WO2008093205A2

WO2008093205A2 - A method for the purification of rosuvastatin intermediate

Info

Publication number: WO2008093205A2
Application number: PCT/IB2008/000189
Authority: WO
Inventors: Upparapalli Sampath Kumar; Subramaniyan Mannathan; Natarajan Sabrinathan; Anand Sivadas; Senthilnathan Palanivel; Siripragada Mahender Rao
Original assignee: Orchid Chemicals & Pharmaceuticals Limited
Priority date: 2007-01-31
Filing date: 2008-01-29
Publication date: 2008-08-07
Also published as: WO2008093205A3

Abstract

The present invention relates to a method for the purification of an intermediate of formula (1), which is useful for the preparation of Rosuvastatin and its pharmaceutically acceptable salts thereof, more particularly purification method comprises the addition of aqueous organic acid such as acetic acid under stirring conditions in presence of an organic solvent such as isopropyl ether or alternatively the purification method comprises the addition of aqueous alcohol such as methanol under stirring conditions in presence of an organic solvent such as isopropyl ether (Formula I)

Description

'A METHOD FOR THE PURIFICATION OF ROSU VASTATIN

INTERMEDIATE'

Field of the invention

The present invention relates to a method for the purification of an intermediate of foπnula (I), which is useful for the preparation of Rosuvastatin and its pharmaceutically acceptable salts thereof.

(ϊ)

Background of the invention

Rosuvastatin and its pharmaceutically acceptable salts are HMG CoA reductase inhibitors and have use in the treatment of, inter alia, hypercholesterolemia and mixed dyslipidemia. Rosuvastatin calcium of formula (II) illustrated below is marketed under the trademark Crestor™ and was developed by Shionogi for the treatment of hyperlipidemia.

(II) European Patent Application, Publication No. 0521471 discloses (E)-7-[4-(4-fluorophenyl)- 6-isopropyl-2-[N-methyl-N-(methylsulfonyl)amino]pyrimidin-5-yl](3R,5S)-3,5-dihydiOxy- (E)-6-heptenoic acid (Rosuvastatin) and its sodium salt and calcium salt (Rosuvastatin calcium) and a process for their preparation.

Among many of the important intermediates of Rosuvastatin, methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsιilfonylamino)pyrimidin-5- yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate of formula (I) illustrated below is one of the key intermediate.

(D

U.S. Reissue Patent No. 37,314 (henceforth '314) discloses the preparation of Rosuvastatin calcium; wherein the key intermediate of formula (I) was purified by subjecting it to column chromatography over silica gel and eluting with methylene chloride. The yield thus obtained is only 71.3%.

PCT Publication No.WO 2003 / 097614 A2₅ discloses the use of cyclohexane for the purification of intermediate of formula (I), wherein the said intermediate is subjected to repeated treatment with cyclohexane at a temperature range of 10 tol2°C with 100% yield.

However, as disclosed in most of the patents and publications that the purification of the said inteπnediate of formula (I) using column chromatography leads to many problems on an industrial scale, moreover PCT publication No. WO 2006 / 091771 A2 revealed that said intermediate of formula (I), obtained by the processes well known in the prior art is only 50% as detected by high performance liquid chromatography (HPLC) by comparing to a standard. It also discloses that salts or non-ultra violet impurities or by-products of degradation, especially in the case of the Wittig reaction, it contaminates the intermediate. Thus there is a need to have a process for the purification of the intermediate methyl 7-[4-(4- fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate of formula (I), which in turn will produce highly pure Rosuvastatin and its pharmaceutically acceptable salts thereof .

Therefore we focused our research on the purification of methyl 7-[4-(4-fluorophenyl)-6- isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate of formula (I) by avoiding column chromatography using substantially better isolation technique using isopropyl ether with either aqueous acetic acid or aqueous methanol in a substantially good yield and high chemical purity and make the process more economical and industrially viable.

Object of the invention

The main objective of the present invention is to provide a method for the purification of compound of formula (I) in good yield and high chemical purity.

Another objective of the present invention is to provide a method for the purification of compound of formula (I), which would be easy to implement on commercial scale and economically viable.

Summary of the invention

The present invention provides a method for the purification of methyl 7-[4-(4-fluorophenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate of formula (I) comprising the steps of:

(D

a) reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde of fonmila (III) and methyl-(3R)-3[[ter-butyl- (dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidine) hexanate of formula (IV) in an organic solvent;

(III) (IV) b) precipitating the by-product (s) using ether as a solvent ; c) isolating the by-product (s) by filtration; d) treating the organic layer with aqueous organic acid; and e) isolating the purified methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo-(E)- 6-heptenate of formula (I).

Alternatively the present invention further provides a method for the purification of methyl 7- [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)- 3-(tert-butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate of formula (I) comprising the steps of:

(I)

a) 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde of foπnula (III) and methyl-(3R)-3[[ter-butyl- (dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidine) hexanate of foπnula (IV) in an organic solvent;

(III) (IV)

b) precipitating the by-product (s) using ether as a solvent; c) isolating the by-product (s) by filtration; d) concentrating the organic layer and treating the residue with aqueous alcoholic solvent; e) isolating the purified methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl- N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-

5-oxo-(E)-6-heptenate of foπnula (I).

Detailed description of the invention Accordingly, the present invention provides a method by which said intermediate of formula (I) is purified using ether and aqueous organic acid.

Alternatively the present invention provides a method by which said intermediate of formula (I) is purified using ether and alcoholic solvent and water.

In one of the embodiments of the present invention the organic solvent employed for the reaction between 4-(4-fiuorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbaldehyde of formula (III) and methyl-(3R)-3[[ter-butyl-(dimethyl)silyl]oxy]- 5-oxo-6-(triphenylphosphoranylidine) hexanate of formula (IV) is acetonitrile. The quantity of solvent acetonitrile used for the reaction is substantially less as compared to the process disclosed in the innovators patent '314, hence the present invention becomes more advantageous, moreover the isolation technique is unique and industrially feasible & commercially viable as compared to the innovators patent '314 by avoiding column chromatography.

In another embodiment of the present invention organic solvent is preferably used in the range of 1 to 5 volumes with respect to a compound of formula (III), most preferably 1 volume

In another embodiment of the present invention, the reaction mass is preferably cooled to

1O⁰C to reflux temperature more preferably 30⁰C to 50° and the solvent is distilled off completely under vacuum.

In another embodiment of the present invention, ether is employed to the reaction mass to precipitate the by product (s) as solid. Said ether is selected from diethyl ether, diisopropyl ether, diisobutyl ether, methyl tertiary butyl ether and the like, most preferably diisopropyl ether.

In another embodiment of the present invention the organic layer is treated with aqueous organic acid which is selected from the group consisting of formic acid, acetic acid and the like most preferably acetic acid.

In yet another embodiment of the present invention the alcoholic solvent employed in the purification step is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.

In yet another embodiment of the present invention the purified intermediate of formula (I) may be converted in to Rosuvastatin and its pharmaceutically acceptable salts by conventional methods.

In the present invention starting material (s) for the preparation of the said intermediate, were prepared according to the known process in the prior art.

The invention is further illustrated by the following examples, which should not be construed to limit the scope of the invention in anyway.

Example (1)

In a reaction vessel 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbardehyde (100 g of formula III), methyl-(3R)-3[[ter-butyl- (dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidine) hexanate (228 g of formula IV) and acetonitrile (10OmL) was added, stirred well and heated to reflux for 10 to 12 hrs. After the completion of the reaction, the reaction mass was cooled to 45° (±5°C), the solvent was distilled off completely under vacuum and diisopropyl ether was added to it at 3O⁰C and stirred at room temperature until the solid precipitates out. The precipitated mass was cooled to 0° to 5°C and stirred for 2 hrs, the solid was filtered under vacuum and washed with cold diisopropyl ether. To the diisopropyl ether layer aqueous acetic acid was added and stirred for about 15 minutes at room temperature. The layers were separated and the organic layer was washed with 5% sodium bicarbonate solution (100 mL), water (100 mL) and brine (100 mL). The solvent was distilled completely under vacuum at 40°C (+5⁰C) to obtain a thick yellowish pasty mass of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyIdimethylsilyloxy)-5-oxo-(E)-6- heptenate of formula (I) with 100 % yield and 88% of purity by HPLC.

Example (2) In a reaction vessel 4-(4-fluorophenyl)-6-isopropyl-2-(N--methyl-N-methylsulfonylamino)-5- pyrimidinecarbardehyde (100 g of formula III) and methyl-(3R)-3[[ter-butyl- (dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidine) hexanate (228 g of formula IV) and acetonitrile (100 mL) was added stirred well and heated to reflux for 10 to 12 hrs. After the completion of reaction the reaction mass was cooled to 45° (+5⁰C), the solvent was distilled off completely under vacuum and diisopropyl ether was added at 30⁰C and stirred at room temperature until the solid precipitates out. The precipitated mass was cooled to 0° to 5⁰C and stirred for 2 hrs, the solid was filtered under vacuum and washed with cold diisopropyl ether. The diisopropyl ether layer was distilled under vacuum completely, methanol (IVoI) and water (lOVol.) was added and stirred for 15 minutes at room temperature. The layers were separated and the organic layer was distilled completely under vacuum at 40°C±5°C to obtain a thick yellowish pasty mass of methyl 7-[4-(4-fluoroρhenyl)- 6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert- butyldimethylsilyloxy)-5-oxo-(E)-6-heptenate of formula (I) with 100% yield and 95% of purity by HPLC.

Claims

WE CLAIM:

1. A method for the purification of methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)- 5-oxo-(E)-6-heptenate of formula (I) comprising the steps of:

(D

a) reacting 4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)-5- pyrimidinecarbardehyde of formula (III) and methyl-(3R)-3[[ter-butyl- (dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidine) hexanate of formula (IV) in an organic solvent;

(III) (IV) b) precipitating the by-product (s) using ether as a solvent ; c) isolating the by-product (s) by filtration; d) treating the organic layer with aqueous organic acid; and e) isolating the purified methyl 7-[4-(4-fluorophenyl)-6-isoρropyl-2-(N-methyl-N- methylsulfonylamino)pyrim i din-5 -yl] -(3R)-3 -(tert-butyldimethylsilyloxy)-5 -oxo- (E)-ό-heptenate of formula (I).

2. A method for the purification of methyl 7-[4-(4-fiuorophenyl)-6-isopropyl-2-(N- methyl-N-methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)- 5-oxo-(E)-6-heptenate of formula (I) comprising the steps of:

(I)

a) 4-(4-fluorophenyl)-6-isopropyl-2-(N -methyl-N-methylsulfonylamino)-5 -pyrimi dinecarbardehyde of formula (III) and methyl-(3R)-3[[ter-butyl-

(dimethyl)silyl]oxy]-5-oxo-6-(triphenylphosphoranylidine) hexanate of formula (IV) in an organic solvent;

(in) (IV) b) precipitating the by-product (s) using ether as a solvent; c) isolating the by-product (s) by filtration; d) concentrating the organic layer and treating the residue with aqueous alcoholic solvent; e) isolating the purified methyl 7-[4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N- methylsulfonylamino)pyrimidin-5-yl]-(3R)-3-(tert-butyldimethylsilyloxy)-5-oxo- (E)-β-heptenate of formula (I).

3. A method according to claim no.l and 2, wherein the said organic solvent is acetonitrile.

4. A method according to claim no. 1 and 2, wherein the said ether is selected from diethyl ether, diisopropyl ether, diisobutyl ether, methyl tertiary butyl ether, most preferably diisopropyl ether.

5. A method according to claim no. 1, wherein the said organic acid is selected from the group consisting of formic acid, acetic acid, most preferably acetic acid.

6. A method according to claim no. 2, wherein the said alcoholic solvent is selected from the group consisting of methanol, ethanol, n-propyl alcohol, isopropyl alcohol, n-butanol, isobutanol, tertiary butanol, and mixtures thereof; most preferably methanol.

7. An intermediate of formula (I) thus obtained from the method claimed in claim no.

1 and 2 is useful in the preparation of Rosuvastatin and its pharmaceutically acceptable salt (s) thereof.

8. A method according to claim no. 1 and 2, wherein the said organic solvent is preferably used in the range of 1 to 5 volumes with respect to a compound of formula (III), most preferably 1 volume.

9. A method according¹ to claim no. 1 and 2, wherein the reaction is performed at a temperature in the range of 10° C to reflux temperature.