COMPLETE AFTER PROVISIONAL
LEFT ON ,2 6 SEP 2006-
FORM 2
THE PATENTS ACT, 1970
(39 of 1970)
&
The Patents Rules, 2003
COMPLETE SPECIFICATION
(See section 10; rule 13)
Title of the invention - "PROCESS FOR THE PREPARATION AND PURIFICATION OF LOVASTATIN"
2. Applicant(s)
(a) NAME : ALEMBIC LIMITED
(b) NATIONALITY : An Indian Company
(c) ADDRESS : Alembic Limited, Alembic Campus, Alembic Road, Vadodara-390 003, Gujarat, India
3. PREAMBLE TO THE DESCRIPTION
The following specification particularly describes the invention and the manner in which it is to be performed:

Field of Invention:
The present invention relates to improved process for preparing Lovastatin of formula
(I).

H3C*^ "^ ^^
Formula (I)
Background of the invention and prior art:
Lovastatin is chemically known as (lS,3R7S,8S,8aR)-l,2,3,7,8,8a-Hexahydro-3,7-dimethyl-8-(2-(2R,4R)-(tetrahydro-4-hydroxy-6-oxo-2H-pyran-2-yl)ethyl)-l-naphthalenyl (S)-2-methyl-butyrate, also sometimes referred as 6-a-Methylcompactin. It is a specific inhibitor of HMG-CoA reductase. This enzyme catalyzes the conversion of HMG-CoA to mevalonate, which has a crucial role in the synthesis of endogenous cholesterol. The enzyme is not completely inhibited in therapeutic doses, therefore the biologically required quantities of mevalonate are available. Since the conversion of HMG-CoA to mevalonate is an early step in biosynthesis of cholesterol, treatment with Lovastatin does not produce accumulation of potentially toxic sterols.
Lovastatin has shown to reduce total cholesterol concentrations by lowering increased LDL chlolesterol concentrations. LDL is formed from VLDL and is catabolized predominantly by the LDL receptors. The mechanism of the LDL-lowering effect of Lovastatin may involve both reduction of VLDL cholesterol concentration, and
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induction of the LDL receptors, leading to reduced production and increased catabolism of LDL cholesterol. In addition, Lovastain can produce moderate increases in HDL cholesterol, and modest reductions in plasma triglyceride.
Lovastatin is particularly useful of reduction in increased total and LDL cholesterol in patients with primary hypercholesterolemia in cases when dietary and other nonpharmcologic measures do not provide the desired result. Lovastatin decreases total plasma cholesterol and LDL cholesterol levels, thereby decreasing the total cholesterol/HDL cholesterol and LDL cholesterol/HDL cholesterol ratios. It is also useful for reduction in increased cholesterol levels in patients with mixed hyperlipidemia (hypercholesterolemia plus hypertiglyceridemia) where hypercholesterolemia is the major abnormality. Lovastatin helps in slowing the progression of coronary artherosclerosis in patients with coronary heart disease.
Lovastatin was first reported in US patent No. 4,231,938 in which Lovastatin is prepared by cultivating microorganism belonging to the genus Aspergillus and then recovering the compound from the cultured broth. The general processes for preparation reported in prior art comprises of isolating Lovastatin acid of formula (II) or mixtures of Lovastatin and Lovastatin acid from the broth and lactonizing it to obtain pure compound. Alternate process comprises of isolating Lovastatin acid salts like sodium or ammonium salt and lactonizing it to obtain Lovastatin. The processes for the isolation and purification of Lovastatin reported in prior art comprise different combinations of extraction, chromatography, lactonization and crystallization methods. Moreover these processes are lengthy and cumbersome to observe on commercial scales.
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Formula (II)
Therefore there is a need to develop a process for preparing Lovastatin which is simple, easy to handle on industrial scales and which also gives product with improved yield and purity.
The inventors of present invention have found that it is possible to isolate Lovastatin directly from the fermented broth without having to carry out separate step of lactonization. Moreover the inventors of the present invention have found the improved process for purification of Lovastatin.
Object of the invention:
It is an object of the present invention to provide an improved process for preparing Lovastatin.
Another object of the present invention is to provide improved process for purification of Lovastatin.
Yet another object of the present invention is to provide a process for preparing Lovastatin which simple, easy to handle, cost effective and commercially applicable.
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Summary of the invention:
Accordingly, present invention provides an improved process for preparing Lovastatin which has reduced operational steps, shorter operational times and commercial viability.
Present invention also provides a process for purification of Lovastatin.
Detailed description of the invention:
The inventors of present invention have found that it is possible to carry out complete conversion of Lovastatin acid in the fermented broth and then isolate Lovastatin from the broth. This step reduces the step of filtering the broth to separate biomass and then carry out lactonization separately.
The broth obtained after fermentation is acidified by making use of mineral acid selected from group comprising of HC1, H2SO4, H3PO4 and the like, preferably H2SO4. The pH of broth is adjusted to about 2 to 4. The acidified broth is heated to about 40°C to about 80°C, more preferably at about 50°C to 70°C to complete lactonization. The conversion takes place about 18 hours to about 25 hours depending upon the rate which is governed by broth characteristics.
After the completion of lactonization the broth is extracted using suitable solvent preferably Toluene. The organic layer is further washed with basic solution preferably sodium bicarbonate. Further solvent is removed by distillation till concentration of product is about 100 to 180 g/liter. The concentrated mass is cooled to about 5°C to obtain Lovastatin which is isolated by conventional' methods like filtration or centrifugation.
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The product thus obtained is further purified by dissolving in chlorinated solvent preferably methylenedichloride at about the reflux temperature of the solvent. The solution is further concentrated to obtain thick slurry. Further toluene is added to it and distillation is continued to remove chlorinated solvent completely. The mixture thus obtained is cooled to about 5°C to obtain Lovastatin with increase in purity levels, which is isolated by conventional methods like filtration or centrifugation.
The process of the present invention is described by the following examples, which are illustrative only and should not be construed so as to limit the scope of the invention in any manner.
Example:
Example 1: Preparation of Lovastatin
Fermented broth was acidified using 15% sulphuric acid till pH is maintained at 2 to 4. Acidified broth was lactonised by heating upto 50-70°C and the conversion of Lovastatin acid to lactone form was monitored. After completion of the conversion the lactonised broth is extracted using toluene. Organic layer is separated and neutralized with 1-2% sodium bicarbonate solution. Further the organic layer is concentrated to 100-180 g/liter concentration and cooled to temperature of about 5°C. The precipitates of Lovastatin are collected and dried.
Example 2: Purification of Lovastatin
The Lovastatin obtained in Example 1 was dissolved in methylenedichloride at about 40°C. The solution was refluxed for about an hour and then methylenedichloride was distilled off to obtain thick slurry. Toluene was added to the thick slurry and distillation was continued at about 40°C to remove methylenedichloride completely. The solution thus obtained is cooled to temperature about 5°C. The precipitates of pure Lovastatin are collected and dried.
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While the present invention has been described in terms of its specific embodiments, certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present invention.
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We claim
1. A process for preparing Lovastatin of formula (I) comprising of, lactonizing Lactonic acid of formula (II) in the fermentation broth, wherein lactonization is carried out without filtering the broth.



H,C
H,C
Formula (I)

Formula (II)

2. A process as claimed in claim 1, wherein lactonization is carried out
comprising steps of,
(a) acidifying the broth using mineral acid
(b) adjusting the pH to about 2 to 4
(c) heating the broth to about 40° to 80°C to complete lactonization
3. A process as claimed in claim 2, wherein said mineral acid in step (a) is
selected from group comprising of HC1, H2SO4 and H3PO4.
4. A process as claimed in claim 2 further comprising steps of,
(d) extracting the broth with suitable solvent
(e) concentrating the organic layer till concentration of the product is about 100 to 180g/litre
(f) cooling the concentrate obtained in step (e) to about 5°C to obtain Lovastatin.
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5. A process claimed in claim 4, wherein suitable solvent is toluene.
6. A process for purification of Lovastaing of formula (I) comprising steps of,
(a') preparing a solution of Lovastatin in chlorinated solvent
(b') concentrating solution obtained in step (g) to obtain a slurry
(c') adding toluene to slurry obtained in step (h) to obtain a reaction
mass
(d') distilling out chlorinated solvent from reaction mass obtained in step
(i)
(e') cooling the distillate obtained in step (j) to about 5°C to obtain pure Lovastatin.
7. A process claimed in claim 6, wherein chlorinated solvent is
methylenedichloride.

Dated this 26th day of September 2006
Sonali Bhokarikar Applicant's agent
Of S. Majumdar & Co.
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Abstract
The present invention relates to improved process for preparing Lovastatin of formula
(I)-


H,C
Formula (I)
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