FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
PROVISIONAL SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION: ——
"AN IMPROVED PROCESS FOR PREPARING SIMVASTATIN"
2. APPLICANT:
(a) NAME: THEMIS MEDICARE LIMITED.
(b) NATIONALITY: Indian Company incorporated under the Indian Companies
ACT, 1956
(c) ADDRESS: 11/12 Udhyog Nagar, S.V. Road, Goregaon west, Mumbai
400104, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION

The following specification describes the invention.


TECHNICAL FIELD OF THE INVENTION:
The present invention relates to an improved cost effective process for preparing Simvastatin of high yield and better purity. More specifically, the present invention relates to an improved process step of preparing Simvastatin cyclohexylamide phenylboronate from Lovastatin cyclohexylamide boronate with an optimized molar ratio of the reactants and reagents to enhance the yield and purity of the final product.
BACKGROUND AND PRIOR ART:
Simvastatin is a hypolipidemic drug related to the class of pharmaceuticals called "statins". It is used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. Simvastatin chemically known as (lS,3R,7S,8S,8aR)-l,2,3,7,8s8a-Hexahydro-3,7-dimethyl-8-[2-[(2R,4R)-tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl]ethyl]-1-naphthalenyl 2,2-dimethyl-butanoate, represented by formula I.

Formula I
US5393893 of Apotex describes a process for preparation of Simvastatin cyclohexylamide phenylboronate from Lovastatin cyclohexylamide boronate, wherein the molar ratios of Lovastatin cyclohexylamide boronate to n-butyl lithium is 1:5.079; Lovastatin cyclohexylamide boronate to pyrrolidone is 1:5.17; and Lovastatin cyclohexylamide boronate to methyl iodide is 1:3.029. Further Simvastatin cyclohexylamide is prepared by charging the solution of crude Simvastatin cyclohexylamide phenylboronate onto a column of activated Amberlite IRA-400 resin, followed by elution with methanol. Finally

Simvastatin is prepared by relactonization of Simvastatin cyclohexylamide in aqueous organic acid in presence of water miscible solvent.
W098/32751 (EP0971913) discloses reduction of acetonide of Lovastatin cyclohexanamide using lithium aluminium hydride to alcohol intermediate and further reacting the alcohol with 2,2-dimethyl butyric acid chloride followed by addition of ammonia solution to give Simvastatin ammonium salt. However, this process requires the use of LiAlH4 which is costly and causes unwanted removal of ester linkage. Also the overall yield of Simvastatin ammonium salt is only 27%.
W098/32751 further discloses another process for preparing Simvastatin, wherein the process for preparing Simvastatin ammonium salt comprises reacting acetonide of Lovastatin butylamide (37.6 mmol) with lithium pyrrolio'e (113ml of 1M) and methyl iodide (5 ml) to yield 80% of Simvastatin ammonium salt.
In the preparation of Simvastatin as disclosed in EP0864569, Lovastatin cyclopropylamide which is formed by reacting Lovastatin (0.03 mol) with cyelopropylamine (0.174 mol), is treated with methyl iodide (0.077 mol) in presence of n-butyl lithium (0.163 mol) and pyrrolidine (0.163 mol) to give ammonium salt of Simvastatin (0.022 mol).
EP1064275 describes the preparation of Simvastatin from Simvastatin ethylamide. In the process, Simvastatin ethylamide bis-tetra hydropyran -2-yl ether is obtained by reaction of Lovastatin ethylamide tetrahydro pyranyl ether (0.018 mol) with n-butyl lithium (0.04 lmol) in hexane and pyrrolidine (0.042 mol) followed by addition of methyl iodide(0.027 mol). Further, solution of crude Simvastatinetfrylamide bis-tetra hydropyran -2-yl ether in methanol is treated with water and methane sulfonic acid to give Simvastatinethylamide. Further purification is done which involves treating with base, extraction with ethyl acetate, washing with organic solvent such as toluene followed by evaporation, crystallization from cyclohexane and recrystallization from methanol/ water to yield Simvastatin.

There is still a need in the art for an improved, cost effective and commercially viable process of preparing pure Simvastatin, which will be suitable for large-scale preparation of Simvastatin, in terms of chemical yield and purity. In order to improve the yield and purity of the desired product Simvastatin, present inventors have come up with an improved process for preparing Simvastatin.
OBJECTS OF THE INVENTION:
The main object of the present invention is to provide an improved cost effective process of preparing Simvastatin of high yield and better purity.
SUMMARY OF THE INVENTION;
The present invention provides an improved process of preparing Simavastatin starting from Lovastatin. More particularly, the present invention provides an improved process step of preparing Simvastatin cyclohexylamide phenyboronate from Lovastatin cyclohexylamide boronate using optimized molar ratios of the reactants and reagents in the process of preparing Simvastatin. The process step comprises methylation of Lovastatin cyclohexylamide boronate with optimized ratios of methyl iodide, n-butyl lithium and pyrrolidine to yield Simvastatin ammonium salt of better yield, which consequently increases the yield of the final product Simvastatin.
DETAILED DESCRIPTION OF THE INVENTION:
The invention will now be described in detail in connection with certain preferred and optional embodiments, so that various aspects thereof may be more folly understood and appreciated. It is not intended to limit the invention to these particular embodiments.
Accordingly, in one embodiment, the invention provides a process for the preparation of
Simvastatin of formula I, starting from Lovastatin, which comprises following three
intermediates/stages.
Stage I: Process for Preparing Lovastatin cyclohexylamide boronate

Stage-I comprises reacting Lovastatin with cyclohexylamine in the presence of toluene to obtain Lovastatin cyclohexyl amide, which further reacted with phenyl boronic acid (protecting agent) to yield Lovastatin cyclohexylamide boronate intermediate.
Synthetic route of the Stage I of the present invention is as depicted in Scheme 1.
Scheme 1

Stage II: Process for preparing Simvastatin ammonium salt
Stage-II comprises methylation of Lovastatin cyclohexylamide boronate intermediate with optimized ratios of methyl iodide, n-butyl lithium and pyrrolidine in presence of THF to obtain Simvastatin cyclohexylamide phenylboronate.
Further, methanol was charged into the reaction mixture and was treated with resin in presence of methanol to obtain deprotected compound Simvastatin cyclohexylamide,

followed by refluxing in aqueous NaOH to obtain sodium salt of Simvastatin, which is further converted into Simvastatin ammonium salt by reacting with methanolic ammonium hydroxide.
Synthetic route of the Stage II of the present invention is as depicted in Scheme 2.
Scheme 2

Simvastatin ammonium salt
Stage III: Process for preparing Simvastatin

Stage-Ill comprises conversion of Simvastatin ammonium salt to the Simvastatin in presence of acetonitrile and HC1, followed by addition of methyl alcohol.
In the preferred embodiment, the present invention provides an improved cost effective process step of preparing Simvastatin cyclohexylamide phenyboronate form Lovastatin cyclohexylamide boronate in the stage II of preparing Simvastatin ammonium salt, wherein the molar ratios of the reactants/reagents are optimized to obtain the Simvastatin ammonium salt and the final product Simvastatin of better yield and purity.
In accordance with the present invention, the optimized molar ratios of methyl iodide, n-butyl lithium and pyrrolidine with respect to Lovastatin cyclohexylamide boronate are 1:1.94; 1:2.91 and 1:3.44 respectively, to easily obtain Simvastatin cyclohexylamide phenylboronate without lengthy workup and further Simvastatin ammonium salt of 94% yield in the stage II of preparing Simvastatin ammonium, salt, which finally resulted into Simvastatin of 81 % yield and of 99.6 % purity.
The invention further comprises deprotection of Simvastatin cyclohexylamide phenylboronate by simply adding methyl alcohol and treating Simvastatin cyclohexylamide phenylboronate with GS-300 Resin to obtain deprotected compound, Simvastatin cyclohexylamide
The following examples, which include preferred embodiments, will serve to illustrate the practice of this invention, it being understood that the particulars shown are by way of example and for purpose of illustrative discussion of preferred embodiments of the invention.
EXAMPLES: Example 1:
Process of preparing Lovastatin cyclohexylamide boromate
Toluene (450 It), Lovastatin (129 Kg) and cyclohexylamine (60 Kg) were charged in the
reactor. Lovastatin was refluxed for 12 hrs to obtain Lovastatin cyclohexylamide, followed

by cooling to room temperature. Further, Toluene (750 It) and Phenyl boronic acid (35 Kg) were charged in the reactor. Temperature was maintained at 50 - 55 °C for 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added. Further, the reaction mass having Lovastatin cyclohexylamide boronate was cooled to 15 °C, followed by filtration, washing with hexane and drying the material. Yield= 180.0 Kg
Example 2:
Process of preparing Simvastatin ammonium salt
THF (360 It) and Pyrrolidine (80 Kg) were charged in the reactor. n-Butyl lithium (61 Kg) was added at - 45°C to -55 °C. Lovastatin cyclohexylamide boronate (200 Kg) and THF (530 It) were added at - 40 °C to - 45 °C, followed by addition of methyl iodide (90 Kg). Reaction Mass was quenched in water and pH was adjusited to 3 - 4 with HCl to obtain Simvastatin cyclohexylamide phenylboronate. Solvent was distilled out under vacuum. Methyl alcohol and GS-300 Resin were added. GS-300 was separated from the organic layer. Further, the pH of the organic layer was adjusted with aqueous NaOH. Mixture was refluxed for 10 Hrs. methanol was distilled out, followed by cooling to 10 to 15 °C. pH was adjusted to 3 to 4 with aqueous HCl, followed by extraction with ethyl acetate. pH was adjusted to 8.0 to 11.0 with methyl alcohol and ammonia solution. Mixture was cooled to -5 to 10 °C, followed by filtration and drying of Simvastatin ammonium salt. Yield = 135 Kg
Example 3:
Process of preparing, Simvastatin
Simvastatin ammonium salt (100 Kg) and acetonitrile were charged in the reactor. 4 N HCl was added at -10 °C to -15 °C. Reaction mass was filtered. Methyl alcohol was charged to the wet cake in the reactor, followed by the addition of activated carbon and filtration of Simvastatin. Purified water was added to the filtrate. Material was filtered and dried. Yield-81%

Purity = 99.6%
Output from Lovastatin to Simvastatin =77%
Lovastatin count in the Simvastatin = < 0.5%
Dated this 01st Day of June, 2009