Imidazole → HCID 178486472, compound

HRID 1014474Notes

Reaction equation

HRID 1014474 reaction equation
[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][NH:25]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5].Br[CH2:34][C:35](Cl)=[O:36].[NH:38]1[CH:42]=[CH:41][N:40]=[CH:39]1.CCN(C(C)C)C(C)C>C1COCC1>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([NH:11][C:12]2[N:17]=[C:16]([NH:18][C:19]3[CH:27]=[C:26]4[C:22]([CH2:23][CH2:24][N:25]4[C:35](=[O:36])[CH2:34][N:38]4[CH:42]=[CH:41][N:40]=[CH:39]4)=[CH:21][C:20]=3[O:28][CH3:29])[NH:15][C:14]3=[N:30][CH:31]=[CH:32][C:13]=23)[C:3]=1[C:4]([NH2:6])=[O:5]

Participants

6

Reactant 4

HCID 795ImidazoleHCID 81531DiisopropylethylamineHCID 89602Bromoacetyl chlorideHCID 178486468HCID 178486468, compound

Product 1

HCID 178486472HCID 178486472, compoundYield 83%

Reagents, catalysts & solvents 1

HCID 8028TetrahydrofuranSolvent2×

Procedure

A −40° C. solution of 2-fluoro-6-[(2-{[5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide (70 mg, 0.16 mmol) in THF (10 mL) was treated with a solution of bromoacetyl chloride (31 mg, 0.19 mmol) in THF (1 mL), followed by imidazole (10 mL) and DIPEA (1 mL). After 3 days the resulting mixture was concentrated onto Celite and purified by silica gel chromatography using 1-10% MeOH (containing 0.2% NH3)/CH2Cl2. The crude product was dissolved in THF (150 mL), diluted with EtOAc (50 mL), washed with a saturated NaHCO3 solution (100 mL), a saturated NaCl solution (100 mL) and a mixture of water (50 mL) and a saturated Na2CO3 solution (50 mL). The organic layer was dried (Na2SO4) and concentrated, and the residue was triturated with CH2Cl2 to obtain 2-fluoro-6-[(2-{[1-(1H-imidazol-1-ylacetyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]benzamide as a white solid (72 mg, 83%). 1H NMR (400 MHz, DMSO-d6) δ ppm 3.18 (t, J=8.15 Hz, 2H), 3.77 (s, 3H), 4.18 (t, J=8.06 Hz, 2H), 6.19 (s, 1H), 6.78-6.94 (m, 3H), 6.97 (s, 1H), 7.07 (s, 1H), 7.29 (q, J=7.69 Hz, 1H), 7.54 (s, 1H), 7.55 (s, 1H), 7.99 (s, 1H), 8.07 (s, 1H), 8.46 (d, J=8.42 Hz, 1H), 8.58 (s, 1H), 10.52 (s, 1H), 11.27 (s, 1H), a CH2 signal with 2 protons is missing, may overlap with water peak in sample; ESIMS (M+H)+=542.11.

Workup

  1. concentrationAfter 3 days the resulting mixture was concentrated onto Celite
  2. custompurified by silica gel chromatography
  3. dissolutionThe crude product was dissolved in THF (150 mL)
  4. additiondiluted with EtOAc (50 mL)
  5. washwashed with a saturated NaHCO3 solution (100 mL)
  6. additiona saturated NaCl solution (100 mL) and a mixture of water (50 mL)
  7. dry with materialThe organic layer was dried (Na2SO4)
  8. concentrationconcentrated
  9. customthe residue was triturated with CH2Cl2

Sources & evidence

ORD record
ord-670fa78b1b13412b9cee4cae496e7c21
Source dataset
uspto-grants-2011_07
Patent number
US07981903B2

Reaction notes

Loading…