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-

HRID 1014445Notes

Reaction equation

HRID 1014445 reaction equation
[Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1.[NH2:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=1[C:25]([OH:27])=[O:26]>CC(O)C.CCN(C(C)C)C(C)C.CCOC(C)=O>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][C:23]2[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[C:24]=2[C:25]([OH:27])=[O:26])[C:5]2[CH:10]=[CH:9][N:8]([S:11]([C:14]3[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=3)(=[O:13])=[O:12])[C:6]=2[N:7]=1

Participants

6

Reactant 2

HCID 5211422-Amino-6-fluorobenzoic acidHCID 534868282,4-dichloro-7-tosyl-7H-pyrrolo[2,3-d]pyrimidine

Product 1

HCID 59441645Benzoic acid, 2-[[2-chloro-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl]amino]-6-fluoro-Yield 92%

Reagents, catalysts & solvents 3

HCID 3776IsopropanolSolventHCID 8857Ethyl AcetateSolventHCID 81531DiisopropylethylamineSolvent

Procedure

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.

Workup

  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.

Sources & evidence

ORD record
ord-5dda5cbe90f04ed0b7c5846dd20a0e37
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

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