Synthesis, spectroscopic, and X-ray structural characterization of pharmacologically active substituted pyrazolyl-acetanilides

Abstract

Five new pyrazole acetanilides were synthesized by N-alkylation of pyrazole and its derivatives with 4 0 -propionyl-2-iodoacetanilide. Compounds 1-5 were characterized by 1 H NMR, 13 C NMR, IR, UV-Vis, MS, and elemental analysis. X-ray structures of representative compounds 1, 3, and 5 established their conformations and solid-state hydrogen bonding preferences. Acute toxicity, local anesthetic, and antiarrhythmic activities were assessed for compounds 1-5 using established protocols. Lower potencies and lower acute toxicities were recorded relative to lidocaine. Enhanced anesthetic activity of compound 3 was attributed to the presence of the propionyl group in the molecule. Experimental Synthesis and characterizationAll compounds referred to in this article, namely the 4 0propionyl-2-chloroacetanilides, 4 0 -propionyl-2-iodoacetanilides, and the substituted pyrazoles, were prepared according to published methods [2,9,10].All melting points were recorded with a Boetius apparatus and are uncorrected. Electronic spectra within the 400-4000 nm range were obtained using a VSU-2P Zeiss-Jena Spectrophotometer, using MgO as a standard. IR spectra (KBr pellets) were measured on a BIO-RAD FTS-135 Spectrometer. NMR spectra were recorded on a Varian Gemini 300 Spectrometer operating at 300 MHz ( 1 H NMR) and 75 MHz ( 13 C NMR), respectively, in CDCl 3 or DMSO-d 6 . The chemical shifts were referred to tetramethylsilane (TMS) as the internal standard. GS-MS were recorded on a Varian Saturn 2000 GC/MS. The general procedure for the synthesis of pyrazoles 1-5 is given below with reference to compound 1. Spectroscopic data for 1-5 follow.2-(Pyrazol-1-yl)-4 0 -propionylacetanilide (1) About 4.0 g (1.26 mmol) 4 0 -propionyl-2-iodoacetanilide and 0.86 g (1.26 mmol) of pyrazole were dissolved in 3 mL of DMF to which an equimolar amount of sodium carbonate was then added. The reaction mixture was heated at 60°C for 5 h and was then treated with 10% sodium carbonate solution. The precipitate was filtered by suction and the product was recrystallized from isopropanol.2-(Pyrazol-1-yl)-4 0 -propionylacetanilide (1).