6-Bromo-4-methylpyridin-2-amine → HCID 86715336, compound

HRID 2272651Notes

Reaction equation

HRID 2272651 reaction equation
CC(C)([O-])C.[K+].[Br:7][C:8]1[N:13]=[C:12]([NH2:14])[CH:11]=[C:10]([CH3:15])[CH:9]=1.Cl[C:17]1[CH:22]=[C:21]([CH:23]([F:25])[F:24])[CH:20]=[CH:19][N:18]=1>C1COCC1.[NH4+].[Cl-].C(Cl)Cl>[Br:7][C:8]1[N:13]=[C:12]([NH:14][C:17]2[CH:22]=[C:21]([CH:23]([F:25])[F:24])[CH:20]=[CH:19][N:18]=2)[CH:11]=[C:10]([CH3:15])[CH:9]=1

Participants

7

Reactant 3

HCID 221765076-Bromo-4-methylpyridin-2-amineHCID 23665647Potassium tert-butoxide4×HCID 457909492-Chloro-4-(difluoromethyl)pyridine

Product 1

HCID 86715336HCID 86715336, compound

Reagents, catalysts & solvents 3

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolventHCID 25517Ammonium ChlorideSolvent

Conditions

Temperature
0 °C

Procedure

Potassium t-butoxide (1.0 M in THF, 198 mL, 198 mmol) was added to a solution of 6-bromo-4-methyl pyridine-2-amine (37 g, 198 mmol) and 2-chloro-4-(difluoromethyl)pyridine (42.1 g, 257 mmol) in THF (60 mL) at 0° C. The resulting mixture was heated to reflux for 30 minutes then cooled to 0° C., and a second portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes, cooled to 0° C., and a third portion of potassium t-butoxide (1.0 M in THF, 80 mL, 80 mmol) was added. The mixture was again heated to reflux for 30 minutes. After cooling to 0° C., a fourth portion of potassium t-butoxide (1.0 M in THF, 20 mL, 20 mmol) was added. Upon refluxing for 30 minutes, the reaction was allowed to cool to room temperature, then diluted with saturated aqueous NH4Cl (500 mL) and diluted with DCM (500 mL). The layers were separated, and the aqueous layer was extracted a second time with DCM (500 mL). The combined organic layers were dried with Na2SO4, filtered through a pad of CELITE (150 g), and concentrated in vacuo. The residue was triturated with DCM (100 mL), filtered, and washed with hexanes (2×50 mL) to afford one portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine. The filtrate was concentrated, absorbed on silica gel and purified via silica gel column chromatography (EtOAc/Hex) to afford a second portion of 6-bromo-N-[4-(difluoromethyl)pyridin-2-yl]-4-methylpyridin-2-amine. MS ESI calc'd. for C12H11BrF2N3 [M+H]+ 314 and 316. found 314 and 316. 1H NMR (600 MHz, DMSO-d6) δ 10.20 (s, 1H), 8.35 (d, f=5.1 Hz, 1H), 7.69 (s, 1H), 7.64 (s, 1H), 7.01 (d, J=5.1 Hz, 1H), 6.96 (t, J=22.3 Hz, 1H), 6.95 (s, 1H), 2.24 (s, 3H).

Workup

  1. temperatureThe resulting mixture was heated
  2. temperatureto reflux for 30 minutes
  3. temperatureThe mixture was again heated
  4. temperatureto reflux for 30 minutes
  5. temperaturecooled to 0° C.
  6. temperatureThe mixture was again heated
  7. temperatureto reflux for 30 minutes
  8. temperatureAfter cooling to 0° C.
  9. temperatureUpon refluxing for 30 minutes
  10. temperatureto cool to room temperature
  11. customThe layers were separated
  12. extractionthe aqueous layer was extracted a second time with DCM (500 mL)
  13. dry with materialThe combined organic layers were dried with Na2SO4
  14. filtrationfiltered through a pad of CELITE (150 g)
  15. concentrationconcentrated in vacuo
  16. customThe residue was triturated with DCM (100 mL)
  17. filtrationfiltered
  18. washwashed with hexanes (2×50 mL)

Sources & evidence

ORD record
ord-8c202cf124144f8880d22ca833f5d16a
Source dataset
uspto-grants-2015_09
Patent number
US09120785B2

Reaction notes

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