氯尼达明的合成工艺改进  

Improved Synthesis of Lonidamine

作　　者：殷剑[1,2] 雷武[1] 王风云[1] 夏明珠[1] 朱其军 马晓明 

机构地区：[1]南京理工大学工业化学研究所,江苏南京210094 [2]盐城格瑞茵化工有限公司,江苏盐城224400

出　　处：《精细化工》2014年第1期72-74,78,共4页Fine Chemicals

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。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-acetyl-aminoisonitrosoacetanilide, which was subsequently hydrolyzed to obtain 1H-indazole-3-carboxylic acid after Beckmann rearrangement and ring shrinking reaction. 2,4-Dichlorobenzyl bromide was prepared from 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-acetyl-aminoisonitrosoacetanilide 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 ） ： n （ sodium sulphate ） = 1 ： 1.3 ： 8.5, reaction temperature 90℃ and reaction time 13 min. The process can get the product in 86.9% yield under the above optimized reaction conditions. The total yield of lonidamine was 31.2%. The structure of product was characterized by means of IR, 1HNMR and MS.

关 键 词：1H-吲唑-3-羧酸 氯尼达明 2 4-二氯溴苄 医药原料 

分 类 号：TQ979.1[化学工程]