Apixaban intermediate and preparation method thereof
A technology for apixaban and intermediates, applied in the field of apixaban intermediates and its preparation, can solve the problems of cumbersome post-treatment process, high equipment requirements, and poor reaction repeatability, and achieve low equipment requirements and low cost , post-processing convenient effect
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[0033] An aspect of the embodiments of the present invention provides a method for preparing an intermediate of apixaban, comprising the following steps:
[0034] Step 1. Add 4-chloroaniline and methyl acrylate to the glacial acetic acid solution in turn, heat up and stir, and after the reaction is over, distill under reduced pressure to recover acetic acid, pour the concentrate into water and wash it, extract it with the extraction solvent, concentrate and recover the solvent, and recrystallize After recrystallization from a solvent, Intermediate 2 was obtained;
[0035] Step 2. Dissolve morpholin 4-ylacetic acid and acid chloride reagent in a solvent. After reacting for a certain period of time, add alkali and intermediate 2 obtained in step 1 in turn, react at room temperature, and stop the reaction until 4-chloroaniline disappears. , adding water and an organic solvent for extraction, washing the organic phase with a 1M sodium hydroxide solution, recovering the solvent und...
Embodiment 1
[0051] This example provides a preparation method for intermediate 2: add 50g of 4-chloroaniline and 37g of methyl acrylate to 100mL of glacial acetic acid solution in sequence, raise the temperature to 50°C and stir for 8 hours, the raw materials disappear, and the acetic acid is recovered by distillation under reduced pressure. The concentrate was poured into 100mL water, extracted twice with 100mL dichloromethane, the dichloromethane phases were combined, and the dichloromethane was recovered by distillation under reduced pressure to obtain an oily liquid. The crude product was refluxed with 200mL petroleum ether for 1 hour and filtered to obtain 80g of off-white solid is intermediate 2, with a yield of 95% and a purity of 98%. LC-MS(m / z)214.2[M+H] + .1H NMR (500MHz, DMSO-d6) δ7.09 (d, J = 8.8Hz, 2H), 6, 56 (d, J = 8.8Hz, 2H), 5.82 (t, J = 5.7Hz, 1H), 3.60(s, 3H), 3.25(m, 2H), 2.56(t, J=6.7Hz, 2H).
Embodiment 2
[0053] This example provides a preparation method of intermediate 3: dissolve 58g of morpholin 4-ylacetic acid in 150mL of dichloromethane, control the temperature at 10°C, add 57g of thionyl chloride, react at room temperature for 2 hours, then add 121g Triethylamine reacted for half an hour, then added 80g of intermediate 2 obtained in step (1), and reacted at room temperature for 2 hours. The raw materials were completely reacted, and water and 100mL dichloromethane were added for extraction and layering. After washing with sodium oxide solution, the solvent was recovered under reduced pressure. The obtained crude product was dissolved by heating under reflux with 100 mL of ethanol, and then crystallized at 0°C. After filtration, 125 g of intermediate 3 was obtained as an off-white solid with a yield of 92% and a purity of 97%. LC-MS(m / z)341.4[M+H] + .1H NMR (500MHz, CDCl 3 )δ7.40(d, J=8.6Hz, 2H), 7.15(d, J=8.5, 2H), 3.96(t, J=7.1Hz, 2H), 3.68(t, J=4.2Hz, 4H), 3.61 (s, 3H...
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