摘要
亚磷酸三乙酯与氯乙酸乙酯进行缩合、重排、脱氯乙烷合成磷酸酯,再与对氟苯甲醛经Kno-evenagel反应合成肉桂酸酯,肉桂酸酯与丙二酸二乙酯胺解合成的N-甲胺基羰基乙酸乙酯环合得到哌啶二酮,环化物用硼氢化钾复合还原剂还原得±4-(4-氟苯基)-3-羟甲基-1-甲基哌啶,对混旋体进行手性拆分得目标产物(4R,3S)-4-氟苯基-3-羟甲基-1-甲基哌啶。选择自制酸载硅胶催化剂cat1#、醋酸-乙二胺催化剂cat2#、复合相转移催化剂cat3#为各步催化剂,反应收率分别为89.1%,96.3%,86.5%,76.3%,87.2%,43.7%,总收率24.3%,比旋光度-36～-38°,纯度大于99%。
The preparation of （-）trans-4R-（4＇-fluorophenyl）-3S-hydroxymethyl-l-methylpiperidine from triethyl phosphite, diethyl malonate,4-fluorobenzaldehyde,ethyl chloroacetate, under the condition of existing cat1#,cat2#, cat3# catalysts was presented. The effect of catalyst 1#,2#,3#, reduction agent, chiral resolving agent and pH control was discussed.The overall yield is 24.27%, the optical rotation is -36～-38°, and the HPLC purity is over 99%.
关键词
亚磷酸三乙酯
氯乙酸乙酯
N-甲胺基羰基乙酸乙酯
4-氟肉桂酸乙酯
triethyl phosphate
diethyl malonate ethyl chloroacetate
4-fluorobenzaldehyde
ethyl 4- florocinnamate
4R-（4＇-fluorophenyl）-3S-hydroxymethyl-l-methylpiperidine
chiral resolving agent
4- （4-flurophenyl）-3-ethoxycarbonyl- 1-methyl piperdine-2,6-dione
