Early Process Development of CH7057288, a Benzofuran-Containing Selective NTRK Inhibitor,Organic Process Research & Development

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Early Process Development of CH7057288, a Benzofuran-Containing Selective NTRK Inhibitor
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2024-01-03 , DOI: 10.1021/acs.oprd.3c00434
Tomohiro Oki ₁ , Junichi Shiina ₂ , Hiroshi Fukuda ₂ , Minoru Yamawaki ₂ , Yasushi Kito ₂ , Masaki Tomizawa ₂ , Hiroshi Iwamura ₁ , Masao Tsukazaki ₁ , Azusa Toya ₁ , Shun Tsuzaki ₁ , Naoto Hama ₃ , Akira Kawase ₁ , Kenichi Nomura ₂ , Hisashi Ito ₃ , Kenji Maeda ₁

Affiliation

This work describes the development of a scalable manufacturing process for CH7057288, a neurotrophic tyrosine receptor kinase (NTRK) inhibitor that selectively targets NTRK positive cancers. NTRK fusions are extremely attractive and promising therapeutic targets, and in order to deliver CH7057288 as a new treatment option for patients, it is crucial to be able to rapidly supply a large amount of this innovative drug for GLP toxicology studies and first-in-human (FIH) studies. By employing an 11-step process, we have been able to synthesize CH7057288 from methyl 2-(3-aminophenyl)-2-methylpropanoate with high purity and in excellent yield. The distinguishing features of this process include sequential double cyclization, leading to four-membered benzofuran-fused heterocycles. By employing this process, we successfully produced a total of 5.5 kg of CH7057288.

中文翻译：

CH7057288（一种含苯并呋喃的选择性 NTRK 抑制剂）的早期工艺开发

这项工作描述了 CH7057288 的可扩展制造工艺的开发，CH7057288 是一种选择性靶向 NTRK 阳性癌症的神经营养性酪氨酸受体激酶 (NTRK) 抑制剂。 NTRK融合是极具吸引力和有前途的治疗靶点，为了将CH7057288作为患者的新治疗选择，能够快速供应大量这种创新药物用于GLP毒理学研究和首次人体试验至关重要（FIH）研究。通过采用 11 步工艺，我们能够以高纯度和优异的收率从 2-(3-氨基苯基)-2-甲基丙酸甲酯合成 CH7057288。该过程的显着特征包括连续双环化，产生四元苯并呋喃稠合杂环。通过采用该工艺，我们成功生产了总计5.5公斤的CH7057288。

更新日期：2024-01-03

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