4-Methylmorpholine → N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-2-fluoro-4-trifluoromethoxybenzamide

HRID 1257066Notes

Reaction equation

HRID 1257066 reaction equation
[F:1][C:2]1[CH:10]=[C:9]([O:11][C:12]([F:15])([F:14])[F:13])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1.[NH2:46][C:47]([CH3:61])([CH2:50][N:51]1[CH:60]=[C:54]2[N:55]=[CH:56][C:57]([Br:59])=[CH:58][C:53]2=[N:52]1)[C:48]#[N:49]>CN(C=O)C>[Br:59][C:57]1[CH:56]=[N:55][C:54]2=[CH:60][N:51]([CH2:50][C:47]([NH:46][C:4](=[O:6])[C:3]3[CH:7]=[CH:8][C:9]([O:11][C:12]([F:15])([F:14])[F:13])=[CH:10][C:2]=3[F:1])([C:48]#[N:49])[CH3:61])[N:52]=[C:53]2[CH:58]=1

Participants

7

Reactant 5

HCID 79724-MethylmorpholineHCID 27239391,3-Propanediamine, N'-(ethylcarbonimidoyl)-N,N-dimethyl-, monohydrochlorideHCID 27960291-Hydroxybenzotriazole hydrateHCID 580723032-Fluoro-4-(trifluoromethoxy)benzoic acidHCID 666201262-Amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile

Product 1

HCID 68710851N-[2-(6-Bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-1-cyano-1-methylethyl]-2-fluoro-4-trifluoromethoxybenzamideYield 9.8%

Reagents, catalysts & solvents 1

HCID 6228DimethylformamideSolvent

Procedure

2-Fluoro-4-trifluoromethoxybenzoic acid (80 mg, 0.357 mmole), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDAC.HCl, 78 mg, 0.4 mmole), 1-hydroxybenzotriazole monohydrate (HOBt.H2O, 69 mg, 0.45 mmole) and N-methylmorpholine (71 μL) were stirred in DMF (2 mL) for 20 minutes at room temperature prior to adding 2-amino-3-(6-bromo-2H-pyrazolo[4,3-b]pyridin-2-yl)-2-methylpropionitrile (100 mg, 0.357 mmole, described in Example 182). The mixture was stirred overnight at room temperature, quenched with a saturated solution of ammonium chloride and extracted with EA. The organic layer was washed with water, dried over magnesium sulfate, filtered and concentrated under reduced pressure to give a residue that was purified by chromatography (SiO2, heptane/EA) to afford the title compound as a white solid (17 mg, 9%). MS (ES): M/Z [M+H]=486. 1H NMR: (400 MHz, CHLOROFORM-d): 1.91 (s, 3H), 4.90 (d, J=14.1 Hz, 1H), 5.08 (d, J=14.1 Hz, 1H), 7.07 (d, J=12.1 Hz, 1H), 7.17 (d, J=8.4 Hz, 1H), 8.02 (d, J=12.1 Hz, 1H), 8.15-8.28 (m, 2H), 8.38 (s, 1H) and 8.62 (d, J=2.0 Hz, 1H). 19F NMR (376 MHz, CHLOROFORM-d): −108.6 (td, J=11.9, 9.2 Hz, 1F) and −58.3 (s, 3F). 2-fluoro-4-trifluoromethoxybenzoic acid was prepared as follows:

Workup

  1. customquenched with a saturated solution of ammonium chloride
  2. extractionextracted with EA
  3. washThe organic layer was washed with water
  4. dry with materialdried over magnesium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customto give a residue that
  8. customwas purified by chromatography (SiO2, heptane/EA)

Sources & evidence

ORD record
ord-4315b9ffd5e844ba9864b73de71d1097
Source dataset
uspto-grants-2013_06
Patent number
US08461176B2

Reaction notes

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