氯尼达明的合成工艺改进

Improved synthesis of lonidamine

摘要:

以苯肼及2,4-二氯甲苯为起始原料，苯肼经乙酰化，然后与水合氯醛、盐酸羟胺及硫酸钠反应生成N-乙酰氨基肟基乙酰苯胺，再经Beckmann重排，缩环，水解生成1H-吲唑-3-羧酸；2,4-二氯甲苯与NBS，在AIBN的催化下生成2,4-二氯溴苄，然后与1H-吲唑-3-羧酸反应生成氯尼达明。通过单因素实验和正交实验考察了N-乙酰氨基肟基乙酰苯胺的合成工艺，确定了最佳工艺条件：物料配比n(N-乙酰苯肼)：n(水合氯醛)：n(硫酸钠)=1：1.3：8.5，反应温度为90 ℃，反应时间为13 min，在该条件下，产物收率达86.9%，氯尼达明的总收率为31.2%。产物结构经红外，核磁和质谱进行了表征确定。

Abstract:

Lonidamine was synthesized from phenylhydrazine and 2,4-dichlorobenzyl bromide as the raw materials. Phenylhydrazine was acetylated, and then reacted with hydroxylamine hydrochloride, chloral hydrate and sodium sulphate to form N-acetyla-minoisonitrosoacetanilide, which was subsequently hydrolyzed to obtain 1H-indazole-3-carboxylic acid after Beckmann rearrangement and ring shrinking reaction. 2,4-dichlorobenzyl bromide was prepared by 2,4-dichlorotoluene and NBS with AIBN as catalyst, and then reacted further with 1H-indazole-3-carboxylic acid to get the product of lonidamine. The influence of process conditions on the yield of N-acetyla-minoisonitrosoacetanilide was studied by single-factor experiment and orthogonal test. The optimal conditions for the reaction were: the molar ratio of n(N-acetylphenylhydrazine), n(chloral hydrate) and n(sodium sulphate) 1:1.3:8.5, reaction temperature 90℃ and reaction time 13min. The process can get the product in 86.9% yield under the above optimized reaction conditions. The total yield of lonidamine was 31.2%. Structure of product was characterized by IR, 1H NMR and MS.