Triethylamine → 1-((2-Fluoro-4-(2-(1-methyl-1h-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid

HRID 2060725Notes

Reaction equation

HRID 2060725 reaction equation
S(Cl)(Cl)=O.[C:5]1([C:11]([OH:13])=O)([C:8]([OH:10])=[O:9])[CH2:7][CH2:6]1.CCN(CC)CC.[F:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH2:41]>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([O:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([C:35]3[CH:36]=[N:37][N:38]([CH3:40])[CH:39]=3)[CH:30]=2)[CH:25]=[CH:24][C:23]=1[NH:41][C:11]([C:5]1([C:8]([OH:10])=[O:9])[CH2:6][CH2:7]1)=[O:13]

Participants

6

Reactant 4

HCID 8471TriethylamineHCID 24386Thionyl ChlorideHCID 690171,1-Cyclopropanedicarboxylic acidHCID 594583192-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)benzenamine

Product 1

HCID 593227731-((2-Fluoro-4-(2-(1-methyl-1h-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acidYield 23.8%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
0 °C

Procedure

Thionyl chloride (1.09 mL, 15.0 mmol) was added slowly over 2 min to a stirring solution of 1,1-cyclopropanedicarboxylic acid (1.95 g, 15.0 mmol) and Et3N (4.29 g, 42.4 mmol) in THF (15 mL) at 0° C. After complete addition, the reaction was further diluted with THF (25 mL) and the reaction was stirred vigorously at 0° C. for 30 min. The hydrochloride salt of Example A1 (4.00 g, 12.5 mmol) was added in three portions and the resulting mixture was allowed to slowly warm to RT over 4 h. The reaction mixture was concentrated to dryness in vacuo and the residue was digested with aqueous MeOH. The remaining solids were collected by filtration. This solid was dissolved in 1 M aq NaOH (30 mL) and methanol. The methanol was removed in vacuo, the remaining aqueous phase was diluted with water to a volume of 150 mL and extracted with EtOAc (3×50 mL). The combined EtOAc extracts were washed with sat aq NaHCO3. The combined aqueous was acidified to pH 6 with 0.5 M HCl. The resultant fine precipitate was collected by filtration, washed with acetonitrile (20 mL) and dried in vacuo to provide 1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid (1.177 g). The remaining aqueous was concentrated in vacuo to about ⅓ volume and the pH was reduced to pH 5 with 1 M aq HCl. The additional precipitate that formed was collected by filtration, washed with acetonitrile and dried in vacuo to provide an additional crop (1.34 g) of 1-((2-fluoro-4-(2-(1-methyl-1H-pyrazol-4-yl)pyridin-4-yloxy)phenyl)carbamoyl)cyclopropanecarboxylic acid (2.517 g total, 51% yield). 1H NMR (400 MHz, DMSO-d6): δ 13.51 (br s, 1H), 11.30 (s, 1H), 8.37 (d, J=5.7 Hz, 1H), 8.25 (s, 1H), 8.19 (t, J=9.0 Hz, 1H), 7.95 (s, 1H), 7.28 (dd, J=11.6, 2.7 Hz, 1H), 7.22 (d, J=1.6 Hz, 1H), 7.01 (m, 1H), 6.69 (dd, J=5.6, 2.3 Hz, 1H), 3.84 (s, 3H), 1.58-1.51 (m, 4H); MS (ESI) m/z: 397.1 (M+H+).

Workup

  1. additionAfter complete addition
  2. temperatureto slowly warm to RT over 4 h
  3. concentrationThe reaction mixture was concentrated to dryness in vacuo
  4. filtrationThe remaining solids were collected by filtration
  5. dissolutionThis solid was dissolved in 1 M aq NaOH (30 mL)
  6. customThe methanol was removed in vacuo
  7. additionthe remaining aqueous phase was diluted with water to a volume of 150 mL
  8. extractionextracted with EtOAc (3×50 mL)
  9. washThe combined EtOAc extracts were washed with sat aq NaHCO3
  10. filtrationThe resultant fine precipitate was collected by filtration
  11. washwashed with acetonitrile (20 mL)
  12. customdried in vacuo

Sources & evidence

ORD record
ord-4af00cc4223545f28514f4977f2dc452
Source dataset
uspto-grants-2012_10
Patent number
US08278331B2

Reaction notes

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