Manufacture of an EGFR inhibitor required the asymmetric synthesis of a key 3,4-trans-substituted pyrrolidine suitable for pilot-plant scale. The initial synthetic route utilized reagents and intermediates that posed safety concerns due to their energetic potential and then required supercritical fluid chromatography to access the desired single enantiomer. Burgess-type reagents provide tremendous utility in organic synthesis but see limited use on large scales because of their high cost and instability. Nevertheless, extensive process development led to a scale-friendly process where in situ formation of a Boc-Burgess reagent enabled access to a chiral cyclic sulfamate from inexpensive materials. ReactIR monitoring was used to study intermediate stability and enabled processing on a multikilogram scale. The sulfamate was converted to trans-3-fluoro-4-aminopyrrolidine 1 with complete stereospecificity. Intermediate crystallinity offered purity control points where byproducts and impurities were rejected, avoiding the need for chromatography.

中文翻译：

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利用Burgess型转化对映体合成（3 R，4 R）-1-苄基-4-氟吡咯烷-3-胺

EGFR抑制剂的生产需要不对称合成适合中试规模的关键3,4-反式取代的吡咯烷。最初的合成路线使用的试剂和中间体由于其能量潜力而引起安全隐患，然后需要超临界流体色谱法才能获得所需的单一对映异构体。伯吉斯型试剂在有机合成中具有巨大的实用性，但由于成本高且不稳定，因此在大规模使用中受到限制。然而，广泛的工艺开发导致了规模友好的工艺，其中Boc-Burgess试剂的原位形成使得能够从廉价的材料中获得手性环状氨基磺酸盐。ReactIR监测用于研究中间稳定性，并能够在多千克规模上进行处理。氨基磺酸盐转化为具有完全立体特异性的反式-3-氟-4-氨基吡咯烷1。中等结晶度提供了纯度控制点，可以排除副产物和杂质，从而无需色谱。