Efficient synthesis of D₆‐clenproperol and D₆‐cimaterol using deuterium isopropylamine as labelled precursor

Abstract

This report presents an efficient synthesis of D -clenproperol and D -cimaterol with 99.5% and 99.7% isotopic abundance in acceptable yields and excellent chemical purities with deuterium isopropylamine as labelled precursor. Their structures and the isotope-abundance were confirmed by proton nuclear magnetic resonance and liquid chromatography-mass spectrometry.

Tetrahydroindoles as Multipurpose Screening Compounds and Novel Sirtuin Inhibitors

“…In the next step, the bromine atom had to be replaced by an amino group in a substitution reaction. Due to steric effects, it was not possible to substitute the bromine atom with nitrogen, neither with azide (Staudinger reaction), phthalimide (Gabriel synthesis) nor methenamine (Delépine reaction). With respect to the published palladium‐catalyzed indole synthesis of β‐amino alcohols reacting with 1,3‐diketones, we planned the alternative route as reduction and subsequent primary amine synthesis of the ester 5 to compound 7 .…”

“…In the next step, the bromine atom had to be replaced by an amino group in asubstitution reaction. Due to steric effects, it was not possible to substitute the bromine atom with nitrogen, neither with azide (Staudinger reaction [9] ), phthalimide (Gabriel synthesis [10] )n or methenamine (DelØpine reaction [11] ). With respectt ot he published palladium-catalyzed indole synthesis [12] of b-amino alcohols reactingw ith 1,3-diketones, we planned the alternative route as reduction and subsequentp rimary amine synthesis of the ester 5 to compound 7.A gain, we did not succeed in formingt he desired reduction product 6,a s neither sodium borohydride [13] nor palladium/hydrogen gas for catalytic reduction were effective in reducing the ketone substructure of 5.T herefore, we envisioned the formationo fi ntermediate 11 and subsequently furan derivative 12 via aF eist-Benary reaction.…”

“…The indole derivative selisistat (2a)e xhibits the most potent SIRT1 inhibition (IC 50 = 98 nm) [8] by far,b oth in vitro and in vivo. [9][10][11] Structure-activity relationship studies revealed that expansion of the partially hydrogenated six-membered ring system of 2a to the homologous derivative 2b is feasible. [8] In fact, selisistat has already passed phaseIIc linical trials for the treatment of Huntington'sdisease.…”