Boron tribromide → (R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,4-difluorophenyl)thiazole-4-carboxamide

To a stirred mixture of [(R)-1-(4-{[5-tert-butoxycarbonylamino-2-(2,4-difluoro-phenyl)-thiazole-4-carbonyl]-amino}-2-methyl-2H-pyrazol-3-yl)-perhydro-azepin-4-yl]-carbamic acid benzyl ester (46.0 mg, 0.067 mmol) in anhydrous DCM (4.0 mL) at −10° C. under N2 was added dropwise 1.0 M boron tribromide in DCM (0.22 mL, 0.22 mmol, 3.3 eq.). The reaction mixture was stirred at ambient temperature for 4 h and then cooled to −20° C. Additional 1.0 M Boron tribromide in DCM (0.11 mL, 0.11 mmol, 1.65 eq.) was added dropwise, and the reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was quenched with saturated aq. NaHCO3 solution and then extracted with ethyl acetate (3×50 mL). The combined organic phases were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified via reverse phase HPLC to afford 200 (12.7 mg, 42.1%) as a white solid. 1H NMR (400 MHz, DMSO) δ 8.93 (s, 1H), 8.39 (s, 1H), 8.33 (dd, J=15.5, 8.8 Hz, 1H), 7.47-7.36 (m, 4H), 7.29 (dd, J=11.6, 5.3 Hz, 1H), 3.66 (s, 3H), 3.26-3.14 (m, 3H), 3.14-3.05 (m, 3H), 2.03-1.89 (m, 2H), 1.88-1.77 (m, 1H), 1.76-1.56 (m, 3H); MS (ESI) m/z: 448.1 [M+H]+

1. temperaturecooled to −20° C
2. stirringthe reaction mixture was stirred at ambient temperature for 16 h
3. customThe reaction mixture was quenched with saturated aq. NaHCO3 solution
4. extractionextracted with ethyl acetate (3×50 mL)
5. washThe combined organic phases were washed with brine
6. dry with materialdried over Na2SO4
7. filtrationfiltered
8. concentrationconcentrated under reduced pressure
9. customThe crude was purified via reverse phase HPLC

ORD-Eintrag

ord-88c75c881641496e9227f9e4124704b3

Quelldatensatz

uspto-grants-2013_05

DOI

10.6084/m9.figshare.5104873.v1

Patentnummer

US08436001B2