(R)-(+)-N,N-二甲基-3-羟基-3-(2-噻吩基)丙胺的消旋

为提高抗抑郁药度洛西汀合成收率,降低生产成本,研究了中间体拆分副产物(R)-(+)-N,N-二甲基-3-羟基-3-(2-噻吩基)丙胺在不同有机羧酸溶剂、反应温度、反应时间、共溶剂剂量下的消旋化反应。实验表明,以乙酸作溶剂,温度90℃,x(水杨醛)=0.1作共溶剂,反应8 h,最后消旋率达到100%,收率为70%。在同样实验条件下将反应投料量扩大至200 g,平均消旋率达99.2%,平均收率达90.8%,所得消旋体可以重新用于光学拆分及合成产物度洛西汀。

Study of Racemization Reaction of (R)-(+)-N,N-Dimethyl-3-hydroxy-3-(2-thienyl)propanamine

To increase the yield of duloxetine and reduce its cost,racemization of the intermediate by-product(R)-(+)-N,N-dimethyl-3-hydroxy-3-(2-thienyl)propanamine(Ⅰ) was studied using carboxylic acids as solvents in the presence of salicylaldehyde.The effects of acid type,temperature,reaction time and molar ratio of salicylaldehyde to Ⅰ on racemization rate and product yield were investigated.Thus,with acetic acid as solvent,salicylaldehyde and Ⅰin molar ratio 0.1 reacting at 90 ℃ for 8 h,the racemization rate and product yield could reach 100% and 70%,respectively.Under the same conditions,when the amount of Ⅰwas increased up to 200 g,the racemization rate and product yield could reach 99.2% and 90.8%,respectively.The product can be reused in the synthesis of duloxetine.