N-bromobutanimide → 5-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamide

HRID 419582Notes

Reaction equation

HRID 419582 reaction equation
[Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][C:27]=2OC)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])=O)[CH:5]=[CH:4][N:3]=1.C1C(=O)N(Br)[C:32](=[O:33])C1.[F:38][C:39]1[CH:44]=[CH:43][N:42]=[C:41]([NH2:45])[CH:40]=1>ClCCl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:42]3[CH:43]=[CH:44][C:39]([F:38])=[CH:40][C:41]3=[N:45][C:9]=2[C:11]2[CH:27]=[CH:26][C:25]([O:33][CH3:32])=[C:13]([CH:12]=2)[C:14]([NH:16][C:17]2[C:18]([F:24])=[CH:19][CH:20]=[CH:21][C:22]=2[F:23])=[O:15])[CH:5]=[CH:4][N:3]=1

Participants

7

Reactant 3

HCID 67184N-bromobutanimideHCID 183278082-Amino-4-fluoropyridineHCID 866251993-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-4-(methyloxy)benzamide

Product 1

HCID 594529085-[3-(2-chloro-4-pyrimidinyl)-7-fluoroimidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)-2-(methyloxy)benzamideYield 61%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-4-(methyloxy)benzamide (Intermediate Example 2, step E) (0.950 g, 2.28 mmol) in dichloromethane (23 mL) at rt under N2 was added NBS (0.426 g, 2.39 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (23 mL) and 4-fluoro-2-pyridinamine (Example 194, step A) (0.765 g, 6.83 mmol) was added. The reaction was stirred under N2, heated to 80° C., and stirred for approximately 16 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed with brine. The combined aqueous layers were extracted with EtOAc (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give the title compound of step A (0.700 g, 1.37 mmol, 61%) as a light tan solid. MS (ESI): 510 [M+H]+.

Workup

  1. concentrationconcentrated under vacuum to a foam like solid
  2. dissolutionThe solid was dissolved in dioxane (23 mL)
  3. stirringThe reaction was stirred under N2
  4. stirringstirred for approximately 16 h
  5. temperaturecooled to rt
  6. customThe organic layer was separated
  7. washwashed with brine
  8. extractionThe combined aqueous layers were extracted with EtOAc (2×)
  9. dry with materialThe combined organic layers were dried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated under vacuum
  12. customThe residue was purified by silica gel chromatography

Sources & evidence

ORD record
ord-d46a025a3b96464794878b8753d9a269
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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