NLG919 (1) with two chiral carbon atoms on its chemical structure is a potent indoleamine 2,3-dioxygenase 1 (IDO1) inhibitor. We developed an effective way to prepare all stereoisomers of 1, the key step being the chiral resolution of racemic intermediate 2. The optimal resolution solvent system was identified as dichloromethane and n-pentane or petroleum ether. Using (−)-di-p-toluoyl-d-tartaric acid as resolution reagent, optical pure (R)-2 (e.e. > 99%, yield = 70%) was obtained. The mechanism of chiral resolution was clarified through single-crystal X-ray diffraction of the diastereomeric salt. The absolute configurations of four stereoisomers of 1 were established through electronic circular dichroism spectra, quantum chemical calculation and transition metal method. Their IDO1 inhibitory activity was assessed by pharmacological experiments in vitro and in mouse, demonstrating that S configuration of C5 played an important role on the inhibition of IDO1, while the stereochemistry on C2′ exerted little effect on the IDO1 inhibitory activity in mouse.

NLG919（1）在化学结构上具有两个手性碳原子，是一种有效的吲哚胺2，3-二加氧酶1（IDO1）抑制剂。我们开发了一种有效的方法来制备1的所有立体异构体，关键步骤是外消旋中间体2的手性拆分。最佳分离度的溶剂系统被确定为二氯甲烷和正戊烷或石油醚。使用（ - ） -二- p -toluoyl- ð -酒石酸作为拆分试剂，光学纯的（- [R ）- 2得到（ee＞ 99％，产率＝ 70％）。通过非对映异构体盐的单晶X射线衍射阐明了手性拆分的机理。通过电子圆二色性光谱，量子化学计算和过渡金属方法建立了四个立体异构体1的绝对构型。通过体外和小鼠药理实验评估了它们对IDO1的抑制活性，表明C5的S构型对抑制IDO1起重要作用，而对C2'的立体化学对小鼠的IDO1抑制活性影响很小。