【摘要】 以对甲苯磺酰氯和邻氨基苯甲酸甲酯为原料,通过酰胺化、酰亚胺和卤代烃的缩合、克曼环化及水解脱羧等反应,合成盐酸考尼伐坦关键中间体N-甲苯磺酰基苯并氮杂卓-5-酮。在合成过程中,分别减少了有毒溶剂吡啶的用量,用叔丁醇钾代替怕水易爆的氢化钠,用容易购买回收的2-甲基四氢呋喃代替丁酮为溶剂,目标化合物的总收率由55%提高至63%,纯度达到99%以上。所得化合物经熔点、核磁共振氢谱等得到确认。该工艺显著地提高了中间体的产量及质量,因而提高了盐酸考尼伐坦的产率。更多还原

【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 and1H 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.更多还原