Synthesis of 4,5-Diaryl-1H-pyrazole-3-ol Derivatives as Potential COX-2 Inhibitors

4,5-Diaryl-1H-pyrazole-3-ol was utilized as a versatile template to synthesize several classes of
compounds such as pyrazolo-oxazines 7, pyrazolo-benzooxazines 9, pyrazolo-oxazoles 10, and its
analogues 11a−c as potential COX-2 inhibitors. Compounds 11b,c were successfully synthesized
with use of pyridinium p-toluenesulfonate mediated cyclization of the ketal intermediate. Diaryl-pyrazolo-benzooxazepine analogues were synthesized by using Cu-mediated cyclization of the
O-alkylated arylbromide intermediate. Arylsulfonamides were synthesized efficiently on a large
scale with 4-[4-(4-fluorophenyl)-5-hydroxy-2H-pyrazol-3-yl]benzenesulfonamide 31 template readily
synthesized from commercially available 4-sulfamoyl benzoic acid 29. The structure of a representative compound from each class was confirmed by X-ray crystallography. Selected compounds tested
for inhibitory activity against COX-1 and COX-2 enzymes showed good selectivity for COX-2 versus
COX-1 enzyme.

4,5-二芳基-1H-吡唑-3-醇被用作一种多功能的模板，用以合成多种类别的化合物，如7号吡唑恶嗪、9号吡唑苯并恶嗪、10号吡唑恶唑及其类似物11a-c，这些化合物作为潜在的COX-2抑制剂。通过使用吡啶盐酸盐介导的缩合反应，成功合成了11b,c号化合物。通过使用Cu催化的环化反应，合成了二芳基-吡唑苯并恶嗪类似物。通过以从市售的4-磺酰基苯甲酸29合成的4-[4-(4-氟苯基)-5-羟基-2H-吡唑-3-基]苯磺酰胺31为模板，高效地大规模合成了芳基硫酰胺。通过X射线晶体学确定了每种类别代表性化合物的结构。在针对COX-1和COX-2酶的抑制活性测试中，所选化合物对COX-2酶的抑制效果优于COX-1酶，显示出良好的选择性。