PROCESS FOR PREPARING BENZODIAZEPINES

摘要

A process for producing a compound which is a benzodiazepine derivative of formula: (I) wherein: represents or R<1> represents C1-6 alkyl, aryl or heteroaryl; each R<3 >is the same or different and represents halogen, hydroxy, C1-6 alkyl, C1-6 alkoxy, C1-6 alkylthio, C1-6 haloalkyl, C1-6 haloalkoxy, amino, mono(C1-6 alkyl)amino, di(C1-6 alkyl)amino, nitro, cyano, -CO2R, -CONRR, -NH-CO-R, -S(O)R, -S(O)2R, -NH-S(O)2R, -S(O)NRRor -S(O)2NRR, wherein each R and R is the same or different and represents hydrogen or C1-6 alkyl; n is from 0 to 3; X represents -NH-, -N(C1-C6 alkyl)-, -CO-, -CO-NR-, -S(O)- or -S(O)2-, wherein Ris hydrogen or a C1-C6 alkyl group; and R<4> represents hydrogen; or -CO-R4' or -CO-NH-R<4>', wherein R<4>' is a C1-C6 alkyl, C1-C6 hydroxyalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group, which group is substituted by a C1-C6 hydroxyalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group or a -(C1-C4 alkyl)-X1-(C1-C4 alkyl)-X2-(C1-C4 alkyl) group, wherein X1 represents -O-, -S- or -NR-, wherein R represents H or a C1-C4 alkyl group and X2 represents -CO-, -SO- or -SO2-; or R<4>' represents -A1-Y-A2, wherein: Al is an aryl, heteroaryl, carbocyclyl or heterocyclyl group; Y represents a direct bond or a C1-C4 alkylene, -SO2-, -CO-, -O-, -S or -NR-, wherein R is a C1-C6 alkyl group; and A2 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group; or R<4> is a group selected from aryl-C(O)-C(O)-, heteroaryl-C(O)-C(O)-, carbocyclyl-C(O)-C(O)-, heterocyclyl-C(O)-C(O)- and -ZR<5>, wherein: Z represents -CO-, -S(O)- or -S(O)2-; and R<5> represents C1-6 alkyl, hydroxy, C1-6 alkoxy, C1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)-, heterocyclyl-(C1-6 alkyl)-, aryl-(C1-6 alkyl)-O-, heteroaryl-(C1-6 alkyl)-O-, carbocyclyl-(C1-6 alkyl)-O-, heterocyclyl-(C1-6 alkyl)-O- or -NRRwherein each R and R is the same or different and represents hydrogen, C1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-(C1-6 alkyl)-, heteroaryl-(C1-6 alkyl)-, carbocyclyl-(C1-6 alkyl)- or heterocyclyl-(C1-6 alkyl)-; or a pharmaceutically acceptable salt thereof; which process comprises: (a) subjecting a racemic benzodiazepine derivative of formula: (IIa): wherein R<1>, R<3>, R<4>, n and X are as defined above