A practical asymmetric synthesis of ortho-substituted 4-pyrazolyl-2-ethylamines |
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Authors: | Donogh JR OMahony Russell J Johnson M Angels Estiarte William T Edwards Matthew AJ Duncton |
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Institution: | Renovis, Inc. (a wholly-owned subsidiary of Evotec SE), Two Corporate Drive, South San Francisco, CA 94080, United States |
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Abstract: | A reliable three-step synthesis of ortho-substituted 4-pyrazolyl-2-ethylamines starting from a pyrazole methyl ketone and N-tert-butanesulfinylamine is described. Strongly dehydrating conditions were required to form the N-tert-butanesulfinyl ketimines, but these intermediates were stable to aqueous work-up and chromatography. Reduction of N-tert-butanesulfinyl ketimines with L-selectride®, or Super-hydride®, in THF afforded excellent yields and diastereoselectivities of the sulfinamides, which were converted into chiral amines with methanolic HCl. The 4-pyrazolyl-2-ethylamines from these investigations are attractive building blocks for medicinal chemists, as they exhibit low molecular weight, and low calculated octanol-water partition coefficient (c Log P values), while disrupting planarity with three-dimensional character. For example, the amine products were utilized in structure-activity studies of the human transient receptor potential vanilloid 1 (TRPV1/VR1). |
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Keywords: | Corresponding author 4-Pyrazolyl-2-ethylamines Asymmetric synthesis Medicinal chemistry |
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