WO2005077928A1

WO2005077928A1 - Improved process for producing simvastatin

Info

Publication number: WO2005077928A1
Application number: PCT/IN2005/000043
Authority: WO
Inventors: Paramvir Bhadwal; Pratima Jain; Rajesh Kumar Thaper; Sushil Kumar Dubey; Jag Mohan Khanna
Original assignee: Jubilant Organosys Limited
Priority date: 2004-02-12
Filing date: 2005-02-11
Publication date: 2005-08-25

Abstract

Disclosed herein is an industrially feasible process for producing HMG-CoA reductase inhibitor, simvastatin, via an improved acylation process using lovastatin ammonium salt as a starting material. The process comprising treating lovastatin ammonium salt with a base to obtain the compound of formula [III], lactonizing the compound of the formula [III] to obtain compound of formula [IV], selectively protecting the hydroxyl group of the compound of formula [IV] to obtain compound of formula [V], acylating the compound of formula [V] with dimethylbutyrylchloride using potassium halide in presence of a solvent to obtain compound of formula [VI], deprotecting compound of formula [VI] followed by hydrolysis to obtain simvastatin ammonium salt of formula [VII] which is lactonized to obtain simvastatin.

Description

IMPROVED PROCESS FOR PRODUCING SIMVASTATIN

Field of the Invention This invention, in general, relates to the field of HMG-CoA reductase inhibitor and in particular to simvastatin. More specifically, the present invention provides an industrially viable process for producing simvastatin via an improved acylation process using lovastatin ammonium salt as a starting material.

Background of the Invention It is known that simvastatin [1] inhibits cholesterol biosynthesis by inhibiting the enzyme HMG-CoA reductase. It possesses a 2,2-dialkylbutyrate C-8 side chain and is a better inhibitor of HMG-CoA reductase than its 2-alkylbutyrate counterpart.

[1]

There are two major approaches for the alkylation of 2-methyl butyrate chain reported in the prior art.

The first approach is direct alkylation of the 2-methylbutyrate chain which involves six steps: (a) deactivation of α- methylene protons at C-5 position of pyranone moiety by protection of the carboxyl group e.g. by making amide derivative; (b) protecting the two hydroxyl groups e.g. via silyl protection; (c) alkylation of α -hydrogen atom of butyrate chain preferably using lithium pyrrolidide; (d) deprotection of hydroxyl groups in acidic medium; (e) hydrolysis of carboxyl protecting group e.g. amides under basic condition to restore simvastatin dihydroxy acid derivative and isolating it preferably as ammonium salt; and (f) relactonization to give lactonized compound. The other approach involves deacylation of the C-8 side chain followed by reacylation through several chemical steps as described in US Pat. No. 4,444,784. The process comprises de-esterification of 2-methylbutyrate side chain of lovastatin; protection of the 4-hydroxyl group of the pyranone ring with t-butyldimethylchlorosilane; re-esterification of the protected lactone compound with 2,2-dimethylbutyryl chloride and deprotection of the hydroxyl group of the pyranone ring. This approach has several disadvantages, like high temperature and long reaction time in the hydrolysis and acylation steps, which leads to a number of undesired side products causing low yield and low purity of simvastatin. Apart from side products, unconverted starting material additionally complicate the isolation of pure simvastatin and lower the yield of the disclosed process.

United States Patent No. 4,845,237 discloses a process wherein acyl chloride is activated by an alkali metal bromide more specifically lithium bromide and 4-dialkylaminopyridine, which is further used for acylation of silyl protected diol lactone. However this process has certain disadvantage that acyl chloride is prepared from carboxylic acid, and the lithium bromide involved in activation of acyl chloride require special treatment such as drying at high temperature at 135°C for three days under vacuum condition and stored in dried condition as it is hygroscopic in nature. If the wet lithium bromide is added, the yield is lower due to the formation of the by-product.

United States Patent No. 5,159,104 relates to a process that comprises sequential acylation of diol lactone [IN] to form bis acylated intermediate followed by selective deacylation and lactone ring closure to form simvastatin.

United States Patent No. 6,384,238, and United States Patent No 6,576,775 discloses a process wherein protected diol lactone is acylated by acyl chloride in presence of metal chloride or bromide, or with activated carboxylic acid; the carboxylic acid is activated with trialkylphosphine and halogen compounds followed by deprotection of the acylated compound to give simvastatin.

The processes disclosed in the prior art suffer from one or more disadvantages like longer reaction time, expensive reagents, multiple steps and low purity of the final product. Therefore, there is a need for an industrially feasible process for the preparation of simvastatin, which involves minimum chemical steps, is less time consuming, economical by use of inexpensive reagents, and uses cheaper starting material. The present invention addresses these needs.

Summary of the Invention In accordance with the principal aspect of the present invention, there is provided an industrially feasible process for producing simvastatin of formula [1], the process comprises of, treating lovastatin ammonium salt of formula [II], with a base to obtain compound 7-[l ',2',6',7^r,88a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)-hydroxy-l '(S)- naphthyl]-3(R),5(R)-dihydroxy heptanoic acid of formula [III], lactonizing the compound of formula [111] to obtain compound 6(R)-[2-(8(S)-hydroxy-2'(S),6'(R)-dimethyl- 1 ',2 ',6 ',1 ',8 ',8a'(R)-hexahydro-naphthyl-l ^,(S))ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro- 2H-pyran-2-one of formula [IN], selectively protecting the hydroxyl group of the compound of formula [IN] to obtain compound 6(R)-[2-(8(S)-hydroxy-2'(S),6'(R)- dimethyl-1 ',2 ',6',7 ',8 ',8a'(R)-hexahydro- naphthyl-1 '(S))ethyl]-4(R)-(dιmethyl-tert- butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one of formula [V], acylating the compound of formula [N] using acyl halide to obtain compound 6(R)-[2-(8(S)-2",2"- dimethylbutyryloxy-2 '(S),6 '(R)-dimethyl-l ',2 ',6 ' ,1 ',8 ',8a'(R)-hexa-hydronaρhthyl- 1 '(S))ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one of formula [VI], deprotecting the compound of formula [VI] followed by hydrolysis to obtain simvastatin ammonium salt of formula [Nil], which is lactonized to obtain simvastatin.

In accordance with the other aspect of the present invention, there is provided an industrially feasible process for producing simvastatin of formula [1] wherein lovastatin ammonium salt of formula [II] is used as a starting material in the de-esterification reaction to produce diol lactone of formula [IN] via the formation of triol acid of formula [III] which provides commercial viable and time efficient process.

In accordance with yet another aspect of the present invention, there is provided an industrially feasible process for producing simvastatin of formula [1] wherein compound 6(R)-[2-(8(S)-2 ' ',2 ' '-dimethylbutyryloxy-2 '(S),6 '(R)-dimethyl-l ',2 ',6 ' ,1 ',8 ',8a'(R)-hexa- hydronaphthyl-r(S))ethyl]-4(R)-(dimethyl-tert-butyl silyloxy)-3,4,5,6-tetrahydro-2H- pyran-2-one of formula [VI] is prepared by acylation of protected intermediate 6(R)-[2- (8(S)-hydroxy-2'(S),6'(R)-dimethyl-l ',2',6',7',8',8a'(R)-hexahydronaphthyl-r(S))ethyl]- 4(R)-(dimethyl-tert-butylsilyloxy)-3,4,5,6-tetrahydro-2H-pyran-2-one of formula [V] using dimethylbutyrylchloride in presence of potassium halide and solvent to effect the faster reaction and better yield.

Description of the Invention The disclosed embodiment of the present invention deals with an improved process for the preparation of simvastatin [1], which is economically viable and is a large scale manufacturing process and obviates the disadvantages mentioned in prior art.

[II] [III] [IV]

[I] R₂= hydroxyl protecting group Synthetic Scheme According to the present invention, lovastatin ammonium salt [H] undergo ester hydrolysis to form compound of the formula [III] in presence of a base and optionally in presence of small amount of water under mild conditions. The base used herein is selected from hydroxides or alkoxides of alkali metal or alkaline earth metal of lithium, sodium, potassium and magnesium in an amount corresponding to 10-12 moles and most preferably 8-9 moles. The reaction takes place in presence of inert organic solvent e.g tetrahydrofuran. The reaction takes place at a temperature of 0 to -30°C most preferably between -10°C to -30°C.

The disclosed compound of the formula [III] obtained after the hydrolysis step undergo lactonization employing suitable lactonizing agent. The lactonizing agent used herein is selected from formic acid, acetic acid, methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid or trifluoroacetic acid. The reaction takes place in presence of water immiscible solvents or mixture thereof. Preferably the solvent is selected from the group comprising ethyl acetate, propyl acetate, butyl acetate, methyl propionate, diethyl ether, diisopropyl ether, methyl tertiary butyl ether, dichloromethane, chloroform, carbon tetra chloride or mixture thereof. The reaction is carried out at an elevated temperature, preferably at the reflux temperature of the reaction mixture depending upon the solvent used.

The use of lovastatin ammonium salt [II] as a starting material in the de-esterification reaction to produce diol lactone of formula [IN] via the formation of triol acid [III] has tremendous commercial benefit in terms of cheaper raw material, enhanced yield, reduced labour cost and less consumption of reagents.

The process disclosed herein also provides an optional process step wherein the hydroxyl group of compound of the formula [IV] is selectively protected with hydroxyl protecting groups in presence of a base e.g. imidazole to obtain protected lovastatin intermediate [N] which can participate in the further process step for producing simvastatin [1], wherein the hydroxyl protecting group is selected from a silylgroup, borate group, cyclic ether group, cyclic thioether group, , an acetal, , cyclic acetals, cyclic ketals and the like. More preferably the protecting groups are selected from the group comprising trimethylsilyl, triethylsilyl, dimethylhexylsilyl, diethylisopropylsilyl, tribenzylsilyl, tri- -xylylsilyl, dimethylisopropylsilyl, tert-butyldimethylsilyl, tβrt-butylmethoxyphenylsilyl, t- butyldiphenylsilyl, diisopropylmethylsilyl, (triphenylmethyl)dimethylsilyl, diphenylmethylsilyl, triisopropylsilyl, triphenylsilyl, t-butylmethoxyphenylsilyl, t- butoxydiphenylsilyl, phenyl boronic acid, tetrahydropyran-2-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydropyran-2-yl, l,4-dioxane-2-yl, 1,3 dioxolanes, 4,6-dimethyl-l,3 dioxane, tetrahydrofuran-2-yl, acetonide and the like.

The reaction takes place optionally in presence of solvent selected from inert organic solvent e.g. tefrahydrofuran. The reaction is carried out at an elevated temperature, preferably at the reflux temperature of the reaction mixture depending upon the solvent used.

The resulting protected intermediate compound of the formula [V] is acylated with acyl chloride preferably 2,2 dimethylbutyrylchloride in presence of potassium halide wherein the halide is selected from F, Cl, Br or I. The reaction takes place in presence of solvent e.g. N methyl morpholine, N-methyl pyrrolidine or mixture to give simvastatin derivative of the formula [VI]. The use of the potassium halide leads to the faster reaction and thus better yield.

The resulting simvastatin derivative of the formula [VI] is subjected to deprotection and I hydrolysis according to the prior art method by treatment with acid such as hydrochloric acid, nitric acid, sulphuric acid in presence of inert organic solvent e.g tefrahydrofuran and the resulting compound is then subjected for base hydrolysis to obtain simvastatin ammonium salt of the formula [VII] which is relactonized in presence of solvent e.g toluene under reflux while removing the water azeotropically in an inert atmosphere. The resulting simvastatin is further purified according to the known methods i.e using a mixture of methanol and water.

The present invention is further described in greater detail as illustrated in non-limiting examples. It should be understood that variation and modification of the process are possible within the ambit of the invention broadly disclosed herein. Example-1

Preparation of 7-f 1 \2. '6 ' .1 P8 P8a^,(R)-hexahvdro-2TS .6 YRVdimethyl-8 YSVhvdroxy- lϊSVnaτ,hthyll-3(R .5(R -dihvdroxyheptanoic acid mil

Tefr_ιhydrofuran (400 ml) and water (10 ml) were taken and cooled to -10°C using ice salt mixture. Lovastatin ammonium salt (100 gm) and potassium tertiary butoxide (203 gm) were added at above temperature. The mixture was stirred for 8-10 hours at 20-25°C. The solvent was distilled off under reduced pressure and water was added. The mixture was acidified by adding 2N HC1 solution. The solution was extracted using ethyl acetate, washed with water and the organic layer was concentrated to obtain 72 gm of title compound. Yield (86%).

Example-2

Preparation of 6(RVf2-(8 (SVhvdroxy-2TS .6 YRVdimethyl-1 ^,.2^,.6^,,7\8^,.8aϊR - hexahydro- naphthyl-1 TS ethyl]-4(R -hvdroxy-3.4,5.6-tetrahvdro-2H-pyran-2-one [IV] 7-[l ',2',6',7',8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8 S)-hydroxy-l '(S)-naphthyl- 3(R), 5(R)-dihydroxyheptanoicacid (72 gm) was dissolved in dichloromethane (300 ml) and p-toluene sulfonic acid (4 gm) was added. The reaction mixture was stirred at 25-30°C for 4-5 hours. After completion of reaction, dichloromethane was distilled off completely under vacuum, followed by addition of ethyl acetate. The ethyl acetate layer was extracted, washed with water and solvent was distilled off to obtain 67.5 gm of title compound. Yield (99%).

Example-3

Preparation of 6(R -[2-(8ΪS -hvdroxy-2ΪS .6ΪR -dimethyl-i;.2 6^,.7\8\8a^,(R - hexahvdro naphthyl-l ϊS ethyll-4(R -(dimethyltertbutylsilyloxy -3.4.5.6-tetrahydro-2H- pyran-2-one [V]

6(R)-[2-(8 '(S)-hydroxy-2 '(S),6 '(R)-dimethyl-l ',2 ',6 ',7 ',8 ',8a'(R)-hexahydronaphthyl- l'(S) ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (60gm) was dissolved in dichloromethane (300 ml). Imidazole (23 gm) and t-butyldimethylchlorosilane (46 gm) were successively added. The reaction mixture was stirred at 20-25°C for 6-8 hours. The mixture was filtered, washed with water and finally with brine solution. The organic layer was separated, dried and solvent was distilled off to obtain 78 gm of title compound. Yield (96%). Example-4

Preparation of 6(RVr2-(8 YSV2 " .2' Pdimethylbutyryloxy-2 '(S\6 YRVdimethyl-

3.4.5.6-tetrahvdro -2H-pyran-2-one TVII

6(R)-[2-(8 '(S)-hydroxy-2 '(S),6 '(R)-dimethyl-l ' ,2 ',6 ' ,1 ',8 ',8a'(R)-hexahydronaphthyl- l'(S)) ethyl]-4(R)-(dimethyltertbutylsilyloxy)-3,4,5,6-tetrahydro-2H-ρyran-2-one (50 gm) was taken in N-methyl morpholine (250 ml) under inert atmosphere. Potassium iodide (9.2 gm) and 2,2-dimethylbutyryl chloride (40 gm) were added and the resulting mixture was refluxed for 4-5 hours. The mixture was cooled and then water and ethyl acetate was added. The organic layer was separated, washed with 2N HC1 and saturated brine solution. The organic layer was distilled off to obtain 58.8 gm of title compound as brown oil. Yield (100%). Example-5

Preparation of ammonium 7-[l \2\6 7^,,8 8a'(R -hexahvdro-2TS .6ΪR -dimethyl-8ΪS - [2,2-dimethylbutanoyl]oxy-l YSVnaphthyl]-3(R .5(R -dihydroxy heptanoate [Vll] 6(R)-[2-(8 '(S)-2 ' ',2 ' '-dimethylbutyryloxy-2 '(S),6 '(R)-dimethyl- 1 2 ',6 ' ,1 ',8 \8a'(R)- hexa-hydronaphthyl-r(S))ethyl]-4(R)-(dimethyltertbutylsilyloxy)-3,4,5,6-tetrahydro-2H- pyran-2-one (90 gm) was taken in tefrahydrofuran (400 ml). The solution was cooled to 5°C, concentrated hydrochloric acid (40 ml) was added. The mixture was stirred for 4-5 hours at above temperature. After completion of reaction, sodium hydroxide solution (30%) was added at a temperature 0-10°C. The temperature of the mixture was then raised upto 60°C and stirrer for 2 hours at same temperature. After completion of reaction, solvent was distilled off under vaccum, and water was added. The solution was acidified with 2N hydrochloric acid and extracted with ethyl acetate. The organic layer was separated and pH was adjusted between 8 and 8.5 using ammonium hydroxide : methanol solution (1:1) to obtain 64 gm of title compound as solid. Yield (80%). Example-6

Preparation of 6(RV f2-(8 TSV2 ' \ ' '-dimethylbutyrylloxy-2 TS .6 YRVdimethyl-

1 XT.β' X 8^8aYRyhexahvdronaphthyl-l ΪS) ethyll-4(R -hvdroxy-3.4.5.6-tetrahvdro-

2H-pyran-2-one [1] Ammonium7-[l ',2 ',6 ' ,1 ',8 ',8a'(R)-hexahydro-2 '(S),6 '(R)-dimethyl-8 '(S)-[2,2-dimethyl butanoyl]oxy-l '(S)-naphthyl]-3(R),5(R)-dihydroxy heptanoate (50 gm) was taken in toluene (1250 ml) and refluxed while removing water azeotropically under a constant flow of nitrogen. After reaction completion, toluene was distilled off under vacuum and cyclohexane was added. The resulting reaction mass was cooled to 10-15°C under stirring. The resulting solid was filtered off, dried under vacuum to obtain 45 gm crude simvastatin. Yield (97%).

ExampIe-7 Preparation of pure 6(R -r2-r8^,(S -2P2^,,-dimethylbutyrylloxy-2YS .6YR -dimethyl- 1 \2\6X 1X8 .8aYR -hexahvdronaphthyl-l YS ethyl]-4fRVhvdroxy-3.4.5.6-tefrahvdro- 2H-pyran-2-one.

Crude 6(R)-[2-(8'(S)-2 " , ' Pdimethylbutyrylloxy-2 '(S),6 '(R)-dimethyl-l ',2 ',6 ' ,1 ',8 ',8a' (R)-hexahydronaphthyl-l '(S))ethyl]-4(R)-hydroxy-3,4,5,6-tetrahydro-2H-pyran-2-one (30 gm) was dissolved in methanol (450 ml). To this solution, water was added and stirred for one hour. The resulting solution was cooled to 10-15°C and stirred for one more hour. The resulting solid was filtered off and dried under vacuum to obtain pure title compound.

Certain modifications and improvements of the disclosed invention will occur to those skilled in the art without departing from the scope of invention, which is limited only by the appended claims.

Claims

We Claim: 1. An improved process for the preparation of simvastatin of formula [ 1 ] ,

[1]

comprising the steps of: (a) treating lovastatin ammomum salt of formula [II] with a base to obtain the compound of formula [III];

cm

[III] (b) lactonizing the compound of formula [ILT] in the presence of a lactonizing agent to obtain the compound of formula [IV],

[IV]

(c) selectively protecting the hydroxyl group of compound of formula [IV] with a hydroxyl protecting group to obtain the compound of formula [V],

M wherein, R₂ is hydroxyl protecting group; (d) acylating the compound of formula [V] with an acylating agent using potassium halide in the presence of solvent to obtain the compound of formula [VI],

[VI] wherein, R₂ is hydroxyl protecting group; (e) deprotecting the compound of formula [VI] in acidic condition followed by hydrolysis in the presence of a base to obtain simvastatin ammomum of formula [VII],

[VII] (f) lactonizing the compound of formula [VII] to produce simvastatin of formula [1].

2. The process according to claim 1, wherein the base used in step (a) is selected from the group comprising hydroxides or alkoxides of alkali metal or alkaline earth metal.

3. The process according to claim 2, wherein said alkali or alkaline earth metal is selected from lithium, sodium, potassium or magnesium.

4. The process according to claim 1, wherein lactonizing agent used in step (b) is selected from any of the group comprising formic acid, acetic acid trifluoroacetic acid., methane sulphonic acid, p-toluene sulphonic acid, benzene sulphonic acid.

5. The process according to claim 1, wherein the hydroxyl protecting group used in step (c) is selected from any of the group comprising silyl, borate, cyclic ether, cyclic thioether, an acetal, cyclic acetals, and cyclic ketals.

6. The process according to claim 5, wherein said hydroxyl protecting group is selected from the group comprising trimethylsilyl, triethylsilyl, dimethylhexylsilyl, diethylisopropylsilyl, tribenzylsilyl, tri- -xylylsilyl, dimethylisopropylsilyl, tert- butyldimethylsilyl, tert-butylmethoxyphenylsilyl, t-butyldiphenylsilyl, diisopropylmethylsilyl, (triphenylmethyl)dimethylsilyl, diphenylmethylsilyl, triisopropylsilyl, triphenylsilyl, t-butylmethoxyphenylsilyl, t-butoxydiphenylsilyl, phenyl boronic acid, tetrahydropyran-2-yl, tetrahydrothiopyran-2-yl, 4-methoxytetrahydropyran- 2-yl, l,4-dioxane-2-yl, 1,3 dioxolanes, 4,6-dimethyl-l,3 dioxane, tetrahydrofuran-2-yl, or acetonide.

7. The process according to claim 1, wherein the acylating agent used in step (d) is 2,2-dimethylbutyrylchloride.

8. The process according to claim 1, wherein halide used in step (d) is any of the halogen selected from F, Cl, Br or I.

9. The process according to claim 1, wherein the solvent used in step (d) is selected from any of N-methyl morpholine or N- methyl pyrrolidine or a mixture thereof.

10. The process according to claim 1, wherein the lactonization process of step (f) is carried out by heating.

11. An improved process for the preparation of compound of formula [VI] ,

[VI] wherein R₃ is C1-5 straight or branched chain alkyl, R₂ is hydroxyl protecting group comprising, treating the compound of formula [V] with an acylating agent using potassium halide in presence of solvent.

[V] 12. The process according to claim 11, wherein the acylating agent is 2,2 dimethylbutyrylchloride.

13. The process according to claim 1, wherein halide used in step (d) is any of the halogen selected from F, Cl, Br or I.

14. The process according to claim 12, wherein the solvent is selected from any of N-methyl morpholine or N-methyl pyrrolidine or a mixture thereof.