A kind of synthetic method of pharmaceutical intermediate
A synthesis method and technology for intermediates, which are applied in the field of synthesis of pharmaceutical intermediates, can solve the problems of many side reactions, high cost, long steps and the like, and achieve the effects of low synthesis cost, cheap raw materials and wide sources.
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Embodiment 1
[0031] Lithium bistrimethylsilylamide (352 mmol) was added into the flask, the temperature was lowered to 0°C, and a solution of p-fluorophenylmagnesium chloride in tetrahydrofuran (178 mmol) was added dropwise. After the dropwise addition was completed, the dehydrated compound I (54.6 mmol) was dissolved in dry tetrahydrofuran (50 ml) at room temperature, and the temperature was lowered to 0°C. Add compound I tetrahydrofuran solution dropwise to the mixed solution of lithium bistrimethylsilylamide catalyst and p-fluorophenyl magnesium chloride, stir, heat up to reflux, and react for 5-7h. After the reaction, add 50g of ammonium acetate aqueous solution (ammonium acetate 7.5g / water 42.5g) to quench the reaction, add water to wash three times (60ml*3), concentrate to remove the solvent, recrystallize the crude product with absolute ethanol, filter, wash and dry to light yellow-green Needle crystal compound II, yield 84%.
Embodiment 2
[0033] Lithium bistrimethylsilylamide (352 mmol) was added to the flask, the temperature was controlled to 20°C, and a solution of p-fluorophenylmagnesium chloride in tetrahydrofuran (178 mmol) was added dropwise. After the dropwise addition was completed, the dehydrated compound I (54.6 mmol) was dissolved in dry tetrahydrofuran (50 ml) at room temperature, and the temperature was controlled to 20°C. The tetrahydrofuran solution of compound I was added dropwise to the mixed solution of lithium bistrimethylsilylamide catalyst and p-fluorophenylmagnesium chloride, stirred, and the temperature was raised to 30°C for 12 hours of reaction. After the reaction, add 50g of ammonium acetate aqueous solution (ammonium acetate 7.5g / water 42.5g) to quench the reaction, add water to wash three times (60ml*3), concentrate to remove the solvent, recrystallize the crude product with absolute ethanol, filter, wash and dry to light yellow-green Needle crystal compound II, yield 80%.
Embodiment 3
[0035] Lithium bistrimethylsilylamide (352 mmol) was added into the flask, the temperature was lowered to 10°C, and a solution of p-fluorophenylmagnesium chloride in tetrahydrofuran (178 mmol) was added dropwise. After the dropwise addition was completed, the dehydrated compound I (54.6 mmol) was dissolved in dry tetrahydrofuran (50 ml) at room temperature, and the temperature was lowered to 10°C. Add compound I tetrahydrofuran solution dropwise to the mixed solution of lithium bistrimethylsilylamide catalyst and p-fluorophenyl magnesium chloride, stir, raise the temperature to 45°C, and react for 5-10h. After the reaction, add 50g of ammonium acetate aqueous solution (ammonium acetate 7.5g / water 42.5g) to quench the reaction, add water to wash three times (60ml*3), concentrate to remove the solvent, recrystallize the crude product with absolute ethanol, filter, wash and dry to light yellow-green Needle crystal compound II, yield 89%.
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