Infigratinib: Synthesis and Introduction
Jan 29,2024
Synthesis of Infigratinib
Infigratinib was synthesized in a modular and convergent fashion via the union of three building blocks. The specific synthesis steps are as follows:
Step 1: Synthesis of Aniline-Containing Building Blocks (a) 32.4, (b) 32.6, and (c) 32.8
Piperidinesubstituted aniline 32.4 was prepared by the SNAr reaction of neat reagents piperidine 32.1 and bromonitrobenzene 32.2 at 80 °C followed by nitro reduction. 2,6-Dichloro-3,5- dimethoxyaniline (32.6) was accessed in 3 steps (acylation, chlorination, and hydrolysis) from commercially available 3,5- dimethoxyaniline (32.5), and 6-chloro-N-methylpyrimidin-4-amine (32.8) was prepared by the SNAr reaction of dichloropyrimidine 32.7 with methylamine.
Step 2: Preparation of Infigratinib
Infigratinib was assembled by the SNAr reaction of aniline 32.4 with chloropyrimidine 32.8 to furnish aryl methyl amine 32.9. Aniline derivative 32.6 was converted to the corresponding isocyanate in situ and coupled with 32.9 to form the urea linkage and complete the synthesis of infigratinib.
Introduction of Infigratinib
Infigratinib is an orally bioavailable inhibitor against fibroblast growth factor receptor (FGFR)-specific tyrosine kinases. Co-developed by QED Therapeutics and Helsinn, infigratinib was approved by the USFDA in May 2021 for use in previously treated patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions or rearrangements. Infigratinib displays highly selective, nanomolar inhibition of FGFR1, FGFR2, FGFR3, and FGFR4 in biochemical and cellular assays. Since activation of the FGFR pathway with underlying genetic abnormalities can cause proliferation of malignant cancer cells, inhibition of FGFR-specific kinases effectively reduces cell proliferation in tumors.
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