Process for producing simvastatin
A technology for simvastatin and its derivatives, applied in the field of preparation of simvastatin, can solve the problems of unreachable total yield, insufficient reaction selectivity, low yield and productivity, etc.
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Embodiment 1
[0057] Embodiment 1 The method for preparing diol lactone (compound of formula (3))
[0058] To a solution of 300 mL of KOH (7.92 g) in tert-butanol was added 8.09 g (20 mmol) of lovastatin and the mixture was stirred at room temperature under argon for 30 minutes. Then, the temperature was raised, and the mixture was refluxed for 4 hours with stirring. The reaction mixture was concentrated under reduced pressure, added with water, acidified with phosphoric acid (pH=3.5), and extracted with ethyl acetate. The extract was concentrated under reduced pressure to obtain a brown oil. The brown oil was dissolved in 200 ml of isopropyl acetate, and after adding 65 μl (1 mmol) of methanesulfonic acid, it was concentrated to about 1 / 5 volume under reduced pressure. The residue was washed with saturated aqueous sodium bicarbonate solution, cooled to -20°C and stirred. The resulting slurry was filtered and dried under vacuum to yield white crystals. This product was identified as the...
Embodiment 2
[0059] Example 2 Preparation of 2,2-dimethyl-6(R)-(2-(8(S)-hydroxyl-2(S),6(R)-dimethyl-1,2,6,7, 8,8a(R)-hexahydronaphthyl-1(S) ethyl)-(R)-(methoxycarbonyl)methyl-1,3-dioxane (compound of formula (4)) method
[0060] To a solution of diol lactone (1.62 g, 5 mmol) in 25 ml of dichloromethane was added 3.69 ml (30 mmol) of 2,2-dimethoxypropane and 48 mg (0.25 mol) p-toluenesulfonic acid, and the mixture was stirred at room temperature under argon for 1 hour. The reaction mixture was neutralized with pyridine, concentrated under reduced pressure, and the concentrate was purified by silica gel column chromatography to obtain a clear oil. This product was identified as the title compound.
[0061] NMR (CDCl 3 , 400MHz) δ: 0.89(d, 3H), 1.1-1.9(m, 16H), 1.2(d, 3H), 2.2-2.6(m, 5H), 3 .65(s, 3H), 3.85(m, 1H), 4.2(m, 1H), 4.3(m, 1H), 5.5(bt, 1H), 5.78(dd, 1H), 6.0(d, 1H)
Embodiment 3
[0062] Example 3 Preparation of 2,2-dimethyl-6(R)-(2-(8(S)-(2,2-dimethylbutyryloxy)-2(S),6(R)- Dimethyl-1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S))ethyl)-4(R)-(methoxycarbonyl)methyl-1,3 - method of dioxane (compound of formula (5))
[0063] 2,2-Dimethyl-6(R)-(2-(8(S)-hydroxy-2(S),6(R)-dimethyl -1,2,6,7,8,8a(R)-hexahydronaphthyl-1(S))ethyl)-4(R)-(methoxycarbonyl)methyl-1,3-diox In alkane (1.96 g, 5 mmol) solution, add 122 mg (1 mmol) of 4-dimethylaminopyridine and 2.69 g (20 mmol) of 2,2-dimethylbutyryl chloride, in The mixture was stirred at 100°C for 6 hours. The reaction mixture was concentrated under reduced pressure, and ethyl acetate was added. The organic layer was washed with 10% aqueous citric acid, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to obtain a clear oil. This product was identified as the title compound.
[0064] NMR (CDCl 3 , 400MHz) δ: 0.88(t, 3H), 0.89(d, 3H), 1.08(d, 3H), 1.11(s, 3H), 1.12(s,...
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