Cesium carbonate → 5-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide

HRID 571467Notes

Reaction equation

HRID 571467 reaction equation
C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Cl.[CH3:48][Si:49]([CH3:76])([CH3:75])[CH2:50][CH2:51][O:52][CH2:53][N:54]1[C:58]2=[N:59][CH:60]=[CH:61][C:62]([C:63]3[CH:64]=[N:65][N:66]([C:68]4([CH2:72][C:73]#[N:74])[CH2:71][NH:70][CH2:69]4)[CH:67]=3)=[C:57]2[CH:56]=[CH:55]1.Br[C:78]1[CH:79]=[CH:80][C:81]([C:84]([NH:86][C@H:87]([CH:89]2[CH2:91][CH2:90]2)[CH3:88])=[O:85])=[N:82][CH:83]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C([O-])(O)=O.[Na+]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:73]([CH2:72][C:68]1([N:66]2[CH:67]=[C:63]([C:62]3[CH:61]=[CH:60][N:59]=[C:58]4[N:54]([CH2:53][O:52][CH2:51][CH2:50][Si:49]([CH3:75])([CH3:48])[CH3:76])[CH:55]=[CH:56][C:57]=34)[CH:64]=[N:65]2)[CH2:69][N:70]([C:78]2[CH:79]=[CH:80][C:81]([C:84]([NH:86][C@H:87]([CH:89]3[CH2:91][CH2:90]3)[CH3:88])=[O:85])=[N:82][CH:83]=2)[CH2:71]1)#[N:74]

Participants

8

Reactant 5

HCID 10796Cesium carbonateHCID 516892Sodium BicarbonateHCID 634876Binap, (A+-)-HCID 712079115-bromo-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamideHCID 71207967{3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride

Product 1

HCID 712080055-{3-(cyanomethyl)-3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamideYield 58.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (91.1 mg, 0.146 mmol, Aldrich: Cat. #481084) was added to a mixture of {3-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride (0.445 g, 1.00 mmol), 5-bromo-N-[(1S)-1-cyclopropylethyl]pyridine-2-carboxamide (0.273 g, 1.01 mmol), and cesium carbonate (0.971 g, 2.98 mmol) in toluene (10 mL) under N2, followed by palladium acetate (32.2 mg, 0.143 mmol). The reaction mixture was stirred at 120° C. overnight. The reaction mixture was worked up with aqueous NaHCO3, and extracted with ethyl acetate (3×30 mL). The combined organic layers were washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-70%) to afford the desired product (0.350 g, 58.6%). LCMS (M+H)+: m/z=597.3.

Workup

  1. extractionextracted with ethyl acetate (3×30 mL)
  2. washThe combined organic layers were washed with brine
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe residue was purified by flash chromatography on a silica gel column with ethyl acetate in hexane (0-70%)

Sources & evidence

ORD record
ord-2234781717264293899a849229163df7
Source dataset
uspto-grants-2015_05
Patent number
US09023840B2

Reaction notes

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