Beilstein Arch. 2020, 202061. https://doi.org/10.3762/bxiv.2020.61.v1
Published 11 May 2020
A novel and facile synthesis of iclaprim was reported. Started from Trimethoprim (TMP), the amino-protection and Friedel-Crafts acetylation with acetic anhydride were simultaneously completed in CH2Cl2 with SnCl4 as catalyst. The Knoevenagel condensation of 2,4-diamino-5-(2-acetyl-3-hydroxy-4,5-dimethoxybenzyl)pyrimidine with cyclopropyl carboxaldehyde followed by the intramolecular Michael addition in the buffer system (pyrrolidine and acetic acid) installed the key framework (chromanone 13). The dehydration was catalyzed by H2SO4 so that the formation of 5-cyclopropyl-2,3-dimethoxy-4,5,6,6a,7,12-hexahydronaphtho[1,8-bc]pyrimido[5,4-f]azepin-9-amine, an impurity of iclaprim reported at the first time, could be minimized. In the end, iclaprim was obtained in a total yield of 21%.
Keywords: synthesis, iclaprim, acetylation, buffer system, chromanone and sulfuric acid.
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Liu, W.; Chen, L.; Pan, J.; Zhou, T.; Lin, K.; Zhou, W. Beilstein Arch. 2020, 202061. doi:10.3762/bxiv.2020.61.v1
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