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6-Amino-1-hydroxy-2,1-benzoxaborolane的实用合成:DNDI-6148的一个关键中间体

Pankaj V Khairnar¹, John M Saathoff¹, Daniel W Cook¹

¹Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.

Organic process research & development

|April 25, 2024

概括

研究人员开发了两种新的,具有成本效益的合成方法,用于有前途的内脏莱什曼病 (VL) 药物DNDI-6148的关键中间体. 这些可扩展的路线提供了改善的6-amino-1-hydroxy-2,1-benzoxaborolane的生产,这对于负担得起的VL治疗至关重要.

科学领域:

药用化学医学化学
有机合成有机合成
寄生虫学的寄生虫学

背景情况:

内脏莱什曼病 (VL) 是一种致命的,被忽视的热带疾病,需要改进的,负担得起的治疗方法.
DNDI-6148是VL的一个有前途的候选药物,但其关键中间体6-amino-1-hydroxy-2,1-benzoxaborolane的合成成本高且难以扩展.
目前这种中间体的生产方法效率低下,并阻碍了广泛获得潜在的VL疗法.

研究的目的:

开发 6-amino-1-hydroxy-2,1-benzoxaborolane 的实用和可扩展的合成途径.
为中期生产确定具有成本效益的原材料和高效的化学转化.
在现有的合成途径中绕过具有挑战性和昂贵的化步骤.

主要方法:

从4-tolunitrile中开发了一种五步合成,涉及霍夫曼重组.
从2-甲基-5-尼特罗阿尼林开发了第二条路径,其中包括阿尼林玻利化和连续流化.
这两种方法都避免了1-基-2,1-糖的有问题的化.

主要成果:

第一个路线的整体收益率为40%.
第二条路线的整体收益率为46%.
第二种方法显示出更大的实用性和可扩展性,因为温和的条件和容易的隔离.

结论:

成功建立了两个可行的合成策略,用于6-amino-1-hydroxy-2,1-benzoxaborolane.
开发的方法利用廉价的原材料,并提供更好的产量和可扩展性.
第二种合成方法对于大规模,经济高效地生产关键的VL药物中间体尤其有希望.

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