Cesium carbonate → tert-butyl [(1S,2R)-2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate

HRID 1504851Notes

Reaction equation

HRID 1504851 reaction equation
Br[C:2]1[CH:3]=[C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=1[C:8]#[N:9].[NH2:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1>[C:8]([C:7]1[N:6]=[CH:5][C:4]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:3][C:2]=1[NH:25][C:26]1[CH:31]=[C:30]([CH3:32])[CH:29]=[C:28]([CH3:33])[N:27]=1)#[N:9]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 215072-Amino-4,6-dimethylpyridineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 86716545tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

Product 1

HCID 86731720tert-butyl [(1S,2R)-2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

To a flask were added tert-butyl {(1S,2R)-2-[(5-bromo-6-cyanopyridin-3-yl)amino]cyclohexyl}carbamate (21.5 g, 54.4 mmol), 2-amino-4,6-dimethylpyridine (9.97 g, 81.7 mmol), Pd2(dba)3 (2.49 g, 2.72 mmol), Xantphos (3.15 g, 5.44 mmol), cesium carbonate (35.4 g, 109 mmol) and dioxane (215 mL). The mixture was degassed by bubbling nitrogen through the reaction mixture. After 15 minutes, the nitrogen purge was ceased and the reaction mixture was heated to 80° C. After 5 hours, the reaction mixture was cooled to ambient temperature, and filtered through CELITE (washing with ethyl acetate). To the filtrate was added silica gel, and the solvent was removed under reduced pressure. The residue was purified via silica gel chromatography to afford tert-butyl [(1S,2R)-2-({6-cyano-5-[(4,6-dimethylpyridin-2-yl)amino]pyridin-3-yl}amino)cyclohexyl]carbamate. MS ESI calc'd. for C24H33N6O2 [M+H]+ 437. found 437. 1H NMR (600 MHz, DMSO-d6) δ 8.61 (s, 1H), 7.72 (d, J=2.4 Hz, 1H), 7.52 (s, 1H), 6.60 (s, 1H), 6.54 (d, J=8.4 Hz, 1H), 6.53 (s, 1H), 6.33 (d, J=7.2 Hz, 1H), 3.71 (s, 1H), 3.55 (s, 1H), 2.56 (s, 3H), 2.16 (s, 3H), 1.74-1.66 (m, 1H), 1.64-1.54 (m, 2H), 1.51-1.42 (m, 3), 1.32-1.23 (m, 10), 1.12-1.08 (m, 1H).

Workup

  1. customThe mixture was degassed
  2. customby bubbling nitrogen through the reaction mixture
  3. customthe nitrogen purge
  4. waitAfter 5 hours
  5. temperaturethe reaction mixture was cooled to ambient temperature
  6. filtrationfiltered through CELITE (washing with ethyl acetate)
  7. additionTo the filtrate was added silica gel
  8. customthe solvent was removed under reduced pressure
  9. customThe residue was purified via silica gel chromatography

Sources & evidence

ORD record
ord-ebd22c60ce484fd4bcefef0367db43b6
Source dataset
uspto-grants-2015_12
Patent number
US09216173B2

Reaction notes

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