6-苯基-[1,2,4]三唑[4,3,a]吡啶-3-胺的合成及工艺优化研究

Synthesis and Process Optimization of 6-Phenyl-[1,2,4]triazolo[4,3-a]Pyridine-3-Amine

摘要:

以5-溴-2-氟吡啶为起始原料，经取代、成环、偶联反应，合成医药中间体6-苯基-[1,2,4]三唑[4,3,a]吡啶-3-胺，其结构经氢谱、碳谱和高分辨质谱进行结构表征证实。考察了反应时间、反应温度、反应物配比、溶剂配比、催化剂用量等因素对目标产物收率的影响，结果表明：化合物6-溴-[1,2,4]三唑[4,3,a]吡啶-3-胺合成的最佳工艺条件为：温度40 ℃，时间15 min；化合物6-苯基-[1,2,4]三唑[4,3,a]吡啶-3-胺合成的最佳工艺条件为：溶剂V（水）：V（二氧六环）=1.0：2.0，反应物物质的量比n（6-溴-[1,2,4]三唑[4,3-a]吡啶-3-胺）：n（苯硼酸）=1.0：1.2，催化剂用量n（6-溴-[1,2,4]三唑[4,3-a]吡啶-3-胺）： n（（Pd(pph3)2Cl2）=1.0：0.1，温度80 ℃。三步反应最终总收率为60%。

Abstract:

A pharmaceutical intermediate 6-phenyl-[1,2,4]-triazole[4,3-a]pyridine-3-Amine was synthetized from 5-bromo-2-fluoropyridine by substitution, ring-formation and coupling reactions. The product was characterized by 1H-NMR, 13C-NMR and HRMS. The reaction process was optimized by tuning the reaction time, reaction temperature, reactant ratio, solvent ratio and catalyst dosage to study the effect of these factors on the reaction yield. The results showed that the optimum conditions for the synthesis of 6-bromo-[1,2,4]-triazole[4,3-a]pyridine-3-Amine were as follows: temperature was 40℃ , time was 15 min. The optimum conditions for the synthesis of 6-phenyl-[1,2,4]-triazole[4,3-a]pyridine-3-Amine were as follows: the solvent was V(water): V(dioxane)=1.0:2.0, the amount of the reactant was n(6-bromo- [1,2,4] triazolo [4,3-a] pyridin-3-amine): n(phenylboronic acid) =1.0:1.2, the amount of the catalyst was n(6-bromo- [1,2,4] triazolo [4,3-a] pyridin-3-amine): n(Pd (pph3) 2Cl2）=1.0：0.1, temperature was 80 ℃. The final yield of the three steps of reactions was 60%