“一锅三步法”合成苯基-2-吡啶基甲醇

Synthesis of phenyl-2-pyridyl methanol by “one-pot three-steps” method

摘要:

以2-苄基吡啶氮氧化物和三氟乙酸酐为原料，通过“一锅三步法”（串联“酰化、[3,3]σ重排和水解”反应）合成了关键药理活性中间体苯基-2-吡啶基甲醇，并对反应条件进行了优化。结果表明：当n（2-苄基吡啶氮氧化物）：n（三氟乙酸酐）=1 : 1.2、N, N-二异丙基乙胺（DIPEA）为碱、甲苯为反应溶剂，室温反应6小时，经硅胶柱层析分离即可得到苯基-2-吡啶基甲醇，收率为81.0%。产物经1H NMR，13C NMR 和HRMS进行结构表征。本文以原子经济学的理念首次实现了由2-苄基吡啶氮氧化物到苯基-2-吡啶基甲醇的直接转化。

Abstract:

Phenyl-2-pyridinyl methanol，as a key pharmacological intermediate, was synthesized via an “one-pot three-steps” method with 2-benzylpyridine nitrogen-oxide and trifluoroacetic anhydride as starting materials, which involved tandem acylation, [3,3]-sigmatropic rearrangement and hydrolysis reaction. The reaction conditions were investigated and the optimal conditions were obtained as follows: trifluoroacetic anhydride was as acylating agent in 1.2 equivalent, N, N-diisopropylethylamine (DIPEA) was as base and the mixture was stirred in toluene for 6 h at room temperature. The phenyl-2-pyridinyl methanol was obtained by silica gel column chromatography with the yield of 81.0%, and the structures of all products were confirmed by 1H NMR，13C NMR and HRMS. This reaction firstly achieved the direct transformation from 2-benzylpyridine nitrogen-oxide to phenyl-2-pyridyl methanol in an atomic economic manner.