Title of Invention

A PROCESS FOR LACTONIZATION TO PRODUCE SIMVASTATIN

Abstract

(57) Abstract:: 1 A process tor Lactoruzation to produce Simvastatin at Formula 1 When comprises healing a compound, namely acid or ammonium salt of compound of Formula II Where Z IS M or NH, in an organic solvent selected from xylenes, ethylbenzena and mixtures tnereof at a temperature of 1 30 to 1 AO ° C, disliing off the solvent and crystallzation from cydatiexmno to give Simvastatin of greater man 99% purity PRICE: THIRTY RUPEES

Full Text

This invention relales to a process for lactonization to produce Bimvastalin. Lovaslatin, simvastatin, pravastatin, atorvastatin and mevastatin are well known potent anlihypercholesterolemic agents that function by limiting ctiolesterol 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 semi-synthetic and totally synthetic means thereof. Two of the most popular compounds in this therapeutic category are simvastatin Hnd atorvastatin The fonner is one of the most prescribed drugs in the treatment of primary hypercholesterolemia with minimum side effects and well established safety pnsfile. The use of highly pure simvastatin is exceedingly desirable in preparation of a phanmaceutical lonn as it would avoid accumulation of impurities during prolonged usage and would reduce the possible side effects during medical treatment. oblajn simvastatin and thus lactonJzation constitutes an essential step of the process. It is of considerable importance lo employ an efficient method for the lactonization that can produce simvastatin of high punty in good yield The process disclosed in the US Patent 4,820,850 involves healing of hydroxyacid ammonium salt in toluene at 100" C under a purge of nitrogen. The ladonizalion completion requires 6-8 hours refluxing and results tn fomiation of increased amounts of dimer (Formula III), This dimer impurity is difficult lo separate from the desired lactone even with repeated crystallization. The presence of dimer lowers the purity of the simvastatin product. US Patent 4,916,239 describes another pmcess where the lactonization reaction has been carried out by treating hydroxyacid ammonium sail in a mixture of acetic acid and water, and in the presence of a strong acid catalyst. This process requires gradual addition of water in several lots to effect crystallization of the lactonized product from the reaction medium to shift the equilibrium to the lactone 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 dimer content obtained is reported to be less than 0,2%. US Patent 5,917,058 provides an alternate process to lactonize hydroxyacid or ils salt by treatment with acetic aad under anhydrous conditions The reaction is to be carried out essentially for a period of 5-7 hours and extensive water washing of the product is required to remove traces of acetic add. The aim of the present invention is to provide a highly efficient method for lactonization to produce simvastatin of greater than 99% puhty in high yield. 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. Brief Statement of the Invention: According to the invention, there is provided a process for Lactonization to produce Simvastatin, of Pormula I The Lactonization reaction (heating) is completed in 20-40 minutes. The organic solvent is preferably xylenes and Z is NH^, Detailed Description of the Invention: As an initial attempt, lactonizaiion ot hydroxyacid ammonium salt was carried out in toluene (Ref: US Patent 4,820,850) and it was observed that dimeric impurity is formed to the extent of 0.5 to 1,0% and duration of reaction to attain starting material left unreacted to less than 2% by HPLC varied from 6 to 8 hours. Further, variation in results was observed depending upon the heating rate and flow of nitrogen purge. Examination of other lactonization procedures reported in Irterature concluded that cydizalion in toluene yields reasonably pure simvastatin, the only disadvantage being the fonnation of excess dimer impurity. We reasoned that this impurity formation is due to longer reaction period in toluene and is not the result of higher reaction temperature of 100" C. The instant invention relates to a novel process of lactonizing hydroxyacid ammonium salt in xylenes at reflux temperature The lactonization reaction is efficiently accomplished within 30 minutes in presence of an antioxideni under a constant purge of nitrogen. The level of dimer impurity in the reaction mixture under the present cyclization conditions is restricted to less than 0,4% and isolation of the simvastatin lactone from the reaction mass reduces it further to less than 0.2% as recommended in Pharma Europa, Vol. 10, No. 3, September. 1998. This kind of smooth reaction and the product stability at high temperature were not anticipated and this observation constitutes an important part of the present invention. The amount of xylenes is 20 to 50 parts by volume per part of the starting material. However, preferably 25 parts by volume is enough to carryout the lactonization recation. The said reaction can be conducted in different solvents having boiling range above 110° C such as ethyibenzene. The reaction is earned out at 110 to 140° C but preferably at 130-140° C, Xylenes employed typically consist of atx)ut 98% orthoxylene, the remaining being meta- and para-xyienes. Further, an antioxident is added and nilrogen is bubbled through the reaction mass. Suitable antioxidenls include butylaled hydroxytoluene and butylated hydroxyanisole. Product is isolated by dtstitlmg off xylenes and crystallization from cyclohexene to give simvastatin of greater than 99% punly. This can be further re-crystallized from methanol and water to consistently attain more than 99.4% puiity. Typically, the lactonization reaction is conducted by heating simvastatin ammonium salt in xylenes at 135-140° C for 30 minutes. However, it has tieen observed that extended heating in xylenes gives dimer to the extent of 0.65% against 1.2% in toluene. The major advantages realized in the present lactonizalion conditions as compared to the prior art are increased process productivity and product purity. The reaction period is typically 30 minutes that demonstrates a greater efficiency Xylenes are fully recovered and recycled in the process and no aqueous effluent is generated The following specific examples illustrate the process of the invention: Example 1 PREPARATION OF (IS, 3R, 7S, 8S, 8aR)- 3, 7- DIMETHYL- 8- (2- [ (2R, 4R}- 4- HYDROXY- 6-OXO- 3, 4, 6, 6- TETRAHYDRO- 2H- PYRAN- 2- YL] ETHYL]- 1, 2, 3, 7, 8, 8a- HEXAHYDRO NAPHTHAUN-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-dimethylbutyryloxy)- 1(S)- naphthyl]- 3(R), 5(R)- dihydroxyheptanoate (Fomiula II) (100 g., 0.220 mols) was added rapidly to xylenes (2500 ml.) at 130-135" C containing butylated hydroxyloluene (0.05 g.) with nitrogen bubbling. Temperature of the reaction was maintained at 135-138° C for 30 minutes. Thereafter it was cooled to 25-30° C and treated with cartoon DC-enoanticromos (5 g.) for 30 minutes. Suspension was filtered through celite and residue washed with xylenes (2x50 ml,). Xylenes were removed at 60-65° C under reduced pressure and the residue was dissolved in cyclohexane (200 ml.) at €0-85" C. The solution was cooled slowly with stimng to 10-15° C and aged for 1 hour. The product was filtered and washed with cyclohexane (75 ml.) and dried in vacuo to yield simvastatin (83 g., 90%) having HPLC purity 99.28%. Crystallization from Methanol/ Water: Simvastatin (83 g., 0.198 moles) was dissolved in methanol (830 ml.) at 10-15° C and DM water (830 ml.) was added slowly over a period of one hour. The product slurry was cooled to 3-5° 0 and was maintained at this temperature for 1 hour. The product was then fittered and washed with chilled methanol/ water mixture (1:1 v/v, 50 ml.) and dried in vacuo at 50-55° C to obtain simvastalin (80 g., 96.4%) in phamiaceulicaliy acceptable 99.55% HPLC purity. The level of dimerwas Example 2 PREPARATION OF (IS, 3R, 7S, 8S, 84R)- 3, 7- DIMETHYL- 8- [2- [ (2R, 4R}- 4- HYDROXY- 6-0x0- 3, 4, 5, 6- TETRAHYDRO- 2H- PYRAN- 2- YL] ETHYLJ- 1, 2. 3, 7, 8, 8a- HEXAHYDRO NAPHTHALIN-1- YL 2, 2- DtMETHYLBUTANOATE Lactonization Ammonium 7- [1, 2, 6, 7, 8, 8a(?^') - hexahydro- 2(S). 6(R)- dimethyl- 8(S)- (2, 2-dimethylbutyryloxy)- 1(S)- naphthyl]- 3(R), 5(R)- dihydroxyheptanoate (Formula II) (5g,, 11 mmol.} was added to xylenes (250 ml.) and the reaction mass was refluxed at 138-140° C with constant nitrogen purging. The reflux was continued for 30 minutes and reaction mass cooled to 25-30° C, HPLC reaction monitoring indicated unreacted ammonium sa(t (190%), simvastalin formation (94.8%) and dimer (0.24%). Xylenes were distilled off at 60-65° C under reduced pressure. The residue was dissolved at 80-85° C in cyclohexane (100 ml.) and then cooled over 1 hour to 10-12° C, Product was filtered and washed with chilled cyclohexane (5 ml.) and dried in vacuo at 45-50° C to yield 4.2 g. (91.4%) of the title compound with HPLC purity 98.9% and dimer content 0.15%. This product was dissolved in methanol (42 ml.) at room temperature and solution was cooled 5-10° C. Water (42 m!,) was added slowly in 30 minutes at 5-10° C. The product thus crystallized was stirred at 5-10° C, filtered and washed with cold methanolMater mixture (i:i v/v, 8 ml.). The product was dried to constant weight in vacuo at 45-50° C to obtain simvastatin {4g., 95.2%). Chromatographic purity (HPLC) 99.5% and dimer 0.16%, Example 3 Hydroxyacid ammonium sail of Fomiiila 11 required m lactonizalion is prepared by the following procedure: Step-I PREPARATION OF N- BENZYL- 7- [1, 2, 6, 7, 8, 8a(R)- HEXAHYDRO- 2(S). 6(R)- DIMETHYL-8(S)- [[2(S)- METHYLBUTANOYL] OXY)- 1(S)- NAPHTHYLl- 3(R), 5(R)- DIHYDROXY HEPTANOIC ACtD AMIDE {LOVASTATIN BENZYLAMtDE) A mixture of lovastatin (50 g, 0.124 mol) and benzylamine (46,32 g, 0.432 mol) was mixed with toluene (25 ml) and heated to 80° C under nitrogen atmosphere for 1 hour. Absence of lovastatin was monitored by HPLG. Excess benzylamir\e and toluene were distilled off at 85-90" C under reduced pressure (5-10 mm Hg). The residue was mixed with xylenes (50 ml) and distilled again at 85-90° C under reduced pressure (5-10 mm Hg) to get product, lovastatin benzylamide. as light brown viscous liquid. Yield: 67.5 g. Step-ll PREPARATION OF N- BENZYL- 7- [1, 2, 6. 7, 8, 8a(R)- HEXAHYDRO- 2(S), 6(R)- DIMETHYL-8{S)- [[2(8)- METHYLBUTANOYL] OXY]- 1(5)- NAPHTHYL]- 3(R), 5(R). BIS [(TERT-BUTYLDIMETHYLSILYL) OXY] HEPTANOIC ACID AMfDE (DIPROTECTED LOVASTATIN BENZYLAMIDE) A solution of lovastatin benzylamide (63.26 g, 0.124 mol) in N.N-dimethylfomiamide (139 ml) was mixed with imidazole (21 g, 0.309 mol) and tert-butyldimethylsilyl chloride (51.42 g, 0.341 mol) at 25-30° C under nitrogen atmosphere. Reaction mixture was healed to 60-65° C and stirred for 4 hours. HPLC indicated complete conversion of lovastatin benzylamide into diprotected derivative. Reaction mixture was cooled to 10-15° C and methanol (2.85 ml) added and stirred for 30 minutes. Then the reaction mass was poured into a mixture of cyclohexane (1500 ml) and 5% aqueous sodium bicarbonate solution (750 ml) at 25-30° C and stirred for 10 minutes. Layers were separated and organic layer was washed sequentially with 5% aqueous sodium bicarbonate solution (750 ml) atwi demineratised water (750 ml). The organic layer was concentrated completely at 55-60° C under reduced pressure to obtain diprotected lovastatin benzylamide as viscous liquid. Yield: 99 g. Step-UI PREPARATION OF N- BENZYL- 7- [1, 2, 6, 7, 8, 8a(R)- HEXAHYDRO- 2(S1, 6(R)- DIMETHYL-SIS)- [[2, 2- DIMETHYLBUTANOYL] OXY]- 1(S) NAPHTHYL]- 3(R), 5(R)- BIS ((TERT-BUTYLDIMETHYLSILYL) OXY] HEPTANOIC ACID AMIDE (DIPROTECTED£\rt/ASTATIN BEN2YLAMIDE) A solution of pyrrolidine (26.1 g, 0.353 mol) in telrahydrofuran (150 ml) was added slowly to a solution of n-butyllittiium in hexanes (13 5%, 224 ml, 0.321 mol) at -25° C to -20^ C over a period of 30 minutes. Reaction mixlure was stirred for another 30 minutes at -25° C lo -20° C. The reaction mirfute was then diluted with letratiydtofuran (450 ml) and cooted to -50" C. Then added a solution of slep-ll diprotected lovastalin benzylamide (91.4 g, 0.123 ml) in telrahydrofuran (450 ml) in 10 minutes while maintaining temperature below -40° C, The leadion mixture was stirred for 2 hours at -30° C to -35° C. Methyl iodide (28.06 g, 0.197 ml) was added in one portion (exothermic reaction, temperature rises lo -16° C) and the reaction mixture was stirred at -30° C for 1.5 hours. Progress of reaction was monitored by HPLC (starting material Step-JV PREPARATION OF AMMONIUM 7- [1, 2, 6, 7, 8, 8a(R)- HEXAHYDRO- 2(3), 6{R) DIMETHYL-SIS)- [[2. 2- DIMETHYLBUTANOYL] OXY- 1(S)- NAPHTHYL]- 3(R), 5{R)-DIHYDROXYHEPTANOATE (SIMVASTATIN AMMONIUM SALT) The above concentrated mass was dissolved in methanol (750 ml) at 25-30° C and added melhanesulphonic acid (2.22 g, 0.023 mol). The reaction mixture was stirred at 30-32° C for 3 hours. Aqueous solution of sodium hydroxide (2N, 375 ml) was added and heated the reaction mixture to 76° C. A mixture of telrahydrofuran and methanol (675 ml) was distilled out and afterwards the remaining reaction mixture was refluxed for 3 hours at 78-79° C. Reaction mixlure was then cooied to 60° C and the solvents were removed in vacuo. The residue was diluted with water (25 ml) and cooled lo 10° C. pH of the solution was adjusted lo 7.0 by adding 3N aqueous hydrochloric acid (265 ml). Ethyl acetate (800 ml) was added and the pH was further lowered to 5.0 wtth 3N aqueous hydrochloric acid. After stirring for 10 minutes at 15' C layers were separated and aqueous layer was extracted with ethyl acetate (125 ml). Combined organic layers were diluted with methanol (250 ml) and wamied to 25-30- C. A mixture of aqueous ammonia (^25%) and methanol (1:3 v/v, 83 ml) was added slowly over a period of 30 minutes at 2^30° C during which time product preciprtates. Precipitated prrxluC was stirred at 25-30° C for 30 minutes and cooled to -10' C for 1 hour. Product was filtered and washed with a mixture of methanol and ethyl acetate (1:3 v/v, 50 ml) at 10° C. Product was finally dried under reduced pressure at 40-15' C. Yield; 40 g (HPLC purity >99%). , we Claim: 1 A process for Lactonization to produce S/mvasIatm of Formula t Wh/ch comprises heating a compound, namely acid or ammonium salt of compound of Formula II. Where Z is H or NH4 in an organic solvent selected from xylenes, ethylbenzene and mixtures thereof at a temperature of 130 10 140 ° C, distilling off Ifie solvent and cfyslallizationfrom cyciohexane to give Simvastatin of greater than 99% purity 2 The process according to Claim -1 where the Lactonization reaction (heating) is completed in 20-40 minutes 3 The Process according to Claim 1 wherein Organic solvent is xylenes and Z is NH4 4. A process for lactonizetion to produce simvastatin substantially as herein described with reference to the examples.

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0401-mas-2001 abstract.pdf

0401-mas-2001 claims.pdf

0401-mas-2001 correspondence-others.pdf

0401-mas-2001 correspondence-po.pdf

0401-mas-2001 description (complete).pdf

0401-mas-2001 form-1.pdf

0401-mas-2001 form-13.pdf

0401-mas-2001 form-26.pdf

0401-mas-2001 form-3.pdf

0401-mas-2001 form-4.pdf

0401-mas-2001 petition.pdf