反应详情

温度

23 °C

There was added, to 21.26 L of N,N-dimethylformamide (DMF), 5.445 kg of Nα-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester, the resulting mixture was stirred at 23° C. and in a nitrogen gas stream to dissolve the isopropyl ester compound. Then 2.46 kg of potassium carbonate and 2.491 kg of methyl p-toluene-sulfonate were added to the resulting solution and the mixture was stirred with heating at 55 to 65° C. After the confirmation of the progress of the N-methylation reaction by HPLC, 2.14 kg of acetic acid was added to the mixture and subsequently the mixture was stirred with heating at 50° C. for one hour. To the reaction solution, there was dropwise added 10.9 L of water, followed by the addition of 6 g of seed crystals and stirring of the mixture at 50° C. for 2 hours. To the resulting slurry, there was further added 10.9 L of water, the mixture was cooled to 25° C. and stirred overnight. The precipitates thus obtained were recovered by the filtration using a centrifuge and the resulting cake was washed with 21.8 kg of water. The resulting wet crystals were dried under reduced pressure at 60° C. to thus give 5.235 kg of the title compound as a white crystalline solid (yield: 94%).

1. stirringthe mixture was stirred
2. temperaturewith heating at 55 to 65° C
3. additionwas added to the mixture
4. stirringsubsequently the mixture was stirred
5. temperaturewith heating at 50° C. for one hour
6. additionfollowed by the addition of 6 g of seed crystals
7. stirringstirring of the mixture at 50° C. for 2 hours
8. temperaturethe mixture was cooled to 25° C.
9. stirringstirred overnight
10. customThe precipitates thus
11. customobtained
12. filtrationwere recovered by the filtration
13. washthe resulting cake was washed with 21.8 kg of water