An Efficient Synthesis of (3S,5S)-5-[3,3-Dimethyl-1-(o-tolyl)-6-oxo-2H-pyridin-4-yl]piperidine-3-carboxamide as Potent Renin Inhibitor

Abstract

We report synthesis and biological evaluation of (3S,5S)-5-[3,3dimethyl-1-(o-tolyl)-6-oxo-2H-pyridin-4-yl]piperidine-3-carboxamide as renin inhibitor. This effective synthetic route involves a zinc mediated Barbier reaction and an intramolecular Horner-Wadsworth-Emmons reaction of sterically hindered ketone as key reactions. The prepared compound 4 exhibited both potent renin inhibitory activity and significant in vivo efficacy in furosemide pretreated cynomolgus monkeys.

Novel Allosteric Ligands of γ-Aminobutyric Acid Transporter 1 (GAT1) by MS Based Screening of Pseudostatic Hydrazone Libraries

“…The hydrolysis of the enol ether group was accomplished by a modified protocol for an analogous reaction from literature using 2 M HCl (instead of 4 and 6 M) and a higher proportion of the solvent THF (6:1 instead of 1:1 of THF/acid). That way the undesired additional hydrolysis of the ester function could be reduced and diastereomeric aldehydes rac - 20 and rac - 21 could be obtained in a yield of 78% as a 1:1 mixture, the separation of which appeared to be laborious due to their nearly identical chromatographic retention.…”

“…This, however, did not lead to the desired Boc-protected hydrazine derivatives. As an alternative, the introduction of the required hydrazine function should be accomplished by a Mitsunobu reaction following a protocol of Brosse et al − Alcohols rac - 27 and rac - 28 required for this purpose were prepared by reduction of aldehydes rac - 20 and rac - 21 (in 1:1 mixture) with sodium borohydride ( rac - 27 and rac - 28 ; 1:1 mixture; 76%). The thus obtained 1:1 mixture of rac - 27 and rac - 28 (yield 76%) was treated with hydrazine derivative 29 , triphenylphosphine, and diisopropyl azodicarboxylate (DIAD) in a Mitsunobu reaction.…”

“…1 H NMR (500 MHz, DMSO-d 6 /D 2 O = 9:1, 25 °C): δ 1.09 (q, J = 12. 5 44 and rac-(3R,5R)-[1-(tert-Butyl) 3-Methyl 5-Formylpiperidine-1,3-dicarboxylate] (rac-21). 26 (1:1 E-/Z-mixture, 424 mg, 1.49 mmol) was dissolved in THF (15 mL).…”