固体光气合成硝唑尼特的工艺研究

Synthesis of nitazoxanid by triphosgene

采用固体光气代替传统的腐蚀性强、污染大的二氯亚砜作为酰氯化试剂,以乙酰水杨酸为起始原料,在无水环己酮溶剂中经酰氯化、酰胺化合成硝唑尼特。通过单因素试验和正交试验考察了原料配比、反应温度、反应时间以及催化剂种类等因素对反应的影响。结果表明:主要因素的影响程度为乙酰水杨酸与固体光气的摩尔比>催化剂种类>酰氯化反应温度>酰氯化反应时间。较佳的工艺条件为乙酰水杨酸与固体光气的摩尔比为1∶0.40,乙酰水杨酸与2-氨基-5硝基噻唑摩尔比为1∶1.1,以三乙胺作催化剂与缚酸剂,酰氯化反应温度为60℃,酰氯化反应时间为8 h,收率可达80.6%(以乙酰水杨酸计)。

Triphosgene can take place of thionyl chloride which is highly corrosive and high pollution as acylating reagent. Nitazoxanid is synthesized via acylation and acylamination with aeetylsalicylic acid as raw material in anhydrous cyclohexanone. The influence of process conditions such as raw material ratio, reaction temperature, reaction time and catalyst type on the yield of Nitazoxanid are investigated by single-factor and orthogonal tests. The influence level of the primary factors is：mole ratio of acetylsalicylic acid and triphosgene 〉 catalyst type 〉 acylation reaction temperature 〉 acylation reaction time. The optimal conditions are ： 1 ： 0.40 of n （ acetylsalicylic acid ） ： n （ triphosgene ）, 1 ： 1.1 of n （ acetylsalicylic acid） ： n （2-Amino-5-nitrothiazole） , Et3 N as acid-binding agent,50 ℃ of acylation reaction temperature and 8 hours of acylation reaction time. The overate yield of the obtained nitazoxanid is 80. 6% （ based on acetylsalicylic acid）.