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Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608

By Biyani, Shruti A.; Qi, Qingqing; Wu, Jingze; Moriuchi, Yuta; Larocque, Elizabeth A.; Sintim, Herman O.; Thompson, David H.

Published on CMKC

Abstract

Developing continuous syntheses of lead compounds to support in vivo studies and preclinical evaluation remains an underdeveloped area. We report a telescoped continuous flow synthesis of an alkynylnaphthyridine lead compound for the treatment of FLT3 mutations in acute myeloid leukemia. Different strategies were used to develop the route, including Design of Experiments (DoE), high-throughput experimentation (HTE), and application of desorption electrospray ionization mass spectrometry (DESI-MS) to optimize and telescope the amidation and Sonogashira couplings to prepare the target compound, HSN608, a potent FLT3 inhibitor. Findings from these statistical design and automation studies helped streamline our workflow to achieve 10-fold and 5-fold reductions in the catalyst and cocatalyst loadings, respectively, in the synthesis. The application of high-throughput tools combined with a telescoped continuous synthesis method enabled an efficient and safe synthesis of this lead compound using the hazardous coupling reagent HATU while minimizing byproduct formation.

Journal

Organic Process Research & Development. Volume 24, 2020, 2240–2251

DOI

10.1021/acs.oprd.0c00289

Type of publication

Peer-reviewed journal

Affiliations

  • Purdue University

Article Classification

Research Article

Classification Areas

  • API

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