(1R, 2R)-反式环己烷二甲酸的合成工艺

Optimization of Synthetic Process of (1R, 2R)-(-)-trans- cyclohexanedicarboxylic acid

摘要:

以六氢苯酐为原料，采用顺反异构化反应合成反式-1，2-环己烷二甲酸；然后选用较为廉价的R-（+）-α-甲基苄胺（R-PEA）作为拆分剂，通过手性拆分、酸化合成（1R, 2R）-反式环己烷二甲酸。探讨了催化剂种类、反应温度和反应时间对产品顺反式比例的影响；同时考察了溶剂种类和用量对手性拆分效果的影响。反式-1，2-环己烷二甲酸的最优合成工艺条件：硫酸为催化剂，反应温度120℃以上，反应时间12 h左右，在该反应条件下产品收率为80%；采用1H NMR测定了产物中反式的含量为99.3%；最佳手性拆分条件：甲醇作溶剂，n（反式-1，2-环己烷二甲酸） ：n（R-PEA） =1 ：1，W（反式-1，2-环己烷二甲酸）：V（甲醇）=1 ：3，在该反应条件下（1R, 2R）-反式环己烷二甲酸•（R）-PEA盐的收率可达38%；经过酸化后得到（1R, 2R）-反式环己烷二甲酸，酸化收率为85%；采用手性柱HPLC测定了目标产物的光学纯度（ee值）为98.48%。

Abstract:

Using cis-1, 2-cyclohexanedicarboxylic anhydride as raw material, trans-1, 2-cyclohexanedicarboxylic acid was obtained by cis-trans isomerization, then, (1R, 2R)-(-)-cyclohexanedicarboxylic acid was prepared via a two-step process of the chemical resolution and acidification by employing R-(+)-alpha-methylbenzylamine as resolving agent. The effects of the reaction conditions, including the type of catalyst, reaction temperature and reaction time, on the content of trans-1, 2-cyclohexanedicarboxylic acid were investigated, and the effects of the type and amount of solvent on the chiral resolution were also studied. The results show that the optimal reaction conditions of the synthesis of trans-1, 2-cyclohexanedicarboxylic acid were found as follows: sulfuric acid as reaction catalyst, the reaction temperature was maintained above 120 °C and the optimal reaction time was 12 h. The yield of trans-1, 2-cyclohexanedicarboxylic acid was approximately 80% under such optimal conditions. Detected by 1H NMR, the content of trans-1, 2-cyclohexanedicarboxylic acid was 99.3%. Using R-(+)-alpha-methyl benzylamine as resolving agent, the yield of (1R, 2R)-(-)-cyclohexanedicarboxylic acid ammonium salt was approximately 38%. The reaction conditions have been optimized as follows: anhydrous methanol as the reaction solvent, n (trans-1, 2-cyclohexanedicarboxylic acid) ∶ n (R-(+)-alpha-methyl benzylamine) = 1 ∶ 1, and W (trans-1, 2-cyclohexane dicarboxylic acid) ∶ V (methanol) = 1 ∶ 3. Detected by chiral HPLC, the ee value of the target compound was 98.48%.