Synthetic studies towards isomeric pyrazolopyrimidines as potential ATP synthesis inhibitors of Mycobacterium tuberculosis. Structural correction of reported N-(6-(2-(dimethylamino)ethoxy)-5-fluoropyridin-3-yl)-2-(4-fluorophenyl)-5-(trifluoromethyl)pyrazolo[1,5- α]pyrimidin-7-amine

Peter J Choi; Guo-Liang Lu; Hamish S Sutherland; Anna C Giddens; Scott G Franzblau; Christopher B Cooper; William A Denny; Brian D Palmer

doi:10.1016/j.tetlet.2021.153611

Synthetic studies towards isomeric pyrazolopyrimidines as potential ATP synthesis inhibitors of Mycobacterium tuberculosis. Structural correction of reported N-(6-(2-(dimethylamino)ethoxy)-5-fluoropyridin-3-yl)-2-(4-fluorophenyl)-5-(trifluoromethyl)pyrazolo[1,5- α]pyrimidin-7-amine

Tetrahedron Lett. 2022 Feb 2:90:None. doi: 10.1016/j.tetlet.2021.153611.

Authors

Peter J Choi^{1

2}, Guo-Liang Lu^{1

2}, Hamish S Sutherland^{1

2}, Anna C Giddens¹, Scott G Franzblau³, Christopher B Cooper⁴, William A Denny^{1

2}, Brian D Palmer^{1

2}

Affiliations

¹ Auckland Cancer Society Research Centre, School of Medical Sciences, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
² Maurice Wilkins Centre, University of Auckland, Private Bag 92019, Auckland 1142, New Zealand.
³ Institute for Tuberculosis Research, College of Pharmacy, University of Illinois at Chicago, 833 South Wood Street, Chicago, IL 60612, USA.
⁴ Global Alliance for TB Drug Development, 40 Wall Street, New York, NY 10005, USA.

Abstract

During our studies into preparing analogues of pyrazolopyrimidine as ATP synthesis inhibitors of Mycobacterium tuberculosis, a regiospecific condensation reaction between ethyl 4,4,4-trifluoroacetoacetate and 3-(4-fluorophenyl)-1H-pyrazol-5-amine was observed which was dependent on the specific reaction conditions employed. This work identifies optimized reaction conditions to access either the pyrazolo[3,4-β]pyridine or the pyrazolo[1,5-α]pyrimidine scaffold. This has led to the structural confirmation of the previously reported pyrazolopyrimidine 17b which was reported as pyrazolo[1,5-α]pyrimidine structure 2 which was corrected to pyrazolo[3,4-β]-pyrimidine 19.

Keywords: Antimicrobial resistance; Pyrazolopyrimidines; Structure-activity relationships; Synthesis; Tuberculosis.