盐酸右哌甲酯及其光学异构体的合成

Synthesis of Demethylphenidate Hydrochloride and Its Related Optical Isomers

为进行抗小儿多动症原料药盐酸右哌甲酯的质量研究,合成了盐酸右哌甲酯及3个有关光学异构体.合成工作从2-氯吡啶2和苯乙腈3出发,经两步反应生成中间体5.5经加压氢化反应生成化合物6,化合物6经叔丁醇钾构型调整得化合物7a顺式消旋体,7a经D-二苯甲酰酒石酸拆分,甲酯化成盐,得化合物1a(盐酸右哌甲酯);7a经L-二苯甲酰酒石酸拆分,甲酯化成盐,得化合物1b;化合物6经乙酸乙酯打浆重结晶得化合物7b反式消旋体,7b经D-酒石酸拆分,甲酯化成盐,得化合物1c;7b经L-酒石酸拆分,甲酯化成盐,得化合物1d.合成的4个光学异构体经MS、NMR确证结构,HPLC确证化学和光学纯度,旋光仪确定旋光,盐酸右哌甲酯1a与化合物1d经X射线单晶衍射确定绝对构型,可作为盐酸右哌甲酯质量控制过程中的光学杂质对照品.

For the purpose of quality control of demethylphenidate hydrochloride （1a）, three related optical substances were synthesized and characterized. （S,S）-Methylphenidate hydrochloride （1b）, （R,S）-methylphenidate hydrochloride （1c） and （S,R）-methylphenidate hydrochloride （1d） were synthesized via the same route with demethylphenidate hydrochloride but changing different intermediates or resolving agents. The structures of four optical isomers were tested by MS and NMR spectra, the chemical and optical purities were analyzed by HPLC spectra, the specific rotation values were also measured, the absolute configurations of compounds 1a and 1d were confirmed by X-ray study. The three optical isomers can be used as the reference substances of the related optical substances in the quality control of demethylphenidate hydrochloride.