DNDI-6148 for Visceral Leishmaniasis

DNDI-6148 for Visceral Leishmaniasis

Starting Material

Summary

This report describes the results of synthetic route scouting (SRS) efforts at the Medicines for All Institute (M4ALL) to discover new, low-cost synthetic strategies to make 6-amino-1-hydroxy-2,1-benzoxaborolane (6-ABB), which is a key intermediate and cost-driver in the synthesis of the Visceral Leishmaniasis (VL) drug candidate DNDI-6148. Herein, we report the development of several commodity-centric synthetic approaches to make 6-ABB which may offer alternative low-cost processes to make this regulatory starting material (RSM) of DNDI-6148. Of these routes that we explored, one promising route afforded 6-ABB in 5 steps from 4- methylbenzonitrile in a 40% overall yield (Key idea I) and the other route afforded 6-ABB in 4 steps with an overall yield of up to 45% from 2-methyl-5- nitroaniline (Key idea II). Techno-economic (TE) cost analysis suggests that, compared to the baseline route starting from 1-hydroxy-2,1-benzoxaborolane, the overall raw material cost (RMC) of the API for Key Idea I was reduced greater than 80%, and for Key Idea II, the RMC was reduced more than 90%.

Summary of Synthetic Route Scouting Work on the Regulatory Starting Material of DNDI-6148

Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148