反应 #3756361
相关文献 (1)
openreactiondata ↗doi:10.6084/m9.figshare.5104873.v1; patent:US08093252B2
反应条件: temp:62.51; pressure:0.00; stir:; See reaction.notes.procedure_details.
实验步骤: To a flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added 5-chloropyrazine-2-carboxylic acid (1.0 eq), DMF (0.069 eq) and toluene (5.52 vols) under a nitrogen atmosphere. The mixture was heated to 60-65° C., and thionyl chloride (1.5 eq) added drop-wise to the batch over approximately 2 hours. The thionyl chloride was washed into the flask with toluene (0.2 vols). The reaction mixture was heated at 60-65° C. for at least 4 hours, then cooled to 40-45° C. and distilled under vacuum, removing approximately 4.5 vol distillates, and distilling to a final volume of 3.2 vols. Toluene (10.6 vol) was added, and the mixture distilled under vacuum at 40-45° C., removing approximately 9.1 vol distillates, and distilling to a final volume of 4.7 vols. The mixture was then cooled to 20-25° C., and dichloromethane (10.6 vols) added. The mixture was cooled to 0-5° C. Meanwhile, to a second flask fitted with overhead stirrer, condenser, thermometer and nitrogen line was added azetidine hydrochloride (0.284 eq), dichloromethane (5.2 vols) under a nitrogen atmosphere. Triethylamine (2.57 eq) was added over at least 15 minutes maintaining the reaction temperature from 20-25° C., the triethylamine was washed into the flask with dichloromethane (0.13 vols), and the mixture cooled to −5° C. to −10° C. The acid chloride solution in the first flask was added to the second flask in portions maintaining the reaction temperature at −5° C. to −10° C. over a time period of 2-5 hours. The pH was tested and adjusted to pH>7 after the acid chloride addition. The reaction mixture was agitated for at least 30 minutes at −5° C. to −10° C. Water (10.6 vols) was added to the second flask and the temperature was allowed to increase to 20-25° C. The mixture was agitated for approximately 25 minutes and then the layers were separated. A 3.17% w/w solution (1.46 eq) of hydrochloric acid (prepared from 32% w/w hydrochloric acid and water) was added to the organic layer B keeping the batch temperature at 20-25° C. The mixture was agitated for 30 minutes at this temperature. The layers were separated, and the organic phase was treated with 26% w/w sodium chloride solution (approximately 8.9 vols) and the batch agitated at 20-25° C. for at least 15 minutes. The layers were separated and the organic layers was heated to reflux, and dichloromethane was removed by atmospheric distillation, distilling to a final volume of approximately 1-2 vols, collecting approximately 11.9 vols distillates. The resulting mixture was cooled to 20-25° C., and heptane (10.5 vols) added. The mixture was heated to reflux for 60 minutes, and then cooled to 90-100° C. The hot solution was filtered through a filter containing 10% w/w of activated charcoal into a clean dry vessel. The filter was washed with heptane (0.43 vols) and the solution cooled to 20-25° C. over at least 2 hours. The resulting crystallised slurry was filtered, and the solid washed with pentane (0.94 vols). After drying in the vacuum oven at 40° C. overnight, the desired product was obtained as a solid (corrected yield 65-78%). 1H NMR δ (400 MHz CDCl3): 2.35-2.42 (2H, m), 4.26 (2H, t), 4.67 (2H, t), 8.52 (1H, d), 9.09 (1H, d); m/z 198 (M+H)+. To a flask fitted with overhead stirrer, condenser The thionyl chloride was washed into the flask with toluene (0.2 vols) The reaction mixture was heated at 60-65° C. for at least 4 hours cooled to 40-45° C. distilled under vacuum removing approximately 4.5 vol distillates distilling to a final volume of 3.2 vols Toluene (10.6 vol) was added the mixture distilled under vacuum at 40-45° C. removing approximately 9.1 vol distillates distilling to a final volume of 4.7 vols The mixture was then cooled to 20-25° C. dichloromethane (10.6 vols) added The mixture was cooled to 0-5° C Meanwhile, to a second flask fitted with overhead stirrer, condenser maintaining the reaction temperature from 20-25° C. the triethylamine was washed into the flask with dichloromethane (0.13 vols) the mixture cooled to −5° C. to −10° C The acid chloride solution in the first flask was added to the second flask in portions maintaining the reaction temperature at −5° C. to −10° C. over a time period of 2-5 hours after the acid chloride addition Water (10.6 vols) was added to the second flask to increase to 20-25° C The mixture was agitated for approximately 25 minutes the layers were separated at 20-25° C The mixture was agitated for 30 minutes at this temperature The layers were separated the organic phase was treated with 26% w/w sodium chloride solution (approximately 8.9 vols) and the batch agitated at 20-25° C. for at least 15 minutes The layers were separated the organic layers was heated to reflux dichloromethane was removed by atmospheric distillation distilling to a final volume of approximately 1-2 vols collecting approximately 11.9 vols distillates The resulting mixture was cooled to 20-25° C. heptane (10.5 vols) added The mixture was heated to reflux for 60 minutes cooled to 90-100° C The hot solution was filtered through a filter containing 10% w/w of activated charcoal into a clean dry vessel The filter was washed with heptane (0.43 vols) the solution cooled to 20-25° C. over at least 2 hours The resulting crystallised slurry was filtered the solid washed with pentane (0.94 vols) After drying in the vacuum oven at 40° C. overnight
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