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Abstract

A process for producing a compound which is a benzodiazepine derivative of formula: (I) wherein: represents or R.sup.1 represents C.sub.1-6 alkyl, aryl or heteroaryl; each R.sup.3 is the same or different and represents halogen, hydroxy, C.sub.1-6 alkyl, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, C.sub.1-6 haloalkyl, C.sub.1-6 haloalkoxy, amino, mono(C.sub.1-6 alkyl)amino, di(C.sub.1-6 alkyl)amino, nitro, cyano, --CO.sub.2R', --CONR'R'', --NH--CO--R', --S(O)R', --S(O).sup.2R', --NH--S(O).sub.2R', --S(O)NR'R'' or --S(O).sub.2NR'R'', wherein each R' and R'' is the same or different and represents hydrogen or C.sub.1-6 alkyl; n is from 0 to 3; X represents --NH--, --N(C.sub.1-C.sub.6alkyl)-, --CO--, --CO--NR'--, --S(O)-- or --S(O).sub.2--, wherein R' is hydrogen or a C.sub.1-C.sub.6 alkyl group; and R.sup.4 represents hydrogen; or --CO--R.sub.4' or --CO--NH--R.sup.4 ', wherein R.sup.4 ' is a C.sub.1-C.sub.6 alkyl, C.sub.1-C.sub.6 hydroxyalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group, which group is substituted by a C.sub.1-C.sub.6 hydroxyalkyl, aryl, heteroaryl, carbocyclyl or heterocyclyl group or a --(C.sub.1-C.sub.4 alkyl)-X.sub.1--(C.sub.1-C.sub.4 alkyl)-X.sub.2--(C.sub.1-C.sub.4 alkyl) group, wherein X.sub.1 represents --O--, --S-- or --NR'--, wherein R' represents H or a C.sub.1-C.sub.4 alkyl group and X.sub.2 represents --CO--, --SO-- or --SO.sub.2--; or R.sup.4 'represents -A.sub.1-Y-A.sub.2, wherein: A.sub.1 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group; Y represents a direct bond or a C.sub.1-C.sub.4 alkylene, --SO.sub.2--, --CO--, --O--, --S or --NR'--, wherein R' is a C.sub.1-C.sub.6 alkyl group; and A.sub.2 is an aryl, heteroaryl, carbocyclyl or heterocyclyl group; or R.sup.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.sup.5, wherein: Z represents --CO--, --S(O)-- or --S(O).sub.2'; and R.sup.5 represents C.sub.1-6 alkyl, hydroxy, C.sub.1-6 alkoxy, C.sub.1-6 alkylthio, aryl, heteroaryl, carbocyclyl, heterocyclyl, aryl-(C.sub.1-6 alkyl)-, heteroaryl-(C.sub.1-6 alkyl)-, carbocyclyl-(C.sub.1-6 alkyl)-, heterocyclyl-(C.sub.1-6 alkyl)-, aryl-(C.sub.1-6 alkyl)-O--, heteroaryl-(C.sub.1-6 alkyl)-O--, carbocyclyl-(C.sub.1-6 alkyl)-O--, heterocyclyl-(C.sub.1-6 alkyl)-O-- or --NR'R'' wherein each R' and R'' is the same or different and represents hydrogen, C.sub.1-6 alkyl, carbocyclyl, heterocyclyl, aryl, heteroaryl, aryl-(C.sub.1-6 alkyl)-, heteroaryl-(C.sub.1-6 alkyl)-, carbocyclyl-(C.sub.1-6 alkyl)- or heterocyclyl-(C.sub.1-6 alkyl)-; or a pharmaceutically acceptable salt thereof; which process comprises: (a) subjecting a racemic benzodiazepine derivative of formula: (IIa): wherein R.sup.1, R.sup.3, R.sup.4, n and X are as defined above, and R.sup.2 represents an amino protecting group, to crystallisation induced dynamic resolution to yield a benzodiazepine derivative of formula (II): wherein, R.sup.1, R.sup.2, R.sup.3, R.sup.4, n and X are as defined above; and (b) deprotecting the benzodiazepine derivative of formula (II) as defined above to yield a benzodiazepine derivative of formula (I) or a pharmaceutically acceptable form thereof as defined above.

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First Claim