Sodium Carbonate → (R)-5-amino-N-(5-(4-aminoazepan-1-yl)-1-methyl-1H-pyrazol-4-yl)-2-(2,5-dichlorophenyl)thiazole-4-carboxamide

온도

130 °C

A mixture of (R)-tert-butyl 2-bromo-4-(1-methyl-5-(4-(2,2,2-trifluoroacetamido)-azepan-1-yl)-1H-pyrazol-4-ylcarbamoyl)thiazol-5-ylcarbamate (122 mg, 0.20 mmol), Na2CO3 (42 mg, 0.40 mmol) and 2,5-dichlorobenzeneboronic acid (38 mg, 0.20 mmol) in DME (1.5 mL) and water (0.5 mL) was degassed by gently bubbling nitrogen through the mixture for 15 min. [1,1′-Bis(diphenylphosphino)ferrocene]dichloro-palladium(II) (16 mg, 0.020 mmol) was added and the mixture degassed for a further 10 min before being heated in a microwave at 130° C. for 35 min. Water was added and the mixture extracted with EtOAc. The combined organic layers were passed through a phase separation cartridge and concentrated under reduced pressure. The residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane). The isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL) and stirred at room temperature for 6 hr. The solvents were removed under reduced pressure and the residue dissolved in a mixture of MeOH/water (3 mL, 1:1) and K2CO3 (55 mg, 0.40 mmol) added. The mixture was heated at 60° C. for 3 hr. The mixture was concentrated under reduced pressure and the residue purified by preparative HPLC to yield 350 as a yellow solid (12 mg, 29%). 1H NMR (400 MHz, d4-MeOD) δ 8.35 (d, J=2.6 Hz, 1H), 7.56 (s, 1H), 7.52 (d, J=8.6 Hz, 1H), 7.39 (dd, J=8.6, 2.6 Hz, 1H), 3.76 (s, 3H), 3.35-3.31 (m, 4H), 3.11-3.09 (m, 1H), 2.04-1.91 (m, 3H), 1.76-1.67 (m, 3H). LCMS (ES+) m/z 480 (M+1).

1. additionwas added
2. customthe mixture degassed for a further 10 min
3. additionWater was added
4. extractionthe mixture extracted with EtOAc
5. customThe combined organic layers were passed through a phase separation cartridge
6. concentrationconcentrated under reduced pressure
7. customThe residue was purified via silica gel column chromatography (0-100% EtOAc/isohexane)
8. dissolutionThe isolated intermediate was dissolved in a mixture of DCM (1.5 mL) and TFA (0.5 mL)
9. customThe solvents were removed under reduced pressure
10. additionadded
11. temperatureThe mixture was heated at 60° C. for 3 hr
12. concentrationThe mixture was concentrated under reduced pressure
13. customthe residue purified by preparative HPLC

ORD 기록

ord-2f95e7fb08454d628491e2e505c3ad44

출처 데이터셋

uspto-grants-2014_03

DOI

10.6084/m9.figshare.5104873.v1

특허 번호

US08669361B2