如何有效去除反应中的三苯基氧磷，简化Appel、Mitsunobu等反应的后处理！

背景介绍

在制药行业中，副产品的去除可能代表了一个过程中的重要工作，有时还会影响药物成分的化学路线。许多有用的有机转化过程都利用了三苯基膦（TPP）作为还原剂，例如Wittig反应、Appel反应和Mitsunobu反应等。在小规模上，三苯基膦氧化物（TPPO）的传统去除方法通常通过柱色谱法进行。然而，在大规模上去除TPPO的挑战，其中色谱法是不切实际的，限制了这些反应的实施以支持超出临床前研究的API交付。当可能时，可以利用依赖于产品的物理化学性质的各种技术。例如，Mitsunobu反应产生的TPPO可以通过产品的结晶来去除，留下母液中的TPPO，或者通过利用提取程序，其中产品可以在适当的pH调节后被拉入水层，留下有机层中的TPPO。不幸的是，如果产品不是晶体，如果TPPO干扰结晶过程，或者如果产品不能在工作过程中在水层中有利地分配，这些策略就不能使用。

目前，有机反应中TPPO副产品的分离问题主要分为三大类：

（1）改进的TPPO去除方法；

（2）通过使用具有更容易分离的磷氧化物的替代磷化物来避免TPPO；

（3）通过开发催化量的磷化物反应或根本不需要磷化物的反应来避免化学计量的磷氧化物废物。

本期小编就给大家介绍如何高效除去有机反应混合液中的三苯基膦氧化物，溶剂的选择至关重要，低极性溶剂，如己烷、甲苯、环己烷和二乙醚对TPPO络合物的溶解性差，同时对产物的溶解性也可能较差。而在极性的溶剂（即乙醇、乙酸乙酯、四氢呋喃等）中沉淀 TPPO 的方法，也可能造成产物的损失，尤其是含氮原子较多的产物，在运用该方法除去TPPO时，更应该注意！

图片来源：J. Org. Chem.

图片来源：J. Org. Chem.

在合成4的Corey−Fuchs反应中，发现TPPO的沉淀效果很好。粗反应混合物用H2O2洗涤，将任何剩余的磷化物和磷鎓物种转化为TPPO，允许用ZnCl2进行一次沉淀即可有效去除（方案2）。化合物4可以在不需要柱色谱法的情况下以82%的产率获得多克规模。

图片来源：J. Org. Chem.

图片来源：J. Org. Chem.

(1R,2S,5R)-2-Isopropyl-5-methylcyclohexyl 4-Nitrobenzoate (6). A 1-L, round-bottom, three-neck flask, equipped with a thermometer, dropping funnel, argon inlet, and magnetic stirrer bar, was charged with l-menthol (6.00 g, 38.4 mmol), TPP (40.1 g, 152.4 mmol), 4-nitrobenzoic acid (25.8 g, 154.4 mmol), and THF (300 mL). While the mixture was stirred under an argon atmosphere, the solution was cooled in an ice bath to 0 °C and diethyl azodicarboxylate (24.2 mL, 154 mmol) was added slowly by addition funnel while maintaining the temperature below 10 °C. Upon completion of the addition, the cooling bath was removed, and the yellow solution was allowed to warm to rt and stir for 18 h. The reaction mixture was warmed to 35−40 °C for 3 h before being transferred to a 2-L separatory funnel and diluted with EtOAc (400 mL). The solution was washed with saturated sodium bicarbonate (2 × 200 mL), 6% hydrogen peroxide (2 × 250 mL), and water (400 mL). The organic layer was isolated and dried over anhydrous sodium sulfate before being filtered and concentrated to dryness by rotary evaporation. The resulting slightly yellow solid was dissolved in 600 mL of ethanol in a 1-L Erlenmeyer flask with gentle warming and stirring. To the stirred solution was added, in a single portion, a warm solution of anhydrous zinc chloride (42.0 g, 310 mmol) in ethanol (200 mL). Stirring was continued while the inner wall of the flask was scratched with a glass rod to initiate the precipitation of the zinc chloride complex of triphenylphosphine oxide. The precipitation was complete after stirring for 1 h at rt, and the mixture was filtered to remove the ZnCl2(TPPO)2. The white solid was rinsed with 50 mL of warm ethanol, and the filtrate was treated with decolorizing carbon (500 mg) before being filtered through a Whatman glass microfiber filter. Analysis (GC with dodecane as an internal standard) showed that 30% of the TPPO had been removed. A second precipitation with ZnCl2 resulted in 85% of the TPPO being removed. The product was recrystallized directly from the second ethanol filtrate as a thick mat of white crystalline needles. The product was isolated by filtration to give 7.9 g (68% yield) of the pure compound (1R,2S,5R)-2-isopropyl-5-methylcyclohexyl 4-nitrobenzoate. Additional yield could be obtained from concentration of the mother liquor and recrystallization but was not combined with the initial recrystallization due to a slight triphenylphosphine oxide impurity. 1H and 13C NMR matched literature data.