A mild protocol for the synthesis of N-methyltransferase G9a inhibitor BIX-01294

A synthetic route to BIX-01294 was designed by means of retrosynthetic analysis and convergent synthesis. Using 2-amino-4,5-dimethoxybenzoic acid and urea as the starting materials, BIX-01294 was synthesized in the four following steps: cyclization, chlorination and two steps of ammonolysis. In contrast to the previously described approaches to BIX-01294, our final step conditions do not require microwave irradiation, utilize cheap and simple methanesulfonic acid as a catalyst to promote the synthesis of the target BIX-01294 under mild conditions ((PrOH)-O-n, reflux, 5 h) in 75.5% yield. The overall yield of BIX-01294 over four steps was 26.4%.

Automated summary

A synthetic route to BIX-01294 was designed and successfully achieved through retrosynthetic analysis and convergent synthesis. The final step conditions were optimized to eliminate the need for microwave irradiation, using inexpensive and simple methanesulfonic acid as a catalyst. The overall yield of BIX-01294 over four steps was 26.4%.