FIElD OF THE INVENTION
The present invention relates to improved process for the preparation of intermediates which is useful for the preparation of rosuvastatin and its pharmaceutically acceptable salts.
BACKGROuND AND PRIOR ART OF THE INVENTION
• Rosuvastatin, described chemically as [(E)-7-[4-(4-fluorophenyl)-6-isoopropyl-2-[methyl (methylsulfonyl) amino] pyrimidin-5yl] (3R, 5S)-3, 5-dihydroxyhept-6-enoic acid] it is commercially available in calcium salt form, which inhibit the HMG-CoA reductase, which plays a main role in the synthesis of cholesterol, and subsequently they suppress the biosynthesis of cholesterol. Therefore, they are useful in the treatment of hypercholesterolemia and hyperlipoproteinemia.
Rosuvastatin and process for its preparation is disclosed in uS Patent uS 5,260,440. The process disclosed therein involves distinct chemical steps and both uneconomical and time consuming.
uS 6,844,437 disclose the process which involves diphenyl phosphene oxide derivative as an intermediate.
Tetrahedron letters, Vol.31, No. 18, pp 2545-2548, 1990 discloses stereo selective synthesis of HMG-COA reductase inhibitors through lactone intermediate. Other patents application(s)/publications which discloses the process for the preparation of Rosuvastatin calcium.
OBJECTIVES OF THE PRESENT INVENTION
The principle objective of the present invention is to develop a process for the preparation of intermediates involved in preparation of rosuvastatin.

Another objective of the present invention is to provide a process for the preparation of intermediates involved in preparation of rosuvastatin and its pharmaceutically acceptable salt.

DETAIlED DESCRIPTION OF THE INVENTION
The present invention is in relation to a process for the preparation of the compound IX comprises,

In another embodiment of the present invention suitable base is selected from the group
Butyl lithium, Potassium carbonate, Sodium ethoxide, sodium methoxide and Cesium
carbonate.
In yet another embodiment of the present invention oxidizing agent is selected from the
group MCPBA, Hydrogen peroxide and Peraceticacid.
In still another embodiment of the present invention alkali and alkaline earth metal bases
are selected from Potassium carbonate, Sodium ethoxide and sodium methoxide
In still another embodiment of the present invention, suitable solvent is selected from the
group toluene, tetrahydrofuran, Dimethylsulfoxide, Dimethylformamide and N-
methylpyrrolidine.



The primary object of the present invention is the provision of improved processes for the preparation of an intermediate (IX) using a compound of formula VIII which is used for the preparation of Rosuvastatin and its pharmaceutically acceptable salts.
Among the particular objects of the invention are: to provide an improved process that produces products of Formula IX and other intermediates in high yield; the provision of such a process which may be implemented with reasonable capital expense and operated at reasonable conversion cost.

Accordingly, the present invention is directed to a series of synthesis schemes for the preparation of HMG CoA reductase inhibitors. The process of the present invention is outlined in Scheme-I and Scheme-II Intermediate of formula IX is prepared using novel intermediate VIII.

in the presence of the base selected from the group Buli, Potassium carbonate, Sodium ethoxide, sodium methoxide and Cesium carbonate to provide the compound of the formula V. which is further oxidized with an oxidizing agent selected from the group MCPBA, Hydrogen peroxide, Peraceticacid to result in formula VIII which is further reacted with an aldehyde of formula X gives the compound of formula IX. The Present invention has following advantages over known method:
1. Clean process
2. Economic
3. Industrially scalable
4. Yields are high and substantially pure product is obtained.
The compound of general formula-IX may be used to form a dihydroxy acid HMG CoA reductase inhibitor by subjecting the compound of formula-IX to acidic conditions to remove the acetonide and form diol compound, which upon treating with a base such as an alkali metal hydroxide to form Formula XII followed by treating with corresponding alkali or alkaline earth metal salts in a suitable solvent to get Rosuvastatin calcium.

The technology of the instant Application is further elaborated with the help of roiiowing examples. However, the examples should not be construed to limit the scope of the invention. The following Examples represent preferred embodiments of the present invention.
Example-1
Preparation of N-[4-(4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-
yl] -N-methyl-methanesulfonamide
N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide lOg was taken in tetrahydrofuran (60ml) and methanol (20ml) and chilled the reaction mixture to 5 to 10°C. Added sodiumborohydride (0.9 Ig) in 4 lots. Stirred for 2 h at 5°C and slowly raised the temperature to 25°C. Quenched the reaction mixture with saturated ammonium chloride solution to pH 7 - 8 . Added 50ml ethylacetate and separated the layers. Extracted the aqueous layer with ethyl acetate (60ml). Combined the organic layers and given water wash (40ml) followed by a brine wash (20ml). Organic layer was dried over anhydrous sodium sulphate and concentrated to get N-[4-(4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide as a white solid. Yield: lOg.
Example-2
Preparation of N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-y,ll-
N-methyl-methanesulfonamide (I)
N-[4-(4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (lOg) was taken in 50ml of toluene and dissolved at 30° C. Added 49% aqueous hydrogenbromide solution(7.5ml) and refluxed at 110°C azeotropically for 3-4 hours. Brought the reaction mixture to 25° C and quenched the reaction mixture with 5% sodium bicarbonate solution to pH 7-7.5. Seperated the organic layer and given water wahes. Extracted the aqueous layer with toluene (20 ml). Combined organic layer was given a brine wash and dried over anhydrous sodium sulphate and concentrated to get solid N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide. Yield: 11.Og

Example-3
Preparation of N-[4-(4-FIuoro-phenyl)-6-isopropyI-5-(pyridin-2-yIsulfanylmethyl)-
pyrimidin-2-yl]-N-methyl-methanesulfonamide(III)
2-mercaptopyridine (II) 3.23g was taken in 16ml tetrahydrofuran and chilled to -25 to -30° C and added 30% n-butyl lithium(ll.Oml) drop wise at -5 to -10 " C and stirred at the same temperature for one hour. Added N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (11.Og) dissolved in 22 ml THF at -60° C to -70°C drop wise and stirred for 15 minutes at -60 to-70° C. Slowly brought the temperature to 25°C and stirred for 2 h. Adjusted the pH of the reaction mixture to 7-8 with saturated ammonium chloride and added 50ml ethyl acetate and separated the layers. Organic layer was given water washes and a brine wash. Organic layer was dried over anhydrous sodium sulphate and concentrated to get solid N-[4-(4-FIuoro-phenyl)-6-isopropyl-5-(pyridin-2-ylsulfanylmethyl)-pyrimidin-2-yI]-N-methyl-methanesulfonamide (V) Yield: 11.Og
Example-4
Preparation of N-[4-(4-Fluoro-phenyl)-6-isopropyl-5-(pyridine-2-sulfonylmethyl)-
pyrimidin-2-yl]-N-methyl-methanesulfonamide (IV)
To N-[4-(4-Fluoro-phenyl)-6-isopropyl-5-(pyridin-2-ylsulfanylmethyl)-pyrimidin-2-yl]-
N-methyl-methanesulfonamide (III) ug was added acetic acid (44ml) and dissolved.
Heated to 50°C and added (30%) hydrogen peroxide solution (8.4ml) slowly.
Maintained heating at 80 °C for 1 h. Water (1 lOml) was added and chilled to 5°C
and filtered the solid. Dissolved the solid in 50ml dichloromethane and dried over anhydrous sodium sulphate and concentrated under vacuum to get the solid title compound. Yield: 11.Og
Example-5
Preparation of (6-Formyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester
(X)
(6-Hydroxymethyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester lOg was taken in 100 ml dichloromethane. Added sodium bicarbonate(1.613) and potassium bromide (0.45 g) dissolved in 30 ml water. Chilled to 0° C and added (2,2,6,6-Tetramethyl-1-piperidinyloxy, free radical) (0.179g) dissolved in 10 ml dichloromethane. Added 60 ml sodium hypochlorite solution (0.5M) maintaining the temperature at 0 °C. Stirred at 0°C for 30 minutes. Added water(10 ml) and separated

the organic layer. Aqueous layer was extracted with dichloromethane (lOml), Organic layers were combined and given (20ml) brine wash. Dried over anhydrous sodium sulphate and concentrated to get the title compound as a syrup. Yield: 7.5g
Example-6
Preparation of N-[5-(3,5-Bis-trifluoromethyl-phenyl sulfanyl methyl)-4-(4-fluoro-
phenyl)-6-isopropy 1-pyrimidin-2-yl] -N-methy 1-methanesuIfonamide (VI)
3,5-Bis(tri fluoromethyl) thiophenol (V) 7.4g was taken in 35ml tetrahydrofuran and chilled to -25 to -30° C and added 30% n-Buli (11.3 ml) drop wise at -5 to -10° C and stirred at the same temperature for one hour. Added N-[5-Bromo methyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide (11.3g) dissolved in 14ml tetrahydrofuran at -60° C to -70° C drop wise and stirred for 15 minutes at -60 to-70° C. Slowly brought the temperature to 25° C and stirred for 2 h. Added saturated ammoniumchloride to the reaction mixture followed by 50ml ethylacetate and separated the layers. Organic layer was given water washe and a brine wash. Organic layer was dried over anhydrous sodiumsulphate and concentrated to get solid N-[5-(3, 5-Bis-trifluoromethyl-phenylsulfanylmethyl)-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide (X) Yield: 13g
Example-7
Preparation of N-[5-(3,5-Bis-trifiuoromethyl-benzene sulfonyl methyl)-4-(4-fluoro-
phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide(VII).
To lOg of N-[5-(3,5-Bis-trifluoromethyI-phenylsulfanylmethyl)-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide (VI) was added acetic acid (40ml) and dissolved. Heated to 50°C and added (30%) hydrogenperoxide solution(5.85 ml) slowly. Maintained heating at 80 °C for 1 h . Water(l lOml) was added and chilled to 5°C and filtered the solid. Dissolved the solid in 50ml dichloromethane and dried over anhydrous sodium sulphate and concentrated under vacuum to get solid N-[5-(3,5-Bis-trifluoromethyl-benzene sulfonyl methyl)-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide(XI). Yield: 9.5g

Example-8
Preparation of (6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyriinidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (IX).
N-[4-(4-Fluoro-phenyl)-6-isopropyl-5-(pyridine-2-sulfonylniethyl)-pyrimidin-2-yl]-N-methyl-methanesulfonamide(IV) 7g was taken in Dimethylsulfoxide (35 ml). Heated to 35-40°C.Added potassium carbonate (6.07g) and stirred for 15 minutes .Added (6-Formyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 4.1g dissolved in 14ml Dimethylsulfoxide drop wise. Heated to 75 - 80° C and stirred for 12 h. Added toluene 70ml and brought the temperature to 25°C. Filtered the insoluble from the reaction mixture and the clear filtrate was washed with water 20ml. Aqueous layer separated was extracted twice with toluene(25 Ml). Organic layers were combined and given water wash (15 ml) followed by a brine wash (15 ml). Concentrated the organic layer after drying over anhydrous sodium sulphate to get the crude solid of title product. The solid obtained was dissolved at 60°C in methanol(35ml) and stirred at 25°C for 1 h and then at 0° C for Ih . Filtered the solid and washed with chilled Methanol .Dried the solid at 45 ° C under vacuum to get (6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyrimidin-5 -yl] -vinyl} -2,2-dimethyl- [ 1,3] dioxan-4-yl)-acetic acid tert-butyl ester (IX). Yield: 6g
Example-9
Preparation of (6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyI-
amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl
ester
N-[5-(3,5-Bis-trifluoromethyl-benzene sulfonyl methyl)-4-(4-fluoro-phenyI)-6-isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide(VII) 7g was taken in Dimethylsulfoxide (35 ml). Heated to 35-40°C. Added potassium carbonate (4.733g) and stirred for 15 minutes. Added (6-Formyl-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester 3.24g dissolved in 14ml dimethylsulfoxide drop wise. Heated to 75 - 80° C and stirred for 12 h. Added toluene 70ml and brought the temperature to 25°C. Filtered the insoluble from the reaction mixture and the clear filtrate was washed with water 20ml. Aqueous layer separated was extracted twice with toluene (25 ml). Organic layers were combined and given water wash (15 ml) followed by a brine wash (15 ml). Concentrated the organic layer after drying over anhydrous sodium sulphate to get the crude solid of title product. The solid obtained was dissolved at 60°C in methanol(35ml)

and stirred at 25°C for 1 h and then at 0° C for Ih . Filtered the soHd and washed with chilled Methanol .Dried the solid at 45 ° C under vacuum to get (6-{2-[4-(4-Fluoro-,phenyl)-6-isopropyI-2-(methanesulfonyl-methyl-amino)-pyrimidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (IX). Yield: 6g
ExampIe-10
Preparation of Rosuvastatin calcium
(6-{2-[4-(4-Fluoro-phenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)-pyriniidin-5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (IX) lOg was taken in 145ml acetonitrile and added 200ml of (0.02M) hydrochloric acid solution slowly at 35° C-40° C and stirred at the same temperature for 3 hrs. Brought the temperature to 25°C and added 20 ml of IM sodium hydroxide solution slowly and continued stirring at 25°C for one hour. Adjusted the pH to 9 using 0.5N hydrochloric acid solution and filtered the reaction mass through celite. The filtrate was concentrated and added acetonitrile 20ml and concentrated completely. Dissolved the concentrated mass in 15ml methanol,30 ml methyltertiarybutyl ether and 100 ml water. Seperated the layers. Aqueous layer was washed twice with methyltertiarybutyl ether (20ml). pH of the aqueous layer was adjusted to 8-8.2 using 0.5N hydrochloric acid solution. Aqueous layer was warmed to 40 °C and added Calcium acetate (2.74g) dissolved in (13.7 ml) water. Reaction mixture was stirred at 40 °C for one hour and then at 25 °C for 3 hours. Solid obtained was filtered and washed with water (10 ml). Dried the material at 45 "C under vacuum to get rosuvastatin calcium. Yield: 7g.

We claim:
1. Process for the preparation of the compound IX comprises,

a. Reacting N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2-yl]-
N-methyl-methanesulfonamide with compound of formula R Wherein R is selected from the group



b. The compound of formula V is oxidized with oxidizing agents results a compound

c. Reacting the compound of formula VIII with an aldehyde of formula X

in presence of an alkali and alkaline earth metal bases in a suitable solvent to provide compound of formula-IX.

2. The process according to claim 1, wherein suitable base is selected from the group
Butyl lithium, Potassium carbonate, Sodium ethoxide, sodium methoxide and
Cesium carbonate.
3. The process according to claim 1, wherein oxidizing agent is selected from the
group MCPBA, Hydrogen peroxide and Peraceticacid.
4. The process according to claim 1, wherein alkali and alkaline earth metal bases
are selected from Potassium carbonate. Sodium ethoxide and sodium methoxide
5. The process according to claim 1, wherein suitable solvent is selected from the
group toluene, tetrahydrofuran, Dimethylsulfoxide, Dimethylformamide and N-
methylpyrrolidine.
6. A compound of formula V



8. A process for preparation of compound IX is substantially as herein described along with accompanying examples.