Cyclopropylamine → Benzyl[2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate

Participants

Reaction Conditions

Reaction Steps

Alternatively, the subtitle compound may be accessed through a telescoped procedure from methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate (Preparation 1g) avoiding the need to isolate methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoate (Preparation 4d), as follows: To a stirred solution of methyl 3-(3,5-dibromo-2-oxo-1(2H)-pyrazinyl)-5-fluoro-4-methylbenzoate (Preparation 1g, 18.7 g, 44.4 mmol) and benzyl [2-[2-(1-aminocyclopropyl)phenoxy]ethyl]methylcarbamate trifluoroacetic acid salt (Preparation 4b, 20.0 g, 44.0 mmol) in toluene (200 mL) under an inert atmosphere was added N,N-diisopropylethylamine (26.9 mL, 154.0 mmol). The reaction mixture was heated to 105° C. (jacket temperature) for 2 h and then cooled slowly to ambient temperature. The resulting orange slurry was quenched with water (200 mL) and the phases separated. The organic phase was washed with aq. sodium bisulfate solution (1 M, 3×200 mL) and brine (200 mL) and then concentrated in vacuo. The residue was purified by dry flash chromatography, gradient eluting with ethyl acetate/toluene. A portion of this solution containing methyl 3-[3-[1-[2-[2-[(benzyloxycarbonyl)methylamino]ethoxy]phenyl]cyclopropylamino]-5-bromo-2-oxo-1(2H)-pyrazinyl]-5-fluoro-4-methylbenzoate (2.0 g, 2.8 mmol) was dried by azeotropic distillation with toluene. The residual toluene solution (˜18 mL) was cooled to 35° C. (jacket temperature) and cyclopropylamine (588 μL, 8.3 mmol) and sodium methoxide (30% w/w, 1.3 mL, 6.9 mmol) were added. The reaction mixture was stirred at 35° C. for 3 h and then quenched with aq. triethylamine (10% v/v, 5 mL). The phases were separated and the organic phase washed with aq. triethylamine (10% v/v, 2×5 mL). The solution was concentrated to dryness in vacuo to afford a yellow foam that was purified by Biotage chromatography, eluting with an ethyl acetate/isohexane gradient, and then crystallised from toluene/isohexane to afford benzyl [2-[2-[1-[[6-bromo-4-[5-(cyclopropylcarbamoyl)-3-fluoro-2-methylphenyl]-3-oxo-3,4-dihydro-2-pyrazinyl]amino]cyclopropyl]phenoxy]ethyl]methylcarbamate (1.06 g, 93.5% w/w) as a colourless solid.

Provenance & Evidence