Development of an Effective Scalable Enantioselective Synthesis of the HIV-1 Entry Inhibitor BNM-III-170 as the Bis-Trifluoroacetate Salt

Junhua Chen; Jun Park; Sharon M Kirk; Hung-Ching Chen; Xiangqin Li; Daniel J Lippincott; Bruno Melillo; Amos B Smith 3rd

doi:10.1021/acs.oprd.9b00353

Development of an Effective Scalable Enantioselective Synthesis of the HIV-1 Entry Inhibitor BNM-III-170 as the Bis-Trifluoroacetate Salt

Org Process Res Dev. 2019 Nov 15;23(11):2464-2469. doi: 10.1021/acs.oprd.9b00353. Epub 2019 Oct 7.

Authors

Junhua Chen¹, Jun Park¹, Sharon M Kirk¹, Hung-Ching Chen¹, Xiangqin Li¹, Daniel J Lippincott¹, Bruno Melillo¹, Amos B Smith 3rd¹

Affiliation

¹ Department of Chemistry, Monell Chemical Senses Center and Laboratory for Research on the Structure of Matter, University of Pennsylvania, Philadelphia, PA 19104.

Abstract

We report here the development and optimization of a process synthesis for the HIV-1 entry inhibitor BNM-III-170 bis-TFA salt (1). The synthesis features a dynamic-kinetic resolution (DKR) to establish the initial stereogenicity. By taking advantage of significant sequence modifications of our first generation synthesis, inconjunction with the low solubility of late-stage intermediates, the overall efficiency of the synthesis has been significantly improved, now to proceed in an overall yield of 9.64% for the 16-steps, requiring only a single chromatographic separation.

Keywords: CD4-mimetic; Gabriel amine synthesis; HIV-1 entry inhibitor; aminolysis; dynamic-kinetic resolution; guanidine formation.

Abstract

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