VII to Rosuvastatin calcium in the presence of calcium source.
In another embodiment, the present invention provides process of preparation of Rosuvastatin or its pharmaceutical acceptable salt comprising:
a) reacting compound of Formula I or compound of formula III
,
wherein, X- is halide selected from chloride, bromide, iodide or fluoride,
with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

to give compound of Formula IV;

b) converting compound of Formula IV to compound of formula VIII
; and
c) converting compound of formula VIII to Rosuvastatin or its pharmaceutically acceptable salts.

In another embodiment, the present invention provides process of preparation of Rosuvastatin or its pharmaceutical acceptable salt comprising:
a) reacting compound of Formula I or compound of formula III
, ,
wherein, X- is halide selected from chloride, bromide, iodide or fluoride,
with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

to give compound of Formula IV;

b) deprotecting compound of Formula IV to give compound of formula VI;

wherein compounds of formulae VI is formed in-situ
c) reacting compound of Formula VI with suitable source of alkali metal or alkaline earth metal to give compound of formula VII;

wherein B+ is selected from alkali metal or alkaline earth metal,
wherein compounds of formula VII is formed in-situ;
d) converting compound of Formula VII to compound of formula VIII
; and
e) converting compound of formula VIII to Rosuvastatin or its pharmaceutically acceptable salts.

In another embodiment reaction at step a) is carried out in presence of base wherein said base is selected from organic or Inorganic base wherein, Inorganic base may be selected from but not limited to Sodium hydride, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, potassium tert. butoxide, potassium acetate, sodium acetate, cesium carbonate, potassium hydroxide, sodium hydroxide, calcium hydroxide, magnesium hydroxide, lithium hydroxide, ammonium hydroxide, sodium methoxide, potassium methoxide, and the like. Organic base may be selected from but not limited to pyridine, dimethyl amine, triethyl amine, ?,?-diisopropylethyl amine, l,8-Diazabicyclo[5.4.0]undec-7-ene, N-methyl morpholine, ?,?-dimethyl piperazine, N-methyl piperidine.

In another embodiment solvent used in the present invention may selected from but not limited to alcohol such as methanol, ethanol, 2-nitroethanol, 2-fluoroethanol, 2,2,2-trifluoroethanol, hexafluoroisopropyl alcohol, ethylene glycol, 1-propanol, 2-propanol (isopropyl alcohol), 2-methoxyethanol, 1-butanol, 2-butanol, t-butyl alcohol, 2-ethoxyethanol, diethylene glycol, 1-, 2-, or 3-pentanol, neo-pentyl alcohol, t-pentyl alcohol, diethylene glycol monomethyl ether, diethylene glycol monoethyl ether, cyclohexanol, phenol, glycerol; halogenated solvent such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; ethers such as diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4-dioxane, dibutyl ether, dimethylfuran, 2-methoxyethanol, 2-ethoxyethanol, anisole; ketones such as acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone; esters solvents such as ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate; hydrocarbon such as toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene and the like; nitriles such as acetonitrile, propionitrile, butanenitrile; dimethyl sulfoxide (DMSO), water; and mixtures thereof

In one another embodiment, the present invention provides an improved process for the preparation of Rosuvastatin Calcium salt by following the process as shown in the scheme below:

In another embodiment, the B+ in compound of Formula VII is selected from alkali metal or alkaline earth metal selected from Li, Na, K, Mg, Ca or Ba and X- is halogen selected from F, Cl, Br, I.

In another embodiment conversion of compound of Formula IV to amine salt is carried out in three steps which involve deprotection of compound of Formula IV using suitable acid in suitable solvent followed by hydrolysis of compound of Formula VI in basic condition and treating the obtained salt of compound of Formula VII with suitable amine source to get amine salt of compound of formula VIII.

In another embodiment suitable acid used for the deprotection of compound of Formula IV is selected from but not limited to hydrochloric acid, hydrobrmomic acid, oxalic acid, acetic acid and the like.

In another embodiment suitable base used for hydrolysis of compound of Formula VI is selected from but not limited to sodium hydroxide, potassium hydroxide, magnesium hydroxide, barium hydroxide, potassium tertiary butoxide, sodium carbonate, potassium carbonate, trimethylamine, triethylamine, ammonia, and the like.

In another embodiment suitable amine source used for the conversion of compound of Formula VII to VIII is selected from but not limited to methylamine, ethylamine, cyclohexyl amine, dicyclohexyl amine, tromethamine, tert-butyl amine, isopropyl amine, n-propyl amine and the like.

In another embodiment conversion of compound of Formula VII or VIII to Rosuvastatin calcium is done by treating compound of formula VII or VIII with suitable calcium source selected from but not limited to calcium chloride, calcium bromide and calcium acetate in presence of suitable solvent selected from but not limited to methanol, ethanol, 2,2,2-trifluoroethanol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene,diethyl ether, diisopropyl ether, methyl t-butyl ether (MTBE), glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene , nitriles such as acetonitrile, propionitrile, dimethyl sulfoxide (DMSO), butanenitrile; water; and mixtures thereof.

In another embodiment, the salts of Formula VII are selected from but not limited to sodium, potassium, calcium, magnesium, barium, and the like.

In another embodiment, the salts of Formula VIII are selected from but not limited to amine salts such as methylamine salt, ethylamine salt, cyclohexyl amine, dicyclohexyl amine, tromethamine salt and the like.

In another embodiment solvent used in any step for the present invention selected from but not limited to methanol, ethanol, 2,2,2-trifluoroethanol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene,diethyl ether, diisopropyl ether, methyl t-butyl ether, glyme, diglyme, tetrahydrofuran, 2-methyltetrahydrofuran, 1,4, acetone, ethyl methyl ketone, diethyl ketone, methyl isobutyl ketone, ethyl acetate, n-propyl acetate, n-butyl acetate, iso propyl acetate, isobutyl acetate, t-butyl acetate, ethyl formate, methyl acetate, methyl propanoate, ethyl propanoate, methyl butanoate, ethyl butanoate, toluene, xylene, hexane, n-heptane, n-pentane, anisole, ethyl benzene , nitriles such as acetonitrile, propionitrile, butanenitrile; water; and mixtures thereof.

In another embodiment, the process used in current invention results in the formation of pure amorphous form of Rosuvastatin calcium.

In another embodiment, the Rosuvastatin and/ or its pharmaceutically acceptable salts obtained by the process of the present invention are used as HMG-CoA reductase inhibitor and for treating high cholesterol and related conditions, and to prevent cardiovascular disease.

In a preferred embodiment, the Rosuvastatin or its pharmaceutical acceptable salt prepared as per the process of the present invention is characterized by particle size distribution wherein, d90 is 1.0 µm to 150µm.

In further embodiment, the Rosuvastatin or its pharmaceutical acceptable salt prepared as per the process of the present invention possess high purity of 99% and above. Preferably, the purity of Rosuvastatin or its pharmaceutical acceptable salt is 99.9% and above.

In still another embodiment, the present invention provides a pharmaceutical composition comprising Rosuvastatin or its pharmaceutical acceptable salts wherein said Rosuvastatin or its pharmaceutical acceptable salts is prepared as per the process of the present invention.

Example 1: Preparation of compound of Formula I:
Charge (4R-Cis)-6-idomethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester and 50ml ethyl acetate in a 100ml, 4 necks round bottom flask at 25-35°C. Heat the reaction mass at 50ºC and then charge methyl diphenyl phosphinite and heat it 60ºC till reaction completion. After completion of reaction cool the reaction mass to 20-25°C. Charge DM water to the reaction mass. Stir & separate the layer. Distil out the organic layer and degas it to obtained crude compound of Formula I.
Example 1: Preparation of compound of Formula III:
Charge (4R-Cis)-6-idomethyl-2,2-dimethyl-1,3-dioxane-4-acetic acid 1,1-dimethylethyl ester and 50ml ethyl acetate in a 100ml, 4 necks round bottom flask at 25-35°C. Heat the reaction mass at 50ºC and then charge triphenyl phosphine and heat it 60ºC till reaction completion. After completion of reaction cool the reaction mass to 20-25°C. Charge DM water to the reaction mass. Stir & separate the layer. Distil out the organic layer and degas it to obtained crude compound of Formula III.
Example 3: Preparation of compound of Formula IV:
Charge DMSO, Sodium hydride, N-(4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl)-N-methylmethanesulfonamide & compound of Formula I in 1 litre, 4 necks round bottom flask at 25-35°C. Stir the reaction mass at 75-80ºC till reaction completion. After completion of reaction mass, cool the reaction mass to 20-30°C. Add slowly isopropyl alcohol and then charge ethyl acetate & DM water in the reaction mass. Stir the reaction mass for 15-20 minute at 25-30°C. Separate the layer. Distil the organic layer to get crude material.
Example 4: Preparation of compound of Formula IV:
Charge DMSO, potassium carbonate, N-(4-(4-fluorophenyl)-5-formyl-6-isopropyl pyrimidin-2-yl)-N-methylmethanesulfonamide & Formula III in 0.5 litre, 4 necks round bottom flask at 25-35°C. Stir the reaction mass at 75-80ºC till reaction completion. After completion of reaction mass, cool the reaction mass to 20-30°C. Add Ethyl acetate & DM water in the reaction mass. Stir the reaction mass for 15-20 minute at 25-30°C. Separate the layer. Distil the organic layer to get crude material.
Example 5: Preparation of Rosuvastatin calcium:
Charge compound of Formula IV, acetonitrile and aqueous hydrochloric acid solution in 1 litre, 4 necks round bottom flask at 25-35°C. Stir the reaction mass till reaction completion. Cool the reaction mass to 15-20°C. Add aqueous sodium hydroxide to the reaction mass. Stir the reaction mass for 2-3 hrs at 25-30°C and monitor by HPLC. After completion of reaction, Distil out the reaction mass. After distillation, charge DM water and wash with MTBE and discard. Distil out 20-30% water from the aqueous layer of the reaction mass at 40-50ºC. Charge the DM water to the distilled mass. Adjust the pH 8.5 to 8.8 with the help of aq. acetic acid solution. Charge calcium acetate solution (aq.) in the above reaction mass. Stir it for 3-4 hrs at 20-30ºC. Filter it, wash with water and suck dry properly. Dry it under vacuum at 50±3ºC for 12-15 hours to get pure Rosuvastatin calcium\, purity 99.7% by HPLC.
Example 6: Preparation of Rosuvastatin calcium:
A. Preparation of form Formula VIII form Formula IV:
Charge compound of Formula IV, acetonitrile and aqueous hydrochloric acid solution in 1 litre, 4 necks round bottom flask at 25-35°C. Stir the reaction mass till reaction completion. Cool the reaction mass to 15-20°C. Add aqueous sodium hydroxide to the reaction mass. Stir the reaction mass for 2-3 hrs at 25-30°C and monitor by HPLC. Charge Sodium chloride to the reaction mass at 30-35°C. Cool the reaction mass to 0 to -5°C. Slowly, add 1N hydrochloric acid Solution to the reaction mass at 0 to -5°C and adjust the pH: between 3.5 to 4.2. Stir the reaction mass for 15-30 minutes at 0 to -5°C. Settle and separate the layers at 0 to -5°C. Charge organic layer into 5 litre, 4 neck round bottom flask charge fresh acetonitrile at 0 to 10°C. Slowly, add 40% aqueous solution of mono methylamine to the reaction mass at 0 to -5°C in 30-40 minutes. Stir for 90-120 minutes at 0 to -5°C. Filter Suck dry and unload. The reaction mass and wash with acetonitrile at 0 to -5°C. Dry the material for 6-8 hours under vacuum at 35-40°C to get pure methyl amine salt of Rosuvastatin.
B. Preparation of Rosuvastatin calcium from Formula VIII:
Charge methyl amine salt of Rosuvastatin obtained above, MTBE & DM water to the round bottom flask and cool it 5-10ºC. Charge 2N Sodium hydroxide solution to maintain the pH: NLT 12.0 at 0 to10ºC. Separate the layer at 20-25ºC. Distil out 20-30% water from the aqueous layer of the reaction mass at 40-50ºC. Charge the same quantity of DM water which is distilled to the distilled mass. Adjust the pH 8.5 to 8.8 with the help of aq. acetic acid solution. Charge calcium acetate solution (aq.) in the above reaction mass. Stir it for 3-4 hrs at 20-30ºC. Filter it, wash with water and suck dry properly. Dry it under vacuum at 50±3ºC for 12-15 hours to get pure Rosuvastatin calcium, purity 99.7% by HPLC.
,CLAIMS:We Claim:
1. A process for the preparation of Rosuvastatin or its pharmaceutically acceptable salts, comprises the steps of:
a) reacting compound of Formula I or Formula III with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethane sulphonamide to give compound of Formula IV;
, , ; and

b) converting compound of Formula IV into Rosuvastatin or its pharmaceutically acceptable salts thereof.

2. The process for the preparation of Rosuvastatin or its pharmaceutically acceptable salts as claimed in claim 1, comprises the steps of:
a) reacting compound of Formula I or compound of formula III
,
wherein, X- is halide selected from chloride, bromide, iodide or fluoride,
with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

to give compound of Formula IV;

b) converting compound of Formula IV to compound of formula VIII
; and
c) converting compound of formula VIII to Rosuvastatin or its pharmaceutically acceptable salts.

3. The process for the preparation of Rosuvastatin or its pharmaceutically acceptable salts as claimed in claim 1, comprises the steps of:
a) reacting compound of Formula I or compound of formula III
, ,
wherein, X- is halide selected from chloride, bromide, iodide or fluoride,
with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

to give compound of Formula IV;

b) deprotecting compound of Formula IV to give compound of formula VI;

wherein compounds of formulae VI is formed in-situ
c) reacting compound of Formula VI with suitable source of alkali metal or alkaline earth metal to give compound of formula VII;

wherein B+ is selected from alkali metal or alkaline earth metal,
wherein compounds of formula VII is formed in-situ;
d) converting compound of Formula VII to compound of formula VIII
; and
e) converting compound of formula VIII to Rosuvastatin or its pharmaceutically acceptable salts.

4. The process as claimed in claim 2 or 3, wherein the amine salt of compound of formula VIII is selected from methylamine, ethylamine, cyclohexyl amine, dicyclohexyl amine, tromethamine, tert-butyl amine, isopropyl amine, and n-propyl amine.

5. The process for the preparation of Rosuvastatin or its pharmaceutically acceptable salts as claimed in claim 1, comprises the steps of:
a) reacting compound of Formula, I or compound of formula III
, ,
wherein, X- is halide selected from chloride, bromide, iodide or fluoride,
with N-(4-(4-fluorophenyl)-5-formyl-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide

to give compound of Formula IV;

b) deprotecting compound of Formula IV to give compound of formula VI;

wherein compounds of formulae VI is formed in-situ;
c) reacting compound of Formula VI with suitable source of alkali metal or alkaline earth metal to give compound of formula VII;

wherein B+ is selected from alkali metal or alkaline earth metal,
wherein compounds of formula VII is formed in-situ;
d) converting the compound of formula VII to Rosuvastatin calcium in the presence of calcium source.

6. The process as claimed in claim 5, wherein the calcium source is selected from calcium chloride, calcium bromide or calcium acetate.

7. The process as claimed in claim 3 or 5, wherein the salt of compound of Formula VII is selected from to sodium, potassium, calcium, magnesium or barium.

8. The process as claimed in claims 1, 2, 3 or 5, wherein the purity of Rosuvastatin calcium is about 99% to 99.99%.

Dated 15th Day of Mar, 2024 For Mankind Pharma Ltd.

Dr. Anil Kumar
Chief Scientific Officer