Cesium carbonate → 3-Methoxy-N-methyl-4-((5-(pyridin-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamide

HRID 529662Notes

Reaction equation

HRID 529662 reaction equation
Cl[C:2]1[N:3]=[C:4]([O:25][CH:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)[C:5]2[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=2[N:7]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1.[NH2:74][C:75]1[CH:84]=[CH:83][C:78]([C:79]([NH:81][CH3:82])=[O:80])=[CH:77][C:76]=1[O:85][CH3:86].C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH3:86][O:85][C:76]1[CH:77]=[C:78]([CH:83]=[CH:84][C:75]=1[NH:74][C:2]1[N:3]=[C:4]([O:25][CH:26]2[CH2:27][CH2:28][O:29][CH2:30][CH2:31]2)[C:5]2[C:10]([C:11]3[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=3)=[CH:9][N:8]([CH2:17][O:18][CH2:19][CH2:20][Si:21]([CH3:23])([CH3:22])[CH3:24])[C:6]=2[N:7]=1)[C:79]([NH:81][CH3:82])=[O:80]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 204444344-Amino-3-methoxy-N-methylbenzamideHCID 867264362-Chloro-5-(pyridin-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine

Product 1

HCID 867264373-Methoxy-N-methyl-4-((5-(pyridin-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)amino)benzamideYield 49.1%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
150 °C

Procedure

To a solution of 2-chloro-5-(pyridin-4-yl)-4-((tetrahydro-2H-pyran-4-yl)oxy)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidine (1 equiv), (9,9-dimethyl-9H-xanthene-4,5-diyl)bis(diphenylphosphine) (0.2 equiv), tris(dibenzylideneacetone)dipalladium(0) (0.1 equiv), 4-amino-3-methoxy-N-methylbenzamide (1.1 equiv) in 1,4-dioxane (0.1 M) was added cesium carbonate (3 equiv). The reaction mixtures were heated, with microwave irradiation, in a microwave reactor at 150° C. for 2 h. The reaction mixture was quenched with saturated aqueous sodium chloride and then washed with ethyl acetate. The organic phase was combined and washed with saturated aqueous sodium chloride. The organic layer was dried (magnesium sulfate), filtered, and concentrated. The crude was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in methanol) in hexane) to give the title compound (49.1% yield) as yellow solid. 1H NMR (400 MHz, DMSO-d6) δ ppm −0.11 (s, 9 H) 0.85-0.93 (m, 2 H) 1.68-1.82 (m, 2 H) 2.06-2.18 (m, 2 H) 2.79 (d, J=4.30 Hz, 3 H) 3.51-3.66 (m, 4 H) 3.77-3.86 (m, 2 H) 3.96 (s, 3 H) 5.47-5.55 (m, 1 H) 5.56 (s, 2 H) 7.50-7.57 (m, 2 H) 7.71-7.76 (m, 2 H) 7.83 (s, 1 H) 7.92 (s, 1 H) 8.34 (q, J=4.43 Hz, 1 H) 8.52-8.60 (m, 3 H); MS (ESI) m/z 605.6 [M+1]+.

Workup

  1. customThe reaction mixtures
  2. customThe reaction mixture was quenched with saturated aqueous sodium chloride
  3. washwashed with ethyl acetate
  4. washwashed with saturated aqueous sodium chloride
  5. dry with materialThe organic layer was dried (magnesium sulfate)
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude was purified by silica gel column chromatography (0-90%) ethyl acetate (with 10% 1N ammonia in methanol) in hexane)

Sources & evidence

ORD record
ord-a2c525cd28af44a1ac3316f94b8f1daa
Source dataset
uspto-grants-2016_05
Patent number
US09346812B2

Reaction notes

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