微反应器中他达拉非的高效合成及其动力学研究

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6.27×1011 mL·mol－1·s－1，活化能为38.92 kJ·mol－1.

Efficient synthesis of tadalafil and its kinetic study in a microreactor system

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-(benzod]1,3]dioxol-5-yl)-2-(2-chloroacetyl)-2,3,4,9-tetrahydro-1H-pyrido3,4-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 6.27×1011 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.