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Practical Synthesis of 6-Amino-1-hydroxy-2,1-benzoxaborolane: A Key Intermediate of DNDI-6148.
Khairnar, Pankaj V; Saathoff, John M; Cook, Daniel W; Hochstetler, Samuel R; Pandya, Urvish; Robinson, Stephen J; Satam, Vijay; Donsbach, Kai O; Gupton, B Frank; Jin, Li-Mei; Shanahan, Charles S.
Afiliación
  • Khairnar PV; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Saathoff JM; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Cook DW; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Hochstetler SR; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Pandya U; Drugs for Neglected Diseases initiative, 15 Chemin Camille-Vidart, 1202 Geneva, Switzerland.
  • Robinson SJ; Drugs for Neglected Diseases initiative, 15 Chemin Camille-Vidart, 1202 Geneva, Switzerland.
  • Satam V; Drugs for Neglected Diseases initiative, 15 Chemin Camille-Vidart, 1202 Geneva, Switzerland.
  • Donsbach KO; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Gupton BF; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Jin LM; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
  • Shanahan CS; Medicines for All Institute, Virginia Commonwealth University, Richmond, Virginia 23284-3068, United States.
Org Process Res Dev ; 28(4): 1213-1223, 2024 Apr 19.
Article en En | MEDLINE | ID: mdl-38660377
ABSTRACT
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.