醋酸氟卡尼合成路线改进

Process improvement on synthesis of flecainide acetate

以商品化2,5-二(2,2,2-三氟乙氧基)苯甲酸(Ⅰ)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(Ⅱ),中间体Ⅱ再与2-氨甲基哌啶反应得到盐酸氟卡尼(Ⅲ),化合物Ⅲ通过碱中和再与醋酸络合成盐得到目标产物醋酸氟卡尼。考察了投料比、反应时间以及溶剂对化合物Ⅲ收率的影响,优选的反应条件为:n(Ⅰ)∶n(2-氨甲基哌啶)=1∶1.8(其中,化合物Ⅰ先活化成酰氯),以四氢呋喃为溶剂,冰浴搅拌2.0 h,得到盐酸氟卡尼。再以乙醇为溶剂,Na OH为碱,回流中和0.5 h,得到氟卡尼(Ⅳ);最后,选用异丙醇为溶剂,中间体Ⅳ与醋酸回流0.5h,冷却析出得到目标产物。4步反应总收率为39.2%,经过两次结晶,最终产物醋酸氟卡尼HPLC纯度高于99.7%。

2,5-Bis(2,2,2-trifluoroethoxy)benzoyl chloride(Ⅱ)was synthesized by acylating chlorination between commercial 2,5-bis(2,2,2-trifluoroethoxy)benzoic acid(Ⅰ)and dichlorosulfoxide.The amination of intermediateⅡand piperidin-2-ylmethanamine led to flecainide hydrochloride(Ⅲ).Targeting compound flecainide acetate was obtained by neutralization of compoundⅢwith alkali and then salification with acetic acid.The effects of molar ratio of raw materials,reaction time and solvent on the yield of compoundⅢwere investigated.The optimized reaction conditions for synthesis of compoundⅢwere as follows:n(Ⅰ)∶n(piperidin-2-ylmethanamine)=1∶1.8(herein,compoundⅠwas first activated to form intermediateⅡ),using tetrahydrofuran as solvent,and reaction for 2.0 h in an ice bath.Subsequently,flecainide(Ⅳ)was prepared by neutralization of compoundⅢwith NaOH using ethanol as solvent and refluxing for 0.5 h.Finally,intermediateⅣwas reflux in the presence of acetic acid for 0.5 h using isopropyl alcohol as solvent and then cooled,and the target product was obtained.The total yield of four-step reaction was 39.2%,and the purity of the final product was higher than 99.7%by HPLC analysis after two crystallization.