WO2007096753A2

WO2007096753A2 - Process for preparing highly pure simvastatin

Info

Publication number: WO2007096753A2
Application number: PCT/IB2007/000429
Authority: WO
Inventors: G. Umesh Upadhyay; Niraj Kumar Shyamial Shah; Rajiv Kumar; Shri Prakash Dhar Dwivedi
Original assignee: Cadila Healthcare Limited
Priority date: 2006-02-21
Filing date: 2007-02-21
Publication date: 2007-08-30
Also published as: WO2007096753A3

Abstract

The present invention discloses a solid compound of silylated simvastatin having formula (I). Said compound of Formula (I) is prepared by hydrolyzing lovastatin to diol lactone; converting said diol lactone to silylated lactone; and acylating said silylated lactone to produce silylated simvastatin.

Description

PROCESS FOR PREPARING HIGHLY PURE SIMVASTATIN

Field of the invention

The present invention relates to a process for the preparation of highly pure Simvastatin though related intermediate (6(R)-[2-8'(S)-2",2"-dimethylbutyryloxy- 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), i.e., silylated Simvastatin with high purity at commercial scale. Background of the invention Metavastatin (also known as compactin) and lovastatin (also known as mevinolin) are naturally occurring HMG-CoA reductase inhibitors. These compounds have been used medicinally in the control of human serum cholesterol levels. Both compounds contain a (2S)-2-methylbutyryloxy substituent at the C-8 position of their hexahydronaphthalene nucleus and both produce medicinal analogues with increased potency towards HMG-CoA reductase, when the aforementioned 2-methylbutyryloxy side chain is converted into a 2,2-dimethylbutyryloxy group. Till date several process related impurities have been identified and disclosed in Pharmacopoeia as well as in literature. Achieving Simvastatin with improved purity profile with respect to its process-related impurities is a challenge. A method for the commercial scale production of simvastatin from lovastatin is the subject of the present invention. Discussion of prior art

Several processes for the preparation of simvastatin from lovastatin are reported. Two of these methods involve a deacylation and reacylation procedure. The prior art discussed in U.S. Pat. No. 4,444,784 and CAl, 199,322 teaches the conversion of lovastatin to several 8-acyloxy derivatives, including simvastatin. This conversion of Lovastatin to Trihydroxy acid was performed in LiOH and in aqueous medium. The patent WO 03/057684 discloses that the hydrolysis of Lovastatin is performed using methanolic KOH in aqueous medium.

Lovastatin is completely hydrolyzed to remove the 2-methylbutyryl side chain and to simultaneously open its 6-membered lactone ring to produce a trihydroxy acid. The trihydroxy acid compound is then heated in order to effect relactonization and dihydroxylactone is obtained. The free hydroxy group in the lactone ring of the dihydroxylactone is protected as a tert-butyldimethylsilyl ether and then the hydroxy group at C-8 of the hexahydronaphthalene ring system is esterified using 2,2- dimethylbutyryl chloride. The t-butyldimethylsilyl protecting group is then removed in the final step using tetrabutylammonium fluoride to produce simvastatin.

Chemically, Simvastatin is 2,2-Dimethylbutanoic acid (lS,3R,7S,8S,8aR)- 1 ,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetra hydro-4-hydroxy-6-oxo-2H- pyran-2yl] ethyl] -1-naphthalenyl ester having formula (I)

Formula- (1)

SIMVASTATIN

U.S. Patents Nos. 4,450,171 and 4,293,496 disclose that Silylated Simvastatin which is formed, can be isolated in the form of yellow oil using column chromatography purification technique, but this process cannot be practiced for bulk production. U.S. Patent Nos. 6,252,091 Bl and EP 0033538 also disclose the isolation of Silylated Simvastatin as an orange oil. The present invention overcomes this problem by isolating Silylated Simvastatin as a white solid of high purity.

U.S. 2004/0068123 discloses that when t-Butyldimethylsilyl group is introduced as a protecting group to obtain Silylated Simvastatin, the deprotection reaction suffers from poor conversion to Simvastatin due to formation of byproducts such as compounds of formula-2 and formula-3. In order to minimize the formation of by-product, the process for preparing Simvastatin has been modified. . In this modification ring opening of the lactone ring and conversion to amide group was introduced. However these processes also have drawbacks, a dimer of the compound of formula-3 is produced as the by-product as reported in /• Org. Chem. 1991, 56, 4929-

Formula-2

Formula-3

These by-products, compound of formula-2 and dimer compound of formula-3 cannot be easily removed by conventional purifications and thus it affects the yield and purity of final product Simvastatin.

U.S. Patent No. 4,845,237 and Korean Patent No. 133599 disclose that 0.4 - 0.8% of the compounds of formula-2 and formula-3 as by-products are produced in the reaction, resulting decrease in purity and yield of Simvastatin.

In comparison of conventional removals of a protecting group, the Scheme- 1 given below is preferable in industrial scale to prepare Simvastatin, but it requires improved method promising high yield and high purity without the formation of the byproducts of formula-2 and formula-3. The yield and purity of Simvastatin varies with reaction conditions, i.e., kind of reagent, amount of reagent, solvent, temperature, reaction time and deprotection of TBDMS protected intermediate.

Many patents are published with improved process for preparing Simvastatin by characterizing each step of the process. Especially, purity of the product varies with the final deprotection step of the process. The problem of formation of by-products during desilylation step in the synthesis of Simvastatin and the long felt need to obtain highly pure Silylated Simvastatin is achieved in the present invention by isolation of Silylated Simvastatin solid. The present invention overcomes this problem of by-product formation by isolating the Silylated Simvastatin as solid, which is highly pure and substantially free of impurities. This Silylated Simvastatin Solid when desilylated gives highly pure Simvastatin. This invention has the advantage of preparing highly pure Simvastatin economically in plant scale operations. This intermediate Silylated Simvastatin Solid of the present invention can be produced in high yield of 90 % using commercially available solvents. This is in contrast to the conventional method in that the yield of Simvastatin Intermediate the Silylated Simvastatin is as low as 80%.

The Simvastatin can be prepared by the process as disclosed below in reference example for the preparation of Simvastatin.

Route of synthesis of Simvastatin (Reference example):

LOVASTATIN TRIOL ACID DIOL LACTONE

SILYLATED LACTONE SILYLATED SIMVASTATIN SIMVASTATIN

Scheme - 1

Summary of the invention

The present invention envisages hydrolysis of Lovastatin in anhydrous conditions. The other embodiment of the present invention is to isolate Silylated Simvastatin as solid of high purity which provides highly pure Simvastatin. This invention relates to new process of synthesis and isolation of stable Silylated Simvastatin solid, 6(R)-[2-8'(S)-2",2"-dimethylbutyryloxy-2'(S),6'(R)-dimethyl- 1 ' ,2' ,6 ' ,7',8 ' ,8a' (R)-hexahydronaρhthyl- 1 ' (S)ethyl]-4(R)-(dimethyl-tert-butylsilyloxy)- 3,4,5,6-tetrahydro-2H-pyran-2-one, having m.p. 85⁰C to 88⁰C with purity more than 98%, and the isolation technique matches with economical aspects and is suitable for the plant operations. When the synthesis is performed without isolating Silylated Simvastatin as solid, it contains impurities more than 10 %. Silylated Simvastatin obtained so far does not come in solid phase and remain in liquid state along with impurities which is difficult while handling unit operations as well as achieving Simvastatin with desired, purity. This problem is overcome in the present invention. Simvastatin synthesized from isolated Silylated Simvastatin solid contains impurities less than 0.1%. Detailed description

Lovastatin hydrolysis as discussed in Patent No. U.S. 4,444,784 is performed by LiOH and many process related patents also used basic conditions in aqueous medium for carrying out hydrolysis of Lovastatin. The present invention carries out hydrolysis step of Lovastatin in methanol and Sodium hydroxide under anhydrous conditions.

Trihydroxy acid used in the formation of diol lactone contains 50% moisture.

Many process related patents have disclosed the fact that Silylated Simvastatin mainly occurs in oily state. On the contrary, the present invention envisages an improved process to obtain highly pure Simvastatin by isolating and using Silylated Simvastatin as solid. The process involves dissolving Silylated Simvastatin (residue) in solvent selected from linear, branched or cyclic alcohols of Ci to C₅ at temperature range 5O⁰C to 7O⁰C, the reaction mass is stirred to get clear solution. The clear solution is charcoalised and filtered through Hyflosupercel bed at 3O⁰C to 4O⁰C. The clear solution is added with 2.0 - 2.5 volumes of water as that of Silylated Lactone and stirred for 1.0 to 2.0 hours at -5⁰C to O⁰C, and further stirred for 12 - 15 hours at O⁰C to 5⁰C. The solid is filtered at 0⁰C to 5°C and dried under vacuum till the moisture content is less than 2.0 % with purity more than 98%. The scope of present invention is not limited by the description, examples and suggested uses described herein, and modifications can be made without departing from the spirit of invention. Example-l Step-1: Preparation of 7-[l',2',6',7'_s8',8a'(R)-hexahydro-2'(S),6'(R)-dimethyl-8'(S)- hydroxy-1 '(S)-napthyl]-3(R),5(R)-dihydroxyheptanoic acid (Triol Acid)

Lovastatin (200 g, 0.617 moles) was added in the methanolic solution of sodium hydroxide (198 g, 6.1 moles in 1.4 1 methanol) at 4O⁰C temperature and the reaction mass was refluxed (65⁰C to 75⁰C) for 15 hours. The progress of reaction was monitored by TLC. After completion of reaction, the mass was cooled to 25⁰C to 35⁰C and 300 ml process water was added followed by pH adjustment (7.5 - 8.0) with concentrated Hydrochloric acid. Subsequently methanol and water was removed under vacuum, and 600 ml water in 300 ml MDC was added. The reaction mass was cooled to 0⁰C to 5°C and further acidified with concentrated Hydrochloric acid (pH = 1.5 - 2.0) at O⁰C to 5⁰C temperature. The mass was stirred for 1.0 hour at O⁰C to 5⁰C and the solid was collected by filtration followed by wash with two portions of 200 ml MDC and dried to afford 164 g of title compound as white solid of melting point 128°C. Purity greater than 99%. Yield 93% ExampIe-2 Step-2: Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(R)-dimethyl- l '^'^'^'^'^a'C^-hexahydronaphthyl-l'CS^ethylj^C^-hydroxy-S^-S^-tetrahydro- 2H-pyran-2-one (Diol Lactone)

156 gm of Triol acid prepared in Example-1 was suspended into 1500 ml of toluene and 120 ml of water was added. The reaction mixture was heated to 11O⁰C and toluene and water up to 50% of reaction mass were distilled out. The reaction mass was refluxed for 2 hrs and again 1.5% of total volume was distilled out. The precipitate obtained in toluene was stirred for two hours at 0° to 5⁰C. The precipitate was filtered and washed with 2 X 50 ml toluene. The wet cake obtained was dried to give a white solid (126 g). Yield 90%. ExampIe-3 [Reference Example]

Step-3: Preparation of 6(R)-[2-(8'(S)-hydroxy-2'(S),6'(R)-dimethyl- l',2',6',7',8',8a'(R)-hexahydronaphthyl-l'(S))ethyl]-4(R)-(dimethyl-tert- butylsilyloxy)-3,4-5,6-tetrahydro-2H-pyran-2-one (Silylated Lactone)

Imidazole (85 g, 4.0 mole) was dissolved in 300 ml of, DMF under nitrogen atmosphere at 25 ⁰C to 30 ⁰C. The reaction mixture was cooled to 15 ⁰C to 20 ⁰C followed by drop-wise addition of tertiary butyldimethyl chlorosilane (t-BuDMSiCl) (94 ml, 2 mole) at 15 ⁰C to 20 ⁰C. Diol lactone (100 g, 1 mole) obtained in example-2 was added in reaction mixture followed by 200 ml of DMF. The reaction mixture was stirred for 3 hours at 15 ⁰C to 20 ⁰C. After completion of reaction 200 ml of water was added in the reaction mixture and stirred for 1 hour at 20 ° to 25°C. The obtained solid was filtered and cake was slurried in 400 ml of water, stirred for 1 hour and filtered. The solid obtained was washed with 2 x 25 ml of water. The wet cake obtained was dissolved in 250 ml cyclohexane and stirred for 1 hour at 20 ° to 25 ⁰C. The resulting precipitate was filtered and washed with 2 X 50 ml cyclohexane and dried to obtain 122 g of titled compound. Yield 1.24% ExampIe-4

Step-4: Preparation of 6(R)-[2-(8'(S)-2",2"-dimethylbutyryloxy-2'(S),6'(R)-dimethyl- l',2',6',7,'8',8a'(R)-hexahydronapthyl-l'(S))-ethyl]-4(R)-(dimethyl-tert- butylsilyloxy)-3 ,4-5 , 6-tetrahydro-2H-pyran-2-one (Silylated Simvastatin) Cyclohexane (1.3 1), Silylated Lactone (100 g, 0.23 mole) and Dimethyl amino pyridine (DMAP) (8.2 g, 0.06 mole) and pyridine (109 g, 1.38 mole) were added under stirring at 2O⁰C to 25⁰C under nitrogen atmosphere. The content was stirred for 15 minutes at 2O⁰C to 25⁰C. 2,2-Dimethyl butyryl chloride (93 g, 0.69 mole) was added followed by flushing with cyclohexane (200 ml) at 2O⁰C to 25⁰C. The temperature slowly raised up to reflux with hot water (9O⁰C). The reaction mass refluxed for 36 hours under nitrogen atmosphere. The progress of the reaction was monitored by HPLC, as the reaction was completed, the reaction mass was cooled to 15⁰C to 2O⁰C ■ and added with 1.0 1 of water and stirred for 30 minutes and settled for 30 minutes at 15⁰C to 2O⁰C. The lower aqueous layer separated followed by the washing of organic phase withl lit-0.2 N HCl, 1 lit. 10% aqueous solution OfNaHCO₃ . Finally the organic layer was washed with 1 lit. water. The organic phase was charcolized with activated carbon (10 g) for 60 minutes at 15⁰C to 2O⁰C and filtered through Hyflosupercel bed. Wash the bed with 2 x 25 ml cyclohexane. Filtrate and washings were combined and cyclohexane was removed under vacuum completely. Residue obtained was mixed with ethanol (460 ml). Heated to obtain clear solution at 55⁰C to 6O⁰C. Stirred for 15 minutes at 55⁰C to 6O⁰C. Cooled to 3O⁰C to 35°C. Charcoal (10 g) was added at 3O⁰C to 35⁰C and stirred for 60 minutes at 3O⁰C to 35⁰C. Filtered through Hyflosupercel at 3O⁰C to 35⁰C. The bed was washed with two portions of 50 ml of ethanol. The filtrate taken in 2.0 1 of RBF and cooled to -5°C to O⁰C. Cool water (1O⁰C to 15⁰C) (200 ml) was added within 30 minutes. The mass was stirred for 1.0 hour at -5⁰C to O⁰C. Stirred for 12 hours at O⁰C to 5⁰C. The mass filtered at O⁰C to 5⁰C. The cake washed with two portions of 25 ml ethanol-water mixture (2:1) at O⁰C to 5⁰C. The wet cake unloaded and dried under vacuum till the moisture content was less than 2.0 %. The Silylated Simvastatin Solid obtained was of purity greater than 99%. ExampIe-5

Step-5: Preparation of 6(R)-[2-(8'(S)-2",2"-dimethylbutyryloxy-2'(S),6'(R)-dimethyl- l',2',6',7,'8',8a'(R)-hexahydronapthyl-l'(S))-ethyl]-4(R)-hydroxy -3,4-5,6-tetrahydro- 2H-pyran-2-one (Simvastatin)

Silylated Simvastatin (100 g, 0.18 mole) and THF (800 ml) were added under stirring in the RBF at 25°C to 35⁰C. Stirred for 15 minutes and added with acetic acid (42.2 g, OJOmole). The reaction mass was cooled to 15°C to 2O⁰C. A solution of Tetrabutyl ammonium fluoride (118 g, 0.37 mole) in 400 ml of THF was added into the reaction mass. Stirred for 30-35 hours at 18⁰C to 22⁰C and the reaction mass dumped in 1.0 1 of water. MDC (1.0 1) was added and pH adjusted to neutral with sodium bicarbonate solution. Stirred for 30 minutes and settled for 30 minutes. The aqueous layer separated and 1.0 1 of water added in organic layer. The organic layer separated and charged in RBF and added with 10.0 g of charcoal. Stirred for 60 minutes and filtered through Hyflosupercel bed. The bed was washed with two portions of 50 ml MDC. The filtrate was charged and MDC distilled off under vacuum. Cyclohexane (100 ml) added and distilled out under vacuum. The reaction mass was heated to 45⁰C to 5O⁰C and stirred for 30 minutes and cooled to 2O⁰C to 25⁰C and stirred for 1.0 hour. The product was filtered at 20⁰C to 25⁰C and dried at 5O⁰C to 55⁰C till LOD was less than 1.0 %. It was crystallized by 300 ml cyclohexane and recrystallized from cyclohexane-toluene to give semi-crude simvastatin. This was finally recrystallized by methanol-water to obtain 49.5 gm of final API as a white solid, (yield: 95%, purity: 99.7%). Advantages of the Invention :

1) The present invention is simple and provides an improved process for the synthesis of highly pure Simvastatin.

2) The other main advantageous of the present invention are as follows : i) Lovastatin hydrolysis was carried out under anhydrous conditions with less reaction time and high yield. ii) Silylated Simvastatin was isolated in the form of white solid with high purity greater than 98% and having melting point 85⁰C to 88⁰C. iii) If the desilylation step is performed without isolating Silylated Simvastatin solid, Simvastatin contains Formula-2 more than 8 - 10% and this is overcome in the present invention by isolating and using Silylated

Simvastatin as solid to get Simvastatin with impurities less than 0.1%. iv) Simvastatin obtained requires less crystallization steps. 3. The present process results in isolating Simvastatin with single individual impurity, less than 0.1%. 4. The process is simple, safe and can be employed for commercial production.

Claims

We claim:

1. A solid compound of silylated simvastatin having formula (I).

2. A process for preparing silylated simvastatin as claimed in claim 1 which comprises a) hydrolyzing lovastatin to diol lactone; b) converting said diol lactone to silylated lactone; and c) acylating said silylated lactone to produce silylated simvastatin.

3. A process as claimed in claim 2 wherein said silylated simvastatin is optionally desylated.

4. A process as claimed in claim 2 or 3 wherein said hydrolysis is carried out in the in the presence of alcoholic alkali solution, preferably, sodium hydroxide in methanol.

5. A process as claimed in any one of claims 2 to 4 wherein the hydrolysis is carried out at a pH adjustment between 7.5 to 8 and preferably, the pH is adjusted to 1.5 to 2.0 by treatment with acids, preferably, hydrochloric acid.

6. A process as claimed in any one of claims 2 to r wherein said acylation is carried out in the presence of a solvent, preferably, cyclohexane.

7. A process as claimed in any one of claims 2 to 6 wherein said acylation is carried out in the presence of a base preferably, pyridine.

8. A process as claimed in any one of claims 2 to 6 wherein said acylation is carried out in the presence of 2,2-dimethyl amino pyridine.

9. A process as claimed in any one of claims 2 to 6 wherein said acylation is carried out using 2,2-dimethyl butyl chloride as reactant.

10. A process as claimed in any one of claims 2 to 9 wherein the product is re- crystallized as a solid product in alcohol, water and their mixture preferably ethanol and water at a ratio of 2: 1.

11. A process as claimed in claim 3 wherein said desilylation is carried out in the presence of an ethereal solvent preferably, tetrahydrofuran.

12. A process as claimed in claim 11 wherein said desilylation is carried out in the presence of acids, preferably, acetic acid.

13. A process as claimed in claim 3 wherein said desilylation is carried out by treatment with tetrabutyl ammonium chloride. .

14. A process as claimed in claim 3 wherein the product is extracted using halogenated solvent preferably, dichloromethane.

15. A process as claimed in claim 3 wherein said desilylation is carried out in the presence of an anti solvent hydrocarbon preferably, cyclohexane.

16. A highly pure Silylated Simvastatin having purity 99% and above, impurity less than 0.1%.

17. A highly pure Simvastatin having purity 99% and above, impurity less then 0.1%.