A novel and practical synthesis of iclaprim

Submitting author affiliation:
China State Institute of Pharmaceutical Industry, Shanghai, China

Beilstein Arch. 2020, 202061. https://doi.org/10.3762/bxiv.2020.61.v1

Published 11 May 2020

This preprint has not been peer-reviewed. When a peer-reviewed version is available, this information will be updated.


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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When a peer-reviewed version of this preprint is available, this information will be updated in the information box above. If no peer-reviewed version is available, please cite this preprint using the following information:

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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