Potassium Carbonate → 2-(4-trifluoromethylphenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide

HRID 1898649Notes

Reaction equation

HRID 1898649 reaction equation
[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21](Br)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2].[F:34][C:35]([F:46])([F:45])[C:36]1[CH:41]=[CH:40][C:39](B(O)O)=[CH:38][CH:37]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)(O)[O-].[Na+]>O1CCOCC1.O.[Cl-].[Cl-].C1(P([C-]2C=CC=C2)C2C=CC=CC=2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Pd+2].C(OCC)(=O)C>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:33])[C@H:8]([NH:12][C:13]([C:15]2[C:23]3[C:18](=[N:19][CH:20]=[C:21]([C:39]4[CH:40]=[CH:41][C:36]([C:35]([F:46])([F:45])[F:34])=[CH:37][CH:38]=4)[N:22]=3)[N:17]([CH2:25][O:26][CH2:27][CH2:28][Si:29]([CH3:32])([CH3:31])[CH3:30])[CH:16]=2)=[O:14])[CH:9]2[CH2:11][CH2:10]2)[CH2:4]1)#[N:2]

Participants

9

Reactant 4

HCID 11430Potassium CarbonateHCID 516892Sodium BicarbonateHCID 27343894-(Trifluoromethyl)phenylboronic acidHCID 58438590HCID 58438590, compound

Product 1

HCID 673864092-(4-trifluoromethylphenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amideYield 66.8%

Reagents, catalysts & solvents 4

HCID 178478645Bis(cyclopenta-1,4-dien-1-yl(diphenyl)phosphane);dichloropalladium;iron(2+)CatalystHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
150 °C

Procedure

In a microwave vial, 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide (80 mg, 0.15 mmol) was dissolved in 1.5 mL of 1,4-dioxane and 0.35 mL of water. The solution was purged with Ar gas then 4-(trifluoromethyl)phenylboronic acid (31 mg, 0.165 mmol), palladium bis-(diphenylphosphino)ferrocene dichloride, dichloromethane complex (6.1 mg, 0.008 mmol) and potassium carbonate (62 mg, 0.45 mmol) were added. The reaction vessel was sealed and heated in a microwave reactor at 150° C. for 30 min. The reaction was cooled and water and ethyl acetate were added. The mixture was poured into ethyl acetate and sodium bicarbonate solution. The layers were separated and the aqueous layer was extracted twice more with ethyl acetate. The combined organic layers were washed with brine and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (methanol/dichloromethane) to give 60 mg (66%) of 2-(4-trifluoromethylphenyl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-cyclopropyl-2-oxo-ethyl]-amide.

Workup

  1. customThe solution was purged with Ar gas
  2. customThe reaction vessel was sealed
  3. temperatureThe reaction was cooled
  4. customThe layers were separated
  5. extractionthe aqueous layer was extracted twice more with ethyl acetate
  6. washThe combined organic layers were washed with brine
  7. dry with materialdried over sodium sulfate
  8. customAfter evaporation
  9. customthe residue was purified by silica gel chromatography (methanol/dichloromethane)

Sources & evidence

ORD record
ord-4dd442c15e564bcdbd6282e403c0b4d7
Source dataset
uspto-grants-2013_08
Patent number
US08518945B2

Reaction notes

Loading…