1,8-Diazabicyclo(5.4.0)undec-7-ene → tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate

HRID 1617362Notes

Reaction equation

HRID 1617362 reaction equation
[C:1]([O:5][C:6]([N:8]1[CH2:11][C:10](=[CH:12][C:13]#[N:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:15]1[CH:19]=[CH:18][C:17]([C:20]2[C:21]3[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=3[N:23]=[CH:24][N:25]=2)=[CH:16]1.N12CCCN=C1CCCCC2>C(#N)C>[C:13]([CH2:12][C:10]1([N:15]2[CH:19]=[CH:18][C:17]([C:20]3[C:21]4[CH:28]=[CH:27][N:26]([CH2:29][O:30][CH2:31][CH2:32][Si:33]([CH3:36])([CH3:35])[CH3:34])[C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16]2)[CH2:11][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]1)#[N:14]

Participants

5

Reactant 3

HCID 811841,8-Diazabicyclo(5.4.0)undec-7-eneHCID 457892161-(tert-Butoxycarbonyl)-3-(cyanomethylene)azetidineHCID 584312944-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine

Product 1

HCID 58431347tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylateYield 83%

Reagents, catalysts & solvents 1

HCID 6342AcetonitrileSolvent

Procedure

A 100 mL round bottom flask fitted with overhead stirring, septa and nitrogen inlet was charged with tert-butyl-3-(cyanomethylene)azetidine-1-carboxylate (1.8 g, 9.5 mmol), 4-(1H-pyrrol-3-yl)-7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 9.5 mmol) and acetonitrile (60 mL). The resulting solution was heterogeneous. 1,8-Diazabicyclo[5.4.0]undec-7-ene (1.4 mL, 9.5 mmol) was added portionwise via a syringe over 3 minutes at room temperature. The solution slowly becomes homogeneous and yellow in color. The reaction was allowed to stir at room temperature for 3 hours. The solution was concentrated by rotary evaporation to remove acetonitrile. EtOAc (100 mL) and brine (100 mL) were added. The organic phase was separated and the aqueous layer was extracted with 3×30 mL EtOAc. The combined extracts were dried over anhydrous MgSO4, filtered and concentrated in vacuo to yield an orange oil which was purified by flash chromatography (120 grams silica, 30-55% EtOAc/hexane, loaded with CH2Cl2). Desired fractions were combined and concentrated to yield a yellow oil which was placed on a high vacuum pump to give 4 g (83%) of tert-butyl 3-(cyanomethyl)-3-[3-(7-{[2-(trimethylsilyl)ethoxy]methyl}-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-1H-pyrrol-1-yl]azetidine-1-carboxylate as a white foam. LC-MS: [M+H]+=509.3.

Workup

  1. customA 100 mL round bottom flask fitted with overhead
  2. stirringto stir at room temperature for 3 hours
  3. concentrationThe solution was concentrated by rotary evaporation
  4. customto remove acetonitrile
  5. additionEtOAc (100 mL) and brine (100 mL) were added
  6. customThe organic phase was separated
  7. extractionthe aqueous layer was extracted with 3×30 mL EtOAc
  8. dry with materialThe combined extracts were dried over anhydrous MgSO4
  9. filtrationfiltered
  10. concentrationconcentrated in vacuo
  11. customto yield an orange oil which
  12. customwas purified by flash chromatography (120 grams silica, 30-55% EtOAc/hexane, loaded with CH2Cl2)
  13. concentrationconcentrated
  14. customto yield a yellow oil which

Sources & evidence

ORD record
ord-ffbbaa6f5c6a443baed05b90806f843c
Source dataset
uspto-grants-2014_07
Patent number
US08765734B2

Reaction notes

Loading…