Session: Heterocycles & Aromatics:

Heterocyclic amino acids are extensively applied as molecular scaffolds in medicinal chemistry. Conjugation of such pharmacologically active substances with functionalized (het)aromatic rings can lead to novel drug candidates such as peptide-based analogs. Notable examples include nipecotic and isonipecotic acids which are closely related to γ-aminobutyric acid (GABA) receptors and act as a GABA uptake inhibitor or as a GABA receptor partial agonist, respectively. Derivatives of these amino acids are also significant building blocks for the synthesis of more complex biological active molecules such as peptides.

Thus, an efficient protocol for the regio-controlled synthesis of novel 3- or 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylate derivatives from N-Boc protected pipecolic, nipecotic and isonipecotic acids (1) was developed (Scheme 1). By following path 1, methyl 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates (2) were obtained as the main products from N-Boc protected piperidine carboxylic acids 1 and various substituted hydrazines. However, by following path 2, N-Boc protected piperidine carboxylic acids 1 were first treated with hydrazine hydrate and obtained tautomeric pyrazole 4 was further N-alkylated with various alkylhalides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates (3) as major products. Regioisomeric ratio was determined by NMR analysis.

In the case of chiral substrates, (N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were obtained with high enantioselectivity. Enantiomeric purity of the synthesized compounds was confirmed by chiral HPLC analysis.

<b>Scheme 1.</b> Synthesis of 3(5)-(<i>N</i>-Boc-piperidinyl)-1<i>H</i>-pyrazole-4-carboxylate derivatives

Scheme 1. Synthesis of 3(5)-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylate derivatives

Algirdas Sackus

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