Development of a Robust Scale-Up Synthetic Route for BPR1K871: A Clinical Candidate for the Treatment of Acute Myeloid Leukemia and Solid Tumors

Julakanti Satyanarayana Reddy, Chih Ming Chen, Mohane Selvaraj Coumar, Hsu Yi Sun, Na Sun, Hsing Pang Hsieh

研究成果: Article同行評審

2 引文 斯高帕斯(Scopus)

摘要

Herein, a robust and scalable procedure for the synthesis of multikinase inhibitor BPR1K871 (1, a quinazoline compound bearing a substituted thiazoline side chain), which is a clinical candidate for the treatment of acute myeloid leukemia and solid tumors, is reported. The previously reported medicinal chemistry synthetic route A with seven steps had encountered several issues during scale-up syntheses such as low yields (7.7% overall yield), the formation of inseparable impurities, particularly in the chlorination step, use of hazardous reagents (NaH/DMF), and laborious column chromatography steps for the purification of the products. A step-by-step approach to overcome the above issues was planned and implemented through two similar routes (B1 and B2) on a gram scale and finally through route B3 on a kilogram scale to synthesize 1. The final optimized synthetic route B3 does not require column chromatography purification steps. It is one step shorter than the original route A and avoided hazardous reagents for the alkylation reaction in step 2. Furthermore, the highlights of the new route B3 include liquid-liquid continuous extraction of compound 13 in step 2, the use of POCl3 instead of SOCl2 to minimize the formation of impurities in the chlorination step 3, and telescoped synthesis of key Boc-protected amino intermediate 15 from 13, in high purity. Using the scale-up route B3, the final product 1 (3.09 kg, yield of 16.5% over six steps with an HPLC purity of 97.8%) was obtained in a single batch for preclinical testing and facilitated clinical testing of 1, which is underway.

原文English
頁(從 - 到)817-830
頁數14
期刊Organic Process Research and Development
25
發行號4
DOIs
出版狀態Published - 2021 4月 16

All Science Journal Classification (ASJC) codes

  • 物理與理論化學
  • 有機化學

指紋

深入研究「Development of a Robust Scale-Up Synthetic Route for BPR1K871: A Clinical Candidate for the Treatment of Acute Myeloid Leukemia and Solid Tumors」主題。共同形成了獨特的指紋。

引用此