Cesium carbonate → Methyl 2-((1r,4r)-4-(4-(5-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)phenyl)cyclohexyl)acetate

HRID 76055Notes

Reaction equation

HRID 76055 reaction equation
[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1.[NH2:25][C:26]1[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C)C=CC=CC=1.C(O)(C)(C)C>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH:5]1[CH2:10][CH2:9][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:22]=[CH:21][C:20]([NH:25][C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:33])[F:34])=[CH:30][CH:31]=4)=[CH:19][N:18]=3)=[CH:13][CH:12]=2)[CH2:7][CH2:6]1

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 27377445-Amino-2-(trifluoromethyl)pyridineHCID 111557942-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenylHCID 66615782Methyl 2-[4-[4-(5-bromopyridin-2-yl)phenyl]cyclohexyl]acetate

Product 1

HCID 24938267Methyl 2-((1r,4r)-4-(4-(5-((6-(trifluoromethyl)pyridin-3-yl)amino)pyridin-2-yl)phenyl)cyclohexyl)acetate

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 22595558Toluene tert-butyl alcoholSolvent

Conditions

Temperature
150 °C

Procedure

A microwave vial was charged with {4-[4-(5-bromo-pyridin-2-yl)-phenyl]-cyclohexyl}-acetic acid methyl ester (3.4 g, 8.8 mmol, 1.0 equiv), 3-amino-6-trifluoromethyl pyridine (2.1 g, 13.1 mmol, 1.2 equiv), cesium carbonate (7.1 g, 21.9 mmol, 2.5 equiv), 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-Phos, 0.42 g, 0.88 mmol, 0.1 equiv) and palladium acetate (0.30 g, 0.44 mmol, 0.05 equiv) in 20 Ml of toluene/t-butanol (9:1). The suspension was sparged with nitrogen for 10 min, then heated to 150° C. under microwave heating for 45 min. The reaction was cooled to room temperature, partitioned between ethyl acetate and water. The organic extracts were washed with brine, then dried over sodium sulphate and concentrated in vacuo. Purification by silica gel chromatography afforded the title compound: 1H NMR (400 MHz, DMSO-d6) δ 1.10-1.21 (m, 1H) 1.51 (qd, J=12.72, 2.78 Hz, 2H) 1.70-1.87 (m, 5H) 2.26 (d, J=6.57 Hz, 2H) 2.50 (m, 1H) 3.61 (s, 3H) 7.33 (d, J=8.34 Hz, 2H) 7.65 (d, J=2.53 Hz, 1H) 7.67-7.74 (m, 2H) 7.89 (d, J=8.59 Hz, 1H) 7.95 (d, J=8.34 Hz, 2H) 8.46 (d, J=2.53 Hz, 1H) 8.54 (d, J=2.53 Hz, 1H) 9.18 (s, 1H); (M+H)+427.3.

Workup

  1. customThe suspension was sparged with nitrogen for 10 min
  2. temperatureheating for 45 min
  3. temperatureThe reaction was cooled to room temperature
  4. custompartitioned between ethyl acetate and water
  5. washThe organic extracts were washed with brine
  6. dry with materialdried over sodium sulphate
  7. concentrationconcentrated in vacuo
  8. customPurification by silica gel chromatography

Sources & evidence

ORD record
ord-b4ecf67b3f4840b590ccb9c4c45b5410
Source dataset
uspto-grants-2014_09
Patent number
US08835451B2

Reaction notes

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