Synthesis of the enantiomers and three racemic metabolites of carvedilol labeled to high specific activity with tritium

Carvedilol (SK&F 105517) possesses unique cardiovascular activity, and is under development for indications such as angina and hypertension. Tritium labeled enantiomers of Carvedilol and racemates of three metabolites were needed for pharmacologic and drug metabolic studies. These compounds were synthesized by catalytic tritium‐halogen exchange using tritium gas and 10% palladium‐on‐carbon catalyst. The precursors were polyhalogenated in the carbazole ring. Direct electrophilic bromination of the enantiomers of Carvedilol gave precursors that were converted to the corresponding tritiated final products by catalytic tritium halogen exchange. Bromination of 4‐(2,3‐epoxypropyloxy)‐9H‐carbazole gave an intermediate that was converted to the halogenated precursors of the racemic metabolites. Elaboration of this intermediate, 1,3,6‐tribromo‐4‐(2,3‐epoxypropyloxy)‐9H‐carbazole, to the desired metabolite precursors was achieved by nucleophilic epoxide opening with suitably functionalized N ‐benzyl aryloxyethylamines. Catalytic tritium‐halogen exchange upon the brominated metabolite precursors was accompanied by cleavage of N ‐ and Q ‐benzyl protecting groups. Radiochemical purities of all tritiated final products were greater than 98% after preparative HPLC. Specific activities of the final products, determined by mass spectrometry, ranged from 35 to 76 Ci/mmol. Optical purity of the Carvedilol enantiomers, determined by chiral HPLC, was greater than 99%