1,8-Diazabicyclo(5.4.0)undec-7-ene → cis-{1-[3-Methoxypiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrile

HRID 1617386Notes

Reaction equation

HRID 1617386 reaction equation
[NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[C:23]([CH:25]=[C:26]1[CH2:29][N:28]([C@H:30]2[CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][C@H:31]2[O:43][CH3:44])[CH2:27]1)#[N:24].N12CCCN=C1CCCCC2>C(#N)C.C1COCC1.O1CCOCC1>[CH3:44][O:43][C@H:31]1[C@@H:30]([N:28]2[CH2:29][C:26]([CH2:25][C:23]#[N:24])([N:1]3[CH:5]=[C:4]([C:6]4[C:7]5[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=5[N:9]=[CH:10][N:11]=4)[CH:3]=[N:2]3)[CH2:27]2)[CH2:35][CH2:34][NH:33][CH2:32]1

Participants

7

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 426313464-(1H-Pyrazol-4-yl)-7-(2-(trimethylsilyl)ethoxy)methyl-7 H-pyrrolo(2,3-d)-pyrimidineHCID 67392031tert-Butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-methoxypiperidine-1-carboxylate

Product 1

HCID 67391296cis-{1-[3-Methoxypiperidin-4-yl]-3-[4-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrazol-1-yl]azetidin-3-yl}acetonitrileYield 86%

Reagents, catalysts & solvents 3

HCID 6342AcetonitrileSolventHCID 8028TetrahydrofuranSolventHCID 312751,4-DioxaneSolvent

Procedure

To a solution of 4-(1H-pyrazol-4-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (0.256 g, 0.812 mmol) in acetonitrile (10 mL) were added tert-butyl cis-4-[3-(cyanomethylene)azetidin-1-yl]-3-methoxypiperidine-1-carboxylate (0.20 g, 0.68 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (0.152 mL, 1.02 mmol). After being stirred at room temperature for 5 minutes, the reaction mixture became a clear solution. Stirring was continued at room temperature overnight. LC-MS indicated the reaction was complete. The solution was concentrated under reduced pressure and ethyl acetate was added. The resulting solution was washed with 1 N HCl and brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (20-100% EtOAc/hexanes) afforded an oily product. The product was dissolved in THF (5 mL). To it was added 4 N HCl in dioxane (5 mL). After being stirred at room temperature for 2 hours, the solution was concentrated under reduced pressure to give 0.30 g (86%) of the title compound as a solid. LCMS: 511.1 (M+1)+.

Workup

  1. stirringStirring
  2. waitwas continued at room temperature overnight
  3. concentrationThe solution was concentrated under reduced pressure and ethyl acetate
  4. additionwas added
  5. washThe resulting solution was washed with 1 N HCl and brine
  6. dry with materialdried over sodium sulfate
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customPurification by silica gel chromatography (20-100% EtOAc/hexanes)
  10. customafforded an oily product
  11. stirringAfter being stirred at room temperature for 2 hours
  12. concentrationthe solution was concentrated under reduced pressure

Sources & evidence

ORD record
ord-c139b8ef22de488a93f77ed8da562b46
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

Loading…