This patent claims priority from 2190/CHE/2006,2305/CHE/2006 & 2036/CHE/2007.

Field of invention:

The present invention relates to Simvastatin and an improved process for preparation thereof.

Background of the invention

Simvastatin is chemically known as [1S-[lcc,3a,7p,8P(2S*,4S*),8ap]]-2,2-dimethylbutanoic acid 1,2,3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-[(tetrahydro-4-hydroxy-6-oxo-2i7-pyran-2-yl]ethyl]-l-naphthalenyl ester and is represented by the following structural Formula.

Simvastatin is a lipid-lowering agent that is derived synthetically from a fermentation product of Aspergillus terreus. After oral ingestion, simvastatin, which is an inactive lactone, is hydrolyzed to the corresponding [beta]-hydroxy acid form. This is an inhibitor of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which is an early and rate-limiting step in the biosynthesis of cholesterol. Pharmaceutical products containing simvastatin as the active ingredient are commercially available in the market as ZOCOR™ in the form of solid oral formulations containing 5 mg, 10 mg, 20 mg, 40 mg or 80 mg as tablets.

U.S. Patent No. 4,444,784 discloses Simvastatin and its pharmaceutical compositions. It also discloses a method for lactonization of the 3,5-dihydroxypentanoic acid derivative by heating the reaction mixture with a dilute acid to give simvastatin.

U.S. Patent No. 4,916,239 discloses the lactonization of simvastatin ammonium salt which comprises agitating the ammonium salt in presence of an acid catalyst in a mixture of a water and water-miscible solvent at 20-3 0°C.

U.S. Patent No. 5,939,564 discloses the lactonization of 3,5-dihydroxypentanoic acid derivative in the presence of a catalyst such as a salt of an organic base with an organic or inorganic acid like pyridine hydrobromide, pyridine hydrochloride or pyridine /j-toluene sulfonate salt in lower alkanol, ketone, ether, nitrile or mixture thereof (20-30 times dilution) at a temperature between ambient and 50°C.

U.S. Patent No. 5,917,058 discloses the process for the preparation of simvastatin which comprises the lactonization of the 3,5-dihydroxypentanoic acid derivative in presence of weak acid such as acetic acid at a temperature below 55°C, and isolating simvastatin by addition of an anti-solvent such as water, hexane, heptane or cyclohexane.

U.S. Patent No. 6,562,984 discloses the lactonization in a solvent such as dichloromethane or acetonitrile and reagents such as methanesulfonic acid, phosphorous pentoxide, acidic ion exchange resin, molecular sieves, acidic clay, acidic silica gel and combinations thereof which binds water produced in a insoluble complex at a temperature not greater than50°C, and preferably between 10-40°C.

U.S. Patent No. 6,649,775 discloses the lactonization of 3,5-dihydroxy acid derivative by refiuxing in a inert organic solvent such as toluene and in the presence of large quantities (2 moles) of dehydrating agents like magnesium sulphate, sodium sulphate, calcium chloride, and molecular sieves for the removal of water and shifting of equilibrium towards formation of the product.

WO 2002/094803 discloses the lactonization of 3,5-dihydroxypentanoic acid derivative or its ammonium salt in a mixture of acetonitrile and glacial acetic acid in anhydrous conditions at 65-70°C and in the absence of a catalyst.

WO2002/094804 discloses a method for lactonization of simvastatin intermediate comprising of heating in xylene at 135-140°C for 20-30 minutes. The reaction is carried out in a very high dilution of 25- 50 times which leads to the formation of dimer impurity in the range of 0.10 to 0.20% without any disclosure about the formation of other impurities.

U.S. Patent Application No. 2003/0109723 discloses the lactonization of 3,5-dihydroxypentanoic acid derivative or its ammonium salt which comprises the refluxing the said hydroxy acid in a mixed organic solvent selected from toluene, ethyl acetate, isopropyl acetate, dichloromethane, chloroform, tetrahydrofuran and acetone, without an acid catalyst and under nitrogen sweep.

WO 2005/095374 discloses a method for lactonization of 3,5-dihydroxypentanoic acid derivative or its ammonium salt in a mixture of toluene and methyl ethyl ketone with optionally usage of phosphoric acid.

WO 2005/095374 discloses the lactonization of 3,5-dihydroxypentanoic acid derivative or its ammonium salt in an organic solvent specifically claimed chlorinated solvents in the presence of phosphoric acid.

Summary of the Invention

The main object of the present invention is to provide a process for the preparation of Simvastatin with high purity.

Another object of the present invention is to provide a process for the preparation of Simvastatin, which comprises:

(a) treating Simvastatin ammonium salt with phosphorous acid in organic solvent;

(b) washing the reaction mass with base;

(c) distilling the solvent and isolating the product in cyclohexane; and

(d) purifying the crude product in methanol/water to get pure Simvastatin.

Detailed Description of the Invention

Thus in accordance with the present invention preparation of Simvastatin comprises the following steps:

In a specific embodiment, the present invention provides a process for the preparation of simvastatin, which involves treating simvastatin ammonium salt with orthophosphoric acid in an organic solvent such as dichloromethane and toluene at a temperature of 30-85°C, preferably 35-75°C optionally under nitrogen atmosphere. After the completion, reaction mass is treated with base followed by water. The organic solvent is distilled off completely and the crude simvastatin as a product is isolated in cyclohexane. The base used herein is selected from the group consisting of triethyl amine, sodium bicarbonate.

The above obtained crude product is purified by dissolving the crude product in methanol, treating with activated carbon followed by filtration. To the obtained filtrate, water is added and crystallized the product at low temperature. The crystallized product is filtered as per the conventional methods and dried under vacuum yields pure Simvastatin.

Experimental

The present invention will now be further explained in the following examples. However, the present invention should not be construed as limited thereby. One of ordinary skill in the art will understand how to vary the exemplified preparations to obtain the desired results.

Example-1 Preparation of crude Simvastatin

To a mixture of ammonium salt of Simvastatin (100 g) in toluene (1900 ml), ortho phosphoric acid (54 g) was added at 25-3 0°C. The reaction mixture was heated to 78-82°C and maintained for 4 hrs. After the completion of the reaction, reaction mixture was cooled to 25-30°C and followed by the addition of aqueous sodium bicarbonate solution (-10%) 1000 ml. The reaction mixture was stirred at 25-30°C and allowed to settle. The layers were separated and the organic layer was washed with water. The organic layer was distilled out under vacuum at 45-50°C to get the residue and to the residue cyclohexane (200 ml) was added. Cyclohexane was distilled out under vacuum at 45-50°C to get residue and followed by the addition of cyclohexane (1000 ml) to the residue. Triethyl amine (11.9gm) was added to the mixture and mixture was heated to 78-80°C and maintained for 30-45 min. The reaction mixture was cooled to 20-25°C gradually. Cooled the mixture to 10°C and stirred. The obtained solid was filtered and washed with cyclohexane (100 ml) and dried under vacuum at 40-45°C.

Example-2 Preparation of crude Simvastatin

To a mixture of ammonium salt of Simvastatin (100 g) in toluene (1900 ml), ortho phosphoric acid (54 g) was added at 25-30°C. The reaction mixture was heated to 78-82°C and maintained for 4 hrs. After the completion of the reaction, reaction mixture was cooled to 25-30°C and followed by the addition of mixture of water and triethylamine (1000 ml). The reaction mixture was stirred at 25-30°C and allowed to settle. The layers were separated and the organic layer was washed with water. The organic layer was distilled out under vacuum at 45-50°C to get the residue and to the residue cyclohexane (200 ml) was added. Cyclohexane was distilled out under vacuum at 45-50°C to get residue and followed by the addition of cyclohexane (1000 ml) to the residue. Triethyl amine (11.9gm) was added to the mixture and mixture was heated to 78-80°C and maintained for 30-45 min. The reaction mixture was cooled to 20-25°C gradually. Cooled the mixture to 10°C and stirred. The obtained solid was filtered and washed with cyclohexane (100 ml) and dried under vacuum at 40-45°C.

Example-3 Preparation of crude Simvastatin

Ammonium salt of Simvastatin (100 g) was added to methylene chloride (1500 ml) at 25-30°C and followed by the refluxing of reaction mixture under nitrogen. Orthophosphoric acid (43.2 g) was added to the mixture at 35-40°C and the reaction mixture was maintained for 7 hrs and separated the water simultaneously from the reaction mixture. The reaction mixture was cooled to 0-5 °C and then filtered followed by washing the solids with methylene chloride. The combined methylene chloride layer was washed with 25% brine solution. The methylene chloride layer was distilled out under vacuum at 25-30°C to get residue followed by the addition of cyclohexane (1500 ml). Cyclohexane was distilled out under vacuum at 45-50°C to get residue and followed by the addition of cyclohexane (1000 ml) to the residue. Triethyl amine (11.6gm) was added to the mixture and mixture was heated to 78-80°C and maintained for 30-45 min. The reaction mixture was cooled to 20-25°C gradually. Cooled the mixture to 10°C and stirred. The obtained solid was filtered and washed with cyclohexane (100 ml) and dried under vacuum at 40-45°C.

Example-4 Purification of crude Simvastatin

To a mixture of crude simvastatin (83 g) and methanol (830 ml), butylated hydroxy anisole (0.5 g) and butylated hydroxy toluene (0.5 g) was added under nitrogen at 25-30°C. Activated carbon (8.3 g) was added to the reaction mixture and stirred for 30-45 min at 25-30°C followed by the filtration through celite bed. The celite bed was washed with methanol (160 ml). To the clear filtrate, water (1080 ml) was added to crystallize the product followed by cooling to 0-5°C and stirred. The solid obtained was filtered at 0-5°C and washed with water (160 ml) and dried under vacuum at 40-45°C till LOD is NMT 0.5% w/w.

We Claim:

1. A process for the preparation of pure simvastatin, which comprises:

(a) treating simvastatin ammonium salt with phosphorous acid in an organic solvent;

(b) washing the reaction mass with base;

(c) distilling the solvent and isolating the product in cyclohexane; and

(d) purifying the crude product in methanol/water to get pure Simvastatin.

2. The process according to claim 1, wherein organic solvent used is toluene, dichloromethane.

3. The process according to claim 1, wherein base used is triethyl amine and sodium bicarbonate.