國家衛生研究院 NHRI:Item 3990099045/13315

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Title:	Development of a robust scale-up synthetic route for BPR1K871: A clinical candidate for the treatment of acute myeloid leukemia and solid tumors
Authors:	Reddy, JS;Chen, CM;Coumar, MS;Sun, HY;Sun, N;Hsieh, HP
Contributors:	Institute of Biotechnology and Pharmaceutical Research
Abstract:	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.
Date:	2021-04-16
Relation:	Organic Process Research and Development. 2021 Apr 16;25(4):817-830.
Link to:	http://dx.doi.org/10.1021/acs.oprd.0c00515
JIF/Ranking 2023:	http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcAuth=NHRI&SrcApp=NHRI_IR&KeyISSN=1083-6160&DestApp=IC2JCR
Cited Times(WOS):	https://www.webofscience.com/wos/woscc/full-record/WOS:000641295300013
Cited Times(Scopus):	https://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=85102033603
Appears in Collections:	[Hsing-Pang Hsieh] Periodical Articles

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