A Practical Synthesis of the TGFβRI Inhibitor N-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide via One-Pot Sequential Sonogashira and Cacchi Reactions Catalyzed by Pd(OAc)2/BINAP,Organic Process Research & Development

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A Practical Synthesis of the TGFβRI Inhibitor N-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide via One-Pot Sequential Sonogashira and Cacchi Reactions Catalyzed by Pd(OAc)2/BINAP
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2020-02-28 , DOI: 10.1021/acs.oprd.0c00015
Jianqing Li ₁ , Daniel Smith ₂ , Subramaniam Krishnananthan ₂ , Arvind Mathur ₂

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N-(4-(3-(6-(Difluoromethyl)pyridin-2-yl)-1H-pyrrolo[3,2-b]pyridin-2-yl)pyridin-2-yl)acetamide (5) is a potent inhibitor of TGFβRI kinase that provides durable antitumor activity when combined with an anti-PD-1 antibody. In order to conduct a full range of preclinical studies, over 150 g of high-quality material was required. The original discovery route through a stepwise copper-mediated Sonogashira reaction, trifluoroacetamide formation, and Cacchi reaction suffered from scale-up issues, mainly associated with tedious chromatographic purification of intermediates. This communication describes a chromatography-free one-pot synthesis of 5 via sequential Sonogashira and Cacchi reactions promoted by the superior catalyst Pd(OAc)₂/BINAP, which was discovered by catalyst screening.

中文翻译：

TGFβRI抑制剂N-（4-（3-（6-（二氟甲基）吡啶-2-基）-1 H-吡咯并[3,2 - b ]吡啶-2-基）吡啶-2-基的实用合成Pd（OAc）₂ / BINAP催化一锅顺序Sonogashira和Cacchi反应合成）乙酰胺

N-（4-（3-（6-（二氟甲基）吡啶-2-基）-1 H-吡咯并[3,2 - b ]吡啶-2-基）吡啶-2-基）乙酰胺（5）是TGFβRI激酶的有效抑制剂，与抗PD-1抗体结合使用时可提供持久的抗肿瘤活性。为了进行全面的临床前研究，需要超过150 g的高质量材料。通过逐步的铜介导的Sonogashira反应，三氟乙酰胺形成和Cacchi反应的原始发现路线存在放大问题，主要与中间体的乏味色谱纯化有关。本交流描述了5的无色谱一锅合成通过高级催化剂Pd（OAc）₂ / BINAP促进的连续Sonogashira和Cacchi反应，这是通过催化剂筛选发现的。

更新日期：2020-02-28

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