Cesium carbonate → HCID 90355898, compound

HRID 1470333Notes

Reaction equation

HRID 1470333 reaction equation
Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[NH2:15][C:16]1[CH:17]=[C:18]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])[CH:19]=[CH:20][C:21]=1[C:22]#[N:23].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)C.[Pd+2].C([O-])(=O)C.O1CCOCC1>[C:22]([C:21]1[CH:20]=[CH:19][C:18]([NH:24][C@H:25]2[CH2:30][CH2:29][CH2:28][CH2:27][C@H:26]2[NH:31][C:32](=[O:38])[O:33][C:34]([CH3:35])([CH3:36])[CH3:37])=[CH:17][C:16]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[N:3]=1)#[N:23]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 876016-Chloro-2-picolineHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 90355905HCID 90355905, compound

Product 1

HCID 90355898HCID 90355898, compound

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
80 °C

Procedure

Dioxane (1.0 mL), 2-chloro-6-methylpyridine (0.035 mL, 0.32 mmol) and cesium carbonate (138 mg, 0.424 mmol) were added to tert-butyl rel-{(1R,2S)-2-[(3-amino-4-cyanophenyl)amino]cyclohexyl}carbamate (70 mg, 0.21 mmol). The reaction mixture was purged with argon, and then palladium (II) acetate (5 mg, 0.02 mmol) and Xantphos (18 mg, 0.032 mmol) were added. The reaction mixture was purged with argon, and then heated to 80° C. After 12 hours, the reaction mixture was cooled to room temperature, filtered through celite (washed with chloroform), and diluted with water. The organics were separated, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-50% acetone/hexanes, linear gradient) to afford tert-butyl rel-[(1R,2S)-2-({4-cyano-3-[(6-methylpyridin-2-yl)amino]phenyl}amino)cyclohexyl]carbamate. The solid was diluted with hydrochloric acid (4.0 M solution in dioxanes, 1.0 mL, 4.0 mmol). After 10 minutes, the mixture was concentrated under reduced pressure. The residue was dissolved in DMSO (0.5 mL). To this solution were added hydrogen peroxide (30% solution in water, 0.020 mL, 0.20 mmol) and sodium hydroxide (4.0 N in water, 0.050 mL, 0.20 mmol). The reaction mixture was stirred until complete consumption of the intermediate nitrile was observed. The reaction mixture was purified directly by reverse phase HPLC (20-60% acetonitrile/water with 0.1% TFA, linear gradient) to afford rel-4-{[(1R,2S)-2-aminocyclohexyl]amino}-2-[(6-methylpyridin-2-yl)amino]benzamide TFA salt. MS ESI calc'd. for C19H26N5O [M+H]+ 340. Found 340. 1H NMR (500 MHz, CD3OD) δ 8.02-7.94 (m, 1H), 7.68 (d, J=8.7 Hz, 1H), 7.40 (d, J=8.9 Hz, 1H), 7.02-6.95 (m, 2H), 6.65 (d, J=8.9 Hz, 1H), 3.97 (s, 1H), 3.56-3.47 (m, 1H), 2.58 (s, 3H), 1.92-1.82 (m, 3H), 1.82-1.73 (m, 1H), 1.73-1.60 (m, 2H), 1.60-1.45 (m, 2H).

Workup

  1. customThe reaction mixture was purged with argon
  2. customThe reaction mixture was purged with argon
  3. temperaturethe reaction mixture was cooled to room temperature
  4. filtrationfiltered through celite (washed with chloroform)
  5. additiondiluted with water
  6. customThe organics were separated
  7. dry with materialdried over sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel chromatography (10-50% acetone/hexanes, linear gradient)

Sources & evidence

ORD record
ord-9dcfc7379e7d4207ad8afc892bec4f88
Source dataset
uspto-grants-2015_04
Patent number
US09006444B2

Reaction notes

Loading…