Diisopropylethylamine → 4-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amide

HRID 2381911Notes

Reaction equation

HRID 2381911 reaction equation
[CH3:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:3]=1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH2:60])[C:55]([CH3:61])=[CH:54]2>CN(C=O)C.O.CCOC(C)=O>[F:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][CH:59]=1)[N:56]([NH:60][C:8]([C:7]1[C:2]([CH3:1])=[N:3][C:4]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=3)=[N:5][CH:6]=1)=[O:10])[C:55]([CH3:61])=[CH:54]2

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 2733179PyBroPHCID 617020254-Methyl-2-(pyridin-2-yl)pyrimidine-5-carboxylic acidHCID 685544085-Fluoro-2-methyl-indol-1-ylamine

Product 1

HCID 250995174-Methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amideYield 14.1%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

A solution of 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (810 mg, 3.76 mmol), PyBrOP (1.76 g, 3.78 mmol), and DIPEA (1.9 mL, 10.89 mmol) in DMF (15 mL) is stirred at rt under N2 for 10 min. 5-Fluoro-2-methyl-indol-1-ylamine (560 mg, 3.41 mmol) is added. The resulting mixture is stirred at rt overnight. The mixture is 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 3% MeOH in DCM to afford 4-methyl-2-pyridin-2-yl-pyrimidine-5-carboxylic acid (5-fluoro-2-methyl-indol-1-yl)-amide (174 mg, 14%) as a solid. MS: 362 (M+H). 1H NMR (300 MHz, DMSO-d6): δ 11.82 (s, 1H), 9.30 (d, 1H), 8.81 (d, 1H), 8.46 (d, 1H), 8.03 (dt, 1H), 7.59 (dd, 1H), 7.43 (dd, 1H), 7.29 (dd, 1H), 6.98 (dt, 1H), 6.35 (s, 1H), 2.79 (s, 3H), 2.38 (s, 3H). IC50=8 nM.

Workup

  1. customThe organic phase is separated
  2. washwashed with saturated aqueous NaHCO3, water and brine
  3. dry with materialdried (MgSO4)
  4. filtrationfiltered
  5. concentrationconcentrated in vacuo
  6. customThe residue is purified by silica gel chromatography
  7. washeluting with 3% MeOH in DCM

Sources & evidence

ORD record
ord-b0ddd483a0f84084a9cc1c8ac5be5865
Source dataset
uspto-grants-2012_09
Patent number
US08258130B2

Reaction notes

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