Title of Invention

A PROCESS TO PRODUCE HIGHLY PURE SIMVASTATIN

Abstract

There is provided a process to produce hi~hly pure Sir:i\!astatin of formula! having less than 0 1 air; dimer impurities Which comprises Lactonization ofa compound of the Fonnula II, , Where Z is H or NH4 in a mixture of acetonitrile and glacial acetic acid under anhydrous conditions at a temperature of 65-700 C and wherein the dimmer impurity of formula III formed is less than 0.1 %f Thereafter adding water to -the reaction mixture thereby causing Simvastatin of formula Ito precipitate from the reaction mixture

Full Text

Background of the Invention: This invention relates to a process for lactonization to produce highly pure impastation, Levitation, simvastatin, pravastatin, atorvastatin and devastation are well known potent antihypercholesterolemic agents that function by limiting cholesterol biosynthesis by inhibiting the enzyme, HMg-COA reductive. This class of compounds referred to generally as stains are produced either by natural fennentation process or through semi-synthetic and totally synthetic means thereof. Two of the most popular compounds in this therapeutic category are simvastatin and atorvastatin. The fonner is one of the most prescribed drugs in the treatment of primary hypercholesterolemia with minimum side effects and well established safely profile. The use of highly pure simvastatin is exceedingly desirable in preparation of a phamiaceutical product as it would avoid accumulation of impurities during prolonged usage and would reduce the possible side effects during medical treatment. In most of the synthetic methods known to manufacture simvastatin (Formula 1) shown below, the compound of formula 11A also shown below, is the common intermediate, which is cyclized to obtain simvastatin and thus lactonization constitutes an essential step of the synthesis. This dime impurity is difficult to separate from the desired lactones even with repeated crystallization. Efforts to minimize the formation of the diner have led to the use of high dilution during lactonization reaction. Nevertheless, this technique results in lower efficiency and is disadvantageous at commercial scale. US Patent 4,916,239 describes another process where the lactonization reaction has been carried out by treating hydrocyanic ammonium salt in a mixture of acetic acid and water, and in the presence of a strong add catalyst. This process requires gradual addition of water in several lots to effect crystallization of the Latinized product from the reaction medium to shift the equilibrium to the lactose side and this drives the lactonization to completion. This process is not amenable to industrial scale due to effluent generation and low purity of simvastatin product even though dimmers content obtained is reported to be less than 0.2%. US Patent 5,917,058 provides an alternate process to lactones hydrocyanic or its salt by treatment with acetic acid under anhydrous conditions. However, the purity of the final product obtained by this procedure is not more than 99%. Furthermore, in this patent, there is no reference to the level of diametric impurity produced in the process. The aim of the present invention is to obtain highly pure simvastatin that contains diametric impurity less than 0.1%. An example where simvastatin of greater than 99.5% purity has been achieved is cited in WO 99/42601 wherein the product was purified by successive crystallizations from aqueous acetone and from ethyl acetate. In this process in Formula II above, preferably Z is NH4 The process further comprises adding water to the reaction mixture, thereby causing simvastatin of Formula 1 to precipitate from the reaction mixture. Detailed Description of the Invention: The instant invention relates to a novel process for lactonization of simvastatin hydroxyacid or its salt that avoids the use of strong capsize adds and drastic heat conditions. This process allows lactonization reaction to proceed in a mixture of acetic acid and acetonitrille at moderate temperatures and consistently provides simvastatin of greater than 99.5% purity with dimer content less than 0.1%. Specifically, the process of this invention comprises heating a solution of simvastatin hydroxyacid in its salt forint. most preferably the ammonium salt (Formula II) in a mixture of acetic add and acetonitrile under anhydrous conditions at a temperature that vary from 50° C to 80° C and preferably at 65-70" C. The lionization reaction is typically accomplished within about 5 to 7 hours. The amount of acetic add used is at least 3 to 5 parts by volume per part of the starting material. The amount of acetonitrile is 10 to 20 parts by volume per part of the starting material and preferably 15 parts by volume may be used. The Latinized product is isolated after completion of reaction by addition of water. Major advantage of the present invention as compared to the prior art procedures is the high product purity where the level of dimer impurity has been greatly reduced to less than 0.1%. The addition of water to the reaction mixture directly provides alone as a homogeneous slurry that makes the filtration operation very easy at large scale and work up involves no solvent concentration or neutralization step prior to product isolation. The invention will now be more fully descript)ed with reference to the following examples which are only illustrative and are not b>e construed as any limitalion thereof. Example 1 PREPARATION OF (IS, 3R, 7S. 8S. 8aR) -3, 7-DIMETHYL-8- [2- [ (2R, 4R) -i-HYDROXY-6-OXO-3, 4, 5, 6-TETRAHYDRO-2H-PYRAN-2-YL1 ETHYL] -1, 2, 3, 7, 8, 8a-HEXAHYDRO NAPHTHALIN-1-YL 2, 2-DIMETHYLBUTANOATE Lactonization Ammonium 7- [1, 2, 6, 7. 8, 8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2, 2-dimethytbutyryloxy) -1 (S) -naphthyl] -3 (R), 5 (R)-dihydroxyheptanoate (Formula II) (10 g., 0.022 moles) was dissolved In a mixture of acetonitrile (150 ml.) and glacial acetic add (30 ml). The solution was then heated to 65-70°C and was maintained at this temperature for 6 hours. At the end of the reaction, HPLC showed simvastatin 97.4%, unreacted starting material 0.69% and dimer 0.07%. The reaction mass was cooled to 15-20° C and water (350 ml.) was added over as period of 30 minutes. The precipitated product was cooled further to 10-15' C and stingy continued for 1 hour. Product was filtered and washed with water (2x10 ml.). 1:2 vA acetonitrlle-water (2x10 ml.) and dried in vacuum at 45-50° C. The product thus otrtained was dissolved in cyclohexene (200 ml.) at 80-85° C and then cooled over 1 hour to 10-12° C. Product was filtered and washed with chilled cydohexene (10 ml.) and dried in vacuum at 45-50° C to yield highly pure 8.2 g. (89%) of the title compound with HPLC purity 99.63% and dimer impurity 0.04%. Example 2 PREPARATION OF (IS, 3R, 7S, 8S, 8aR) -3, 7-DIMETHYL-8- [2- [ (2R, 4R) -4-HYDROXY-6-OXO-3, 4, 5, 6-TETRAHYDRO-2H-PYRAN-2-YL] ETHYL] -1, 2, 3, 7, 8, 8a-HEXAHYDRO NAPHTHALIN-I-YL 2. 2-DIMETHYLBUTANOATE Lactonization Ammonium 7- [1, 2, 6, 7, 8, 8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2, 2-dimethylbutyryloxy) -1 (S) -naphthyl] -3 (R), 5 (R) -dihydroxyheptanoate (Formula II) (10 g., 0.022 moles) was dissolved in a mixture of acetonitrile (150 ml.) and gladal acetic add (30 ml.). The reaction mixture was heated to 65-70° C under anhydrous conditions for 6 hours. Progress of reaction was checked by HPLC. At the end of the reaction, simvastatin vi«s 97.55%. unreacted starting material 0.66% and dimer impurity 0.07%. Thereafter, reaction mixture was cooled to 10-15° C and water (350 ml.) was added slowly over as period of 30 minutes and stirring was continued for 30 minutes. The product was filtered, washed with water (2x10 ml.) and dissolved in / methanol (90 ml.) at 25-30°C. The solution was cooled to 5-10" C and water (82 ml.) was added in 30 minutes. The product thus crystallized was stirred at 5-10° C, filtered and washed with cold methanol/water mixture (1:1 v/v, 8 ml.). Product was dried to constant weight in vacuum at 45-50" C to obtain simvastatin (8.3 g., 90%). Chromatographic purity (HPLC) 99.55% and dimer impurity 0.07%. WE CLAIM: ., A process to produce highly pure Simvastatin of formula I having less than 0.1 % dimer impurities. 2. The process according to Claim 1 wherein Z is NH4. 3. A process for lactonization to produce highly pure simvastatin of fomiula I substantially as herein described.

Documents:

0402-mas-2001 claims.pdf

0402-mas-2001 correspondence-others.pdf

0402-mas-2001 correspondence-po.pdf

0402-mas-2001 description(complete).pdf

0402-mas-2001 form-1.pdf

0402-mas-2001 form-13.pdf

0402-mas-2001 form-26.pdf

0402-mas-2001 form-3.pdf

0402-mas-2001 form-4.pdf

0402-mas-2001 pct search report.pdf

0402-mas-2001 petition.pdf

0402-mas-2001abstract.pdf

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