Synthesis of benzodiazepine derivatives

A process for producing a compound of formula (I):

• or a pharmaceutically acceptable salt thereof, wherein
• R1 is:
• (i) —CH2C(O)C(R2)(R3)—L—R4 or —CH2CHOHC(R2)(R3)—L—R4, in which:
• R2 and R3 are each, independently, H or C1-3 aliphatic, halo, or C1-3 haloaliphatic, or wherein R2 and R3 together with the intervening carbon atom to which they are bonded, form a C3-6 carbocyclic moiety;
• L is a bond or C1-3 alkylene;
• and
• R4 is —OR5 or —SR5, wherein R5 is hydrogen, optionally substituted alkyl, a protecting group or —C(O)R6, wherein R6 is optionally substituted aliphatic, heteroaliphatic, aromatic or heteroaromatic moiety;
• or
• (ii) —CH2CHOH(CH2)aR7 or —CH2C(O)(CH2)aR8 in which a is 0 or 1 and R7 and R8 are selected from alkyl, cycloalkyl groups and saturated heterocyclic groups optionally substituted at a hetero-atom;
• W and X are, independently, hydrogen, halo, C1-8 alkyl or C1-8 alkoxy;
• and
• rings A and B are each, independently, a monocyclic aryl or heteroaryl, optionally substituted with one or more substituents independently selected from halo, hydroxy, amino, nitro, carboxyl, carboxamido, cyano, —SO3H, and optionally substituted C1-8 alkyl, C1-8 alkoxy, C1-8 alkylamino or di(C1-8 alkyl)amino,
• wherein any one or more substituent on R1, ring A or ring B may be unprotected or in a protected form;
• wherein the process comprises:
• providing a reaction mixture by adding a compound of formula (I-A), a compound of formula (I-B) and a phosgene synthetic equivalent or phosgene to an aprotic solvent, to form a compound of formula (I)
• wherein the phosgene synthetic equivalent is carbonyldiimidazole (CDI), diphosgene, triphosgene, a chloroformate or disuccinimidyl carbonate;
• and
• wherein the reaction is maintained at a temperature of no more than 30° C. and the reaction is carried out in the absence of a base.