大規(guī)模加氫反應(yīng)由于使用易燃?xì)錃?、易自燃的催化劑以及累積不穩(wěn)定的中間體從而導(dǎo)致安全問(wèn)題。間歇釜式工藝雖然通過(guò)攪拌可增大氣-液兩相界面積、延長(zhǎng)氫氣在液相的滯留時(shí)間，但仍面臨氣-液傳質(zhì)效率低、安全性差及反應(yīng)時(shí)間長(zhǎng)等問(wèn)題，例如，部分芐基加氫過(guò)程需長(zhǎng)達(dá)72 h。微填充床反應(yīng)器相較于高壓釜式反應(yīng)器，具有體積小、氫氣保留量低、固載化催化劑易分離等優(yōu)勢(shì)，因而增強(qiáng)了加氫反應(yīng)的安全性。同時(shí)，其軸向返混較小、停留時(shí)間分布窄，提高了目標(biāo)產(chǎn)物的選擇性。再者，微填充床反應(yīng)器通過(guò)增大氣-液-固三相界面接觸面積、提高傳熱傳質(zhì)效率，極大縮短反應(yīng)時(shí)間，實(shí)現(xiàn)高效、綠色且安全的加氫過(guò)程。目前，國(guó)內(nèi)已有商業(yè)化連續(xù)流氫化反應(yīng)系統(tǒng)，如歐世盛科技已經(jīng)展示了其在工業(yè)應(yīng)用中的潛力。
圖2 歐世盛全自動(dòng)微反應(yīng)設(shè)備
經(jīng)硝基芳烴氫化制備芳香胺在藥物合成領(lǐng)域中獲得廣泛應(yīng)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]的研究證實(shí)，采用H-Cube微填充床反應(yīng)器進(jìn)行硝基苯化合物的氫化反應(yīng)（表1），僅需2 min停留時(shí)間，所合成的苯胺衍生物產(chǎn)率達(dá)85%~98%。
表1 H-Cube微填充床反應(yīng)器內(nèi)加氫反應(yīng)的結(jié)果Table 1 Results for hydrogenation reaction in micropacked-bed reactor of H-Cube
在多步反應(yīng)合成藥物過(guò)程中，均相催化劑后處理煩瑣。微填充床反應(yīng)器采用固體催化劑，可簡(jiǎn)化反應(yīng)液與催化劑的分離過(guò)程。Tsubogo等[11]利用四個(gè)串聯(lián)的微填充床反應(yīng)器，通過(guò)四步反應(yīng)合成抗炎、抗腫瘤的羅利普蘭，此過(guò)程中分別使用非均相非手性催化劑和手性催化劑成功制備(S)-羅利普蘭和(R)-羅利普蘭。實(shí)驗(yàn)證實(shí)該系統(tǒng)可穩(wěn)定運(yùn)行一周以上，產(chǎn)量達(dá)997.8 mg/24 h。此連續(xù)流合成系統(tǒng)結(jié)構(gòu)簡(jiǎn)單、穩(wěn)定性高且無(wú)金屬催化劑浸出，經(jīng)過(guò)程放大后實(shí)現(xiàn)了羅利普蘭的千克級(jí)合成，且無(wú)須分離任何中間體及催化劑。由于填充的非均相催化劑顆粒剪切及破碎反應(yīng)流體，能夠強(qiáng)化多相傳質(zhì)以及提高催化劑活性位點(diǎn)與反應(yīng)物間的接觸概率，可實(shí)現(xiàn)環(huán)保、高效的藥物生產(chǎn)過(guò)程。
盡管固體催化劑需定期再生或更換，且流速過(guò)大時(shí)易導(dǎo)致微填充床反應(yīng)器的壓降過(guò)大，但該類微反應(yīng)器在復(fù)雜手性物質(zhì)/藥物的連續(xù)流合成中仍具明顯優(yōu)勢(shì)，是含有固體的兩相或者氣-液-固三相反應(yīng)的首選微反應(yīng)器設(shè)備。
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