Visceral leishmaniasis (VL), a parasitic, poverty-linked, neglected disease, is endemic across multiple regions of the world and fatal if untreated. There is an urgent need for a better and more affordable treatment for VL. DNDI-6148 is a promising drug candidate being evaluated for the treatment of VL; however, the current process for producing the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane, is expensive and difficult to scale up. Herein, we describe two practical approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from inexpensive and readily available raw materials. Starting with 4-tolunitrile, the first approach is a five-step sequence involving a Hofmann rearrangement, resulting in an overall yield of 40%. The second approach utilizes 2-methyl-5-nitroaniline as the starting material and features borylation of aniline and continuous flow hydrogenation as the key steps, with an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane, which is challenging and expensive to scale. In particular, the second approach is more practical and scalable because of the mild operating conditions and facile isolation process.

中文翻译：

---

6-氨基-1-羟基-2,1-苯并氧硼杂环戊烷的实际合成：DNDI-6148 的关键中间体

内脏利什曼病 (VL) 是一种与贫困相关且被忽视的寄生虫病，在世界多个地区流行，如果不及时治疗可能致命。迫切需要一种更好、更实惠的 VL 治疗方法。 DNDI-6148 是一种有前途的候选药物，正在评估其治疗 VL 的效果；然而，目前生产 DNDI-6148 关键中间体 6-氨基-1-羟基-2,1-苯并氧硼杂硼烷的工艺成本昂贵且难以扩大规模。在这里，我们描述了两种从廉价且容易获得的原材料合成 6-氨基-1-羟基-2,1-苯并氧硼杂硼烷的实用方法。从 4-甲苯腈开始，第一种方法是涉及霍夫曼重排的五步序列，总产率为 40%。第二种方法以2-甲基-5-硝基苯胺为起始原料，以苯胺硼化和连续流动氢化为关键步骤，总收率为46%。两条路线都绕过了 1-羟基-2,1-苯并氧杂硼杂硼烷的硝化，该硝化具有挑战性且规模化成本昂贵。特别是，第二种方法由于温和的操作条件和简便的隔离过程而更加实用和可扩展。