We describe the development of a one-pot preparation process of (E)-3,5-dichloro-4-(3-ethoxy-2-methyl-3-oxoprop-1-en-1-yl)benzoic acid (3), which is a key carboxylic acid intermediate of lusutrombopag. This one-pot reaction process is composed of lithiation of 3,5-dichlorobenzoic acid with lithium diisopropylamide (LDA), formylation using N-formylmorpholine, followed by olefination employing the Horner–Wadsworth–Emmons reaction with triethyl 2-phosphonopropionate. This method enabled kilogram-scale manufacturing of carboxylic acid 3, a key intermediate of lusutrombopag with high purity, together with a reduced number of steps, improvement of yield, and avoidance of a cumbersome procedure for isolation of the intermediate.

中文翻译：

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Lusutrombopag羧酸关键中间体的生产工艺开发：甲酰化的一锅反应过程和霍纳-沃兹沃思-埃蒙斯反应

我们描述了（E）-3,5-二氯-4-（3-乙氧基-2-甲基-3-氧代丙-1-烯-1-基）苯甲酸的一锅法制备工艺的发展（3） ，它是鲁舒莫巴的关键羧酸中间体。一锅法反应过程包括3,5-二氯苯甲酸与二异丙基氨基化锂（LDA）的锂化，使用N-甲酰基吗啉的甲酰化，然后使用Horner-Wadsworth-Emmons反应与2-膦酸丙酸三乙酯的烯化。该方法使公斤级规模的羧酸3（鲁舒通帕的关键中间体）具有高纯度，并减少了步骤数，提高了收率，并且避免了繁琐的中间体分离步骤。