Toluene → 4-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide

HRID 571503Notes

Reaction equation

HRID 571503 reaction equation
Cl.Cl.[CH3:3][Si:4]([CH3:31])([CH3:30])[CH2:5][CH2:6][O:7][CH2:8][N:9]1[C:13]2[N:14]=[CH:15][N:16]=[C:17]([C:18]3[CH:19]=[N:20][N:21]([C:23]4([CH2:27][C:28]#[N:29])[CH2:26][NH:25][CH2:24]4)[CH:22]=3)[C:12]=2[CH:11]=[CH:10]1.Cl[C:33]1[C:46]([F:47])=[CH:45][C:36]([C:37]([NH:39][C@@H:40]([CH:42]2[CH2:44][CH2:43]2)[CH3:41])=[O:38])=[C:35]([F:48])[CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+].C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[C:28]([CH2:27][C:23]1([N:21]2[CH:22]=[C:18]([C:17]3[C:12]4[CH:11]=[CH:10][N:9]([CH2:8][O:7][CH2:6][CH2:5][Si:4]([CH3:30])([CH3:3])[CH3:31])[C:13]=4[N:14]=[CH:15][N:16]=3)[CH:19]=[N:20]2)[CH2:24][N:25]([C:33]2[C:46]([F:47])=[CH:45][C:36]([C:37]([NH:39][C@@H:40]([CH:42]3[CH2:43][CH2:44]3)[CH3:41])=[O:38])=[C:35]([F:48])[CH:34]=2)[CH2:26]1)#[N:29]

Participants

7

Reactant 5

HCID 1140TolueneHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 67391464{3-[4-(7-{[2-(Trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochlorideHCID 712080524-chloro-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide

Product 1

HCID 712079354-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamideYield 36.1%

Reagents, catalysts & solvents 1

HCID 167845palladium(II) acetateCatalyst

Conditions

Temperature
105 °C

Procedure

A mixture of {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile dihydrochloride (1.0 g, 2.1 mmol), 4-chloro-N-[(1R)-1-cyclopropylethyl]-2,5-difluorobenzamide (0.54 g, 2.1 mmol), cesium carbonate (2.0 g, 6.2 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.13 g, 0.21 mmol) and palladium acetate (0.046 g, 0.21 mmol) in toluene (20 mL, 200 mmol) was stirred at 105° C. overnight. After the reaction mixture was cooled to room temperature, the solid was filtered off by celite, washed with ethyl acetate. The filtrate was concentrated. The residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-60%) to afford the desired product (0.48 g, 36%). LCMS (M+H)+: m/z=633.3.

Workup

  1. temperatureAfter the reaction mixture was cooled to room temperature
  2. filtrationthe solid was filtered off by celite
  3. washwashed with ethyl acetate
  4. concentrationThe filtrate was concentrated
  5. customThe residue was purified by flash chromatography on a silica gel column with ethyl acetate in dichloromethylene (0-60%)

Sources & evidence

ORD record
ord-3b42ea1d1f3047eb977d0f3880f5b5c3
Source dataset
uspto-grants-2015_05
Patent number
US09023840B2

Reaction notes

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