A novel and practical synthesis of Iclaprim

Abstract

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%.

Graphical Abstract

Keywords:

• Acetylation
• buffer system
• chromanone
• Iclaprim
• sulfuric acid
• synthesis