Cesium carbonate → (S)-tert-butyl (1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

HRID 2170377Notes

Reaction equation

HRID 2170377 reaction equation
[Br:1][C:2]1[C:3]([C@@H:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][C:5](Br)=[CH:6][CH:7]=1.Cl.[CH3:28][C:29]1([OH:33])[CH2:32][NH:31][CH2:30]1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1(C)C=CC=CC=1.C([O-])(=O)C.C([O-])(=O)C.[Pd+2]>[Br:1][C:2]1[C:3]([C@@H:9]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[CH2:10][C:11]2[CH:16]=[C:15]([F:17])[CH:14]=[C:13]([F:18])[CH:12]=2)=[N:4][C:5]([N:31]2[CH2:32][C:29]([OH:33])([CH3:28])[CH2:30]2)=[CH:6][CH:7]=1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 115427813-methylazetidin-3-ol HydrochlorideHCID 90290190tert-Butyl (S)-(1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

Product 1

HCID 90290192(S)-tert-butyl (1-(3-bromo-6-(3-hydroxy-3-methylazetidin-1-yl)pyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
150 °C

Procedure

(S)-tert-butyl (1-(3,6-dibromopyridin-2-yl)-2-(3,5-difluorophenyl)ethyl)carbamate (150 mg, 0.3 mmol), 3-methylazetidin-3-ol hydrochloride (75 mg, 0.6 mmol) was combined with cesium carbonate (397 mg, 1.2 mmol), palladium diacetate (10 mg, 0.015 mmol) and 2,2′-bis-(diphenylphosphino)-1,1′-binaphthyl (19 mg, 0.03 mmol) in 2 mL of toluene. The system was degassed and purged with argon and heated to 150° C. heating bath for 1 hour, the reaction mixture was cooled and diluted with ethyl acetate. The organic layer was washed with water and brine, and then dried over sodium sulfate. The crude was purified by flash chromatography eluting with EtOAc/hexanes to provided the title compound. MS (m/z) 499.72 [M+H]+.

Workup

  1. customThe system was degassed
  2. custompurged with argon
  3. temperatureheating bath for 1 hour
  4. temperaturethe reaction mixture was cooled
  5. additiondiluted with ethyl acetate
  6. washThe organic layer was washed with water and brine
  7. dry with materialdried over sodium sulfate
  8. customThe crude was purified by flash chromatography
  9. washeluting with EtOAc/hexanes

Sources & evidence

ORD record
ord-63abe716d610486b9e3aa07ef2dc712c
Source dataset
uspto-grants-2015_06
Patent number
US09050344B2

Reaction notes

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