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

Visceral leishmaniasis (VL), a parasitic, poverty-linked, neglected disease, is endemic across multiple regions of the world and fatal if untreated. There is an urgent need for a better and more affordable treatment for VL. DNDI-6148 is a promising drug candidate being evaluated for the treatment of VL; however, the current process for producing the key intermediate of DNDI-6148, 6-amino-1-hydroxy-2,1-benzoxaborolane, is expensive and difficult to scale up. Herein, we describe two practical approaches to synthesizing 6-amino-1-hydroxy-2,1-benzoxaborolane from inexpensive and readily available raw materials. Starting with 4-tolunitrile, the first approach is a five-step sequence involving a Hofmann rearrangement, resulting in an overall yield of 40%. The second approach utilizes 2-methyl-5-nitroaniline as the starting material and features borylation of aniline and continuous flow hydrogenation as the key steps, with an overall yield of 46%. Both routes bypass the nitration of 1-hydroxy-2,1-benzoxaborolane, which is challenging and expensive to scale. In particular, the second approach is more practical and scalable because of the mild operating conditions and facile isolation process.


HPLC/LCMS Method
LC with UV detection was used for the analysis of reaction mixtures and isolated product and intermediates.An Agilent 1100 series LC equipped with a diode array detector was used with the parameters shown below.

Setup for synthesis of 3-bromo
was added slowly (portion wise, over 20 minutes).The mixture was stirred at room temperature for 24 h.
After completion (monitored by HPLC), the product was extracted by EtOAc (50 mL x 3).The combined organic phase was washed with brine and dried over anhydrous sodium sulfate.Solvent was removed to afford 2-Bromo-4-nitrotoluene 8 (14.42 g, 92% yield) as a yellow solid.
The residue was stirred in hexanes (20 mL) for 30 min at rt, then the solid was collected by filtration and washed with hexanes (10 mL x 3) to afford a pure compound 9a, 2.1 g, 86% yield.
Figure S1.DSC (left) and TGA (right) results of the diazonium salt collected directly from a reaction mixture.DSC TGA

Table S1 . Synthesis of amide 5 by hydrolysis of nitrile 4.
a SM was consumed.Decomposition occurred.b 76 A% carboxylic acid was formed.