FIELD OF THE INVENTION
The present invention relates to novel compounds of Formula-I and use of said compounds as intermediates for the preparation of rosuvastatin and pharmaceutical acceptable salts thereof,
N'

F
Formula-I
wherein X is S or SO2.
The present invention further relates to the process for the preparation of above said novel compounds of Formula-I.
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 was marketed under trade name as Crestor having rosuvastatin calcium of as active ingredient which is chemically known as (£',3R,5S)-7-[4-(4-fluorophenyl)-2-[methyl(methylsulfonyl)amino]-6-propan-2-ylpyrimidin-5-yl]-3,5-dihydroxyhept-6-enoic acid.
Rosuvastatin was first disclosed in US patent number 5,260,440. European patent
publication no. EP 0521471 discloses (E)-7-[4(4-fluorophenyl)-6-isopropyl-2-
[methyl (methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydroxyhept-6-
enoic acid and its sodium salt and calcium salt as represented below:


PCT application, WO 2015/037018 Al discloses a process for the preparation of rosuvastatin through an intermediate as represented below:

In addition to this, many different strategies to prepare statin compounds are reported in literature, for example US 6,777,552, US 7,371,865 and the like. US patent US 7,371,865 discloses a process to prepare statins using amide intermediates but specifically describes the synthesis of only fluvastatin and pravastatin.
US 7,312,329 discloses process for the preparation of rosuvastatin calcium by following the method as disclosed in the scheme below:



CH2Br
CH2OH
MeQ2S.
Me02S.N-^N
N-MeQ2S.NAN,

^PPh3+Br-

y
o o o



Ot-Bu
+NH,Me **>*->*■
Me02S.N^N
Rosuvastatin calcium

Although there are currently many methods reported in literature for the preparation of rosuvastatin and its salts, still there is a continuous 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.
The present invention focusses on the development of novel intermediates which are easy to scale up and are prepared through a cost effective process which is found to be more convenient to use in a process for manufacturing rosuvastatin API, when compared to previously known processes.
OBJECT OF THE INVENTION

The main object of the present invention is to develop novel compounds of Formula I which can be used as intermediates for the preparation of rosuvastatin and its pharmaceutical acceptable salts,

F
Formula-I
wherein X is S or SO2.
Another object of the present invention is to develop a process for the preparation of novel compounds of Formula I.
SUMMARY OF THE INVENTION
In one aspect, the present invention provides compounds of Formula-I


F
Formula-I
wherein X is S or SO2.
In another aspect, the present invention further provides compounds of Formula I having structure as represented by Formula la and lb

N'\
In one another aspect, the present invention provides a process for the preparation of compound of Formula la, wherein said process comprises the steps of: a) reacting compound of Formula III with oxazole-2-thiol in organic solvent

F Formula III
to give compound of Formula la

; and b) optionally purifying the compound of Formula la.
In further aspect, the present invention provides a process for the preparation of compound of Formula lb, wherein said process comprising oxidation of compound of Formula la in presence of an oxidizing agent and optionally in presence of catalyst.
In further aspect, the present invention provides a process for the preparation of rosuvastatin and/ or its pharmaceutical acceptable salts, wherein said process comprises the steps of:
a) preparing compound of Formula III by reacting compound of Formula II with brominating agent in an organic solvent;

O N

OH

O N

Br

'/ N N O i

'' N N O i

Formula II Formula III
b) substituting compound of Formula III with oxazole-2-thiol to give compound of Formula la;

Formula la
c) oxidizing sulphur in presence of oxidizing agent and base, optionally in presence of catalyst to give compound of Formula lb;

Formula lb
d) condensing compound of Formula lb with amide intermediate of Formula IV


o
o

o o o
Formula IV

in presence of base in an organic solvent to give compound of Formula V

Formula V

; and

e) converting compound of Formula V to rosuvastatin of Formula VI or its pharmaceutical acceptable salts thereof
OH OH O
vOH
Formula VI
DETAILED DESCRIPTION
Definitions:
The term "salts" as used in context of the present invention refers to alkali and alkaline earth metal salts such as sodium, potassium, lithium, calcium, magnesium, zinc, barium and the like, and preferably calcium salt.
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 compounds of Formula I X" V
Formula I
wherein X is S or SO2.
In another embodiment, the present invention provides compounds of Formula I having structure as represented by Formula la and lb



N^

Formula la

Formula lb

In one more embodiment, the present invention provides a process of preparation of compound of Formula la, wherein said process comprises the steps of: a) reacting compound of Formula III with oxazole-2-thiol in organic solvent

to give compound of Formula la

; and b) optionally purifying the compound of Formula la.
In another embodiment, the organic solvent used for preparing compound of Formula la is selected from the group comprising of esters, alcohols, ethers, nitriles, sulfoxides, acetamides, halogenated solvents, ketones, substituted or unsubstituted C1-C8 alkanes. Preferably the organic solvent used for preparing compound of Formula la is selected from the group comprising of ethyl acetate, propyl acetate, propylene acetate, butyl acetate, t-butyl acetate, methanol, ethanol, isopropanol, butanol, iso-butanol, t-butanol, dioxane, tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-methyl acetamide, dichloromethane, dichlorobenzene, tetrachloromethane, acetone, methyl tert-butyl ketone, acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexane, hexane, heptane, and mixture thereof.
In further embodiment, the present invention provides a process for the preparation of compound of Formula lb wherein said process comprising oxidation of compound of Formula la in presence of oxidizing agent selected from sodium hypochlorite; hydrogen peroxide; metachloroperbenzoic acid; peracetic acid; tertiary butyl hydrogen peroxide; cumene hydro peroxide; or oxone.

In further embodiment, the present invention provides a process for the preparation of compound of Formula lb wherein said process comprising oxidation of compound of Formula la in presence of oxidizing agent and optionally in presence of catalyst selected from ammonium molybdate, ammonium hepta molybdate tetra hydrate, and alkali metal tungstate.
In one more embodiment, the present invention provides a process for the preparation of rosuvastatin and/or its pharmaceutical acceptable salts, by employing compounds of Formula I, wherein said process comprises the steps of: a) preparing compound of Formula III by reacting compound of Formula II with brominating agent in an organic solvent;


F ^ F
Formula II Formula III
b) substituting compound of Formula III with oxazole-2-thiol to give compound of Formula la:

Formula la
c) oxidizing sulphur in presence of oxidizing agent and base, optionally in presence of catalyst to give compound of Formula lb;


NA

Formula lb
d) condensing compound of Formula lb with intermediate of Formula IV


o o o
o
o
Formula IV
in presence of base in an organic solvent to give compound of Formula V

Formula V

; and

e) converting compound of Formula V to rosuvastatin of Formula VI or its pharmaceutical acceptable salts thereof


OH OH O
OH

Formula VI
In a preferred embodiment, the brominating agent used in step a) is phosphorus tribromide.

In further embodiment, the organic solvent used to perform bromination of compound of Formula II is selected from the group comprising of esters such as ethyl acetate, butyl acetate, propyl acetate, isopropyl acetate, propenyl acetate; alcohols such as ethanol, methanol, butanol, tert-butanol, propanol, isopropanol; ethers such as diethyl ether, tetrahydrofuran, methyl tetrahydrofuran, dioxane; nitriles such as acetonitrile, sulfoxides such as dimethyl sulfoxide, acetamides such as N-methyl acetamide; halogenated solvents such as dichloromethane, chloroform, tetrachloromethane, dichlorobenzene, dichloroethane; ketones such as acetone, methyl isobutyl ketone, methyl tertbutyl ketone; substituted or unsubstituted Ci-Cs alkanes such as heptane, cyclohexane, hexane; and mixture thereof. In a preferred embodiment, the organic solvent selected is halogenated solvents.
In furthermore embodiment, the oxidizing agent is selected from the group comprising of sodium hypochlorite; hydrogen peroxide; metachloroperbenzoic acid; peracetic acid; tertiary butyl hydrogen peroxide; cumene hydro peroxide; or oxone optionally in presence of an appropriate catalyst such as ammonium molybdate, ammonium hepta molybdate tetra hydrate, alkali metal tungstate; and the base used in oxidation reaction is selected from alkali metal carbonates, alkali metal bicarbonates, alkali metal hydroxides, alkali metal alkoxides, organic amines and the like.
In another embodiment, the suitable base used in condensation reaction of compound of Formula lb with intermediate of Formula IV can be selected from alkali metal carbonates such as potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, or the like; alkali metal bicarbonates such as potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium bicarbonate, or the like; alkali metal alkoxide such as sodium methoxide, sodium ethoxide, sodium propoxide, sodium tertiary butoxide, potassium methoxide, potassium ethoxide, potassium tertiary butoxide, magnesium tertiary butoxide, or the like; amines such- as lithium diisopropylamine, lithium hexamethylpyrimidine or the like; metal disilazides such as sodium bis(trimethylsilyl)amide, potassium

bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or the like, or mixtures thereof.
The organic solvent used in said condensation reaction is selected from polar aprotic solvents, such as acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide; aliphatic ethers such as C3-C9 ether, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dimethyl ether, methyl ethyl ether, 1,2-diethyl ether; hydrocarbons such as toluene and xylene; ethers such as ethyl acetate, butyl acetate; halogenated solvents such as dichloromethane; or mixture thereof.
The conversion of compound of Formula-V to rosuvastatin and/or its pharmaceutical acceptable salts can be carried out by any of the conventional methods or known prior arts.
In another embodiment, the present invention provides a process for the preparation of rosuvastatin calcium salt, by employing compounds of Formula I, wherein said process comprises the steps of:
a) preparing compound of Formula III by reacting compound of Formula II with brominating agent in an organic solvent;


F ^ F
Formula II Formula III
b) substituting compound of Formula III with oxazole-2-thiol to give compound of Formula la;

Formula la
c) oxidizing sulphur in presence of oxidizing agent and base, optionally in presence of catalyst to give compound of Formula lb;

Formula lb
d) condensing compound of Formula lb with intermediate of Formula IV


o o o
o
o
Formula IV
in presence of base in an organic solvent to give compound of Formula V

Formula V

; and

e) converting compound of Formula V to rosuvastatin calcium salt of Formula XIV


OH OH O
Ca+

Formula XIV
In one another embodiment, the present invention provides an alternate process for the preparation of rosuvastatin calcium salt by following the process as shown in the scheme below:


0^0 0

H

0^0 O

Formula VIII

Formula IX

Formula IV

PPh^r-

Formula II

Formula III

Formula X


H

0^0 0
O
Formula IV

Formula X

Formula V

OH OH 0
'0"Na+
Rosuvastatin calcium Formula XIV

Formula XII

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 one another embodiment, the rosuvastatin or its pharmaceutical acceptable salt prepared as per the process of the present invention is characterized by particle size distribution wherein, d% is 0.1 um to 200um.
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, d% is 2.0 um to 150um.

In further embodiment, the rosuvastatin or its pharmaceutical acceptable salt prepared as per the process of the present invention possess high purity of 98% and above. Preferably, the purity of rosuvastatin or its pharmaceutical acceptable salt is 99.5% 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.
EXAMPLES
EXAMPLE 1: Preparation of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-
dioxan-4-yl)acetate Formula IV
To tert-butyl 2-((4R, 6S)-6-(acetoxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (50g, 0.16mole) of Formula VIII was added methanol (500ml) and potassium carbonate (10.35g, 0.075mole). Heated the mixture for 1 hour to get oily material which is then transferred to hydrochloric acid solution followed by addition of ethyl acetate. Separated the layers and concentrated the organic layer under vacuum to get tert-butyl 2-((4R,6S)-6-(hydroxymethyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of Formula IX (39g, 0.15mole). The compound so obtained is taken into the solution of dichloromethane (200ml) and dimethyl sulfoxide (12ml) and cooled the reaction mixture below room temperature. Added oxalyl chloride (10ml) and stirred at room temperature till completion of reaction. Quenched the reaction with triethyl amine (35ml) followed by addition of water. Separated the organic layer and concentrated under vacuum to get oily tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate Formula IV (37.5gm).
EXAMPLE 2: Preparation of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide of Formula III

Added N-(4-(4-fluorophenyl)-5-(hydroxymethyl)-6-isopropylpyrimidin-2-yl)-N-
methylmethanesulfonamide (lOOgm, 0.28mole) of Formula II and dichloromethane
(500ml) to the reactor. Added phosphorus tribromide (80gm) and water under
stirring followed by stirring the obtained reaction mixture at room temperature till
completion of reaction. After completion of reaction, extracted the organic layer
(dichloromethane) and washed it with water. Concentrated the organic layer to get
oily material and recrystallized said oily material in toluene and methanol to get
pure N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-
methylmethanesulfonamide of Formula III (112.3gm).
EXAMPLE 3: Preparation of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)triphenylphosphonium bromide of Formula X
To the solution of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (108.3gm, 0.26mole) of Formula III in toluene (500ml) was added a solution of triphenyl phosphine (70gm) in toluene (150ml). Heated the reaction mixture at 50-60°C for 5-6hours. Centrifuged the material and cake so obtained is washed with toluene (2><200ml) to get white powder of ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl) methyl)triphenylphosphonium bromide of Formula X (170gm).
EXAMPLE 4: Preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5-((oxazol-2-ylthio)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula la
To the solution of N-(5-(bromomethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl)-N-methylmethanesulfonamide (108.3gm, 0.26mole) of Formula III in ethyl acetate (700ml) was added oxazole-2-thiol (27gm, 0.26mole) and solution of potassium carbonate (12gm) in ethyl acetate was added and the reaction mixture and was stirred for 1-2 hours at 25 to 30°C. After completion of reaction, the reaction mass was quenched with water. The organic layer was separated and

aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with brine, dried on anhydrous sodium sulphate and concentrated. Isopropyl ether (250ml) was added to the residue and stirred for 30 minutes at 25-30°C and the resulting solid was filtered, washed with diisopropyl ether and dried to give N-(4-(4-fluorophenyl)-6-isopropyl-5-((oxazol-2-ylthio)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide (109gm) of Formula la.
EXAMPLE 5: Preparation of N-(4-(4-fluorophenyl)-6-isopropyl-5-((oxazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide of Formula lb
Added N-(4-(4-fluorophenyl)-6-isopropyl-5-((oxazol-2-ylthio)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide (109gm, 0.25mole) of Formula la in dichloromethane at 0 to 5°C, m-chloroperbenzoic acid (9.6g) was then added and stirred for 12 hours at 28 to 32°C. After completion of reaction, the mass was filtered and the filtrate was successively washed with solution of sodium sulphite and sodium bicarbonate, and concentrated. Ethyl acetate was added to the resulting residue at 50°C and then cooled slowly to 35°C followed by addition of hexane. The reaction mass was further stirred for 30 minutes and then filtered, washed with n-hexane and dried at 50°C for 12 hours to giveN-(4-(4-fluorophenyl)-6-isopropyl-5-((oxazol-2-ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide (117gm) of Formula lb.
EXAMPLE 6: Preparation of tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate of Formula V
Method A: Added tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate (37.5gm, 0.145mole) Formula IV and ((4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)methyl)triphenylphosphonium bromide (lOOgm, 0.145mole) of Formula X in dimethyl sulfoxide followed by

addition of potassium carbonate (20gm). Heated the reaction mass to 80-85°C and after completion of reaction, quenched the reaction mass with water. Extracted the compound from aqueous layer by extracting the aqueous layer by toluene. Combined the organic layer and concentrated under vacuum to get oily material. Recrystallized in methanol to get pure tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (75gm) of Formula V.
Method B: Added N-(4-(4-fluorophenyl)-6-isopropyl-5-((oxazol-2-
ylsulfonyl)methyl)pyrimidin-2-yl)-N-methylmethanesulfonamide (117gm,
0.25mole) of Formula lb in dimethyl sulfoxide followed by addition of tert-butyl 2-((4R,6S)-6-formyl-2,2-dimethyl-l,3-dioxan-4-yl)acetate Formula IV (65gm, 0.25moles) and potassium carbonate (40gm). Heated the reaction mass to 50-60°C and after completion of reaction, quenched the reaction mass with water. Extracted the compound from aqueous layer by extracting the aqueous layer by toluene. Combined the organic layer and concentrated under vacuum to get oily material. Recrystallized in methanol to get pure tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-yl)acetate (142gm) of Formula V.
EXAMPLE 7: Preparation of rosuvastatin of Formula VI
Added tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-
methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-
yl)acetate (144gm, 0.25mole) of Formula V to mixture of toluene and methanol followed by addition of aqueous hydrochloric acid. Stirred the reaction mass at room temperature till completion of reaction. After completion of reaction, aqueous sodium hydroxide solution (10%) was added to adjust pH between 12.0- 12.5 and stirred for 1 hour. The reaction mass was filtered and concentrated under vacuum. To the resulting residue was added methyl-tertiary butyl ether and water and separated the layers. Concentrated the organic layer to get sodium (3R,5S,E)-7-(4-

(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (125gm) of Formula VIII which was then taken in water followed by addition of dilute hydrochloric and desired product was extracted in ethyl acetate. Organic layer was washed with brine solution and concentrated under vacuum to get crude rosuvastatin (117gm) of formula VI.
EXAMPLE 8: Preparation of rosuvastatin calcium salt of Formula XIV
Added tert-butyl 2-((4R,6S)-6-((E)-2-(4-(4-fluorophenyl)-6-isopropyl-2-(N-
methylmethyl sulfonamido)pyrimidin-5-yl)vinyl)-2,2-dimethyl-l,3-dioxan-4-
yl)acetate (144gm, 0.25mole) of Formula V to mixture of toluene and methanol followed by addition of aqueous hydrochloric acid. Stirred the reaction mass at room temperature till completion of reaction. After completion of reaction, aqueous sodium hydroxide solution (10%) was added to adjust pH between 12.0-12.5 and stirred for 1 hour. The reaction mass was filtered and concentrated under vacuum. To the resulting residue was added methyl-tertiary butyl ether and water and separated the layers. Concentrated the organic layer to get sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate of Formula VIII. To the sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethylsulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate of Formula VIII as obtained above, was taken in ethyl acetate (1.19L) and the reaction mass was cooled to 10-15°C. Water was added and the pH was adjusted to 1-2 with dilute hydrochloric acid, layers were separated and extracted with ethyl acetate. Organic layer was washed successively with FN hydrochloric acid and water at 40-45°C. Organic layer was concentrated and compound was dissolved in methyl-tertiary butyl ether (1.19L) and cooled to 10-15°C. Water (1.19L) was added and pH of reaction mass was adjusted to 9.0-1 1 .0 with 10% sodium hydroxide solution, stirred and layers were separated. Organic layer was concentrated and aqueous solution of calcium acetate (42.5 g in 340ml) was added to the reaction mass and stirred for 1 hour at 25-30°C. Product was filtered, washed with water and dried to obtain pure of rosuvastatin calcium (123 gm with purity of 99.6% by HPLC).

EXAMPLE 9: Preparation of rosuvastatin calcium salt of Formula XIV
Sodium (3R,5S,E)-7-(4-(4-fluorophenyl)-6-isopropyl-2-(N-methylmethyl
sulfonamido)pyrimidin-5-yl)-3,5-dihydroxyhept-6-enoate (123gm, 0.245mole) of Formula VIII was taken in ethyl acetate (1.19L) and the reaction mass was cooled to 10-15°C. Water was added and the pH was adjusted to 1-2 with dilute hydrochloric acid, layers were separated and extracted with ethyl acetate. Organic layer was washed successively with IN hydrochloric acid and water at 40-45°C. Organic layer was concentrated and compound was dissolved in methyl-tertiary butyl ether (1.19L) and cooled to 10-15°C. Water (1.19L) was added and pH of reaction mass was adjusted to 9.0-11.0 with 10% sodium hydroxide solution, stirred and layers were separated. Organic layer was concentrated and aqueous solution of calcium acetate (42.5 g in 340ml) was added to the reaction mass and stirred for 1 hour at 25-30°C. Product was filtered, washed with water and dried to obtain pure of rosuvastatin calcium (122gm with 99.7% purity).

WE CLAIM
1. Compounds of Formula-I

Formula-I
wherein X is S or SO2.
2. The compounds as claimed in claim 1, wherein said compounds are represented by Formula la and lb

Formula la

Formula lb

3. A process for the preparation of compound of Formula la as claimed in claim 2,
wherein said process comprises the steps of:

Formula III
to give compound of Formula la
a) reacting compound of Formula III with oxazole-2-thiol in organic solvent


; and b) optionally purifying the compound of Formula la.
4. The process as claimed in claim 3, wherein said organic solvent is selected from the group comprising of ethyl acetate, propyl acetate, propylene acetate, butyl acetate, t-butyl acetate, methanol, ethanol, isopropanol, butanol, iso-butanol, t-butanol, dioxane, tetrahydrofuran, methyl tert-butyl ether, methyl tetrahydrofuran, acetonitrile, dimethyl sulfoxide, N-methyl acetamide, dichloromethane, dichlorobenzene, tetrachloromethane, acetone, methyl tert-butyl ketone, acetone, methyl isobutyl ketone, methyl ethyl ketone, cyclohexane, hexane, heptane, and mixture thereof.
5. A process for the preparation of compound of Formula lb as claimed in claim 2, wherein said process comprising oxidation of compound of Formula la in presence of oxidizing agent and optionally in presence of catalyst.
6. The process as claimed in claim 5, wherein said oxidizing agent is selected from sodium hypochlorite; hydrogen peroxide; metachloroperbenzoic acid; peracetic acid; tertiary butyl hydrogen peroxide; cumene hydro peroxide; and oxone; and wherein said catalyst is selected from ammonium molybdate, ammonium hepta molybdate tetra hydrate, and alkali metal tungstate.
7. A process for the preparation of rosuvastatin and/or its pharmaceutical acceptable salts, wherein said process comprises the steps of:
a) preparing compound of Formula III by reacting compound of Formula II with brominating agent in an organic solvent;

O N

OH

O N

Br

'/ N N O i

'' N N O i

Formula II Formula III
b) substituting compound of Formula III with oxazole-2-thiol to give compound of Formula la;

Formula la
c) oxidizing sulphur in presence of oxidizing agent and base, optionally in presence of catalyst to give compound of Formula lb;

Formula lb
d) condensing compound of Formula lb with intermediate of Formula IV


o
o

o o o
Formula IV

in presence of base in an organic solvent to give compound of Formula V

Formula V . md
e) converting compound of Formula V to rosuvastatin of Formula VI or its pharmaceutical acceptable salts thereof
OH OH O
vOH
Formula VI
8. The process as claimed in claim 7, wherein said base used in step d) is selected
from potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate,
potassium bicarbonate, sodium bicarbonate, lithium bicarbonate, cesium
bicarbonate, sodium methoxide, sodium ethoxide, sodium propoxide, sodium
tertiary butoxide, potassium methoxide, potassium ethoxide, potassium tertiary
butoxide, magnesium tertiary butoxide, lithium diisopropylamine, lithium
hexamethylpyrimidine sodium bis(trimethylsilyl)amide, potassium
bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, or mixture thereof.
9. The process as claimed in claim 7, wherein said organic solvent used in step d) is selected from acetonitrile, dimethyl sulfoxide, dimethyl acetamide, dimethyl formamide, tetrahydrofuran, methyl tetrahydrofuran, 1,2-dimethyl ether, 1,2-diethyl ether; methyl ethyl ether, toluene and xylene, ethyl acetate, butyl acetate, dichloromethane, or mixture thereof.

10. The compounds as claimed in claim 1, wherein said compounds are used as intermediates for preparing rosuvastatin and/or its pharmaceutical acceptable salts.