FIELD OF THE INVENTION:

The present invention particularly relates to a process for lactonization to produce simvastatin. More particularly, the invention relates to a process for lactonization of simvastatin hydroxyacid or its salts that avoids use of strong corrosive acids and drastic heat conditions. Specifically the process can be carried out at moderate temperature resulting in the title product with purity greater than 99% and dimer impurity to a level of less than 0.05%. Still more particularly, the invention relates to a process for lactonization to produce simvastatin involving using a mixture of carboxylic acid anhydride and water miscible organic solvent. Preferably, the solvent used may be nitrile solvent.

BACKGROUND OF THE INVENTIQN- Lovastatin, Simvastatin, Pravastatin, Atorvastatin, and Mevastatin are well known potent antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMG-CoA reductase. This class of compounds, referred to generally as statins, are produced either by natural fermentation process or through semisynthetic and totally synthetic routes. Two of the most popular compounds in this therapeutic category are Simvastatin and Atorvastatin. The former is one of the most prescribed drugs in the treatment of primary hypercholesterolemia with minimum side effects & well established safety profile. The use of highly pure statins is exceedingly desirable in preparation of pharmaceutical compositions/ formulations as it would avoid accumulation of impurities during prolonged usage and reduce the possible side effects during medical treatment. In most of the preparative methods dihydroxy acid or its salt of formula I is the common

intermediate for producing statins of formula II.

II

Where R is H or CH3 and X ix H or a metal cation or a NH4 cation.

The above common intermediate is cyclized making lactonization as an essential step of the synthesis. The lactonization of ammonium compound I is a process wherein, a dihydroxy acid losses one molecule each of ammonia and water to form an intramolecular ester (lactone). The reaction is catalyzed by an acid and a dehydrating agent, Lactonization is an equilibrium process represented, in the case of statins, by the following equation:

Dihydroxy acid ammonium salt <===> Lactone + Water + Ammonia. In order to obtain high yield of the lactone, it is necessary to remove water and ammonia ■from the reaction mass to shift the equilibrium towards right. Thus, The main problem associated with lactonization is to shift the equilibrium to lactone side in order to yield statins with high purity and yield.

One known way is the physical removal of produced water from the reaction mixture, e.g. by means of azeotropic distillation. The other problem is the formation of dimeric impurity. Statins are sensitive to heating and so the use of elevated temperatures for laconization gives rise to the risk of impurities

being formed. One of the most common impurities is dimer of formula III, which arises from dimerization of the starting material where in R is H or CH3..

III The prior art known to the inventor includes US 4,820,850 ('85O). The process described in patent '850 involves heating the free acid or its salt preferably ammonium salt to reflux

temperature, usually = 100 ⁰ C in high boiling inert hydrocarbon solvent such as toluene

for 7 to 8 hours in presence of strong acid catalyst. The ambient acidty of the acid is believed to be responsible for lactonization. The process results in high-level impurity of dimmer. Further, the process is cost extensive due to high dilution requirements and thus not feasible for industrial operation. The shift in equilibrium was achieved by continuously removing water by azeotropic distillation. Removal of ammonia may be increased by passing a stream of inert gas through the hot reaction mixture

US patent no. 5,393,893, discloses a process wherein the lactonization is carried out in a two-phase system of an organic system, in which the lactone is soluble, and an aqueous acid, whereby the formed water is displaced from the organic layer containing the lactone, to the aqueous layer.

US patent 4, 916, 239 ('239) teaches reacting hydroxy acid salt at ambient temperature with a mixture of water miscible organic solvent and strong acid catalyst under inert

atmosphere. According to this process continuous and selective removal of lactone by adding water gradually to effect crystallization of lactone helps in shifting equilibrium. Further using water miscible organic solvent enables selective solubility of desired compound. The process claims to reduce the level of impurities to < 0.2% as against 0.4 to 0.8% present in the product produced by the prior art. The process is associated with disadvantages such as using strong acid catalyst and addition of water in controlled manner making the process cost extensive and difficult to operate on industrial scale. Moreover, though the process claims use of water miscible organic solvent, the description only supports to using acetic acid. US 5,917,058 ('058) advocates eliminating using strong acid catalyst performing Iactonization at ambient temperature there by eliminating problems arising through strong acid catalyst. According to the process disclosed in this invention, hydroxy acid salt is reacted with weak organic acid in absence of strong acid catalyst below temperature of

55 ⁰ C and recovering title compound. The preferred weak acid is acetic acid and

recovering is carried out by using anti-solvent such as hexane, heptane, cyclohexane or water, preferably water. The yield of the product as exemplified ranges from 87% to 95% and purity of the compound obtained varies from >95% to>98%.

US 20040077884 ('884) claims that the process disclosed in this invention yields a product having impurities < 0.1%. The process comprises lactonizing hydroxy acid salt with a mixture of glacial acetic acid and acetonitrile in anhydrous conditions at a temperature in the range of about 50 to 8O ⁰ C and precipitating statins by adding water.

The invention claims consistent production of simvastatin at moderate temperature with more than 99.5% purity and dimmer content less than 0.1 Vo. The examples illustrate the yield in the range of 89 to 90 %, HPLC purity of 99.55 to 99.63% and dimer impurity of

0,04 to 0.07%. The main change is employing acetonitrile in conjunction with acetic acid and precipitating with water in turn making process user and environment friendly, economic and easy to scale up for commercial manufacture. The mechanism in this process, as described relates to removal of ammonia formed, as a by-product, using mixture of acetic acid and acitonitrile however, it is unable to remove water which is also formed as a by-product of lactonisation reaction. Typically the reaction gets completed in about five to seven hours. The amount of acetic acid used is at least three to five parts by volume per part of starting material and the amount acitonitrile used is 10 to 20 parts by volume preferably 15 parts by volume of the starting material. The process also claims an advantage of easy isolation by addition of water.

After continuous research, we discovered that use of carboxylic acid anhydride in combination with nitrile helps in removal of both the by-products of lactonisation process i.e. water and ammonia. Under the conditions selected for the present process the reaction byproduct water reacts with anhydride and converts the same to respective acid which in turns consume another by-product i.e. ammonia. Ammonium salt thus, produced further helps in gradual removal of water and helps continuously shifting the equilibrium to lactone side in a sustained manner and in turn helps completion of reaction. Thus, the process of the present invention become more advantageous over the one disclosed herein above. Further, the dimeric impurity level is reduced to less than 0.05%, which meets the ICH guidelines and makes the title product highly pure. SUMMARY OF THE INVENTION

The main aim of the present invention is to provide a process of lactonization to produce highly pure statins. The other object of the present invention is to provide a process for lactonization to produce simvastatin.

Another object of the present invention is to provide a process for lactonization of simvastatin hydroxyacid or its salts that avoids use of strong corrosive acids and drastic heat conditions thereby making the process environment friendly on industrial scale. Yet other object of the present invention is to provide a process that can be carried out at moderate temperature resulting in the title product with higher yield and purity.

Yet another object of the present invention is to provide a process for lactonization to produce simvastatin with reduced dimeric impurity to a level of less than 0.05%. Still other object of the present invention is to provide a process for lactonization to produce simvastatin involving using a mixture of carboxylic acid anhydride and water miscible organic solvent. Specifically, the solvent used may be nitrile solvent Still another object of the present invention is to provide a process for lactonization to produce simvastatin that is convenient to operate on commercial scale. STATEMENT OF INVENTION: According to this invention, there is provided an improved process for lactonization to

produce highly pure statins of Formula II, where in R is H or CH ₃

I II comprising lactonization of compound of Formula I where R is H or CH ₃ and X is H, a

metal cation or NH ₄ cation in a mixture of an organic solvent and carboxylic acid anhydride under anhydrous condition and recovering the statin of formula II by conventional methods optionally purifying the said title compound employing ethyl

acetate and hexane for recrystallisation wherein (a) the solvent used is nitrile solvents, ketonic solvents, hydrocarbon solvents, ethereal solvents, ester solvents and/or halogenated solvents and (b) recovery of statins is conducted by adding water proviso the solvent used is water miscible or by conventional crystallization method in case solvent used is water immiscible.

The reaction is performed in presence of a stabilizer like butylated hydroxyl toluene, butylated hydroxyl anisole.

The carboxylic acid anhydride employed may be such as acetic anhydride or propionic anhydride. The laconization may be performed at a temperature of 10-40° C and typically for a period of 5 to 30 hours.

Solvents used may be nitrile solvents like acetonitrile, propionitrile; ketonic solvents like acetone, methyl isobutyl ketone, methyl ethyl ketone; hydrocarbon solvents like hexanes, heptanes, cyclohexane, benzene, toluene, xylenes; ester solvents like, ethyl acetate; ether solvents like, diethyl ether, diisopropyl ether, tetrahydrofuran and halogenated solvents like dichloromethane, chloroform.

The amount of acid anhydride used is 1 to 5 parts by volume per part of the starting material. The amount of solvent is 2 to 20 parts by volume per part of the starting material. Crystallization of the title product from reaction mass may be conducted using alkanolic solvents like C1-C5 alkanols, water or a mixture thereof

Major advantages of the present invention as compared to the prior art procedures are: 1) The product obtained is highly pure having dimer impurity reduced to fairly less than 0.05%. 2) No corrosive acids and solvent immiscible solid reagents are used, which complicate

the operations of filtration etc.

3) Volumes of reactants and solvents are greatly reduced.

4) The process is very easy to operate at large scale, cost efficient and environment friendly. 5) Work up and product isolation procedure is very simple and easy and does not require any special infrastructure of plant and machinery.

The process is further illustrated by non limiting examples, which should not restrict scope of the invention.

EXAMPLE l : Simvastatin ammonium salt (50 g) of formula I is reacted with acetic anhydride (125 g) in acetonitrile (750 ml) at 20-25 ⁰ C for 20-25 hours. Reaction mass is cooled and water is added slowly to bring about crystallization of the product. Slurry is filtered and washed with water followed by drying of the cake to yield 45 g of Simvastatin, which is purified to give the final Simvastatin having dimer impurity <0.05%. EXAMPLE:

Simvastatin ammonium salt (50g) of formula 1 is reacted with acetic anhydride (75g) in

250 ml acetonitrile at 20 to 25°C for 5 to 15 hours. Reaction mass is cooled and water is

added slowly to bring out crystallization of the title product. The slurry is filtered and washed with water followed by drying to isolate the product. Dried product thus obtained is dissolved in ethyl acetate and recrystallized with n-hexane. The recrystallized product is further charcolized in methanol and water is added slowly to facilitate crystallization of highly pure product having purity of more than 99% and dimeric impurity of less than 0.05%.