醋酸氟卡尼合成工艺改进Q

Process Improvement on the Synthesis of Flecainide Acetate

摘要:

以商品化2,5-二(2,2,2-三氟乙氧基)苯甲酸为原料，二氯亚砜为酰氯化试剂，得到2,5-二(2,2,2-三氟乙氧基)苯甲酰氯，再与2-氨甲基哌啶反应得到盐酸氟卡尼，选用不同醇溶剂通过碱中和再与醋酸络合成盐，得到目标产物醋酸氟卡尼。考察了原料配比、反应时间以及溶剂对收率的影响，优选的反应条件为：n〔2,5-二(2,2,2-三氟乙氧基)苯甲酸〕∶n（2-氨甲基哌啶）= 1∶1.8，其中原料酸先活化成酰氯，再与2-氨甲基哌啶在THF为溶剂，冰浴搅拌2h，得到盐酸氟卡尼；再以乙醇为溶剂，氢氧化钠为碱，回流中和0.5 h，近似定量得到氟卡尼；最后选用异丙醇为溶剂，与醋酸回流0.5 h，冷却析出得到目标产物。四步反应总收率为39.2%，经过路线中两次固体结晶，最终产物醋酸氟卡尼液相色谱纯度高于99.7%。

Abstract:

The 2,5-bis(2,2,2-trifluoroethoxy)benzoyl chloride was synthesized from commercial 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid through acylating chlorination with dichlorosulfoxide. Then piperidin-2-ylmethanamine was used for amination to obtain flecainide hydrochloride. Different alcohol solvents were selected for neutralization and salification. Flecainide was complexed with acetic acid to form target flecainide acetate. The ratio of raw materials, reaction time, and solvent on the yield were investigated. The optimized reaction conditions are as following: 1) n(2,5-bis(2,2,2-trifluoroethoxy)benzoic acid) ∶n(piperidin-2-ylmethanamine) =1∶1.8, 2) following converting the starting acid into acyl chloride, the acyl chloride was reacted with piperidine in THF for 2 hours to obtain flecainide hydrochloride, 3) with ethanol as the solvent, the quantity of flecainide was obtained by neutralization with NaOH in 0.5 h, 4) isopropyl alcohol was used as the solvent, refluxing with acetic acid for 0.5 h, leading to the target product. After two recrystallization process, the total yield of the 4-step reaction was 39.2%, and the purity of the final product was higher than 99.7% by HPLC analysis.