微反应器中他达拉非的高效合成及其动力学研究

Efficient synthesis of tadalafil and its kineticstudy in a microreactor system

他达拉非是一种重要的医药原料,其传统的合成工艺是在间歇反应釜中进行,具有产率低和反应时间长等缺点.为提高他达拉非的生产效率,该文研究了在微反应器中由(1R,3R)-1,2,3,4-四氢-2-氯乙酰-(3,4-亚甲基苯基)-9H吡啶并[3,4-b]吲哚-3-羧酸甲酯(四氢咔啉衍生物)与甲胺反应制备他达拉非.结果表明,与间歇反应釜相比,微通道反应器显著提高了他达拉非的产率,缩短了反应时间.当温度为65℃,四氢咔啉衍生物浓度为2.5 mmol·mL^(-1),甲胺与四氢咔啉衍生物物质的量的比为5,停留时间为20 min时,他达拉非产率达到88.3%.而在间歇釜中,他达拉非最佳产率仅为79.7%,反应时间为2 h.同时该文建立了该反应简化动力学模型,确定该反应总级数为2,指前因子为6.27×10^(11 )mL·mol^(-1)·s^(-1),活化能为38.92 kJ·mol^(-1).

Tadalafil is an important pharmaceutical raw material.The general method for synthetic tadalafil has many disadvantages.In order to improve the production efficiency of tadalafil,methy(1R,3R)-1-(benzo[d][1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido[3,4-b]indole-3-carboxylate(carboline derivatives)were reacted with methylamine to prepare tadalafil using a microreactor in this study.The results showed that,compared with batch reactors,the microreactor significantly improved the yield of tadalafil and shortens the reaction time.When the temperature is 65℃,the concentration of tetrahydrocarboline derivatives is 2.5 mL·mol^(-1) and the molar ratio of methylamine to tetrahydrocarboline derivatives is 5,with the residence time of 20 min and the yield of 88.3%.While in the bath reactor,the best yield of tadalafil is only 79.7%,and the reaction time is 2 h.The reaction kinetic model was established,and the total order of the reaction was 2,with the pre-exponential factor of 6.27×10^(11) mL·mol^(-1)·s^(-1),and the activation energy of 38.92 kJ·mol^(-1).This kinetic model has important theoretical significance and practical value for optimizing reactor design and industrial production.