反应详情

温度

130 °C

117.5 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 23.3 kg of calcium oxide and 59.4 kg of cyclopropylamine (molar ratio: 1:1:2.5) are heated to between 135° and 145° C. in 235 l ofdiglyme (diethylene glycoldimethylether) in a 500 l VA autoclave over a period of 6 to 8 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 58.8 l of diglyme. The filtrates are combined and initially 200 l of solvent is distilled off. The residue is then diluted with a further 117.5 l of diglyme. The resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 55.8 l of diglyme, and the mixture is stirred at a temperature of between 130° and 140° C. for a further 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 470 l of water. After cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid are added to the reaction mixture. The mixture is then stirred for about 1 hour at temperature of 10° to 25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol. In this way, after drying, 92.5 kg (83.5% of theory) of 11-cyclopropyl-5,11-dihydro-4-methyl-6H-dipyrido[3,2-b:2',3'-e][1,4]diazepin-6-one (nevirapine) is isolated.

1. temperatureThe reaction mixture is then cooled to a temperature of 20° to 30° C.
2. filtrationfiltered
3. washThe filter cake is washed with 58.8 l of diglyme
4. distillationinitially 200 l of solvent is distilled off
5. additionThe residue is then diluted with a further 117.5 l of diglyme
6. additionThe resultant diluted solution is added over a period of 20 to 40 minutes to a suspension of 45.0 kg of 60% sodium hydride in 352.5 l of diglyme
7. washThe storage vessel and conduits are rinsed with a further 55.8 l of diglyme
8. distillationThe majority of the diglyme is then distilled off
9. additionFinally, the remaining residue is carefully mixed with 470 l of water
10. temperatureAfter cooling to a temperature of about 25° C., 235.0 l of cyclohexane and 57.11 of glacial acetic acid
11. additionare added to the reaction mixture
12. stirringThe mixture is then stirred for about 1 hour at temperature of 10° to 25° C
13. washthe centrifuged material is then washed with 235.0 l of methyl-tert.-butylether and subsequently with 353.5 l of water and finally with 235 l of ethanol
14. customIn this way, after drying