First-Generation Route for CXCR7 Antagonist ACT-1004-1239 (1)

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Org. Process Res. Dev. 2024, 28, 2090 − 2102. DOI: 10.1021/acs.oprd.3c00445 ◆ The original discovery route to ACT-1004-1239 relied on the small-scale commercial availability of three main building blocks ◆ A small amount of (Z)-oxime isomer 15 was formed during the reaction, which was found to be unreactive toward cyclization. Fortunately, unreacted 15 was fully purged into the mother liquor. ◆ The addition of base (e.g., NEt3) was highly detrimental and led to the appearance of several side products and nearly complete suppression of product formation. This indicated the necessity of having a proton transfer which helped with the elimination of H2O during the isoxazole cyclization. ◆ The formation of enamine 19 from piperidone 16 was intensively optimized, especially with regard to product isolation. 17-TFA was isolated as a white solid in 87% yield with excellent purity (>99% a/a, 97% w/w, cis:trans ∼ 2:1) on 800 g scale. ◆ The only identified organic solvent in which ………………………………