Method for refining and crushing rivaroxaban bulk drug
A technology of rivaroxaban and raw materials, applied in the direction of organic chemistry, etc., can solve the problems of difficult cleaning of mother liquor, high requirements for drop rate control, and difficult filtration
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Embodiment 1
[0020] Preparation of crude rivaroxaban: add 10.9kg of drinking water and 1.3kg of anhydrous sodium carbonate to a 50L reaction kettle, and stir until dissolved completely. Then add 3.7kg of acetone, cool down and stir to 5±5℃. Keeping the system temperature at 5±5°C, 2.0kg of 4-[4-[(5S)-5-(aminomethyl)-2-oxo-3-oxazolidinyl]phenyl]-3- Morpholinone hydrochloride was added in the reaction kettle, and then the toluene solution of 5-chlorothiophene-2-formyl chloride was slowly added dropwise (1.7kg of 5-chlorothiophene-2-formyl chloride was added to 3.5kg of toluene), and the stirring 30min. The reaction system was heated to 55±5°C and kept stirring for 1 hour, and then the reaction system was cooled to 25±5°C and kept stirring for 2 hours for crystallization. The reaction solution was transferred to a centrifuge and filtered for 20 minutes, washed once with 16.0kg of acetone / water (mass ratio 1:5), and the obtained solid was transferred to a baking tray, at 55±5°C, vacuum degre...
Embodiment 2
[0022] Preparation of rivaroxaban to be pulverized: add 10.8kg of glacial acetic acid and 2.5kg of crude rivaroxaban (prepared in Example 1) into a 50L reactor, heat up and stir to reflux. After the solid was completely dissolved, a mixture of 0.1 kg of activated carbon and 0.5 kg of acetic acid was added, and the mixture was stirred under reflux for 0.5 hours. Gradient cooling of the reaction system to 25±5°C (naturally cooling to 80±5°C first, then naturally cooling to 50±5°C, and finally naturally cooling to 25±5°C), stirring and crystallization for 5 hours. The reaction solution was transferred to a centrifuge for filtration for 30 min, washed once with 4.0 kg of acetic acid and 10.5 kg of water, respectively, and the obtained solid was transferred to a baking tray, and dried to Constant weight, 1.9kg of rivaroxaban to be pulverized, yield 76.00%, after measurement, the particle size of rivaroxaban to be pulverized is X 90 = 279.53 μm.
Embodiment 3
[0024] Preparation of finished rivaroxaban: turn on the airflow pulverizer, set the feeding pressure to be 0.70-0.75Mpa, the pulverization pressure to be 0.50-0.75Mpa, and add 1.9kg of rivaroxaban to be pulverized (prepared in Example 2) into the airflow The feeding port of the pulverizer is used for pulverization. The pulverized sample was weighed and sealed to obtain 1.5kg of rivaroxaban finished product with a yield of 78.95%. The particle size of the rivaroxaban finished product was determined to be X 90 =5.60μm<15μm.
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