Cesium carbonate → methyl 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylate

HRID 2363296Notes

Reaction equation

HRID 2363296 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][N: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]([O:86][CH3:87])=[O:85])=[N:82][CH:83]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>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[C:57]4[CH:56]=[CH:55][N:54]([CH2:53][O:52][CH2:51][CH2:50][Si:49]([CH3:75])([CH3:48])[CH3:76])[C:58]=4[N:59]=[CH:60][N:61]=3)[CH:64]=[N:65]2)[CH2:69][N:70]([C:78]2[CH:79]=[CH:80][C:81]([C:84]([O:86][CH3:87])=[O:85])=[N:82][CH:83]=2)[CH2:71]1)#[N:74]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 7016458Methyl 5-bromopyridine-2-carboxylateHCID 71143531{3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride

Product 1

HCID 71143566methyl 5-{3-(cyanomethyl)-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-1-yl}pyridine-2-carboxylateYield 63.6%

Reagents, catalysts & solvents 2

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of 2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (660 mg, 1.1 mmol), {3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile hydrochloride (4.76 g, 10.7 mmol), methyl 5-bromopicolinate (3.00 g, 13.9 mmol), palladium acetate (240 mg, 1.1 mmol) and cesium carbonate (10 g, 32 mmol) in toluene (120 mL) was de-gassed and recharged with nitrogen for three times. The reaction mixture was stirred at 100° C. overnight. After cooling the reaction mixture was quenched with water, and extracted with ethyl acetate (3×50 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 MeOH in dichloromethylene (0-5%) to afford the desired product (3.70 g, 63.6%). LCMS (M+H)+: m/z=545.3.

Workup

  1. customwas de-gassed
  2. temperatureAfter cooling the reaction mixture
  3. customwas quenched with water
  4. extractionextracted with ethyl acetate (3×50 mL)
  5. washThe combined organic layers were washed with brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by flash chromatography on a silica gel column with MeOH in dichloromethylene (0-5%)

Sources & evidence

ORD record
ord-bf88cf2224314c7fae4da4097eae38d7
Source dataset
uspto-grants-2014_04
Patent number
US08691807B2

Reaction notes

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