来那度胺合成工艺研究

Study on the Synthetic Process of Lenalidomide

本文以2-溴甲基-3-硝基苯甲酸甲酯与3-氨基哌啶-2,6-二酮盐酸盐缩合反应得到3-(4′-硝基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮(L-IM1),L-IM1经醋酸铵、铁粉还原得到3-(4′-氨基-1-氧-1,3-二氢-2H-异吲哚-2-基)哌啶-2,6-二酮(L-IM2),L-IM2重结晶得到来那度胺,对每步合成及纯化进行了工艺优化,总收率为42.86%,纯度为99.8%,并用熔点、IR、LC-MS和1H NMR对产物进行了表征。

This article mainly studied the synthetic process and the optimization of the reaction conditions ofLenalidomide. Starting from methyl 2-bromomethyl-3-nitrobenzoate and 3-amino-2,6-piperidinedionehydrochloride, the intermediate product 3-(4-nitro-1-oxo-2-isoindolinyl) piperidine-2,6-dione( L-IM1) can be obtained via condensation reaction. Through reduction process in the presence of ammonium acetate andiron powder, 1-oxo-2-(2,6-dioxopiperidin-3-yl)-4-aminoisoindoline( L-IM2) which is crudeLenalidomide then can be obtained. By crystallization of L-IM2 we got the final product Lenalidomide. Each processof synthesis and purification was optimized. The total yield was 42. 86% and the purity was 99. 8%. And the productswere characterized by melting point, IR、LC-MS and 1 H-NMR.