PROCESS FOR PREPARING SIMVASTATIN
INTRODUCTION TO THE INVENTION
The present invention relates to a process for the preparation of simvastatin and intermediates thereof.
Simvastatin is chemically known as 2,2-dimethylbutanoic acid (1S, 3R, 7S, 8aR)-1 ,2,3,7,8,8a-hexahydro-3, 7-dimethyl-8- [2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl ester, or butanoic acid, 2,2-dimethyl-,1,2I3,7,8,8a-hexahydro-3,7-dimethyl-8-[2-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)-ethyl]-1-naphthalenyl ester, [1S-[1a,3a,7p,8p(2S*,4S*),-8aP]], (hereinafter referred to by the generic name "Simvastatin"), which is represented by Formula I.

Simvastatin is a potent anti-hypercholesterolemic agent. It inhibits the enzyme 3-hydroxy-3-methyl-glutaryl coenzyme A reductase ("HMG-CoA reductase"), which catalyzes the formation of mevalonic acid, and thus inhibits the cholesterol biosynthesis. It also increases the number of cellular LDL-receptors that remove the LDL cholesterol circulating in the blood, and thereby lower blood cholesterol levels. It is now commercially available under brand name Zocor® in the market in various strengths.
U.S. Patent No. 4,444,784 discloses Simvastatin or pharmaceutically acceptable salts, pharmaceutical compositions and their use in antihyperchlostrema. It also discloses a process for the synthesis of simvastatin, which involves deacylation of lovastatin followed by a subsequent acylation with the 2,2-dimethylbutyryl moiety.

The aforementioned process involves expensive raw materials such as t-butyldimethyl silyl chloride and tetrabutyl ammonium fluoride which result in increase of total manufacturing cost and the time required for hydrolysis is as long as 72 hours. It also suffers from the disadvantage of poor yields.
Subsequently several processes has been described for the preparation of simvastatin.
PCT Application Publication No. WO 2005/058861 A1 discloses a process for the preparation of simvastatin by using dialky silyl dichloride protection. The process given in the above application also involves usage of dialkyl silyl dichloride for protection and fluoride salts for deprotection, which is an expensive to operate on commercial scale.
Hence, it is desirable to provide a simple, industrially feasible, inexpensive, scaleable process for the synthesis of simvastatin of Formula I.
SUMMARY OF THE INVENTION
The present invention provides a commercially suitable process for the preparation of simvastatin of Formula I.
In one embodiment, the present invention provides a process for the synthesis of simvastatin, compound of Formula I comprising the steps of:
a) reacting lovastatin of Formula II with an alkyl diamine in the presence of a suitable solvent to give lovastain alkyl diamide of Formula III;
b) methylating lovastain alkyl diamide of Formula III with a suitable methylating agent in presence of a suitable base in a suitable solvent to give simvastain alkyl diamide of Formula IV;
c) hydrolyzing simvastain alkyl diamide of Formula IV in presence of a suitable base in a suitable solvent to give simvastatin ammonium salt of Formula V; and
d) converting the simvastatin ammonium salt of Formula V in a suitable solvent to give simvastatin compound of formula I.
In another embodiment, the invention includes usage of the intermediates prepared by this process that can be converted into simvastatin.

DETAILED DESCRIPTION OF THE INVENTION
The present invention provides a process for the synthesis of simvastatin, compound of Formula I comprising the steps of:
a) reacting lovastatin compound of Formula II with an alkyl diamine in presence of a suitable solvent to give lovastain alkyl diamide of Formula III;

b) methylating lovastain alkyl diamide of Formula III with a suitable methyiating agent in presence of a suitable base in a suitable solvent to give simvastain alkyl diamide of Formula IV;


c) hydrolyzing simvastain alkyl diamide of Formula IV in presence of a suitable
base in a suitable solvent to give simvastatin ammonium salt of Formula V;

d) converting simvastatin ammonium salt of Formula V, in a suitable solvent to
give simvastatin compound of Formula I.
Step a) involves reacting lovastatin compound of Formula II with an alkyl diamine in presence of a suitable solvent to give lovastain alkyl diamide of Formula III.
Suitable solvents which can be used in step a) include but are not limited to any solvent or mixture of solvents, in which the required compounds are soluble. Examples include: ethers such as diethyl ether, disiopropyl ether, tetrahydrofuran, 1,4-dioxane and the like; hydrocarbon solvents such as toluene, xylene and the like; nitrile solvents such as acetonitrile, propionitrile and the like; protic solvents such as dimethyl formamide, dimethyl acetamide and the like; or any mixtures of two or more thereof.
The alkyl diamine that is useful in step a) include C1-C12 straight chain, branched or cyclic alkyl or aryl diamines such as methylene diamine, ethylene diamine, propylene

diamine and the like. A heteroatom can substitute some of the carbon atoms in the alkyl groups.
The temperature for conducting the reaction can range from about 40 to 120 °C, or at 60 to 110 °C, or at the reflux temperature of the solvent used.
Step b) involves methylating lovastain alkyl diamide of Formula III with a suitable methylating agent in presence of a suitable base in a suitable inert solvent to give simvastain alkyl diamide of Formula IV.
Suitable methylating agents include but are not limited to methyl chloride, methyl bromide, methyl iodide, dimethyl sulphate and the like.
Suitable bases include organolithium compounds such as C-i-C6 alkyl lithium compounds optionally condensed with CrC6 straight chain, branched or cyclic alkyl amines.
Suitable inert solvents include but are not limited to any solvent or mixture of solvents, in which the required components are soluble. Examples include ether solvents such as dimethylether, diethyl ether, di-isopropylether, methyltertiary butylether, tetrahydrofuran, 1,4-dioxane and the like; aliphatic hydrocarbon solvents such as C1-C10 straight chain or branched hydrocarbons, and the like; aromatic hydrocarbons such as toluene, xylene, and the like; or mixtures thereof.
The temperature for conducting the reaction is from -60 to 0°C, or -50 to -20° C, or-45 to-40° C.
Step c) involves hydrolyzing of simvastain alkyl diamide of Formula IV in presence of a base in a solvent to give simvastatin, which is subsequently converted into an ammonium salt of Formula V.
The bases used in this reaction include: hydroxides of alkali metals such as lithium hydroxide, sodium hydroxide, potassium hydroxide and the like; carbonates of alkali metals such as sodium carbonate, potassium carbonate and the like; bicarbonates of alkali metals such as sodium bicarbonate, potassium bicarbonate and the like; as solids or in the form of a solution in water.
Suitable solvents include but are not limited to any solvent or mixture of solvents, in which the required compounds are soluble. Examples include C-|-C4 straight chain or

branched alcohols such as methanol, ethanol, isopropanol and the like or mixtures thereof.
The temperature for conducting the reaction is ranging from 60 to 120°C, or 70 to 110°C, or80to90°C.
Step d) involves converting simvastatin ammonium salt of Formula V, in a suitable solvent to give simvastatin the compound of Formula I
Suitable solvents for lactonization include but are not limited to any solvent or mixture of solvents that are immiscible with water. Examples include ether solvents such as diethyl ether, di-isopropylether, methyltertiary butylether, and the like; aliphatic hydrocarbon solvents such as Ci-C10 straight chain or branched hydrocarbons, and the like; aromatic hydrocarbons such as toluene, xylene, and the like; or mixtures thereof.
Suitable temperatures for conducting the reaction range from 60 to 130°C, or 80 to 120° C,or 100 to 110° C.
Water that is formed as byproduct during the reaction can be removed continuously from the reaction mass by azeotropic distillation or by any other conventional method.
The novel and simple process of the present invention is eco-friendly, industrially well-suited, commercially viable, reproducible and cost effective with improved yield.
Certain aspects of the present invention are described in detail in the examples given below that are provided by the way of illustration only and therefore should not be construed to limit the scope of the invention.
EXAMPLES
EXAMPLE 1
PREPARATION OF LOVASTATIN ETHYLENE DIAMIDE
50 g of Lovastatin was charged in a 4 neck round bottom flask containing 250 ml of tetrahydrofuran and 3.17 g of ethylenediamine under stirring. The reaction mixture was heated to reflux and maintained for about 3-5 hours. Completion of the reaction was confirmed by thin layer chromatography, and the reaction mass was concentrated under reduced pressure to get 61 g of the title compound as a residue.

EXAMPLE 2 PREPARATION OF SIMVASTATIN ETHYLENE DIAMIDE
46.2 ml of pyrrolidine was charged in a 4 neck round bottom flask containing a mixture of tetrahydrofuran (30 ml) and n-hexane (90 ml). The reaction mixture was cooled to -25 to -20°C and 342 ml of n-butyl lithium was added slowly and was maintained at same temperature for about 20-30 minutes and then cooled to about -45 to -40°C. 30 g of lovastatin ethylene diamine dimer, dissolved in 240 ml of tetrahydrofuran, was added to the reaction mass at -45 to -40°C. Stirred the contents at the same temperature for 1 hour and a mixture of 17.3 ml of methyl iodide and 30 ml of tetrahydrofuran (THF) was added slowly. Maintained the reaction at the same temperature for 2 hours and then quenched the reaction mass with 10% aqueous hydrochloric acid solution (240 ml) and stirred for about 20-30 minutes and the organic layer was separated. Organic layer was washed with 240 ml of saturated sodium chloride solution. All the aqueous layers were extracted with 138 ml of n-hexane. Both the organic layers were combined and concentrated under reduced pressure to get 30.2 g of the title compound as a residue.
EXAMPLE 3 PREPARATION OF SIMVASTATIN ACID AMMONIUM SALT
29 g of simvastatin ethylene diamine dimer was charged in to a 4 neck round bottom flask containing a mixture of methanol (377 ml) and 2N aqueous sodium hydroxide solution (377 ml). The reaction mixture was heated to reflux and stirred for 5-8 hours. Confirmed the reaction completion by thin layer chromatography, and methanol was removed completely under reduced pressure the reaction mass was cooled to 25-35°C and 194 ml of water was added. The resultant solution pH was adjusted to 3-4 with 2N aqueous hydrochloric acid solution and extracted the product with ethyl acetate (319 ml). To this organic layer added a mixture of 28 ml of methanol and 28 ml of aqueous ammonium hydroxide and stirred for 60 minutes. It was then cooled to 0-5°C

and the formed solid was filtered, washed with 15 ml of ethyl acetate and dried at 35-45°C to get the title compound as a crystalline solid.
EXAMPLE 4 PREPARATION OF SIMVASTATIN
10 g of simvastatin ammonium salt was charged in to a 4 neck round bottom flask containing 200 ml of toluene. The contents were heated to reflux and maintained for 3-4 hours. Water that formed during the reaction was separated by azeotropic distillation. It was then cooled to about 25-35°C and 0.1 g of activated charcoal was added and was stirred for 30 minutes then removed the charcoal by filtration through perlite. The resultant filtrate was concentrated under reduced pressure to a volume of 10-15% of original and 80 ml of cyclohexane was charged and stirred for 1 hour at 25-35°C. Cool to 10-15°C, filter the solid and wash with 20 ml of cyclohexane. The solid was dried at about 30-35°C under vacuum for about 3-5 hours to afford 7.1 g of the title compound as a crystalline solid.

We claim:
1. A process for preparing simvastatin comprising
reacting lovastatin with an alkyl diamine to afford lovastain alkyl diamide;
further reacting the product with a methylating reagent to give simvastain alkyl diamide;
hydrolyzing simvastatin alkyl diamide with a suitable base; and
converting the simvastatin base addition salt to simvastatin comprises removing water.
2. The process of claim 1, wherein the alkyl diamine comprises C1-C12 straight chain, branched, cyclic alkyl or aryl diamines.
3. The process of claim 2, wherein the C1-C12 straight chain alkyl diamine comprises methylene diamine, ethylene diamine or propylene diamine.
4. The process of claim 1, wherein the methylating agent comprises methyl chloride, methyl bromide, methyl iodide or dimethyl sulphate.
5. The process of claim 1, wherein the methylating agent is used in the presence of C1-C6 alkyl lithium derivatives.
6. The process of claim 5, wherein the C1-C6 alkyl lithium derivatives comprises n-butyl lithium.
7. The process of claim 1, wherein base used for hydrolysis comprises lithium hydroxide, sodum hydroxide, potassium hydroxide or ammonium hydroxide
8. The process of claim 1, wherein the simvastatin base addition salt is simvastatin ammonium salt.
9. The process of claim 1, wherein the simvastatin base addition salt is converted to simvastatin comprises removing the water by azetropic distillation.
10. A process for preparing simvastatin comprising
reacting lovastatin with ethylene diamine to afford lovastain ethylene diamide;
further reacting the product with methyl iodide to give simvastain ethylene diamide;
hydrolyzing simvastain ethylene diamide with ammonia; and
converting the simvastatin ammonium salt to simvastatin comprises removing water by azeotropic distillation.