ChemInform Abstract: Catalytic Enantioselective Hydrogenation of N‐Alkoxycarbonyl Hydrazones: A Practical Synthesis of Chiral Hydrazines.

Yoshikawa, Naoki; Tan, Lushi; McWilliams, J. Christopher; Ramasamy, Deepa; Sheppard, Ruth L.

doi:10.1002/chin.201022062

Cited by 2 publications

(3 citation statements)

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“…The stereochemistry was established by converting 5 (R = Me) to its benzoylhydrazide and comparing to the compound of known stereochemistry . For large-scale preparation of hydrazine 5 (R = Me), an asymmetric synthesis was developed based on enantioselective hydrogenation of N -alkoxycarbonyl hydrazones . The boronic acids used in Schemes and were either commercially available or synthesized as described in detail in the Experimental Section.…”

Section: Synthesismentioning

confidence: 99%

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Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

et al. 2012

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A potent, selective glucagon receptor antagonist 9m, N-[(4-{(1S)-1-[3-(3,5-dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine, was discovered by optimization of a previously identified lead. Compound 9m is a reversible and competitive antagonist with high binding affinity (IC(50) of 6.6 nM) and functional cAMP activity (IC(50) of 15.7 nM). It is selective for glucagon receptor relative to other family B GPCRs, showing IC(50) values of 1020 nM for GIPR, 9200 nM for PAC1, and >10000 nM for GLP-1R, VPAC1, and VPAC2. Compound 9m blunted glucagon-induced glucose elevation in hGCGR mice and rhesus monkeys. It also lowered ambient glucose levels in both acute and chronic mouse models: in hGCGR ob/ob mice it reduced glucose (AUC 0-6 h) by 32% and 39% at 3 and 10 mpk single doses, respectively. In hGCGR mice on a high fat diet, compound 9m at 3, and 10 mpk po in feed lowered blood glucose levels by 89% and 94% at day 10, respectively, relative to the difference between the vehicle control and lean hGCGR mice. On the basis of its favorable biological and DMPK properties, compound 9m (MK-0893) was selected for further preclinical and clinical evaluations.

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Section: Synthesismentioning

confidence: 99%

“…29 For large-scale preparation of hydrazine 5 (R = Me), an asymmetric synthesis was developed based on enantioselective hydrogenation of N-alkoxycarbonyl hydrazones. 30 The boronic acids used in Schemes 1 and 2 were either commercially available or synthesized as described in detail in the Experimental Section.…”

Section: ■ Synthesismentioning

confidence: 99%

Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

et al. 2012

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“…The use of Rh complexes in the AH of hydrazones had been described early this decade, but with lower ee values. 207,208 The use of chiral Ir complexes in the AH of hydrazones was described by X. Zhang, using f-binaphane as the chiral ligand. Of note, they reported a direct catalytic asymmetric reductive amination of simple aromatic ketones with phenylhydrazide, thus offering an attractive route for the synthesis of chiral hydrazine-derived compounds.…”

Section: N-heteroatom-substituted Iminesmentioning

confidence: 99%

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

2021

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Chiral amines are key structural motifs present in a wide variety of natural products, drugs, and other biologically active compounds. During the past decade, significant advances have been made with respect to the enantioselective synthesis of chiral amines, many of them based on catalytic asymmetric hydrogenation (AH). The present review covers the use of AH in the synthesis of chiral amines bearing a stereogenic center either in the α, β, or γ position with respect to the nitrogen atom, reported from 2010 to 2020. Therefore, we provide an overview of the recent advances in the AH of imines, enamides, enamines, allyl amines, and N-heteroaromatic compounds.

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ChemInform Abstract: Catalytic Enantioselective Hydrogenation of N‐Alkoxycarbonyl Hydrazones: A Practical Synthesis of Chiral Hydrazines.

Cited by 2 publications

References 1 publication

Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

Discovery of a Novel Glucagon Receptor Antagonist N-[(4-{(1S)-1-[3-(3, 5-Dichlorophenyl)-5-(6-methoxynaphthalen-2-yl)-1H-pyrazol-1-yl]ethyl}phenyl)carbonyl]-β-alanine (MK-0893) for the Treatment of Type II Diabetes

Recent Advances in the Enantioselective Synthesis of Chiral Amines via Transition Metal-Catalyzed Asymmetric Hydrogenation

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