EP1294706A1 - A process for lactonization to produce simvastatin - Google Patents

Abstract

There is disclosed a process for the manufacture of simvastatin of Formula (I) which comprises heating a compound namely an acid or ammonium salt of compound of Formula (II), where Z is H or NH4 in an organic solvent at a temperature of 130 to 140 °C.

Description

Title:

A process for lactonization to produce sϊmvastatin

Field of the Invention:

_{1 . A} process for lactonization to produce simvastat'm of Formuia ⁽

This invention relates to a process for lactonization to produce simvastatin

Lovastatin, simvastatin, pravastatin, atorvastatϊn 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 semi-synthetic and totally synthetic means thereof. 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 and well established safety profile. The use of highly pure simvastatin is exceedingly desirable in preparation of a pharmaceutical form 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,

hydroxyacid ammonium salt (FoπmuJa II) also shown below is the common intermediate, which is cyclized to

FϋRMuLft J obtain simvastatin and thus lactonization constitutes an essential step of the process. It is of considerable importance to employ an efficient method for the lactonization that can produce simvastatin of high purity in good yield.

The process disclosed in the US Patent 4,820,850 involves heating of hydroxyacid ammonium salt in toluene at 100° C under a purge of nitrogen. The lactonization completion requires 6-8 hours refluxing and results in formation of increased amounts of dimer (Formula III).

Formula III

This dimer impurity is difficult to 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 process where the lactonization reaction has been earned out by treating hydroxyacid ammonium salt in a mixture of acetic add 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 its salt by treatment with acetic acid 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 acid.

The aim of the present invention is to provide a highly efficient method for lactonization to produce simvastatin of greater than 99% purity 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, Formula 1.

which comprises heating a compound namely acid or ammonium salt of compound of Fomiula II.

PORt U R

where Z is H or NFL, in an organic solvent elected from xylenes, ethylbenzene and mixtures thereof at a temperature of 130 to 140° C.

The lactonization reaction (heating) is completed *n 20-40 minutes.

The organic solvent is preferably xylenes and Z is NH₄ Detailed Description of the Invention:

As an initial attempt, lactonization of hydroxyacid ammonium salt was earned out in toluene (Ret: US Patent 4,82(0.850) and it was observed that dimeric impurity is formed to the extent of 0.6 to 1.0% and duration of reaction to attain starting material left unreacted to less than 2% by HPLC varied from 6 te> 8 hours. Further, variation in results was observed depending upon the heating rate and flow <ύf nitrogen purge. Examination of other lactonization procedures reported in literature coπchuded that cyclization in toluene yields reasonably pure simvastatin, the only disadvantage teeing the formation of excess dimer impurity. We reasoned that this impurity formation is du>e to longer reaction period in toluene and is not the result of higher reaction temperature of 1100° 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 pres«ence of an antioxident under a constant purge of nitrogen. The level of dimer impurity in the rseaction 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 ethylbenzene. The reaction is carried out at 110 to 140° C but preferably at 130-140° C. Xylenes employed typically consist of about 98% orthoxyiene, the remaining being meta- and para-xylenes. Further, an antioxident is added and nitrogen is bubbled through the reaction mass. Suitable antioxidents include butylated hydroxytoluene and butylated hydroxyanisole.

Product is isolated by distilling off xylenes and crystallization from cyclohexene to give simvastatin of greater than 99% purity. This can be further re-crystaliized from methanol and water to consistently attain more than 99.4% purity.

Typically, the lactonization reaction is conducted by heating simvastatin ammonium salt in xylenes at 135-140° C for 30 minutes. However, it has been 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 lactonization 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-DI ETHYL-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-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 (Formula II) (100 g., 0.220 moles) was added rapidly to xylenes (2500 ml.) at 130-135° C containing butylated hydroxytoluene (0.05 g.) with nitrogen bubbling. Temperature of the reaction was maintained at 135-138° C for 30 minutes. It was cooled to 25-30° C and treated with carbon 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 80-85° C. The solution was cooled slowly with stirring to 10- 15" C and aged for 1 hour. The product was filtered and washed with cyclohexene (75 ml.) and dried in vacuo to yield simvastatin (83 g., 90%) having HPLC purity 99.28%.

Crystallization from Methaπol/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° C and was maintained at this temperature for 1 hour. The product was then filtered and washed with chilled methanol/water mixture (1:1 v/v, 50 ml.) and dried in vacuo at 50-55° C to obtain simvastatin (80 g., 96.4%) in pharmaceutically accepted 99.55% HPLC purity. The level of dimer was <0.2% (0.18%). Example 2

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 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- dimethylbutyryloxy) -1 (S) -naphthyf] -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 salt (1.90%), simvastatin 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 cydohexane (100 ml.) and then cooled over 1 hour to 10-12° C. Product was filtered and washed with chilled cydohexane (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 ml.) was added slowly in 30 minutes at 5-10° C. The produd thus crystallized was stirred at 5-10° C, filtered and washed with cold methanolΛvater mixture (1:1 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

Hydroxyadd aκnmonium salt of Formula II required in lactonization is prepared by the following procedure:

Steρ-1

Preparation of N-Benzyl- 7- [1, 2, 6, 7, 8, 8a(R)- Hexahydro- 2(S), 6(R)- Dimethyl- 8(S)- [[ 2(S)- Methyϋbutanoyl] Oxy]- 1(S)- Naphthyl]- 3(R), 5(R)- Dihydroxy Heptanoic Acid Amide

(Lovastatin Benzylamide)

A mbcture of lovastatin (50 g, 0.124 mol) and benzylamine (46.32 g, 0.432 mol) was mixed with toluene (25 mf) and heated to 80° C under nitrogen atmosphere for 1 hour. Absence of lovastatin was monitored by HPLC. Excess benzylamine 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(S)- MethylbutanoyQ Oxy]- 1(S)- Naphthyl]- 3(R), 5(R)- Bis [(tert-Butyldimethylsilyl) Oxy] Heptanoic Acid Amide (Diprotected Lovastatin Benzylamide)

A solution of lovastatin benzylamide (63.26 g, 0.124 mol) in N,N-dimethylformamide (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. Readion mbcture was heated to 60-65° C and stirred for 4 hours. HPLC indicated complete conversion of lovastatin benzylamide into diproteded derivative.

Readion mixture was cooled to 10-15° C and methanol (2.85 ml) added and stirred for 30 minutes. Then the readion mass was poured into a mixture of cydohexane (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) and demineralised water (750 ml). The organic layer was concentrated completely at 55-60° C under reduced pressure to obtain diproteded lovastatin benzylamide as viscous liquid. Yield: 99 g. Step-lll

Preparation! of N-Benzyl- 7- [1 , 2, 6, 7, 8, 8a(R)- Hexahydro- 2(S), 6(R)- Dimethyl- 8(S)- [ [2, 2- Dimethylbutanoyl] Oxy]- 1(S) Naphthyl]- 3(R), S(R)- Bis [ (tert- Butyldimethylsilyl) Oxy] Hexρtanoκc Acid Amide (Diproteded Simvastatin Benzylamide)

A solution (of pyrrolidine (25.1 g, 0.353 mol) in tetrahydrofuran (150 ml) was added slowly to a solution of tn-butyllithium in hexanes (13.5%, 224 ml, 0.321 mol) at -25° C to -20° C over a period of 30 miniaftes. Readion mixture was stirred for another 30 minutes at -25° C to -20° C. The readion mδxture was then diluted with tetrahydrofuran (450 ml) and cooled to -50° C. Then added a solution χθf step-ll diproteded lovastatin benzylamide (91.4 g, 0.123 ml) in tetrahydrofuran (450 ml) ira 10 minutes while maintaining temperature below -40° C. The readion 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 readion, temperature rises to -16° C) and the reaction mixture was stirred at -30° C for 1.5 hours. Progress of readion was monitored by HPLC (starting material <0.1%). Temperature of readion mixture was then slowly raised to -10° C and stirred for 30 minutes. Readion was then quenched by adding water (550 ml) and the contents were stirred for 10 minutes at 10° C. Layers were separated and organic layer was washed with 1N aqueous hydrochloric add (550 ml) at 10° C. The organic layer was concentrated partially at 40-45° C under reduced pressure to get crude produd, diproteded simvastatin benzylamide, as brown liquid whicfi is taken as such in the next step.

Step-IV

Preparation of Ammonium 7- [1, 2, 6, 7, 8, 8a(R)- Hexahydro- 2(S), 6(R) Dimethyl- 8(S)- [ [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 methanesulphonic acid (2.22 g, 0.023 mol). The readion mixture was stirred at 30-32° C for 3 hours. Aqueous solution of sodium hydroxide (2N, 375 ml) was added and heated the readion mixture to 78° C. A mixture of tetrahydrofuran and methanol (675 ml) was distilled out and afterwards the remaining reaction mixture was refluxed for 3 hours at 78-79° C.

Reaction mixture was then cooled to 60° C and the solvents were removed in vacuo. The residue was diluted with water (25 ml) and cooled to 10° C. pH of the solution was adjusted to 7.0 by adding 3N aqueous hydrochloric add (265 ml). Ethyl acetate (800 ml) was added and the pH was further lowered to 5.0 with 3N aqueous hydrochloric add. After stirring for 10 minutes at 15° C, layers were separated and aqueous layer was extraded with ethyl acetate (125 ml). Combined organic layers were diluted with methanol (250 ml) and warmed to 25-30° C. A mbcture of aqueous ammonia (~25%) and methanol (1:3 v/v, 83 ml) was added slowly over a period of 30 minutes at 25-30° C during which time produd precipitates. Precipitated produd was stirred at 25-30° C for 30 minutes and cooled to -10° C for 1 hour. Produd was filtered and washed with a mixture of methanol and ethyl acetate (1:3 v/v, 50 ml) at 10° C. Produd was finally dried under reduced pressure at 40-45° C. Yield: 40 g (HPLC purity >99%).

Claims

We Claim:

1. A process for ladonization to produce simvastatin of Formula I

F θft V\υL_0_ which comprises heating a compound, namely add or ammonium salt of compound of Formula II.

FθR^»MULβ JX

where Z is H or NH₄ in an organic solvent seleded from xylenes, ethylbenzene and mixtures thereof a temperature of 130° to 140° C.

2. The process according to daim-1 where the ladonoization readion (heating) is completed in 20-40 minutes.

3. The process according to dai 1 wherein organic solvent is xylenes and Z is NH₄

4. A process for lactonization to produce simvastatin substantially as herein described with reference to the examples.