- Use of High-Throughput Tools for Telescoped Continuous Flow Synthesis of an Alkynylnaphthyridine Anticancer Agent, HSN608
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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.
- Biyani, Shruti A.,Larocque, Elizabeth A.,Moriuchi, Yuta,Qi, Qingqing,Sintim, Herman O.,Thompson, David H.,Wu, Jingze
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- ALPHA, BETA-UNSATURATED AMIDE COMPOUND
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An object of the present invention is to provide an α,β-unsaturated amide compound or a pharmaceutically acceptable salt or the like thereof having anticancer activity and the like. The α,β-unsaturated amide compound represented by the following formula (I) or a pharmaceutically acceptable salt or the like thereof has anticancer activity and the like: [wherein, "A" represents optionally substituted heterocyclic diyl, R1 represents hydrogen atom or optionally substituted lower alkyl, R2 represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group, X represents -O-, -S-, -SO2-, -NRX1- (wherein, RX1 represents hydrogen atom or lower alkyl), -CHRX2- (wherein, RX2 represents hydrogen atom or hydroxy), -CH=CH-, -CO- or -NH-CO-, and n1 and n2 are the same or different, and each represents 0 or 1].
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Paragraph 1121
(2020/12/10)
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- a, ? UNSATURATED AMIDE COMPOUND
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The present invention provides an α,β-unsaturated amide compound or a pharmaceutically acceptable salt or the like thereof having anticancer activity and the like represented by the following formula (I): [wherein, "A" represents optionally substituted heterocyclic diyl, R1 represents hydrogen atom or optionally substituted lower alkyl, R2 represents optionally substituted aryl, optionally substituted cycloalkyl, optionally substituted aliphatic heterocyclic group or optionally substituted aromatic heterocyclic group, X represents -O-, -S-, -SO2-, -NRX1- (wherein, RX1 represents hydrogen atom or lower alkyl), -CHRX2- (wherein, RX2 represents hydrogen atom or hydroxy), -CH=CH-, -CO- or -NH-CO-, and n1 and n2 are the same or different, and each represents 0 or 1].
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Paragraph 0934
(2018/11/27)
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