A kind of synthetic preparation method of rivaroxaban key intermediate
A technology for rivaroxaban and intermediates, which is applied in the field of synthesis and preparation of key intermediates of rivaroxaban, can solve the problems of high cost, many side reactions and impurities, and difficulty in industrialization, and achieve low production cost, stability and High controllability and environment-friendly effect
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Embodiment 1
[0064] Embodiment 1: the synthetic preparation of the compound shown in formula IV
[0065] The reaction formula is as follows:
[0066]
[0067] Add 500 mL of isopropanol in the reaction flask, start stirring, then add 42.0 grams (223.1 mmol) of compound shown in formula II and 87.5 grams (455.2 mmol) of compound shown in formula III, start heating, and after reflux reaction for 10 hours, Evaporate the solvent under reduced pressure, add 700 mL of dichloromethane to the residue to dissolve, then add 86.8 g (535.3 mmol) of N,N'-carbonyldiimidazole, heat to reflux for 8 hours, filter, and the filtrate with 200 mL of saturated sodium bicarbonate solution and 200 mL of saturated brine were washed once, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to obtain 120.2 g of the compound represented by formula IV as a light yellow solid, with a yield of 86.3%.
Embodiment 2
[0068] Embodiment 2: the synthetic preparation of the vicinal diol compound shown in formula V
[0069] The reaction formula is as follows:
[0070]
[0071] Add 300mL of 65% aqueous acetic acid solution to the reaction flask, start stirring, then add 96.0 grams (153.7mmol) of the compound shown in formula IV, react at room temperature for 2 hours, evaporate the solvent under reduced pressure, and wash the residue with 800mL dichloromethane dissolved, washed with saturated sodium bicarbonate solution (300mL×2), and washed once with 200mL saturated brine, the organic phase was dried with anhydrous sodium sulfate, filtered, and the solvent was distilled off under reduced pressure to obtain the ortho-dimethoxy compound shown in formula V The alcohol compound is 86.7 grams of off-white solid, and the yield is 96.9%.
Embodiment 3
[0072] Embodiment 3: the synthetic preparation of the aldehyde compound shown in formula VI
[0073] The reaction formula is as follows:
[0074]
[0075] In the reaction flask, add 600 mL of methanol, start stirring, add 85.0 g (145.9 mmol) of the vicinal diol compound shown in formula V, stir to dissolve, cool the reaction solution to 0°C, and add 200 mL of saturated sodium bicarbonate solution dropwise , control the temperature of the reaction solution at 0-5°C, slowly add 34.5 grams (161.3 mmol) of sodium periodate, after the addition is complete, the reaction solution is warmed up to room temperature, and the reaction is vigorously stirred for 2 hours, then anhydrous sodium sulfate is added, and after stirring for 10 minutes Filter, distill the filtrate to remove the solvent under reduced pressure, dissolve the residue completely with 600mL of dichloromethane, wash with 200mL of saturated sodium bicarbonate solution and 200mL of saturated brine each time, dry the organ...
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