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

Abstract

Carvedilol (SK&F 1055 17) 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 phannacologic 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 mtiated 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 U-benzyl aryloxyethylamines. Catalytic tritium-halogen exchange upon the brominated metabolite precursors was accompanied by cleavage of u-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%

Tritium: a coming of age for drug discovery and development ADME studies

“…Similarly, tritium‐labelled enantiomers of carvedilol (46), a racemic agent with stereoselective ADME properties, used in the treatment of angina and hypertension, were prepared by direct electrophilic bromination of the enantiomers followed by tritiodebromination; the labelled enantiomers, which retained optical purities of >99%, were then utilised for drug metabolism studies …”

Synthesis ofβ3 adrenergic receptor agonistLY377604 and its metabolite 4-hydroxycarbazole, labeled with carbon-14 and deuterium

“…Our goal was to introduce four deuteria into the molecule of LY377604 through initial aromatic bromination of this compound, followed by catalytic reduction of the resulting polybromide with deuterium. The known examples of halogenation of structurally similar compounds include carvedilol bromination on microscale using bromine and potassium carbonate in chloroform to give tribromide isolated by preparative HPLC, 15 and the bromination of carbazole itself with N-bromosuccinimide on silica gel to provide dibromide as a main product. In an attempt to reach a high level of bromine incorporation in the molecule of LY377604, we investigated its bromination with excess of bromine under acidic conditions.…”