Development of Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common Intermediate Approach,Organic Process Research & Development

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Development of Flexible and Scalable Routes to Two Phosphatidinylinositol-3-kinase Delta Inhibitors via a Common Intermediate Approach
Organic Process Research & Development ( IF 3.1 ) Pub Date : 2018-02-27 00:00:00 , DOI: 10.1021/acs.oprd.8b00006
Dean Edney ₁ , David G. Hulcoop ₁ , John H. Leahy ₁ , Lois E. Vernon ₁ , Mark D. Wipperman ₁ , Robert N. Bream ₁ , Michael R. Webb ₁

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This paper describes the discovery and development of a flexible route to two candidate drug molecules by a common intermediate approach. Key reactions include Negishi and Suzuki couplings to form biaryl bonds. Conditions for a Miyaura borylation of heteroaryl bromides were also developed. Heteroaryl trifluoroborates and aryl chlorides were used as coupling partners in the Suzuki reaction, thereby minimizing detrimental side reactions such as protodeboronation and oxidative homocoupling. A complementary set of reaction conditions using pinacolboronates with potassium bifluoride as an additive were also developed and used to make 5 kg of drug substance for use in early-phase clinical trials.

中文翻译：

通过共同的中间方法开发两种磷脂酰肌醇-3-激酶Delta抑制剂的灵活和可扩展途径的发展。

本文介绍了通过一种常见的中间方法开发和灵活地合成两种候选药物分子的途径。关键反应包括Negishi和Suzuki偶联形成联芳基键。还开发了对杂芳基溴进行宫浦硼化的条件。杂芳基三氟硼酸酯和芳基氯化物在Suzuki反应中用作偶联伙伴，从而使有害的副反应（如原脱硼烷基化和氧化均偶联）最小化。还开发了一套使用频哪醇硼酸酯与氟化氢钾作为添加剂的补充反应条件，并将其用于制备5千克用于早期临床试验的原料药。

更新日期：2018-02-27

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