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

Abstract

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.

Key words

pyrrolidinone - pyrazole - cyclocondensations - amidations - histamine analogues

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16

The filtrates were always transferred back to the reaction tubes and evaporated together with the remainder of the reaction mixtures. However, subsequent triturations with other solvents did not produce another portion of the corresponding product.