Sodium Hydroxide → 3-(2-Fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethoxy)-amide

HRID 2264968Notes

Reaction equation

HRID 2264968 reaction equation
C(O[C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[F:24])=[O:5])C.[OH-].[Na+].[NH2:27][O:28][C:29]([CH3:33])([CH3:32])[CH2:30][OH:31].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>>[OH:31][CH2:30][C:29]([CH3:33])([CH3:32])[O:28][NH:27][C:4]([C:6]1[NH:14][C:13]2[CH:12]=[CH:11][N:10]=[CH:9][C:8]=2[C:7]=1[NH:15][C:16]1[CH:21]=[CH:20][C:19]([S:22][CH3:23])=[CH:18][C:17]=1[F:24])=[O:5]

Participants

6

Reactant 5

HCID 14798Sodium HydroxideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 142934292-(Aminooxy)-2-methylpropan-1-olHCID 595966043-(2-Fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester

Product 1

HCID 595965513-(2-Fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid (2-hydroxy-1,1-dimethyl-ethoxy)-amideYield 5%

Conditions

Temperature
60 °C

Procedure

3-(2-Fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid ethyl ester (0.13 g, 0.38 mmol) was dissolved in IMS (5 ml) before 1M NaOH (0.45 ml, 0.45 mmol) was added and the mixture heated at 60° C. for 2 hours. The reaction mixture was concentrated in vacuo and the residue was re-dissolved in THF (3 ml). 2-Aminooxy-2-methyl-propan-1-ol (100 mg, 0.56 mmol), DIPEA (0.20 ml, 1.1 mmol) and HATU (210 mg, 0.56 mmol) were added and the mixture stirred at room temperature. On completion of the reaction, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate and water. The organic extract was washed with water, dried (MgSO4), and concentrated in vacuo. The resultant residue was purified by flash chromatography (Si-PPC, DCM:MeOH, gradient 99:1 to 90:10) to give an orange solid. The orange solid was then purified by reversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl 0.1% HCO2H in water on a gradient of acetonitrile) to provide the title compound (semiformate) as a yellow solid (7 mg, 5%). LCMS (method A): RT=5.87 min, M+H+=405. 1H NMR (d6-DMSO, 400 MHz) 1.10 (6H, s), 2.42 (3H, s), 3.20 (2H, s), 6.58 (1H, t, J=8.58 Hz), 6.91 (1H, dd, J=8.42, 2.06 Hz), 7.20 (1H, dd, J=12.05, 2.11 Hz), 7.37 (1H, dd, J=5.84, 1.11 Hz), 7.81 (1H, s), 8.23 (1H, d, J=5.83 Hz), 8.52 (1H, d, J=1.07 Hz).

Workup

  1. additionwas added
  2. concentrationThe reaction mixture was concentrated in vacuo
  3. dissolutionthe residue was re-dissolved in THF (3 ml)
  4. customOn completion of the reaction
  5. customthe solvent was removed in vacuo
  6. customthe residue was partitioned between ethyl acetate and water
  7. extractionThe organic extract
  8. washwas washed with water
  9. dry with materialdried (MgSO4)
  10. concentrationconcentrated in vacuo
  11. customThe resultant residue was purified by flash chromatography (Si-PPC, DCM:MeOH, gradient 99:1 to 90:10)
  12. customto give an orange solid
  13. customThe orange solid was then purified by reversed phase HPLC (Phenomenex Luna 5 phenyl/hexyl 0.1% HCO2H in water on a gradient of acetonitrile)

Sources & evidence

ORD record
ord-39ac37a7175b4ab783115e7c3dc304d1
Source dataset
uspto-grants-2010_12
Patent number
US07855216B2

Reaction notes

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