Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin),Organic Process Research & Development

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Development of a Scalable Asymmetric Process for the Synthesis of GLYT1 Inhibitor BI 425809 (Iclepertin)
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2023-03-03 , DOI: 10.1021/acs.oprd.2c00373
Rogelio Frutos ₁ , Thomas G. Tampone ₁ , Jason Mulder ₁ , Joe Gao ₁ , Joshua D. Sieber ₁ , Sonia Rodriguez ₁ , Nizar Haddad ₁ , Katrin Baer ₁ , Jack Brown ₁ , Bing-Shiou Yang ₁ , Riccardo Giovannini ₁ , Jinhua J. Song ₁ , Nelu Grinberg ₁ , Heewon Lee ₁ , Chris H. Senanayake ₁

Affiliation

A robust and scalable synthesis process for BI 425809 (Iclepertin), a GLYT1 inhibitor with potential therapeutic properties for the treatment of central nervous system disorders, was developed and implemented on a multikilogram scale. Key aspects of the process include the efficient asymmetric synthesis of intermediate 3-((1R,5R)-3-azabicyclo[3.1.0]hexan-1-yl)-5-(trifluoromethyl)isoxazole·HCl from raw materials readily available in bulk and the synthesis of (R)-5-(methylsulfonyl)-2-((1,1,1-trifluoropropan-2-yl)oxy)benzoic acid through a novel Rh-catalyzed asymmetric hydrogenation.

中文翻译：

开发用于合成 GLYT1 抑制剂 BI 425809 (Iclepertin) 的可扩展不对称工艺

BI 425809 ( Iclepertin )是一种稳健且可扩展的合成工艺，它是一种 GLYT1 抑制剂，具有治疗中枢神经系统疾病的潜在治疗特性，已开发并以数千克规模实施。该工艺的关键方面包括从原料中高效不对称合成中间体 3-((1 R ,5 R )-3-氮杂双环[3.1.0]hexan-1-yl)-5-(三氟甲基)异恶唑·HCl通过新型 Rh 催化的不对称氢化，可大量获得并合成 ( R )-5-(甲基磺酰基)-2-((1,1,1-三氟丙-2-基)氧基)苯甲酸。

更新日期：2023-03-03

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