大规模加氢反应由于使用易燃氢气、易自燃的催化剂以及累积不稳定的中间体从而导致安全问题。间歇釜式工艺虽然通过搅拌可增大气-液两相界面积、延长氢气在液相的滞留时间,但仍面临气-液传质效率低、安全性差及反应时间长等问题,例如,部分苄基加氢过程需长达72 h。微填充床反应器相较于高压釜式反应器,具有体积小、氢气保留量低、固载化催化剂易分离等优势,因而增强了加氢反应的安全性。同时,其轴向返混较小、停留时间分布窄,提高了目标产物的选择性。再者,微填充床反应器通过增大气-液-固三相界面接触面积、提高传热传质效率,极大缩短反应时间,实现高效、绿色且安全的加氢过程。目前,国内已有商业化连续流氢化反应系统,如欧世盛科技已经展示了其在工业应用中的潜力。
图2 欧世盛全自动微反应设备
经硝基芳烃氢化制备芳香胺在药物合成领域中获得广泛应用,例如用于合成一系列抗HIV-1型病毒的二芳基苯胺(DAAN)化合物。Jones等[10]的研究证实,采用H-Cube微填充床反应器进行硝基苯化合物的氢化反应(表1),仅需2 min停留时间,所合成的苯胺衍生物产率达85%~98%。
表1 H-Cube微填充床反应器内加氢反应的结果Table 1 Results for hydrogenation reaction in micropacked-bed reactor of H-Cube
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在多步反应合成药物过程中,均相催化剂后处理烦琐。微填充床反应器采用固体催化剂,可简化反应液与催化剂的分离过程。Tsubogo等[11]利用四个串联的微填充床反应器,通过四步反应合成抗炎、抗肿瘤的罗利普兰,此过程中分别使用非均相非手性催化剂和手性催化剂成功制备(S)-罗利普兰和(R)-罗利普兰。实验证实该系统可稳定运行一周以上,产量达997.8 mg/24 h。此连续流合成系统结构简单、稳定性高且无金属催化剂浸出,经过程放大后实现了罗利普兰的千克级合成,且无须分离任何中间体及催化剂。由于填充的非均相催化剂颗粒剪切及破碎反应流体,能够强化多相传质以及提高催化剂活性位点与反应物间的接触概率,可实现环保、高效的药物生产过程。
尽管固体催化剂需定期再生或更换,且流速过大时易导致微填充床反应器的压降过大,但该类微反应器在复杂手性物质/药物的连续流合成中仍具明显优势,是含有固体的两相或者气-液-固三相反应的首选微反应器设备。
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