Cesium carbonate → tert-butyl (1S,2R)-2-(5-(5-bromo-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

HRID 1504754Notes

Reaction equation

HRID 1504754 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].[Br:25][C:26]1[CH:27]=[CH:28][C:29]([NH2:33])=[N:30][C:31]=1[CH3:32].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>[Br:25][C:26]1[CH:27]=[CH:28][C:29]([NH:33][C:2]2[CH:3]=[C:4]([NH:10][C@@H:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]3[NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH:5]=[N:6][C:7]=2[C:8]#[N:9])=[N:30][C:31]=1[CH3:32]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 1706782-Pyridinamine, 5-bromo-6-methyl-HCID 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 86731651tert-butyl (1S,2R)-2-(5-(5-bromo-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate

Reagents, catalysts & solvents 2

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

Conditions

Temperature
85 °C

Procedure

Dioxane (25 ml) was added to a nitrogen purged flask containing tert-butyl (1S,2R)-2-(5-bromo-6-cyanopyridin-3-ylamino)cyclohexylcarbamate (PrepEx 1.1) (2500 mg, 6.32 mmol), 5-bromo-6-methylpyridin-2-amine (1540 mg, 8.22 mmol), Xantphos (732 mg, 1.27 mmol), Pd2(dba)3 (579 mg, 0.632 mmol) and cesium carbonate (3090 mg, 9.49 mmol). Nitrogen was bubbled through the reaction mixture for 5 minutes, and the reaction mixture was heated at 85° C. for 4.5 hours. The reaction was then cooled to room temperature and poured into 10% aq. KHSO4 (300 mL). The pH was adjusted to 4 with 10% aq. KHSO4, and the mixture was sonicated. The solids were collected by filtration, dried under nitrogen, and diluted with DCM (50 mL). Sonication of the resulting suspension afforded a thick slurry. The solids were collected by filtration, and washed with DCM (10 mL) and hexanes (20 mL) to afford tert-butyl (1S,2R)-2-(5-(5-bromo-6-methylpyridin-2-ylamino)-6-cyanopyridin-3-ylamino)cyclohexylcarbamate. MS ESI calc'd. for C23H30BrN6O2 [M+H]+ 501 and 503 found 501 and 503. 1H NMR (500 MHz, CD3OD) δ 7.78 (s, 1H), 7.73-7.71 (m, 2H), 7.75 (d, J=8.8 Hz, 1H), 3.85 (br s, 1H), 3.75 (br s, 1H), 2.54 (s, 3H), 1.90-1.10 (m, 8H), 1.34 (s, 9H).

Workup

  1. customNitrogen was bubbled through the reaction mixture for 5 minutes
  2. temperatureThe reaction was then cooled to room temperature
  3. additionpoured into 10% aq. KHSO4 (300 mL)
  4. customthe mixture was sonicated
  5. filtrationThe solids were collected by filtration
  6. customdried under nitrogen
  7. additiondiluted with DCM (50 mL)
  8. customSonication of the resulting suspension
  9. customafforded a thick slurry
  10. filtrationThe solids were collected by filtration
  11. washwashed with DCM (10 mL) and hexanes (20 mL)

Sources & evidence

ORD record
ord-ce4c20558eee47a4b2cc9549b6dce431
Source dataset
uspto-grants-2015_12
Patent number
US09216173B2

Reaction notes

Loading…