Synthesis method of N-1 crystal form Apixaban
A synthesis method, the technology of apixaban, applied in the field of synthesis of apixaban, achieves the effects of mild process conditions, reduced discharge of a large amount of nitrogen-containing wastewater, and easy subsequent treatment and recovery
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Embodiment 1
[0039] Embodiment 1: Preparation of Apixaban
[0040] At room temperature, add 4.88g of intermediate 1, 4.5g of formamide, 0.14g of tetrabutylammonium chloride, and 50mL of dichloromethane into a 250mL three-necked flask, stir, and cool in an ice bath to 0-5°C. Add 5.4g of sodium methoxide, after dropping, keep the temperature at 0-5°C and stir for 30min, then remove the ice bath and naturally rise to 20-25°C, react for 4h, TLC monitors the disappearance of intermediate 1, add 100ml of water to the synthesis solution, stir After half an hour, the reaction solution was allowed to stand for layers. The dichloromethane layer was separated and the dichloromethane was concentrated to dryness. The residue was vacuum-dried to obtain 4.50 g of a light yellow solid with a yield of 97.8% and a purity of 98.35%.
[0041] Add 135 mL of methanol solution of acetic acid with a mass fraction of 6% to 4.50 g of the crude apixaban obtained above, heat to reflux to dissolve, then stir and natur...
Embodiment 2
[0046] Embodiment 2: Preparation of Apixaban
[0047] At room temperature, add 4.88g of intermediate 1, 4.5g of formamide, 0.16g of tetrabutylammonium bromide, and 50mL of dichloromethane into a 250mL three-neck flask, stir, and cool in an ice bath to 0-5°C. Add 5.4g of sodium methoxide, after dropping, keep the temperature at 0-5°C and stir for 30min, then remove the ice bath and naturally rise to 20-25°C, react for 4h, TLC monitors the disappearance of intermediate 1, add 100ml of water to the synthesis solution, stir After half an hour, the reaction solution was allowed to stand for layers. The dichloromethane layer was separated and the dichloromethane was concentrated to dryness. The residue was vacuum-dried to obtain 4.35 g of a light yellow solid with a yield of 94.5% and a purity of 98.21%.
[0048] Add 130 mL of methanol solution of acetic acid with a mass fraction of 6% to 4.35 g of the crude apixaban obtained above, heat to reflux to dissolve, then stir and naturall...
Embodiment 3
[0053] Embodiment 3: Preparation of Apixaban
[0054] At room temperature, add 4.88g of intermediate 1, 4.5g of formamide, 0.11g of benzyltriethylammonium chloride, and 50mL of dichloromethane into a 250mL three-necked flask, stir, and cool in an ice bath to 0-5°C. Slowly add 5.4g of sodium methoxide to the mixture, after dropping, keep the temperature at 0-5°C and stir for 30min, then remove the ice bath and naturally rise to 20-25°C, react for 4h, TLC monitors that intermediate 1 disappears, add 100ml of water to the synthesis solution , stirred for half an hour, the reaction solution was left to stand and separated, the dichloromethane layer was separated and the dichloromethane was concentrated to dryness, and the residue was vacuum-dried to obtain 4.40 g of a light yellow solid, yield: 95.6%, purity 98.43%.
[0055] Add 132 mL of methanol solution of acetic acid with a mass fraction of 6% to 4.40 g of the crude apixaban obtained above, heat to reflux to dissolve, then sti...
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