Synthesis of (S)-5-fluoro-3-methylisobenzofuran-1(3H)-one (6), a key intermediate to lorlatinib, is described. A few synthetic methodologies, that is, boron reduction, enzymatic reduction, asymmetric hydrogenation, and asymmetric transfer hydrogenation, were evaluated for the chiral reduction of the substituted acetophenone intermediate (8). A manufacturing process, on the basis of the asymmetric transfer hydrogenation, was developed. This process was successfully scaled up to prepare 400 kg of 6.

中文翻译：

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开发不对称转移加氢工艺的（S）-5-氟-3-甲基异苯并呋喃-1（3 H）-一，洛拉替尼的关键中间体

描述了（S）-5-氟-3-甲基异苯并呋喃-1（3 H）-一（6）的合成，这是洛来替尼的关键中间体。对于取代的苯乙酮中间体的手性还原，评估了几种合成方法，即硼还原，酶还原，不对称氢化和不对称转移氢化（8）。在不对称转移氢化的基础上，开发了一种制造方法。此过程已成功扩大规模，以制备400公斤6。