title: Design, synthesis, and biological evaluation of a library of 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides.
abstract: A library of 422 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxamides was prepared in five steps using solution-phase chemistry. The first step in the synthesis was the reaction of ethyl 2-ethoxymethylene-3-oxo-4,4,4-trifluorobutanoate with thiosemicarbazide, which is reported in the literature to afford a 1:1 mixture of ethyl 1-thiocarbamoyl-5-(trifluoromethyl)pyrazole-4-carboxylate and ethyl 1-thiocarbamoyl-3-(trifluoromethyl)pyrazole-4-carboxylate. We reassigned the structure of the product to be a single compound, ethyl 5-hydroxy-1-thiocarbamoyl-5-(trifluoromethyl)-4,5-dihydro-1H-pyrazole-4-carboxylate. This common intermediate was diversified by reaction with 17 alpha-bromoketones affording, in two steps, 17 1-(2-thiazolyl)-5-(trifluoromethyl)pyrazole-4-carboxylic acids. Scavenger resins were used to facilitate formation and purification of up to 27 amides from each of these acids in the last step. In addition, the Curtius reaction was applied to 12 of the acids followed by quenching with alcohols to afford a 108-member carbamate library. Certain compounds in the two libraries were toxic to C. elegans.
authors.affiliation: Rohm and Haas Company, 727 Norristown Road, Spring House, Pennsylvania 19477-0904, USA.
authors.forename: Bridget A
authors.initials: BA
authors.lastname: Donohue
authors.forename: Enrique L
authors.initials: EL
authors.lastname: Michelotti
authors.forename: John C
authors.initials: JC
authors.lastname: Reader
authors.forename: Valerie
authors.initials: V
authors.lastname: Reader
authors.forename: Matthew
authors.initials: M
authors.lastname: Stirling
authors.forename: Colin M
authors.initials: CM
authors.lastname: Tice
mesh_terms: D000577:Amides / Q000138:chemical synthesis* / Q000494:pharmacology; D000818:Animals; D000969:Antinematodal Agents / Q000138:chemical synthesis / Q000494:pharmacology; D017173:Caenorhabditis elegans / Q000187:drug effects; D002219:Carbamates / Q000737:chemistry / Q000494:pharmacology; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D015195:Drug Design; D004353:Drug Evaluation, Preclinical; D006845:Hydrocarbons, Fluorinated / Q000737:chemistry*; D009348:Nematoda / Q000187:drug effects; D011720:Pyrazoles / Q000138:chemical synthesis* / Q000494:pharmacology; D013844:Thiazoles / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D000577:Amides; D000969:Antinematodal Agents; D002219:Carbamates; D006845:Hydrocarbons, Fluorinated; D011720:Pyrazoles; D013844:Thiazoles