Triethylamine → 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-3-carboxylic acid

HRID 227676Notes

Reaction equation

HRID 227676 reaction equation
Cl.[C:2]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([NH2:19])=[CH:15][CH:14]=1)(=[O:4])[NH2:3].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33].C(N(CC)CC)C>O1CCCC1.CCCCC>[C:2]([C:5]1[NH:9][CH:8]=[C:7]([C:10]([OH:12])=[O:11])[C:6]=1[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:32]([NH:31][C:22]2[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=2[F:20])=[O:33])=[CH:15][CH:14]=1)(=[O:4])[NH2:3]

Participants

6

Reactant 3

HCID 8471TriethylamineHCID 27333802-Fluoro-5-(trifluoromethyl)phenyl isocyanateHCID 69056464HCID 69056464, compound

Product 1

HCID 577568685-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-3-carboxylic acidYield 46.9%

Reagents, catalysts & solvents 2

HCID 8003PentaneSolventHCID 8028TetrahydrofuranSolvent

Conditions

Temperature
20 °C

Procedure

To 0.14 g (0.497 mmol) of 5-carbamoyl-4-(4-aminophenyl)-1H-pyrrole-3-carboxylic acid hydrochloride dissolved in 18 cm3 of tetrahydrofuran are added, at a temperature in the region of 20° C. under an argon atmosphere, 0.072 cm3 (0.497 mmol) of 2-fluoro-5-trifluoromethylphenyl isocyanate and 0.07 cm3 (0.497 mmol) of triethylamine. After stirring for 5 hours at a temperature in the region of 20° C., the reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa) to give a residue, which is purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (gradient of from 90/5/5 to 80/10/10 by volume)]. After concentrating the fractions under reduced pressure, a solid is obtained, which is then stirred in 5 cm3 of pentane for 3 hours. After filtering through a No. 3 sinter funnel, the solid is washed with twice 1 cm3 of pentane and then dried under reduced pressure (2.7 kPa) at a temperature in the region of 30° C. for 15 hours to give 0.105 g of 5-carbamoyl-4-{4-[3-(2-fluoro-5-trifluoromethylphenyl)ureido]-phenyl}-1H-pyrrole-3-carboxylic acid in the form of a yellow solid melting at 194° C.; 1H NMR (400 MHz, DMSO d6, δ in ppm): 5.37 (broad m, 1H); 7.23 (d, J=8.5 Hz, 2H); 7.23 (masked m, 1H); 7.39 (m, 1H); 7.42 (d, J=3.0 Hz, 1H); 7.49 (d, J=8.5 Hz, 2H); 7.50 (partially masked m, 1H); 8.64 (dd, J=2.5 and 7.5 Hz, 1H); 8.97 (d, J=2.0 Hz, 1H); 9.35 (s, 1H); 11.6 (broad m, 1H); 12.05 (broad s, 1H); ES+: m/z=451: [M+H]+; ES−: m/z=449: [M−H]−.

Workup

  1. additionare added, at a temperature in the region of 20° C. under an argon atmosphere
  2. concentrationthe reaction mixture is concentrated to dryness under reduced pressure (2.7 kPa)
  3. customto give a residue, which
  4. customis purified by flash chromatography [eluent: dichloromethane/methanol/acetonitrile (gradient of from 90/5/5 to 80/10/10 by volume)]
  5. concentrationAfter concentrating the fractions under reduced pressure
  6. customa solid is obtained
  7. filtrationAfter filtering through a No
  8. wash3 sinter funnel, the solid is washed with twice 1 cm3 of pentane
  9. customdried under reduced pressure (2.7 kPa) at a temperature in the region of 30° C. for 15 hours

Sources & evidence

ORD record
ord-902a678bbe4743b0a89edc81ce8699ad
Source dataset
uspto-grants-2009_07
Patent number
US07560571B2

Reaction notes

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