Nevirapine-D4

287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 l of diglyme (diethylene glycol-dimethylether) to 135°-145° C. for about 30 minutes in a 1200 l VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material (4) is reacted. To this mixture, over about 30 minutes at 135°-145° C., a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material (4) is reacted. The mixture is then kept at 135°-145 ° C. for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 144 l of diglyme. The filtrates are combined and 400 l of solvent is distilled off. The residue is then diluted with a further 287 l of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 144 l of diglyme and the mixture is stirred at a temperature of 130° to 140° C. for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 l of water. After the reaction mixture has been cooled to a temperature of about 25° C., 575 l of cyclohexane and 147 l of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 l of methyl-tert.-butylether, followed by 862 l of water and finally with 575 l of ethanol. In this way, after drying, 225 kg (83.0% 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 obtained.

287.2 kg of 2-chloro-N-(2-chloro-4-methyl-3-pyridyl)-3-pyridine carboxamide (4), 57.0 kg of calcium oxide and 87.1 kg of cyclopropylamine (molar ratio: 1:1:1.5) are heated in 574 l of diglyme (diethylene glycol-dimethylether) to 135°-145° C. for about 30 minutes in a 1200 l VA stirring apparatus. This produces a pressure of 1.2-1.5 bar and about 50% of the starting material (4) is reacted. To this mixture, over about 30 minutes at 135°-145° C., a further 58.1 kg of cyclopropylamine is added producing a pressure of 3.0-3.5 bar, and another 25% of the starting material (4) is reacted. The mixture is then kept at 135°-145 ° C. for a period of 5 to 6 hours. The reaction mixture is then cooled to a temperature of 20° to 30° C. and filtered. The filter cake is washed with 144 l of diglyme. The filtrates are combined and 400 l of solvent is distilled off. The residue is then diluted with a further 287 l of diglyme. Over 20-40 minutes, the resultant diluted solution is added to a suspension of 110 kg of 60% sodium hydride in 862 l of diglyme, heated to 130° C. The storage vessel and conduits are rinsed with a further 144 l of diglyme and the mixture is stirred at a temperature of 130° to 140° C. for another 30 to 60 minutes. The majority of the diglyme is then distilled off. Finally, the remaining residue is carefully mixed with 1150 l of water. After the reaction mixture has been cooled to a temperature of about 25° C., 575 l of cyclohexane and 147 l of glacial acetic acid are added. The mixture is then stirred for about 1 hour at a temperature of 10°-25° C. The resultant suspension is centrifuged and the centrifuged material is then washed with 575 l of methyl-tert.-butylether, followed by 862 l of water and finally with 575 l of ethanol. In this way, after drying, 225 kg (83.0% 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 obtained.