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Synthesis 2011(17): 2822-2832  
DOI: 10.1055/s-0030-1261034
PAPER
© Georg Thieme Verlag Stuttgart ˙ New York

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

Peter Perdiha, Jernej Baškovča, Georg Dahmannb, Uroš Grošelja, Drago Kočara, Ana Novaka, Branko Stanovnika, Jurij Svete*a
a Faculty of Chemistry and Chemical Technology, University of Ljubljana, Aškerčeva 5, P.O. Box 537, 1000 Ljubljana, Slovenia
Fax: +386(1)2419220; e-Mail: Jurij.svete@fkkt.uni-lj.si;
b Boehringer Ingelheim Pharma GmbH & Co. KG, Medicinal Chemistry, 88397 Biberach, Germany
Further Information

Publication History

Received 5 May 2011
Publication Date:
08 August 2011 (online)

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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.