Parallel Synthesis of 1-Substituted 5-(5-Oxopyrrolidin-3-yl)-1H-pyrazole-4- carboxamides.

A parallel solution-phase synthesis of 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-carboxamide derivatives as conformationally constrained pyrazole analogues of histamine starting from itaconic acid was developed. The synthetic method comprises a five-step preparation of 1-substituted 5-(5-oxo-1-phenylpyrrolidin-3-yl)-1H-pyrazole-4-carboxylic acids followed by parallel amidation with various primary and secondary amines to give a library of 24 histamine analogues in good overall yields and in very high purities. The method is general and substrate-independent. All the amidations proceed smoothly and no major difference in reactivity is observed with respect to the structures of the reactants. [ABSTRACT FROM AUTHOR]