WO2010023678A1

WO2010023678A1 - A process for preparation of rosuvastatin intermediate

Info

Publication number: WO2010023678A1
Application number: PCT/IN2008/000655
Authority: WO
Inventors: Sreenivasa Prasad Anegondi; Shanmughasamy Rajmahendra; Jibin Joseph; Pullela Venkata Srinivas
Original assignee: Biocon Ltd
Current assignee: Biocon Ltd
Priority date: 2008-08-27
Filing date: 2008-10-10
Publication date: 2010-03-04
Anticipated expiration: 2011-02-27

Abstract

The present invention provides an improved process for the preparation of intermediates involved in the preparation of rosuvastatin. Particularly, the proposed invention is able to overcome the disadvantages associated with the known methods. Thus, the instant invention provides a process which is clean, economic, industrially scalable and provides high yields with substantially pure product.

Description

A PROCESS FOR PREPARATION OF ROSUVASTATIN INTERMEDIATE

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, arid 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, VoL31, 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. STATEMENT OF THE INVENTION

Accordingly, the present invention provides for a 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

in the presence of a suitable base with a suitable solvent to provide a novel sulfide compound of formula V.

Wherein Ri is

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

Wherein R₂ is

or

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; a compound of formula V

V Wherein Ri is

and a compound of formula

VII

Wherein R₂ is

or

DETAILED DESCRIPTION OF THE INVENTION

The present invention is in relation to a process for the preparation of the compound IX comprises,

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

Wherein R_x is

Or

VIII

Wherein R₂ is

or

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.

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 present invention relates to a compoμnd of formula V

Wherein Ri is

or

The present invention relates to a compound of formula

VII

Wherein R₂ is

or

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.

IX

VIII

Wherein Rj is

_or

Wherein R₂ is

or

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. N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2;yl]-N-methyl- methanesulfonamide is reacted with thiol compound of formula R

Where R is

or 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 {Hoi 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.

Intermediate IX is an important intermediate for the preparation of Rosuvastatin calcium which is a HMG Co-A reductase inhibitors.

1. Reacting N-[5-Bromomethyl-4-(4-fluoro-phenyl)-6-isopropyl-pyrimidin-2- yrj-N-methyl-rnethanesulfonamide with compound of formul R

Where R is

or . in presence of a suitable base selected from the group BuLi, Potassium carbonate, Sodium ethoxide, sodium methoxide and. Cesium carbonate with or without a suitable solvent to provide a novel sulfide compound of formula V.

2. The compound obtained from step 1 is oxidized with oxidizing agents selected from the group MCPBA, Hydrogen peroxide, Peraceticacid results novel compound of formula VIII.

3. 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 polar aprotic solvent selected from Dimethylsulfoxide, Dimethylformamide and N- methylpyrrolidine to provide compound of formula-IX.

The process of the present invention is an improved, economical, commercially feasible and clean method for preparing novel intermediate used for the preparation of HMG CoA reductase inhibitors. The process of the present invention is outlined in Scheme-I, Scheme-II and Scheme-Ill.

The present invention details a process for the preparation of novel intermediate of formula V from compounds of the Formula

Further oxidation of formula V will lead to get novel intermediate of formula VIII.

Scheme-I

Scheme-II

Scheme-Ill

ROSUVASTATIN CALCroM The technology of the instant Application is further elaborated .with the help of following 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-methyI-methanesuIfonamide

N-[4-(4-Fluoro-phenyl)-5-formyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methanesulfonamide 1Og was taken in tetrahydrofuran (6OmL) and methanol (2OmL) and chilled the reaction mixture to 5 to 1O⁰C. Added sodiumborohydride (0.9Ig) 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 5OmL ethylacetate and separated the layers. Extracted the aqueous layer with ethyl acetate (6OmL). Combined the organic layers and given water wash (4OmL) followed by a brine wash (2OmL). 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: 1Og.

Example-2

Preparation of N-[5-Bromomethyl-4-(4-fluoro-phenyI)-6-isopropyI-pyrimidin-2- yI]-N-methyI-methanesulfonamide (I)

N-[4~(4-Fluoro-phenyl)-5-hydroxymethyl-6-isopropyl-pyrimidin-2-yl]-N-methyl- methanesulfonamide (1Og) was taken in 5OmL of toluene and dissolved at 30° C. Added 49% aqueous hydrogenbromide solution(7.5mL) and refluxed at HO⁰C 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. Separated 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-ylsulfanylmethyl)- pyrimidin-2-yI]-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(l 1.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 -70⁰C drop wise and stirred for 15 minutes at -60 to-70° C. Slowly brought the temperature to 25⁰C and stirred for 2 h. Adjusted the pH of the reaction mixture to 7-8 with saturated ammonium chloride and added 5OmL 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- Fluoro-phenyl)-6-isopropyl-5-(pyridin-2-ylsulfanylmethyl)-pyrimidin-2-yl]-N-methyl- methanesulfonamide (V) Yield: 11. Og

Example-4

Preparation of N-[4-(4-FIuoro-phenyl)-6-isopropyI-5-(pyridine-2-sulfonyImethyl)- pyrimidin-2-yl]-N-methyI-methanesuIfonamide (IV) To N-[4-(4-Fluoro-phenyl)-6-isopropyl-5-(pyridin-2-ylsulfanylmethyl)-pyrimidin-2- yl]-N-methyl-methanesulfonamide (III) Hg was added acetic acid (44mL) and dissolved. Heated to 50⁰C and added (30%) hydrogen peroxide solution (8.4mL) slowly. Maintained heating at 80 ⁰C for 1 h. Water (HOmL) was added and chilled to

5°C and filtered the solid. Dissolved the solid in 5OmL 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-dimethyI-[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 1Og 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 lO mL dichloromethane. Added 60 mL sodium hypochlorite solution (0.5M) maintaining the temperature at 0 ⁰C. Stirred at 0⁰C for 30 minutes. Added water(10 mL) and separated the organic layer. Aqueous layer was extracted with ^' dichloromethane (1OmL). Organic layers were combined and given (2OmL) 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 methyI)-4-(4-fluoro- phenyl)-6-isopropyI-pyrimidin-2-yl]-N-methyI-methanesulfonamide (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 5OmL 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-trifluoromethyl-benzene sulfonyl methyl)-4-(4-fluoro- phenyl)-6-isopropyI-pyrimidin-2-yI]-N-methyl-methanesulfonamide(VII).

To 1Og of N-[5-(3,5-Bis-trifluoromethyl-phenylsulfanylmethyl)-4-(4-fluoro-phenyl)-6- isopropyl-pyrimidin-2-yl]-N-methyl-methane sulfonamide (VI) was added acetic acid (4OmL) and dissolved. Heated to 50⁰C and added (30%) hydrogenperoxide solution(5.85 mL) slowly. Maintained heating at 80 ⁰C for 1 h . Water(l lOmL) was added and chilled to 5°C and filtered the solid. Dissolved the solid in 5OmL 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)-pyrimidin-5-yI]-vinyl}-2,2-dimethyI-[l,3]dioxan-4-γπ-acetic acid tert-butyl ester (IX).

N-[4-(4-Fluoro-phenyl)-6-isopropyl-5-(pyridine-2-sulfonylmethyl)-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 7OmL and brought the temperature to 25⁰C. Filtered the insoluble from the reaction mixture and the clear filtrate was washed with water 2OmL. 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 60⁰C 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- [l,3]dioxan-4-yl)-acetic acid tert-butyl ester (IX).

Yield: 6g

Example-9

Preparation of (6-{2-[4-(4-FIuoro-phenyI)-6-isopropyl-2-(methanesulfonyl-methyl- 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-phenyl)-6- isopropyl-pyrimidin-2-yl]-N-methyl-methanesulfonamide(VII) 7g was taken in Dimethylsulfoxide (35 mL). Heated to 35-4O⁰C. 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 7OmL and brought the temperature to 25⁰C. Filtered the insoluble from the reaction mixture and the clear filtrate was washed with water 2OmL. 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 60⁰C 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-[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)-pyrimidin- 5-yl]-vinyl}-2,2-dimethyl-[l,3]dioxan-4-yl)-acetic acid tert-butyl ester (IX) 1Og 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 25⁰C 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 2OmL 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 (2OmL). pH of the aqueous layer was adjusted to 8-8.2 using 0.5N hydrochloric acid solution. Aqueous layer was warmed to 40 ⁰C and added Calcium acetate (2.74g) dissolved in (13.7 mL) water. Reaction mixture was stirred at 40 ⁰C for one hour and then at 25 ⁰C for 3 hours. Solid obtained was filtered and washed with water (10 mL). Dried the material at 45 ⁰C under vacuum to get rosuvastatin calcium. Yield: 7g.

Claims

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

Wherein Ri is

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

VIII

Wherein R₂ is

or

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

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, Dimethyϊformamide and N- methylpyrrolidine.

6. A compound of formula V

Wherein Ri is

or

7. A compound of formula

VII Wherein R₂ is

or