IDO1抑制剂INCB024360的合成工艺

Optimization of the Synthetic Process of INCB024360 as IDO1 Inhibitor

以丙二腈为原料,采用4个连续反应,得到3-氨基-4-氨基肟基呋咱(Ⅰ),经Sandmeyer反应生成3-氨基-4-酰氯肟基呋咱(Ⅱ),再与3-氯-4-氟苯胺反应得到吲哚胺2,3-双加氧酶抑制剂4-氨基-N-(3-氯-4-氟苯基)-N'-羟基-1,2,5-口恶二唑-3-甲脒(INCB024360)。Ⅱ的工艺优化路线:在0℃下,加入化合物Ⅰ2.0 g,浓盐酸6.5 m L,Na NO20.96 g,Cu Cl 2.87 g,水8 m L,反应时间5 h;INCB024360的工艺优化路线:25℃下,加入反应物Ⅱ1.0 g,3-氯-4-氟苯胺1.58 g,三乙胺0.17 m L,无水乙醇25 m L,反应时间5 h。总产率从10.0%提高到43.1%,HPLC纯度为99.6%,其结构经1HMOL/LR,13CMOL/LR,MS表征。

3-Amino-4-amino oximidofurazan（ Ⅰ） was obtained from malononitrile through the one pot method of four-step consecutive reaction,which was diazotized by the Sandmeyer reaction to get 3-amino-4-acid chloride oximidofurazan（ Ⅱ）. Then,it was converted into 4-amino-N-（ 3-chloro-4-fluorophenyl）-N＇-hydroxy-1,2,5-oxadiazole-3-carboximidamide（ INCB024360） via the substitution with 3-chloro-4-fluoro aniline with the overall yield increased from 10. 0% to 43. 1% and the HPLC purity of 99. 6% in the best synthetic process. Process optimization route Ⅰ： To a stirred solution of compound Ⅰin HCl（ conc,6. 5 m L） and water（ 8 m L） was added Na NO2（ 0. 96 g） and Cu Cl（ 2. 87g） at 0 ℃ for 5 hrs. Process optimization route INCB024360： To a stirred solution of 3-chloro-4-fluoroaniline（ 1. 58 g） in Et OH（ 25 m L） was added triethylamine（ 0. 17 m L） at 25 ℃ for 5 hrs. The structures were characterized by1 H MOL / LR,13 C MOL / LR,MS.