FORM 2
THE PATENTS ACT 1970
(39 of 1970)
AND
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10 and rule 13)
1. TITLE OF THE INVENTION:
"AN IMPROVED ENVIRONMENT FRIENDLY PROCESS FOR THE SYNTHESIS OF SIMVASTATIN"
2. APPLICANT:
(a) NAME: THEMIS MEDICARE LIMITED.
(b) NATIONALITY: Indian Company incorporated under Indian Companies
Act, 1956
(c) ADDRESS: 11/12 Udhyog Nagar, S.V. Road, Goregaon (West),
Mumbai - 400 104, Maharashtra, India.
3. PREAMBLE TO THE DESCRIPTION
The following specification describes the invention and the manner in which it is to be performed.

Technical Field of invention:
The present invention relates to an improved cost-effective process for preparation of Simvastatin from Lovastatin using eco-friendly reagents resulting in pharmaceutically acceptable grade Simvastatin. More specifically, the invention relates to the route of synthesis from Lovastatin to Lovastatin cyclohexylamide phenylboronate and then to Simvastatin, wherein the deprotection of Simvastatin cyclohexylamide is carried out using oxidising agent which decomposes into water, thereby resulting into cost effective synthesis of Simvastatin.
Background of invention:
Simvastatin is chemically known as (1S,3R,7S,8S,8αR)-8-{2-[(2R,4R)-4-hydroxy-6-oxooxan-2-yl]ethyl}-3,7-dimethyl-l,2,3, 7,8,8a-hexahydronaphthalen-l-yl 2,2-dimethyl butanoate. It belongs to the class of pharmaceuticals called "statins". It is a hypolipidemic drug & used to control hypercholesterolemia (elevated cholesterol levels) and to prevent cardiovascular disease. it is a powerful lipid-lowering agent which mainly decreases low density lipoprotein (LDL) levels.
Various processes of producing Simvastatin are known in the art. The most important step of these processes include protection of-OH groups using protecting agents and removal of the protecting agents in the later steps which is called deprotection. Methylation of Lovastatin alkylamide boronate is also important step in conversion of Lovastatin to Simvastatin. This stage further involves the removal of protecting groups which is also a very important step. Various prior arts were studied for protection of adjacent hydroxyl group, methylation and de-protection of protecting groups.
USS393893 discloses a preparation of Simvastatin cyclohexylamide phenyl boronate from Lovastatin cyclohexylamide boronate by methylation. It involves reaction of n-butyllithium in hexane and pyrrolidine with solution of Lovastatin cyclohexylamide boronate in Tetrahydrofuran/ cyclohexane mixture followed by addition of methyl iodide to form Simvastatin cyclohexylamide phenylboronate. Further removal of protecting groups involves reaction of Simvastatin cyclohexylamide phenylboronate with NaOH in presence of aqueous protic solvent and passing through anionic exchange resin. The use of ion exchange resins again increases the total cost of the manufacturing process.

US6686481 discloses formation of acetonide of Simvastatin cycloalkylamide. It teaches reaction of lovastatin acetonide with Tetrahydrofuran in presence of lithium pyrrolidone (prepared from pyrrolidine and n-butyl lithium) and methyl iodide to form Acetonide of Simvastatin cycloalkylamide. Here removal of the protecting groups is done by hydrolysis in a mixture of water and organic solvent in the presence of 4-dimethylaminopyridine as a catalyst.
US2005239885 discloses in its second step the formation of tert-butylamine salt of simvastatin intermediate by employing reaction of tert-butylamine salt of Lovastatin with lithiating agent (methyl iodide, n-butyl lithium (base) and pyrrolidone) in presence of Tetrahydrofuran. The process involves formation of a carboxylic acid amine salt in an aqueous medium followed by formation of its 2, 2-dimethylbutyrate intermediate using lithiation. Further lactonization of this intermediate is carried out to obtain simvastatin. This process does not hint about protection and deprotection of hydroxyl group of the pyranone ring.
US2007129437 provides a process for preparing lovastatin amide in its first step. The second step discloses silylation process for protection of alcoholic groups using silylation catalyst and hexamethyldisilazane (hmds) and formation of bislovastatin amide derivative by keeping the previous mixture for certain period at particular temperature. Simvastatin dihydroxyamide derivative is formed in the later stage via methylation. This step is followed by de-protection stage using methanol and finally formation of Simva ammonium salt. Again this process also involves the use of environmentally hazardous and expensive solvent like methanol.
US2002/0035274 discloses preparation of lovastatin alkylamide in its first step followed by protection using protecting agent other than phenyl boronic acid. Further methylation step involves reaction of n-butyl lithium in hexane with pyrrolidine in anhydrous tetrahydrofuran in presence of methyl iodide to form Simvastatin amide compound. Herein the deprotection is carried out with the use of strong acidic resin.

US6294680 discloses a process for preparing Simvastatin alkylamide intermediate but the deprotection step employs the step of hydrolysis in a mixture of water and organic solvent in presence of catalyst (HCl/Sulfuric acid/TsOH). The process uses corrosive liquid.
US5763653 is about the key intermediates in the manufacture of Simvastatin. It gives a process for preparing Simvastatin from lovastatin or mevinolinic acid in salt form comprises treating either starting material with cyclopropyl or butyl amine, the pyranone ring thereby being opened when lovastatin is the starting material, adding a methyl group to the 2-methylbutyrate side chain, and thereafter closing the open pyranone ring to produce Simvastatin. The process is performed without protecting and deprotecting the two hydroxy groups of the open pyranone ring.
US6100407 discloses the process of producing Simvastatin and/or its derivatives. It employs the use of hydroxyl protected intermediates which allow for direct alkylation of the butyrate side chain followed by deprotection and reformation of the lactone ring. Here, the deprtoection of hydroxyl groups is carried out using solvents like methanol and methanesulphonic acid which are hazardous environmentally.
US7205415 describes the process for manufacturing Simvastatin using novel intermediates, for example lovastatin is reacted with methoxyethylamine, alpha methylated 2-methylbutyryl side chain of the amide formed, hydrolyzed and lactonized to finally produce Simvastatin of high purity. Here, methylation of lovastatin alkylamide is carried out followed by deprotection of hydroxyl groups using solvents like methnol and methanesulphonic acid which are again hazardous to the environment either directly or indirectly. Moreover the process requires high temeprature condition upto 100 °C for the conversion of Simvastatin ammonium salt to Simvastatin.
US20090048335 discloses improved process for the preparation of Simvastatin and premixes containing Simvastatin by lactonisation of 3, 5-dihydroxy acid or salt where X is H, Na, K, or NH4. The solution of this salt or acid is treated with acid to protonate the acid or salt & adjusting the pH from 5 to 7 & then grinding it with antioxidant solution.

From above prior arts it can be observed that all the available methods in the prior art are lengthy, requiring expensive reagents or large quantity of mineral acids which makes the above processes costly and non-eco friendly and concluded by person skilled in the art of synthetic process that the available methods are complicated, requires expensive reagent & reactants or large quantity of mineral acids, alcohols which also makes process costly & harmful to envoirnment.
The annotate from prior art is that, there is a consistent need to use a eco friendly reagents, which obviates the large use of methanol which is costly as well as harmful to the environment. It is also harmful when ingested or absorbed voluntariliy or by involuntary passive process due to absorption through skin or inhalation.
Thus, there is a need to develop a simple process with the use of reagents and reactants which are non-hazardous involving green chemistry
Therefore, the applicants worked in the direction of using innocuous reagents during the steps of methylation resulting in to excellent process which meets the pharmacopeal standards.
The present method is advantageous to give excellent pharmaceutically acceptable grade of Simvastatin and meeting the pharmacopoeal standards.
Summary of invention:
The present invention discloses the process for preparation of Simvastatin from the starting material lovastatin. The process described specifically involves use of reagent which is eco friendly to produce an intermediate Simvastatin ammonium salt which is later on converted to pharmaceutical grade Simvastatin. The starting material i.e. lovastatin is converted to an amide and then boronated with phenyl boronic acid which leads to protection of the hydroxyl group, after that the compound is methylated. The Simvastatin cyclohexylamide boronate is deboronated using suitable oxidizing agent like hydrogen peroxide or diols which is then converted to sodium salt of Simvastatin, which is further converted into Simvastatin ammonium salt in presence of suitable reactants.

The Simvastatin ammonium salt is then converted to Simvastatin using suitable reagents in controlled temperature & pH conditions.
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 fully understood and appreciated.
The present invention provides an economically beneficial process to prepare pharmaceutical grade Simvastatin by minimizing the use of large volume of methanol and resins, resulting into a final reaction product of high purity with minimum possible impurities in it. The improved process disclosed herein have advantages like significant reduction in solvent consumption and use of hazardous chemicals like methanol without affecting quality of the product, also the process excludes the costly deboronation process which requires resins.
In a preferred embodiment the present invention provides an improved process for producing Simvastatin which requires lovastatin as starting material. The process involves the key steps like coronation, methylation, deboronation and lactonization in the presence of suitable reactants and reagents at low temperature conditions and controlled pH levels.
The process described herein shows significant improvement in the effluent output by reducing the volume of effluent, obviating the use of resins column thereby avoiding the operation and handling loss of solvents like methanol in large volume thereby reducing the environmental hazard. There is also reduction in the complete process cycle time thus increasing the efficiency. Further, there is significant reduction in effluent load which increases the efficiency and reduction in the cost of the process.
The invention proposes a simple process for deboronation with suitable oxidizing agent. According to the invention, the oxidizing agent is selected from the group of hydrogen peroxide and its equivalent or salts thereof, diols, Peracetic Acid in acetic acid, Trifluoroperacetic acid in trifluroacetic acid or meta-chloro perbenzoic acid any mild

oxidizing agent which can cleave the bondage of boronate from hydroxyl groups of pyranone ring.
The salts can be ammonium, potassium, lithium or potassium alkaline earth element peroxides. The diols can be ethylene glycol, propylene glycol or suitable glycols which can competitively remove the boronate.
The improved method for preparing Simvastatin (as shown in formula I) according to the invention uses Lovastatin (as shown in formula II) as starting material.

Simvastatin (Formula I) Lovastatin (Formula II)
The new improved process according to the invention specifically involves the step for preparation of one of intermediate i.e. Simvastatin ammonium salt and further Simvastatin active pharmaceutical ingredient of high purity from this intermediate.
The route of synthesis according to the improved process disclosed in this present invention comprises the following steps as given below.
STEP 1. Conversion of Lovastatin to Lovastatin cyclohexylamide phenylboronate (Formula III)
This step involves the use of toluene, cyclohexylamine and boroinc acid in appropriate quantity under controlled temperature and pH conditions.


Lovastatin cydohexylamide phenyl boronate (formula III)
STEP 2. Conversion of Lovastatin cydohexylamide phenyl boronate to Simvastatin cydohexylamide phenyl boronate (Formula IV)

Simvastatin cydohexylamide phenylboronate (Formula IV)
This step involves the use of Methyl Iodide, Pyrrolidine and Tetrahydrofuran.


STEP 3. Conversion of Simvastatin cyclohexylamide phenyl boronate to Simvastatin cyclohexylamide
Simvastatin cyclohexylamide phenylboronate (Formula IV)
This step involves removal of protecting group phenyl boronate using Hydrogen peroxide at controlled temperature and pH conditions.


Simvastatin Cyclohexylamide (Formula V)
STEP 4. Conversion of Simvastatin cyclohexylamide to Simvastatin sodium salt (Formula VI).


Simvastatin sodium salt (Formula VI)
STEP 5. Conversion of Simvastatin Sodium salt to Simvastatin ammonium salt (Formula VII)

Simvastatin sodium salt (Formula VI)


STEP 6. Conversion of Simvastatin ammonium salt (Formula VII) to Simvastatin (Formula I)


Simvastatin ammonium Simvastatin (Formula I)
salt (Formula VII)
Hydrogen peroxide (H2O2) is one of the most powerful oxidizers known, stronger than chlorine, chlorine dioxide, and potassium permanganate. Moreover, Hydrogen peroxide is safe, easily available and cheap compared to methanol and various resins. The use of hydrogen peroxide is not limiting and its salts can be used in an alkaline condition.
Further, washing with Sodium thiosulphate removes all the oxidizing impurities and yields a Simva ammonium salt of pharmaceutical quality. Other reagents which can be used as cleavage agents apart from hydrogen peroxide include acetic anhydride, butyl iodide, and silver oxides.
Thus, employing hydrogen peroxide, Peracetic Acid in acetic acid, Trifluoroperacetic acid in trifluroacetic acid or meta-chloro perbenzoic acid as oxidizing agent, one can

prepare the Simvastatin with the process which is less time consuming, efficient, economically viable and easy for industrial application.
The innovative process of the present invention is effective in terms of final product output and reduction in lengthy step which gives an added advantage over other processes known in the art. The improved process is also efficient and easy to implement in the industry.
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:
Preparation of Lovastatin Boronate:
Toluene, Lovastatin and cyclohexylamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55°C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at - 45°C to -55°C . Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at - 40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboronate. Solvent was distilled out under vacuum. The Peracetic Acid in Acetic Acid (5% - 50%) was charged into reactor at room temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and

separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.
Tetrahydrofuran & hexane were distilled out after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70°-75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C-50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0-5.5 by HC1. This was followed by addition of ethyl acetate into reaction with adjustment of pH 3.5 - 4.0 by HC1 at 10- 15°C. Further, Sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 00C to 50C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastatin of high purity.
Example 2:
Preparation of Lovastatin Boronate:
Toluene, Lovastatin and cyclohexylamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 550C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.

Preparation of Simvastatin Ammonium Salt:
Tetrahydrofiiran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at - 45°C to -55°C . Lovastatin cyclohexylamide boronate and Tetrahydrofiiran (THF) were mixed at - 40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboronate. Solvent was distilled out under vacuum. The Trifluoroperacetic in Trifluoro acetic acid (5% - 50%) was charged into reactor at room temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.
Tetrahydrofiiran & hexane were distilled out after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70°-75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C-50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0-5.5 by HC1. This was followed by addition of ethyl acetate into reaction with adjustment of pH 3.5 - 4.0 by HCl at 10- 15°C. Further, Sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 00C to 50C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon.

The filtrate was treated with purified water which on drying yields a simvastatin of high purity.
Example 3:
Preparation of Lovastatin Boronate:
Toluene, Lovastatin and cyclohexylamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55 DC for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15 DC, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at - 45°C to -55°C . Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at - 40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboronate. Solvent was distilled out under vacuum. The meta-chloro perbenzoic acid (Assay 25% - 70%) was charged into reactor at room temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.
Tetrahydrofuran & hexane were distilled out after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70°-75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C-50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted

to 5.0-5.5 by HC1. This was followed by addition of ethyl acetate into reaction with adjustment of pH 3.5 - 4.0 by HC1 at 10- 15°C. Further, Sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 00C to 50C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastatin of high purity.
Example 4:
Preparation of Lovastatin Boronate:
Toluene, Lovastatin and cyclohexylamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50-55°C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at - 45°C to -55 °C . Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at - 40 °C to 45 °C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboronate. Solvent was distilled out under vacuum. The hydrogen peroxide was charged into reactor at room temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic

layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.
Tetrahydrofuran & hexane were distilled out after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70°-75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C-50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0-5.5 by HC1. This was followed by addition of ethyl acetate into reaction with adjustment of pH 3.5 - 4.0 by HC1 at 10- 15°C. Further, Sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 0°C to 5°C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastatin of high purity.
Example: 5
Preparation of Lovastatin Boronate:
Toluene, Lovastain and cyclohexlamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55°C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out

and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at -45°C to -55°C. Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at -40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboranate. Hydrogen peroxide was charged into reactor at room temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.
Tetrahydrofuran & hexane were distilled our after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70° -75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C - 50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0 - 5.5 by HC1. This was followed by addition of ethyl acetate into reaction with adjusted of pH 3.5 - 4.0 by HCl at 10 - 15°C. Further, sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 0°C to 5°C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:

Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastain of high purity.
Example 6:
Preparation of Lovastatin Boronate:
Toluene, Lovastain and cyclohexlamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55°C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at -45°C to -55°C Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at -40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboranate. Solvent was distilled out under vacuum. MDC was added. Hydrogen peroxide was charged into reactor at room temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with MDC. The organic layer was washed with water followed by its separation.
MDC was distilled our after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70° - 75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum

at 40°C - 50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0 - 5.5 by HCl. This was followed by addition of ethyl acetate into reaction with adjusted of pH 3.5 - 4.0 by HCl at 10 - 15°C. Further, sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 0°C to 5°C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastain of high purity.
Example7
Preparation of Lovastatin Boronate:
Toluene, Lovastain and cyclohexlamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55°C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at-45°C to -55°C Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at -40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HCl to obtain Simvastatin cyclohexylamide phenylboranate. Solvent was distilled out under vacuum. Toluene was added. Hydrogen peroxide was charged into reactor at room temperature and maintained

for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using toluene and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with toluene. The organic layer was washed with water followed by its separation.
Toluene was distilled our after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70° - 75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C - 50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0 -5.5 by HCl. This was followed by addition of ethyl acetate into reaction with adjusted of pH 3.5 - 4.0 by HCl at 10 - 15°C. Further, sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 0°C to 5°C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastain of high purity.
Example 8:
Preparation of Lovastatin Boronate:
Toluene, Lovastain and cyclohexlamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55°C for

approximately 8 hrs. Activated Carbon was added and filtered. Toluente was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at-45°C to -55°C Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at -40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HCl to obtain Simvastatin cyclohexylamide phenylboranate. Solvent was distilled out under vacuum. Hydrogen peroxide was charged into reactor at room temperature. Reaction mixture was heated to 50 - 55°C and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.
Tetrahydrofuran & hexane were distilled our after which methanol was charged. Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70° -75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C - 50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0 - 5.5 by HCI. This was followed by addition of ethyl acetate into reaction with adjusted of pH 3.5 - 4.0 by HCl at 10 - 15°C. Further, sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (]: 1) was added at 20°C to 23°C and pH was adjusted to 10 - 10.2. The mass was cooled at 0°C to 5°C, maintained for one hour, filtered, washed with ethyl acetate and dried.

Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastain of high purity.
Example: 9
Preparation of Lovastatin Boronate:
Toluene, Lovastain and cyclohexlamine were charged in the reactor and were refluxed for about 12 hrs to obtain lovastatin cyclohexylamide, followed by cooling to room temperature. Further, sufficient quantity of Toluene and Phenyl boronic acid were charged in the reactor. Temperature was maintained at about 50 - 55°C for approximately 8 hrs. Activated Carbon was added and filtered. Toluene was distilled out and Hexane was added; further, the reaction mass having Lovastatin Boronate was cooled to 15°C, followed by filtration, washing with hexane and drying the material.
Preparation of Simvastatin Ammonium Salt:
Tetrahydrofuran and Pyrrolidine were charged in the reactor. n-Butyl lithium was added at -45°C to -55°C. Lovastatin cyclohexylamide boronate and Tetrahydrofuran (THF) were mixed at -40°C to 45°C followed by addition of methyl iodide. Reaction mass was quenched in water and pH was adjusted suitably with HC1 to obtain Simvastatin cyclohexylamide phenylboranate. Solvent was distilled out under vacuum. Cooled to 5 -10°C. Hydrogen peroxide was charged into reactor at 5-10°C temperature and maintained for two hours. The aqueous layer was extracted with n-hexane and organic layer was separated. The organic layer was washed with sodium hydroxide solution and separated. Again the aqueous layer was extracted using n-hexane and the organic layer was separated. The separated organic layer was washed with sodium thiosulphate solution. The organic layer was separated & aqueous layer was extracted one more time with n-hexane. The organic layer was washed with water followed by its separation.

Tetrahydrofuran & hexane were distilled our after which methanol was charged- Again 2N Sodium hydroxide was charged in the reactor & refluxed for 8 hours at about 70° -75°C. The mass was cooled to 35 to 40°C and transferred to reactor. Methanol was distilled out under vacuum at 40°C - 50°C till the appearance of turbidity. Then water was charged into reaction mass and cooled to 10°C and pH of the reaction mass was adjusted to 5.0 - 5.5 by HC1. This was followed by addition of ethyl acetate into reaction with adjusted of pH 3.5 - 4.0 by HC1 at 10 - 15°C. Further, sodium chloride was charged into the reaction mass with stirring for 15 min and later mass was allowed to settle for half an hour. Organic layer was separated and transferred to reactor. Ammonia and Methanol mixture (1:1) was added at 20°C to 23°C and pH was adjusted to 10- 10.2. The mass was cooled at 0°C to 5°C, maintained for one hour, filtered, washed with ethyl acetate and dried.
Preparation of Simvastatin:
Simvastatin Ammonium salt was taken in acetonitrile, acidified with mineral acid, cooled and filtered. The obtained material was treated with methanol and treated with carbon. The filtrate was treated with purified water which on drying yields a simvastain of high purity.

We Claim,
1. An improved, cost-effective process for preparing Simvastatin comprising a step of deprotecting Simvastatin cyclohexylamide phenyl boronate in presence of oxidizing agent to yield Simvastatin cyclohexylamide.
2. The process according to claim 1, wherein the oxidizing agent is selected from the group of hydrogen peroxide, its equivalent or salts thereof, Peracetic acid in acetic acid, Trifluoroperacetic acid in trifluroacetic acid, meta-chloro perbenzoic acid, diols, acetic anhydride, butyl iodide, silver oxides and mild oxidizing agents which can cleave the bondage of boronate from hydroxyl groups of pyranone ring.
3. The equivalent or salt of hydrogen peroxide according to claim 2 is selected from the group of ammonium, potassium, lithium or potassium alkaline earth element peroxides.
4. The diol according to claim 2 is selected from the group of ethylene glycol,
propylene glycol and other suitable glycols which can competitively remove the boronate.
5. An improved, cost effective process for preparing Simvastatin according to claim
I, comprising the steps of: a) converting lovastatin to Lovastatin cyclohexylamide
phenylboronate using cyclohexylamine and boroinc acid in appropriate quantity
under controlled temperature and pH conditions; b) converting Lovastatin
cyclohexylamide phenylboronate to Simvastatin cyclohexylamide phenylboronate
by methylating Lovastatin cyclohexylamide boronate with methyl iodide and
pyrrolidine in presence of THF; c) removing protecting group by treating
Simvastatin cyclohexylamide phenyl boronate with an oxidizing agent to obtain
Simvastatin cyclohexylamide; e) converting Simvastatin cyclohexylamide to
Simvastatin sodium salt; f) further converting Simvastatin sodium salt to
Simvastatin ammonium salt; and g) finally converting Simvastatin ammonium salt
to Simvastatin.

6. The process for preparing Simvastatin according to claim 5, wherein the oxidizing agent is selected from the group of hydrogen peroxide, its equivalent or salts thereof, diols, acetic anhydride, butyl iodide, silver oxides and mild oxidizing agents which can cleave the bondage of boronate from hydroxyl groups of pyranone ring.