Hexane → 3-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamide

HRID 419572Notes

Reaction equation

HRID 419572 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][CH:27]=2)[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(=O)C1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:43]=[CH:42][N:41]=[C:40]([NH2:44])[CH:39]=1.CCCCCC>C(Cl)Cl.CCOC(C)=O.C([O-])(O)=O.[Na+]>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[N:41]3[CH:42]=[CH:43][C:38]([C:37]([F:45])([F:36])[F:46])=[CH:39][C:40]3=[N:44][C:9]=2[C:11]2[CH:12]=[C:13]([CH:25]=[CH:26][CH:27]=2)[C:14]([NH:16][C:17]2[C:22]([F:23])=[CH:21][CH:20]=[CH:19][C:18]=2[F:24])=[O:15])[CH:5]=[CH:4][N:3]=1

Participants

8

Reactant 4

HCID 8058HexaneHCID 67184N-bromobutanimideHCID 27783152-Amino-4-(trifluoromethyl)pyridineHCID 598602583-[(2-Chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)benzamide

Product 1

HCID 594528983-[3-(2-chloro-4-pyrimidinyl)-7-(trifluoromethyl)imidazo[1,2-a]pyridin-2-yl]-N-(2,6-difluorophenyl)benzamideYield 46%

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolvent2×HCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
80 °C

Procedure

To a stirred solution of 3-[(2-chloro-4-pyrimidinyl)acetyl]-N-(2,6-difluorophenyl)-benzamide (Intermediate Example 1, step B) (0.4 g, 1.03 mmol) in DCM (10 mL) at rt under N2 was added NBS (0.193 g, 1.09 mmol). The reaction was stirred approximately 30 min, then concentrated under vacuum to a foam like solid. The solid was dissolved in dioxane (10 mL) and 4-(trifluoromethyl)-2-pyridinamine (0.5 g, 3.10 mmol) was added. The reaction was stirred under nitrogen, heated to 80° C., and stirred for approximately 48 h, then cooled to rt. The reaction was diluted with EtOAc and half-saturated aqueous NaHCO3. The organic layer was separated and washed brine. The combined aqueous layers were extracted with EtOAc (3×). The combined organic layers were dried over MgSO4, filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography to give a yellow solid. The solid was dissolved in minimal DCM and hexane was added until a precipitate formed. The slurry was filtered, washing the solids with cold hexane. The solids were dried under vacuum, however proton NMR indicates impurities so the solid was dissolved in minimal DCM and ether was added until a precipitate formed. The slurry was filtered, washing the solids with cold ether. The solids were dried under vacuum to give the title compound of step A (0.250 g, 0.47 mmol, 46%) as a white solid. MS (ESI): 530 [M+H]+.

Workup

  1. concentrationconcentrated under vacuum to a foam like solid
  2. dissolutionThe solid was dissolved in dioxane (10 mL)
  3. stirringThe reaction was stirred under nitrogen
  4. stirringstirred for approximately 48 h
  5. temperaturecooled to rt
  6. customThe organic layer was separated
  7. washwashed brine
  8. extractionThe combined aqueous layers were extracted with EtOAc (3×)
  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
  13. customto give a yellow solid
  14. customformed
  15. filtrationThe slurry was filtered
  16. washwashing the solids with cold hexane
  17. customThe solids were dried under vacuum, however proton NMR
  18. dissolutionwas dissolved in minimal DCM
  19. additionether was added until a precipitate
  20. customformed
  21. filtrationThe slurry was filtered
  22. washwashing the solids with cold ether
  23. customThe solids were dried under vacuum

Sources & evidence

ORD record
ord-90e347f2bc084976a57c2a423a5201bb
Source dataset
uspto-grants-2012_01
Patent number
US08093239B2

Reaction notes

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