2-Amino-6-fluorobenzoic acid → Benzoic acid, 2-[[2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-

A slurry of 2,4-dichloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidine (50 g, 146 mmol) and 2-amino-6-fluorobenzoic acid (27.2 g, 175 mmol) (for instance from Acros Organics, Belgium) in iPrOH (1200 mL) and 30 mL of DIEA was heated to reflux. After 1 h, the solution turned a clear brown color, at which time about 450 mL of solvent were removed via distillation. The remaining mixture was treated with DIEA (90 mL) and heated to reflux for 16 hours. The reaction mixture was then further concentrated by distilling more solvent off (400 mL over 4 hours), then continued heating at reflux overnight. The resulting mixture was cooled to room temperature and concentrated under reduced pressure to obtain a thick oil which was diluted with EtOAc (1.3 L), then sequentially washed with a 1N HCl solution (2×500 mL), and a saturated NaHCO3 solution (500 mL). Further dilution of the separated organic layer with a saturated NaCl solution (500 mL) led to the formation of a thick precipitate. The entire mixture was filtered and the solid was washed with Et2O. The solid was dried overnight in a vacuum oven at 60° C. to obtain 2-({2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluorobenzoic acid as a yellow solid (61.63 g, 92%). 1H NMR (400 MHz, DMSO-d5) δ ppm 2.37 (s, 3H), 6.67 (d, J=3.85 Hz, 1H), 6.71-6.81 (m, 1H), 7.31 (td, J=8.33, 6.04 Hz, 1H), 7.48 (d, J=8.24 Hz, 2H), 7.74 (d, J=4.03 Hz, 1H), 7.98 (d, J=8.42 Hz, 2H), 8.36 (d, J=8.24 Hz, 1H); ESIMS (M+H)+=461.06.

1. customat which time about 450 mL of solvent were removed via distillation
2. additionThe remaining mixture was treated with DIEA (90 mL)
3. temperatureheated
4. temperatureto reflux for 16 hours
5. concentrationThe reaction mixture was then further concentrated
6. distillationby distilling more solvent off (400 mL over 4 hours)
7. temperaturecontinued heating
8. temperatureat reflux overnight
9. concentrationconcentrated under reduced pressure
10. customto obtain a thick oil which
11. washsequentially washed with a 1N HCl solution (2×500 mL)
12. filtrationThe entire mixture was filtered
13. washthe solid was washed with Et2O
14. customThe solid was dried overnight in a vacuum oven at 60° C.

ORDレコード

ord-5dda5cbe90f04ed0b7c5846dd20a0e37

出典データセット

uspto-grants-2011_07

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US07981903B2