Diisopropylethylamine → 2-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)amide

HRID 2381896Notes

Reaction equation

HRID 2381896 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([CH3:14])[C:11]([C:15]([OH:17])=O)=[CH:10][N:9]=2)[CH:5]=[CH:6][CH:7]=1.C1C=NC2N(O)N=NC=2C=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[N:58]([NH2:62])[C:57]([CH3:63])=[CH:56]2.CCN(C(C)C)C(C)C>CN(C=O)C.O.CCOC(C)=O>[F:52][C:53]1[CH:54]=[C:55]2[C:59](=[CH:60][CH:61]=1)[N:58]([NH:62][C:15]([C:11]1[C:12]([CH3:14])=[N:13][C:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=3)=[N:9][CH:10]=1)=[O:17])[C:57]([CH3:63])=[CH:56]2

Participants

9

Reactant 5

HCID 81531DiisopropylethylamineHCID 181649HOAtHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 617025872-(3-Fluorophenyl)-4-methylpyrimidine-5-carboxylic acidHCID 685544085-Fluoro-2-methyl-indol-1-ylamine

Product 1

HCID 250994732-(3-Fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)amideYield 55%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (340 mg, 1.46 mmol, prepared according to the general procedure described in Example 1, steps 3 and 4), HOAt (248 mg, 1.82 mmol), and HATU (645 mg, 1.70 mmol) in DMF (15 mL) is stirred at rt under N2 for 20 min. 5-Fluoro-2-methyl-indol-1-ylamine (237 mg, 1.44 mmol) and DIPEA (380 μL, 2.18 mmol) are added. The resulting mixture is stirred at 80° C. overnight. The mixture is cooled and portioned between EtOAc and water. The organic phase is separated, washed with saturated aqueous NaHCO3, water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel chromatography eluting with 20% EtOAc in heptane to afford 2-(3-fluoro-phenyl)-4-methyl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)amide (300 mg, 55%) as a solid. MS: 379 (M+H). 1H NMR (300 MHz, CD3OD): δ 9.14 (s, 1H), 8.38-8.20 (m, 3H), 7.56-7.52 (m, 1H), 7.30-7.27 (m, 2H), 7.19-7.16 (m, 1H), 6.96-6.90 (m, 1H), 6.32 (s, 1H), 2.83 (s, 3H), 2.42 (s, 3H).

Workup

  1. stirringThe resulting mixture is stirred at 80° C. overnight
  2. temperatureThe mixture is cooled
  3. customThe organic phase is separated
  4. washwashed with saturated aqueous NaHCO3, water and brine
  5. dry with materialdried (MgSO4)
  6. filtrationfiltered
  7. concentrationconcentrated in vacuo
  8. customThe residue is purified by silica gel chromatography
  9. washeluting with 20% EtOAc in heptane

Sources & evidence

ORD record
ord-c8a37735f73e4a2ab2f74f36694f023c
Source dataset
uspto-grants-2012_09
Patent number
US08258130B2

Reaction notes

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