Synthesis and Characterization of Novel Methyl (3)5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates.

Gita Matulevičiūtė,Greta Ragaitė,Eglė Arbačiauskienė,Neringa Kleizienė,Aurimas Bieliauskas,Frank A Sløk,Algirdas Šačkus,Vaida Milišiūnaitė,Miglė Dagilienė,Vilija Kederienė

doi:10.3390/molecules26133808

Gita Matulevičiūtė, Greta Ragaitė + Show 8 more

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https://doi.org/10.3390/molecules26133808

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Abstract

Series of methyl 3- and 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates were developed and regioselectively synthesized as novel heterocyclic amino acids in their N-Boc protected ester form for achiral and chiral building blocks. In the first stage of the synthesis, piperidine-4-carboxylic and (R)- and (S)-piperidine-3-carboxylic acids were converted to the corresponding β-keto esters, which were then treated with N,N-dimethylformamide dimethyl acetal. The subsequent reaction of β-enamine diketones with various N-mono-substituted hydrazines afforded the target 5-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates as major products, and tautomeric NH-pyrazoles prepared from hydrazine hydrate were further N-alkylated with alkyl halides to give 3-(N-Boc-piperidinyl)-1H-pyrazole-4-carboxylates. The structures of the novel heterocyclic compounds were confirmed by 1H-, 13C-, and 15N-NMR spectroscopy and HRMS investigation.

Highlights

The most common synthetic method for the production of pyrazoles is the condensation of the corresponding hydrazine derivative, which acts as a double nitrogen nucleophile, with three carbon units containing compounds such as 1,3-dicarbonyl and 2,3-unsaturated carbonyl, or enamine [45,46,47]
Our strategy for the synthesis of methyl 3(5)-(N-Boc-piperidinyl)-1H-pyrazole-4carboxylates according to the enamine method is described in Schemes 1 and 2, and Figure 2
Further investigation of the reaction of β-enamino diketones with various aryl and alkyl hydrazines in various solvents at room temperature proved the regioselective formation of 5-(N-Bocpiperidinyl)-1H-pyrazole-4-carboxylates in ethanol compared to polar aprotic or nonprotic solvents

Summary

Introduction

(RS)-piperidine-3-carboxylic acid (DL-nipecotic acid) is one of the most potent inhibitors of neuronal and glial γ-aminobutyric acid (GABA) uptake in vitro [6]. Heterocyclic amino acids are important scaffolds and building blocks for the preparation of heterocyclic systems, hybrids, and peptides [8,9,10,11]. D-Nipecotic acid, a building block for (R)-1-[4,4-bis-(3methyl-2-thienyl)-3-butenyl]-3-piperidine carboxylic acid, named (R)-tiagabine, which amplifies neurotransmission of GABA, the predominant inhibitory neurotransmitter in the brain [21,22,23]. New derivatives of nipecotic acid, guvacin, and homo-β-proline are very potent and selective analogs of GABA uptake inhibitors [24,25,26]

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