Abstract: An improved method for the preparation of N-toluenesulfonyl benzodiazepine-5-ketone, a key intermediate used for conivaptan hydrochloride synthesis, was developed. The starting materials are p-toluene sulfonyl chloride and methyl anthranilate, and the synthesis procedure includes amidation, imide and halogenated hydrocarbon condensation, Bechmmann cyclization, hydrolysis and decarboxylation, etc. In the synthesis process, the amount of the toxic solvent pyridine is reduced; sodium hydride, which is explosive in water, is replaced by potassium tert-butyl alcohol; and methyl tetrahydrofuran, which is commercially available and easily recovered, is used as the solvent instead of butanone. The total yield of the target compound increases from 55% to 63%, and the purity is 99% or more. The obtained compound was confirmed by the melting point measurement and 1H NMR spectroscopy. The yield of this intermediate and its quality have been significantly improved, and the yield of the conivaptan hydrochloride is thereby greatly increased.

Key words: intermediate of conivaptan hydrochloride, N-toluenesulfonyl benzodiazepine-keton, synthesis improvement