PD-189659, CI-1044
Chemical Name: N-[9-Amino-4-oxo-1-phenyl-3,4,6,7-tetrahydropyrrolo[3,2,1-jk][1,4]benzodiazepin- 3(R)-yl]pyridine-3-carboxamide
CAS No. 197894-84-1
项目整合开发状态: Preclinical
项目研究机构: Pfizer (Originator)
合成路线:Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III),which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine.The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide,followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1).The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII).Nitration of (VIII) with KNO3 in H2SO4 gave (IX),which was reduced to the diamino derivative (X) using stannous chloride.Finally,regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.
📌 参考资料/链接：
参考文献标题:Diazepino-indoles as phosphodiesterase IV inhibitors
文献作者:Pascal,Y.; Jacobelli,H.; Calvet,A.; Payne,A.; Dahl,S.G.(Institut de Recherche Jouveinal)
参考来源:EP 0828742; US 5972927; WO 9736905
📄 详细内容
合成路线:Friedel-Crafts condensation of indoline (I) with benzonitrile (II) in the presence of BCl3 and AlCl3 produced ketone (III),which was subsequently cyclized to (V) by treatment with ethyl glycinate (IV) in refluxing pyridine.The primary amino group was then introduced by conversion of (V) into oxime (VI) with isoamyl nitrite and potassium tert-butoxide,followed by catalytic hydrogenation over Ru/C to produce amine (VII) (1).The racemic amine was resolved by recrystallization as the corresponding salt with N-acetyl-L-phenylalanine to yield the desired (R)-isomer (VIII).Nitration of (VIII) with KNO3 in H2SO4 gave (IX),which was reduced to the diamino derivative (X) using stannous chloride.Finally,regioselective coupling of (X) at the aliphatic amino group with nicotinic acid (XI) by means of O-[(ethoxycarbonyl)cyanomethyleneamino]-N,N,N',N'-tetramethyluronium tetrafluoroborate (TOTU) provided the target amide.
参考文献标题:Synthesis,structure-activity relationships,and pharmacological profile of 9-amino-4-oxo-1-phenyl-3,4,6,7-tetrahydro[]1,4]diazepino[6,7,1-]indoles: Discovery of potent,selective phosphodiesterase type 4 inhibitors
文献作者:Burnouf,C.; Auclair,E.; Avenel,N.; Bertin,B.; Bigot,C.; Calvet,A.; Chan,K.; Durand,C.; Fasquelle,V.; Feru,F.; Gilbertsen,R.B.; Jacobelli,H.; Kebsi,A.; Lallier,E.; Maignel,J.; Martin,B.; Milano,S.; Ouagued,M.; Pascal,Y.; et al.
参考来源:J Med Chem 2000,43(25),4850
产品链接: CAS No. 197894-84-1››