Cesium carbonate → 1-{6-[3-(Morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyridin-2-yl}cyclobutanol

HRID 2207354Notes

Reaction equation

HRID 2207354 reaction equation
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+].Cl[C:50]1[N:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[CH:52][N:51]=1.[NH2:60][C:61]1[CH:62]=[C:63]([C:73]2[N:78]=[C:77]([C:79]3([OH:83])[CH2:82][CH2:81][CH2:80]3)[CH:76]=[CH:75][CH:74]=2)[CH:64]=[C:65]([N:67]2[CH2:72][CH2:71][O:70][CH2:69][CH2:68]2)[CH:66]=1>O1CCOCC1.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[N:67]1([C:65]2[CH:64]=[C:63]([C:73]3[N:78]=[C:77]([C:79]4([OH:83])[CH2:82][CH2:81][CH2:80]4)[CH:76]=[CH:75][CH:74]=3)[CH:62]=[C:61]([NH:60][C:50]3[N:55]=[C:54]([C:56]([F:59])([F:58])[F:57])[CH:53]=[CH:52][N:51]=3)[CH:66]=2)[CH2:72][CH2:71][O:70][CH2:69][CH2:68]1

Participants

8

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 27739122-Chloro-4-(trifluoromethyl)pyrimidineHCID 1180927791-[6-[3-Amino-5-(4-morpholinyl)phenyl]-2-pyridinyl]cyclobutanol

Product 1

HCID 1180925891-{6-[3-(Morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyridin-2-yl}cyclobutanol

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 962WaterSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
100 °C

Procedure

Xantphos (93 mg, 0.161 mmol), palladium(II) acetate (24.2 mg, 0.108 mmol), and cesium carbonate (350 mg, 1.08 mmol) were added to a degassed solution of 2-chloro-4-(trifluoromethyl)pyrimidine (103 mg, 0.565 mmol), 1-{6-[3-amino-5-(morpholin-4-yl)phenyl]pyridin-2-yl}cyclobutanol (175 mg, 0.538 mmol) in dioxane (45.3 mL) and the reaction mixture was heated to 100° C. for 2 hours and then for 5 hours at 115° C. Then, the reaction mixture was cooled to room temperature, diluted with water, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified by silica gel chromatography (ethyl acetate:hexanes) to afford 1-{6-[3-(morpholin-4-yl)-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl]pyridin-2-yl}cyclobutanol as an off-white solid. MS APCI calc'd for C24H25F3N5O2 [M+H]+ 472. found 472. 1H NMR (NMR Hz 400 MHz, Acetone-d6): δ 9.26 (s, 1H), 8.82 (d, J=4.8 Hz, 1H), 8.16 (s, 1H), 7.90 (t, J=7.8 Hz, 1H), 7.84-7.77 (m, 2H), 7.66 (d, J=7.8 Hz, 1H), 7.53 (s, 1H), 7.23 (d, J=4.9 Hz, 1H), 3.86 (t, J=4.4 Hz, 4H), 3.30 (t, J=4.4 Hz, 4H), 2.74-2.63 (m, 2H), 2.43 (m, 2H), 2.04 (m, 2H).

Workup

  1. temperatureThen, the reaction mixture was cooled to room temperature
  2. extractionextracted with ethyl acetate
  3. washwashed with brine
  4. dry with materialdried over sodium sulfate
  5. filtrationfiltered
  6. concentrationconcentrated under reduced pressure
  7. customThe crude product was purified by silica gel chromatography (ethyl acetate:hexanes)

Sources & evidence

ORD record
ord-6c2d76a9b29245d99182d5f3776f80bf
Source dataset
uspto-grants-2016_06
Patent number
US09376418B2

Reaction notes

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