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

HRID 878415Notes

Reaction equation

HRID 878415 reaction equation
Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]#[N:9])=[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)[CH:3]=1.Cl.[NH2:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23].C(=O)([O-])[O-].[Cs+].[Cs+].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>O1CCOCC1.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]>[C:8]([C:5]1[C:4]([NH:10][C:11]2[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[N:12]=2)=[CH:3][C:2]([NH:20][CH2:21][C@@H:22]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[CH3:23])=[N:7][CH:6]=1)#[N:9]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 53350397(S)-tert-Butyl (1-aminopropan-2-yl)carbamate hydrochlorideHCID 894867076-Chloro-4-[(4,6-dimethyl-2-pyridinyl)amino]-3-pyridinecarbonitrile

Product 1

HCID 131732614tert-butyl [(2S)-1-({5-cyano-4-[(4,6-dimethylpyridin-2-yl)amino]pyridin-2-yl}amino)propan-2-yl]carbamate

Reagents, catalysts & solvents 2

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

Conditions

Temperature
80 °C

Procedure

To a solution of 6-chloro-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carbonitrile (PrepEx 1.2) (50 mg, 0.19 mmol) in 1,4-dioxane (0.8 mL) was added tert-butyl [(2S)-1-aminopropan-2-yl]carbamate hydrochloride (61 mg, 0.29 mmol) and cesium carbonate (126 mg, 0.387 mmol). The mixture was purged with argon, and then Pd2(dba)3 (4 mg, 0.004 mmol) and Xantphos (7 mg, 0.012 mmol) were added. The reaction mixture was heated to 80° C. After complete consumption of starting material (as determined by LCMS analysis), the reaction mixture was cooled to ambient temperature, filtered through CELITE (washed with chloroform), and diluted with water. The organics were separated, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography (10-40% acetone/hexanes, linear gradient) to afford tert-butyl [(2S)-1-({5-cyano-4-[(4,6-dimethylpyridin-2-yl)amino]pyridin-2-yl}amino)propan-2-yl]carbamate. The isolated material was diluted with hydrochloric acid (2.0 M in dioxanes, 1 mL, 2 mmol) and stirred at ambient temperature. After 1 hour, the reaction mixture was concentrated under reduced pressure (azeotroping with toluene). The residue was diluted with DMSO (0.5 mL). To this mixture was added hydrogen peroxide (35% solution in water, 0.020 mL, 0.23 mmol) and sodium hydroxide (4.0 N in water, 0.050 mL, 0.20 mmol). After 1 hour, the reaction mixture was filtered and purified directly by reverse phase HPLC (5-60% acetonitrile/water with 0.1% TFA, linear gradient) to afford 6-{[(2S)-2-aminopropyl]amino}-4-[(4,6-dimethylpyridin-2-yl)amino]pyridine-3-carboxamide TFA salt. MS ESI calc'd. for C16H23N6O [M+H]+ 315. found 315. 1H NMR (500 MHz, CD3OD) δ 8.37 (s, 1H), 8.28 (s, 1H), 6.90 (s, 1H), 6.80 (s, 1H), 3.74-3.50 (m, 3H), 2.51 (s, 3H), 2.34 (s, 3H), 1.41 (br s, 3H).

Workup

  1. customThe mixture was purged with argon
  2. customAfter complete consumption of starting material (as determined by LCMS analysis)
  3. temperaturethe reaction mixture was cooled to ambient temperature
  4. filtrationfiltered through CELITE (washed with chloroform)
  5. additiondiluted with water
  6. customThe organics were separated
  7. dry with materialdried over anhydrous sodium sulfate
  8. filtrationfiltered
  9. concentrationconcentrated under reduced pressure
  10. customThe residue was purified by silica gel chromatography (10-40% acetone/hexanes, linear gradient)

Sources & evidence

ORD record
ord-715470dafe744f60901abe5ab586d057
Source dataset
uspto-grants-2015_03
Patent number
US08987456B2

Reaction notes

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