Syntheses of the tricyclic cores of clozapine, dibenzo[b,f][1,4]thiazepin-11(10H)-one, and dibenzo[b,f][1,4]oxazepin-11(10H)-one in C-14 labeled form by [14C]carbonylation

Clozapine has been demonstrated to bind covalently to proteins as a result of metabolic activation that has been proposed to be a precursor to the serious side effects including death that occur in a small percentage of the population. The covalent modification of proteins by clozapine has been studied by several groups and is well documented; therefore, the department of drug metabolism desired to use [C-14]clozapine as a positive control for covalent binding assays. The preparation of [C-14]clozapine was first conducted using a previous reported route and then using a new route that utilized [C-14]carbonylation as the isotope incorporating step. While this route worked, it was not deemed superior to the previous route. However, this methodology proved quite effective in preparing C-14 labeled dibenzothiazepine and dibenzoxapine ring systems.