(R)-tert-butyl (5-(4-aminophenyl)pent-4-yn-1-yl)(2-((tert-butyldimethylsilyl)oxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)carbamate → (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl(5-(4-(2-((1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methylamino)-3,4-dioxocyclobut-1-enylamino)phenyl)pent-4-ynyl)carbamate

Participants

Reaction Conditions

Reaction Steps

A mixture of Intermediate 38 (0.11 g, 0.19 mmol) and Intermediate 28 (0.15 g, 0.36 mmol) in ethanol (2 mL) was heated for 3 days in a 70° C. oil bath. The mixture was concentrated under reduced pressure and was then purified by automated flash silica gel chromatography, using a 12 g Silicycle SiliSep flash column (dichloromethane/methanol) to give the impure intermediate, (R)-tert-butyl 2-(tert-butyldimethylsilyloxy)-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl(5-(4-(2-((1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methylamino)-3,4-dioxocyclobut-1-enylamino)phenyl)pent-4-ynyl)carbamate. This material was then subjected to reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1 TFA) to provide, after concentration, the intermediate (R)-tert-butyl 5-(4-(2-((1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl)methylamino)-3,4-dioxocyclobut-1-enylamino)phenyl)pent-4-ynyl(2-hydroxy-2-(8-hydroxy-2-oxo-1,2-dihydroquinolin-5-yl)ethyl)carbamate. This intermediate was dissolved in methanol (5 mL) and treated with palladium on carbon (10% w/w, wet Degussa-type, catalytic amount). The suspension was stirred under a balloon of hydrogen gas until LC/MS analysis indicated the complete reduction of the triple bond. The mixture was then filtered through a pad of Celite diatomaceous earth, and the filtrate was concentrated to dryness under reduced pressure. The residue was taken up in dichloromethane/methanol (1:1, 5 mL) and treated with a solution of hydrogen chloride in dioxane (4 N, 2 mL). Once LC/MS analysis showed the complete removal of the Boc-protecting group, the mixture was concentrated to dryness. The residue was purified by reverse-phase high performance liquid chromatography (RP-HPLC, acetonitrile/water/0.1% TFA) to provide, after concentration, the trifluoroacetic acid salt of the title compound as a pale yellow powder (28 mg).

Provenance & Evidence