Preparation method of benzodiazepine nerve inhibitor intermediate compound
A technology for compounds and intermediates, applied in the field of medicinal chemistry preparation, can solve the problems of long reaction time, low yield, easily exceeding the standard of isomers, etc., and achieve the effects of improving synthesis efficiency, reducing production cost and simple post-processing.
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Embodiment 1
[0061]Embodiment 1 The preparation method of remazolam intermediate Ia
[0062] N,N-dimethylformamide (14.2g) was added to the reaction flask, stirring was started, intermediate IIa (7.5g) was added, the temperature was lowered to 5-10°C, morpholine (3.7g) was added, the addition was completed, and the mixture was controlled Warm to 25~30℃ and react for 2.5h. After the reaction was completed, the reaction solution was cooled to 2-6° C., stirred for 20 min, and suction filtered to obtain the N,N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride solution (138 g) and n-heptane (81 g), and stirred at 5 to 10° C. for 1 h. Crude intermediate Ia was obtained by centrifugation.
[0063] Add ethyl acetate (12.6g) to the glass reaction flask, add the crude intermediate Ia, heat up to reflux, slowly add n-heptane (38.4g), after the addition, heat up to 60°C and stir for 1h, then the system is reduced to 20 ~ 30 ℃, stirring an...
Embodiment 2
[0066] Embodiment 2 The preparation method of remazolam intermediate Ia
[0067] N,N-dimethylformamide (15.6g) was added to the reaction flask, stirring was started, intermediate IIa (8.3g) was added, the temperature was lowered to 5-10°C, morpholine (4.1g) was added, and the addition was completed, and the mixture was controlled Warm to 22~29℃ for 2h. After the reaction was completed, the reaction solution was cooled to 0-5° C., stirred for 20 min, and suction filtered to obtain the N,N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 10% aqueous sodium chloride solution (152 g) and n-heptane (90 g), and stirred at 0 to 15° C. for 1 h. Crude intermediate Ia was obtained by centrifugation.
[0068] Add ethyl acetate (14g) to the glass reaction flask, add the crude product of Intermediate Ia, heat up to reflux, slowly add n-heptane (85g), after the addition, heat up to 60°C and stir for 1h, then reduce the system to 20~ 30° C., stirring for c...
Embodiment 3
[0069] Embodiment 3 The preparation method of remazolam intermediate Ia
[0070] N,N-dimethylformamide (101g) was added to the reaction flask, stirring was started, intermediate IIa (53.5g) was added, the temperature was lowered to 5-10°C, morpholine (26.7g) was added, and the temperature was controlled. Reaction at 20~30℃ for 2~3h. After the reaction was completed, the reaction solution was cooled to 2-8° C., stirred for 20 min, and suction filtered to obtain the N,N-dimethylformamide filtrate of Ia. The filtrate was poured into a mixed solvent of 20% aqueous sodium chloride solution (942 g) and n-heptane (138 g), and stirred at 5 to 15° C. for 1 h. Crude intermediate Ia was obtained by centrifugation.
[0071] Add ethyl acetate (90g), intermediate Ia crude product to the glass reaction flask, heat up to reflux, then add n-heptane (275g), after adding, heat up to 60°C and stir for 1h, then reduce the system to 20~30 ℃, stirring and crystallization for 2 hours, centrifugati...
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