Development and Optimisation of an Unsymmetrical Hantzsch Reaction for Plant-Scale Manufacture

Abstract

(S)-3-(5-Oxo-2-(trifluoromethyl)-1,4,5,6,7,8-hexahydroquinolin-4-yl)benzonitrile is a potassium-channel opener developed for the treatment of urinary urge incontinence. The key step in the synthesis is an unsymmetrical Hantzsch reaction to give a 2-hydroxy-1,2,3,4-tetrahydropyridine. In our study the order of addition of reagents was found to be critical in the optimisation of the yield and the control of impurity levels in this reaction. The yield and the relative charges of the reagents were further optimised by the use of factorial experimental design. The chemistry has been scaled up to plant scale to produce multikilogram amounts of the Hantzsch product in close to 60% yield.

Chemistry and Biology Of Multicomponent Reactions

“…173 The unsymmetrical Hantzsch reaction using two different β-keto-esters has been optimized for a plant-scale manufacture of the potassium-channel opener ZD0947. 174 The Hantzsch MCR is also nicely working with C-glycosylated reagents as displayed in 2,4-dihydropyridine 215 (Fig 32). 175 …”

Stimuli‐Responsive Multifunctional Phenylboronic Acid Polymers Via Multicomponent Reactions: From Synthesis to Application

“…[ 15 b, 21 ] Aldehyde and ammonia react with β‐ketoester to obtain corresponding intermediates, then these intermediates undergo intermolecular addition and elimination reactions to form 1,4‐DHPs. [ 22 ]…”

Similarity and Competition between Biginelli and Hantzsch Reactions: an Opportunity for Modern Medicinal Chemistry

“…Several past reviews provide a complete survey on the synthetic methodologies for realizing the Hantzsch reaction, as well as on the libraries of the resulting structurally different 1,4-DHPs. [40][41][42] The mechanism of the Hantzsch reaction is one of the most complex among all MCRs.…”