NRX-1074的合成新方法

A new synthetic method of NRX-1074

目的改进NRX-1074的合成方法。方法以Cbz-脯氨酸乙酯为初始原料,经双三甲基硅基胺基锂(LIHMDS)夺氢后与溴化苄反应得到消旋体苄基取代产物,氢化反应脱除Cbz保护基,然后采用L-二苯甲酰酒石酸进行手性拆分得光学纯(R)-2-苄基脯氨酸乙酯。随后采用液相肽合成方法,逐步分别与Boc-Pro-OH、Boc-Thr(t Bu)-OH缩合,最后与Thr-NH_2·HCl缩合后脱除保护基,得到目标化合物NRX-1074。结果与结论改进后的液相合成方法条件温和,操作简便,收率高,易于大量合成NRX-1074。

NRX-1074 is a partial N-methyl-D-aspartate receptor （NMDAR） agonist that shows rapid antidepressant activity without psychotomimetic side effects. To improve the current synthetic process, we prepared NRX-1074 by using （R）-2-benzyl proline ethyl ester as the starting material. Then, the target compound was synthesized by six-step reactions with the overall yield of 26.1%[calculated from （R） -2- benzyl proline ethyl ester ] and purity of 98.2% （HPLC）. The whole process avoided using chiral preparative HPLC, which was different from the existing method. The improved process with high yield and less steps is easy to operate and suitable for large scale preparation.