Rivaroxaban synthesis method
A technology of rivaroxaban and compounds, applied in the production of bulk chemicals, organic chemistry, etc., can solve the problems of increasing the cost of chromatographic columns
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Embodiment 1
[0085] Embodiment 1: Preparation of 4-(4-carbaaminophenyl)-3-morpholinone (formula III):
[0086]
[0087] Add 192.2g (1.0mol) of 4-(4-aminophenyl)-3-morpholinone (formula II) into the reaction flask, stir and dissolve with 700ml dichloromethane, cool to 25°C, add dropwise 45.0g (1.5 mol) formaldehyde, the temperature of the dropping process is controlled at 20°C to 30°C, the dropwise addition is completed, and the reaction is stirred for 5 hours, controlled by TLC (dichloromethane:methanol:triethylamine=20:1:0.5, volume ratio), the reaction Completely, stop stirring, distill dichloromethane under reduced pressure (-0.1MPa~-0.09MPa), add 600ml ethyl acetate to raise temperature and reflux, cool down naturally under stirring, drop to 10°C to 15°C for 8 hours, filter, reduce After drying under pressure, 185.4 g of off-white intermediate III was obtained, with a molar yield of 90.8% and an HPLC purity of 98.8%.
[0088] The detection data of the title product obtained by NMR ...
Embodiment 2
[0089] Embodiment 2: Preparation of 4-(4-carbaaminophenyl)-3-morpholinone (formula III):
[0090] Add 192.2g (1.0mol) of 4-(4-aminophenyl)-3-morpholinone into the reaction flask, stir and dissolve with 700ml of dichloromethane, cool to 25°C, add 75.0g (2.5mol) of formaldehyde dropwise, The temperature of the dropping process was controlled at 20°C to 30°C. After the dropwise addition was completed, the reaction was stirred for 2 hours. TLC was controlled (dichloromethane:methanol:triethylamine=20:1:0.5, volume ratio), the reaction was complete, and the stirring was stopped. , dichloromethane was evaporated under reduced pressure (-0.1MPa~-0.09MPa), 600ml of ethyl acetate was added to raise the temperature and reflux, the temperature was naturally lowered under stirring, and the crystallization was carried out at 10°C to 15°C for 8 hours, filtered, and dried under reduced pressure. 188.1 g of off-white intermediate III was obtained, the molar yield was 92.1%, and the HPLC purit...
Embodiment 3
[0092] Example 3: Preparation of (S)-1-chloro-2-[2-(1,3-dioxoisoindol)yl]ethyl chloroformate (Formula V):
[0093]
[0094] In this embodiment, X in the above is Cl.
[0095] Add 270.7g (1.2mol) of (S)-2-(2-chloro-2-hydroxyethyl)isoindole-1,3-dione (formula IV), 158.2g (2.0mol) Pyridine and 1000ml tetrahydrofuran, stir evenly, cool down to 10°C to 20°C, add 267.1g (0.9mol) triphosgene, keep stirring and react for 2 hours, then add 89.0g (0.3mol) triphosgene, continue stirring for 3 hours, Under the control of HPLC, the raw materials basically disappeared, and the reaction was stopped. The tetrahydrofuran was evaporated under reduced pressure (-0.1MPa~-0.09MPa), and 800ml of dichloromethane was added to the residual oil and stirred to dissolve. Wash with purified water in sequence until the pH value of the aqueous phase is about 6, and distill the organic layer obtained by liquid separation under reduced pressure (-0.1MPa~-0.09MPa) to remove dichloromethane to obtain 294.6g...
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