SK702003A3 - 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 DEG C.

Description

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Lactonization process for the production of simvastatin

Technical field

The invention relates to a lactonization process for the production of simvastatin

BACKGROUND OF THE INVENTION

Lovastatin, simvastatin pravastatin. atorvastatin and mevastatin are well known potent antihypercholesterolemic agents that act by limiting cholesterol biosynthesis by blocking the reductase enzyme HMG-CoA. This class of compounds, commonly referred to as statins, are produced either by a natural fermentation process or by a semi-synthetic and entirely synthetic method. The two most popular compounds of this treatment category are simvastatin and atorvastatin. The first is one of the most prescribed medicines for the treatment of primary hypercholesterolaemia with minimal side effects and a well established safety profile. The use of very pure simvastatin is very suitable for the preparation of a pharmaceutical form in order to prevent the accumulation of impurities during prolonged use and to reduce possible side effects during medical treatment.

For most known synthetic methods of simvastatin production (Formula I below),

Formula 1 ammonium salt of hydroxy acid (Formula IIA below) is a conventional intermediate that is cyclized to

Formula IIA

Obtaining simvastatin and thus lactonization is an essential step in the method. It is very important to use an effective method for lactonization to obtain high purity simvastatin with good spreading capacity.

The process disclosed in US Patent 4,820,850 involves heating the ammonium salt of the hydroxy acid in toluene at 100 ° C with nitrogen purification. The completion of lactonization requires 6-8 hours of reflux and results in an increased amount of dimer (Formula III)

This dimer contamination is difficult to separate from the desired lactone even by repeated crystallization. The presence of the dimer reduces the purity of the simvastatin produced.

US Patent 4,916,239 discloses another process wherein the lactonization reaction is formed by treating the ammonium salt of a hydro acid in a mixture of acetic acid and water in the presence of a strong acid catalyst. This procedure requires the addition of a certain amount of water to effect crystallization of the lactonized product from the reaction medium in order to shift the equilibrium to the lactone side, leading to completion of the lactonization. This process is not suitable for industrial processing due to the generation of liquid waste and low purity of the product due to the dimer content of less than 0.2%.

US Patent 5,917,058 provides an altered process for lactonizing a hydroxy acid or salt thereof by treatment with acetic acid under anhydrous conditions. The reaction is to be carried out in essentially 5-7 hours, and substantial washing of the product with water is required to remove trace amounts of acetic acid.

It is an object of the present invention to provide a highly efficient lactonization process for the production of simvastatin with a purity greater than 99% with a high yield. An example in which simvastatin with a purity greater than 99.5% was obtained is given in WO 99/42601, wherein the product was purified by successive crystallization from hydration acetone and ethyl acetate

SUMMARY OF THE INVENTION

According to the invention there is provided a lactonization process for the production of simvastatin,

Formula 1 which comprises heating a compound, namely an acid or an ammonium salt, of a compound of Formula II,

cooz he

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Wherein Z is H or NH ₄ in an organic solvent selected from xylenes, ethylbenzene, and mixtures thereof at a temperature of 130 to 140 ° C.

The lactonization reaction (heating) is complete within 20-40 minutes.

Preferred organic solvents are xylenes and Z is NH 4

As a starting experiment, the lactonization of the ammonium salt of the hydroxy acid in toluene was performed (see US patent 4,820,850) and it was found that a dimeric contamination in the range of 0.6 to 1.0% was formed and a reaction to reach the starting material with less than 2% by HPLC takes from 6 to 8 hours. Furthermore, variations in the results depending on the heating and purge nitrogen flow were found. By testing other lactonization processes reported in the literature, we conclude that cyclization in toluene yields reasonably pure simvastatin, the only drawback being the formation of excess dimeric contamination. We conclude that this contamination is due to a longer reaction time in toluene and not is the result of a higher 100 ° C reaction temperature.

The present invention relates to a novel process for the lactonization of an ammonium salt of a hydro acid in xylenes at reflux temperature. The lactonization reaction is efficiently carried out within 30 minutes in the presence of an antioxidant with continuous nitrogen purification. The level of dimeric contamination in the reaction mixture under these cyclization conditions is limited to less than 0.4% and the separation of simvastatin lactone from the reaction mass further reduces it to less than 0.2% as recommended in Pharma Europe, Vol. 10. No.3, September, 1008. This quiet reaction method and the high temperature stability of the article were not anticipated and this feature is an important part of the present invention.

The amount of xylene is 20 to 50 parts by volume per part by volume of the starting material. However, 25 parts by volume are preferred as sufficient to carry out the lactonization reaction. Said reaction can be carried out in various solvents having a boiling point above 110 ° C, such as ethylbenzene. The reaction is carried out at 110 to 140 ° C, but preferably 130-140 ° C. The xylenes used typically contain about 98% ortoxylene, the remaining amounts being meta and para-xylenes. An antioxidant is then added and nitrogen is bubbled through the reaction mass. Suitable antioxidants are butylated hydroxytoluene and butylated hydroxyanisole.

The product is separated by distillation of xylenes and crystallization from cyclohexene to give simvastatin of greater than 99% purity. This can be further recrystallized from methanol and water to obtain a purity greater than 99.4%.

Typically, the lactonization reaction is accomplished by heating the ammonium salt of simvastatin in xylenes at 135-140 ° C. However, prolonged heating in xylenes was found to result in a dimer in the range of 0.65 versus 1.2% in toluene.

The greatest advantage realized under these lactonization conditions compared to the prior art is the higher productivity and purity of the product. The reaction time is typically 30 minutes which means higher efficiency. The xylenes are completely recovered and recycled in the process and no liquid waste is generated.

DETAILED DESCRIPTION OF THE INVENTION

Example # 1

Embodiment 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-hexahydronaphthalene-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 grammol molecules) was quickly added to xylene (2500 mL) at 130-135 ° C containing butylated hydroxytoluene (0.05 g) with bubbling nitrogen. The reaction temperature 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. The suspension was filtered through a cuvette and the residue washed with xylene (1 x 50 mL). The xylene was removed at 60-65 ° C under reduced pressure and the residue was dissolved in cyclohexane (200 mL) at 80-85 ° C. The solution was slowly cooled with stirring to 10-15 ° C and allowed to lie for 1 hour. The product was filtered and washed with cyclohexene (75 mL) and dried in vacuo to give sinvastatin (83 g, 90%) with an HPLC purity of 99.28%.

Crystallization from methanol / water:

Simvastatin (83 g, 0.198 mol) was dissolved in methanol (830 mL) at 10-15 ° C and DM water (830 mL) was added slowly over 1 hour. The suspension was cooled to 35 ° C and held at this temperature for 1 hour. The product was then filtered and washed with a cooled mixture of methanol and water (1: 1 v / v, 50 mL) and dried under vacuum at 5055 ° C to obtain simvastatin (80 g, 96.4%) with a pharmaceutically acceptable HPLC purity of 99, 55%. The diner level was <0.2% (0.18%).

Example # 2

Embodiment of (IS, 3R, 7S, 8S, 8aR) -3,7-dimethyl-8- {2 - [(2R, 4R) -4-hydroxy-6-oxo-3,4,6-tetrahydro-2H-pyran] -2-YL] ethyl} -1, 2,3,7,8,8a-hexahydronaphthaline-1-YL 2,2-dimethylbutanoate

lactonization

7- [1,2,6,7,7,8,8a (R) -hexahydro-2 (S), 6 (R) -dimethyl-8 (S) - (2,2-dimethylbutyryloxy) -1 (S) -naphthyl 1 -3 (R), 5 (R) -dihydroxyheptanoate (Formula II) (5g, 11 mmol) was added to xylene (250 mL) and the reaction mass was refluxed at 138-140 ° C with constant nitrogen purification. Reflux was continued for 30 minutes and the reaction mass was cooled to 25-30 ° C. Monitoring of the HPCL reaction showed a non-reaction ammonium salt (1.90%), formed simvastatin (94.8% δ and dimer (0.24%). Xylene was distilled at 60-55 ° C under reduced pressure. The residue was dissolved at 80 ° C. -85 ° C in cyclohexane (100 mL) and then cooled to 10-12 ° C for 1 hour.The product was filtered and washed with cooled cyclohexane (5 mL) and dried under vacuum at 45-50 ° C to give 4, 2 g (91.4%) of a compound having an HPLC purity of 98.9% and a dimer content of 0.15%.

This product was dissolved in methanol (42 mL) at room temperature and the solution was cooled to 5-10 ° C. Water was slowly added over 30 minutes at 5-10 ° C. The product thus crystallized was stirred at 5-10 ° C, filtered and washed with a cold mixture of methanol and water (1: 1 v / v, 8 mL). The product was dried to constant weight under vacuum at 45-50 ° C to give simvastatin (4g, 95.2%), Chromatographic purity (HPLC) 99.5% and Dimer 0.16%.

Example # 3

The ammonium salt of the hydroxy acid of formula II required for lactonization is prepared as follows:

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) -naphthyl} -3 (R), 5 (R) - dihydroxy heptanoic acid amide (lovastatin benzylamide)

A mixture of lovastatin (50g, 0.124 mol) and benzylamine was mixed with toluene (25 mL) and heated to 80 ° C under nitrogen for 1 hour. The lack of lovastatin was monitored by HPLC. Excess benzylamine and toluene were distilled at 85-90 ° C under reduced pressure (5-10 mm Hg). The residue was mixed with xylene (50 mL) and distilled again at 85-90 ° C under reduced pressure (5-10 mm Hg) to give the product, lovastatin benzylamide, as a light brown viscous liquid. Yield: 67.5 g.

Step II

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) -naphthyl] -3 (R), 5 (R) -bis [(tert-butyldimethylsilyl) oxy] heptaniic 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. The reaction mixture was heated to 6065 ° C and stirred for 4 hours. HPCL indicated complete conversion of lovaststin benzylamide to the diprotected derivative

The reaction mixture was cooled to 10-15 ° C and methanol (2.85 mL) was 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. The layers were separated and the organic layer was washed successively with a 5% aqueous solution of sodium bicarbonate (750 mL) in demineralized water (750 mL).

The organic layer was completely evaporated at 55-60 ° C under reduced pressure to obtain diprotected lovastatin benzylamide as a viscous liquid. Yield: 99g.

Step III

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), 5 (R) - Bis (tert-butyldimethylsilyl) oxy] hexptanolic acid amide (diprotected simvastatin benzylamide)

A solution of pyrrolidine (25.1 g, 0.353 mol) in tetrahydrofuran (150 mL) was slowly added to a solution of n-butyllithium in hexane (13.5%. 224 mL, 0.321 mol) at -25 ° C to 20 ° C for 30 min. minutes. The reaction mixture was stirred for an additional 30 minutes at -25 ° C to 20 ° C. The reaction mixture was then diluted with tetrahydrofuran (450 mL) and cooled to 50 ° C. Then, a solution of diprotected lovastatin benzylamide from step II (91.4 g, 0.123 mL) in tetrahydrofuran (450 mL) was added over 10 minutes, maintaining the temperature below -40 ° C. The reaction mixture was stirred at -30 ° C to -35 ° C for 2 hours. Methyl iodide (28.06 g, 0.197 mL) was added in one portion (exothermic reaction, temperature increased to 16 ° C) and the reaction mixture was stirred at -30 ° C for 1.5 hours. The progress of the reaction was monitored by HPLC (starting material <0.1%. The temperature of the reaction mixture was slowly increased to -10 ° C and stirred for 30 minutes. The reaction was then quenched by the addition of water (550 mL) and stirred for 10 minutes at The layers were separated and the organic layer was washed with 1 N hydrochloric acid (550 mL) at 0 ° C. The organic layer was partially concentrated at 40-45 ° C under reduced pressure to give the crude product, diprotected simvastatin benzylamide, as a brown liquid which is taken to the next step.

Step IV

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 methanesulfonic acid (2.22 g, 0.023 mol) was added. The reaction mixture was stirred at 30-32 ° C for 3 hours. Aqueous sodium hydroxide solution (2N, 375 mL) was added and the reaction mixture was heated to 78 ° C. A mixture of tetrahydrofuran and methanol (675 mL) was distilled and then the remaining reaction mixture was refluxed at 78-79 ° C for 3 hours.

The reaction mixture was then cooled to 60 ° C and the solvent was removed in vacuo. The residue was diluted with water (25 mL) and cooled to 10 ° C, the pH of the solution was adjusted to 7.0 by the addition of 3N hydrochloric acid (265 mL). Ethyl acetate (800 mL) was added and the pH was further reduced to 5.0 with 3N hydrochloric acid. After stirring at 15 ° C for 10 min, the layers were separated and the aqueous layer was taken up in ethyl acetate (125 mL). The combined organic layers were diluted with methanol (250 mL) and warmed to 25-30 ° C. A mixture of hydration ammonia (-25%) and methanol (1: 1 v / v, 83 mL) was added slowly at 25-30 ° C over 30 minutes, during which time the product precipitated. The precipitated product was stirred at 25-30 ° C for 30 minutes and cooled to -10 ° C for one hour. The product was filtered and washed with a mixture of methanol and ethyl acetate (1: 3 v / v. 50 mL) at 10 ° C. The product was finally dried under reduced pressure at 40-45 ° C. Yield: 40 g (HPLC purity > 00%).

Claims (4)

PATENT CLAIMS A lactonization process for the preparation of simvastatin according to formula I which comprises heating a compound, namely an acid or an ammonium salt of the compound according to formula II. Wherein Z is H or NH 4 in an organic solvent selected from xylene, ethylbenzene, and mixtures thereof at 130 to 140 ° C. The method of claim 1, wherein the lactonization reaction (heating) is completed in 20-40 minutes. The process of claim 1, wherein the organic solvent is xylene and Z is NH 4 A lactonization process for the production of simvastatin substantially as described with reference to examples.