A Practical Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate, the Key Intermediate of Rho–Kinase Inhibitor K-115

doi:10.1055/S-0032-1316771

Paper

A Practical Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate, the Key Intermediate of Rho–Kinase Inhibitor K-115

Published Aug 31, 2012 · N. Gomi, Akiyasu Kouketsu, T. Ohgiya

Synthesis

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Abstract

A practical synthesis of (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate has been established for supplying this key intermediate of Rho–kinase inhibitor K-115 in a multikilogram production. The chiral 1,4-diazepane was constructed by intramolecular Fukuyama–Mitsunobu cyclization of a N-nosyl diamino alcohol starting from the commercially available (S)- or (R)-2-aminopropan-1-ol. In the same manner, an enantiomeric pair of a structural isomer were prepared for demonstration of the synthetic utility.

Study Snapshot

This study successfully synthesized (S)-tert-butyl 3-methyl-1,4-diazepane-1-carboxylate, a key intermediate in Rho-kinase inhibitor K-115, in a multikilogram production capacity using intramolecular Fukuyama-

PopulationOlder adults (50-71 years)

Sample size24

MethodsObservational

OutcomesBody Mass Index projections

ResultsSocial networks mitigate obesity in older groups.

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Paper

A Practical Synthesis of (S)-tert-Butyl 3-Methyl-1,4-diazepane-1-carboxylate, the Key Intermediate of Rho–Kinase Inhibitor K-115

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References

Citations

Synthesis of oxidative metabolites of K-115, a novel Rho-kinase inhibitor

K-115, a novel Rho-kinase inhibitor, can be synthesized by rearrangement of isoquinoline N-oxide and/or using (S)-5-keto-2-methyl-1,4-diazepane moiety as a key structure.

Small Molecule Kinase Inhibitor Drugs (1995-2021): Medical Indication, Pharmacology, and Synthesis.

Small molecule kinase inhibitor drugs have revolutionized cancer treatment, with 73 approved by the FDA and other regulatory agencies until 2021, and a new batch approved in 2021.

Drugs for the treatment of glaucoma: Targets, structure-activity relationships and clinical research.

Drugs lowering intraocular pressure are the first-line therapy for treating glaucoma, with targets, structure-activity relationships, and clinical progress reviewed.

Ripasudil hydrochloride hydrate: targeting Rho kinase in the treatment of glaucoma

Ripasudil hydrochloride hydrate, a Rho kinase inhibitor, may be an ideal adjunctive medication for treating glaucoma due to its unique mechanism of action on trabecular meshwork and Schlemm's canal endothelial cells.

Synthetic approaches to the 2014 new drugs.

This review reviews the synthesis of 37 new drugs approved in 2014 and one drug approved in 2013, providing insights into molecular recognition and leads for future drug design.