Optimization of N ‐alkylation in the Synthesis of Methotrexate and Pteridine‐based Derivatives Under Microwave‐Irradiation

Abstract Methotrexate (MTX) and its pteridine‐based derivatives represent an attractive chemotype for the development of bioactive molecules. However, the synthesis of pteridines suffers from several drawbacks. Here we describe a new efficient and improved microwave‐assisted lab‐scale process for the preparation of MTX and congeners. Starting from the commercially available 2,4‐diamino‐6‐(hydroxymethyl)pteridine (Pt‐OH), MTX was obtained with an overall 94% yield through a three steps procedure. The crucial yield‐limiting and time‐consuming step of S N 2 substitution between halogenated pteridine and nucleophilic aromatic amine was taken. The innovative process, conducted under microwave irradiation, improved yield and purity, and in particular reduced the reaction time from days to 20 minutes. The optimized protocol was successfully applied to the synthesis of diverse pteridine‐based derivatives and to the preparation in gram‐scale of antiparasitic MTX derivatives for in vivo studies. This new optimized synthetic procedure therefore represents a worthy alternative to the current protocols for the preparation of pteridine‐based derivatives.