Synthesis method for simvastatin ammonium salt, used intermediate and preparation methods for both
An intermediate and inert gas technology, which is applied in the field of synthesis of simvastatin ammonium salt, can solve the problems of low purity of the final product, long reaction time, and many by-products, and achieve the effect of high purity, short time and simple operation
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Embodiment 1
[0024] Example 1 Preparation of 4-acetyl simvastatin methyl ester (IV, R is methyl)
[0025] Under nitrogen protection, dissolve 5.0g (10.87mmol) of 4-acetyl simvastatin in 20ml (15.84g, 495mmol) of methanol, add 0.1g (0.53mmol) of p-toluenesulfonic acid monohydrate, room temperature (25°C) After stirring, TLC detected that the reactant was consumed (2.0h). Distill the methanol under reduced pressure, dissolve the residue with 50ml of toluene, and then use 3×10.0ml of 5% NaHCO 3 solution and 10.0ml saturated NaCl solution, the organic layer was washed with anhydrous MgSO 4 After drying, the solvent was distilled off under reduced pressure to obtain a light yellow oil (4.9 g, yield 91.6%) with a purity of 96.5% (as determined by HPLC).
[0026] 1 H-NMR (400MHz, CDCl 3 )δ5.98(d,J=10.0Hz,1H),5.76(dd,J=6.4,9.2Hz,1H),5.49(s,1H),5.35(m,1H),4.93(m,1H), 4.09(m,1H),3.70(s,3H),3.01(s,1H),2.66~2.53(AB of an ABX,J=6.4,16.0Hz,2H),2.04(s,3H),1.12(s ,6H), 1.08(d,J=7.6Hz,3H),0.87(d,J=6....
Embodiment 2
[0029] Example 2 Preparation of 4-acetyl simvastatin methyl ester (IV, R is methyl)
[0030] Under the protection of nitrogen, 5.0 g (10.87 mmol) of 4-acetyl simvastatin (Formula I) was dissolved in 10.5 g (328.1 mmol) of methanol, and 0.2 g (1.05 mmol) of p-toluenesulfonic acid monohydrate was added at room temperature ( 30°C) and stirred, TLC detected that the reactant was consumed (1.5h), distilled off methanol under reduced pressure, dissolved the residue in 50ml of toluene, and then dissolved it with 3×10.0ml 5% NaHCO 3 solution and 10.0ml saturated NaCl solution, the organic layer was washed with anhydrous MgSO 4 After drying, the solvent was distilled off under reduced pressure to obtain a light yellow oil (5.0 g, yield 93.5%) with a purity of 97.3% (as determined by HPLC).
Embodiment 3
[0031] Example 3 Preparation of 4-acetyl simvastatin methyl ester (IV, R is methyl)
[0032] Under the protection of nitrogen, 5.0 g (10.87 mmol) of 4-acetyl simvastatin (Formula I) was dissolved in 13.9 g (434.4 mmol) of methanol, 0.06 g (0.58 mmol) of 36 wt % hydrochloric acid aqueous solution was added, stirred at 0 ° C, TLC Detect that the reactant is consumed (3.0h), evaporate the methanol under reduced pressure, dissolve the residue with 50ml of toluene, and then use 3×10.0ml of 5% NaHCO 3 solution and 10.0ml saturated NaCl solution, the organic layer was washed with anhydrous MgSO 4 After drying, the solvent was distilled off under reduced pressure to obtain a light yellow oil (4.8 g, yield 89.7%) with a purity of 96.3% (as determined by HPLC).
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