Trifluoroacetic acid → 6-(3-Hydroxyazetidin-1-yl)-5-(1H-pyrazol-5-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide

온도

110 °C

1-(Tetrahydro-2H-pyran-2-yl)-1H-pyrazole-5-boronic acid pinacol ester (209 mg, 0.752 mmol), K3PO4 (368 mg, 1.735 mmol) and Pd(PPh3)4 (33.4 mg, 0.029 mmol) were added to a mixture of 5-bromo-6-(3-hydroxyazetidin-1-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 37.1, 250 mg, 0.578 mmol) in toluene (2.5 mL) in a vial, which was sealed, purged with argon and the RM was stirred at 110° C. for 3 h. The cooled mixture was treated with brine (25 mL) and extracted with EtOAc. The combined extracts were washed with brine (25 mL), dried over Na2SO4 and the solvent was evaporated off under reduced pressure. The residue (100 mg, 0.199 mmol) was dissolved in DCM (0.5 mL), treated with TFA (0.3 mL, 3.89 mmol) and stirred at RT for 8 h. Aq. Na2CO3 (0.5 mL) was added and the solvent was evaporated off under reduced pressure to give a crude product which was purified by SFC (Column NH2, from 21% to 26% over 6 min) and lyophilized in water/MeCN to give the title product. UPLC-MS (Condition 3) tR=0.86 min, m/z=420.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 3.53-3.59 (m, 2H) 3.91-4.00 (m, 2H) 4.35-4.42 (m, 1H) 6.43 (d, J=1.88 Hz, 1H) 7.35 (d, J=8.66 Hz, 2H) 7.79 (br. s, 1H) 7.86 (d, J=9.03 Hz, 2H) 8.09 (d, J=2.07 Hz, 1H) 8.71 (d, J=2.07 Hz, 1H) 10.26 (s, 1H).

1. customwas sealed
2. custompurged with argon
3. additionThe cooled mixture was treated with brine (25 mL)
4. extractionextracted with EtOAc
5. washThe combined extracts were washed with brine (25 mL)
6. dry with materialdried over Na2SO4
7. customthe solvent was evaporated off under reduced pressure
8. stirringstirred at RT for 8 h
9. customthe solvent was evaporated off under reduced pressure
10. customto give a crude product which
11. customwas purified by SFC (Column NH2, from 21% to 26% over 6 min)

ORD 기록

ord-9f192665862f484c845add79a9d5068e

출처 데이터셋

uspto-grants-2016_05

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US09340537B2