Cesium carbonate → 1-Cyclopropyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester

HRID 2264949Notes

Reaction equation

HRID 2264949 reaction equation
[CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:16][CH2:15]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH2:17])=[O:4].[F:18][C:19]1[CH:24]=[C:23]([Si:25]([CH3:28])([CH3:27])[CH3:26])[CH:22]=[CH:21][C:20]=1OS(C(F)(F)F)(=O)=O.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C([O-])([O-])=O.[Cs+].[Cs+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:13]([CH:14]2[CH2:15][CH2:16]2)[C:12]2[CH:11]=[CH:10][N:9]=[CH:8][C:7]=2[C:6]=1[NH:17][C:20]1[CH:21]=[CH:22][C:23]([Si:25]([CH3:27])([CH3:26])[CH3:28])=[CH:24][C:19]=1[F:18])=[O:4]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 59596436Trifluoromethanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl esterHCID 595965463-Amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester

Product 1

HCID 595964891-Cyclopropyl-3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl esterYield 71.7%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
105 °C

Procedure

To a degassed suspension of 3-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (215.0 mg, 0.93 mmol), and trifluoro-methanesulfonic acid 2-fluoro-4-trimethylsilanyl-phenyl ester (323.5 mg, 1.02 mmol, 1.1 eq) in anhydrous toluene (6.2 mL) was added Pd2dba3 (85.2 mg, 0.09 mmol, 0.1 eq), Xantphos (107.6 mg, 0.186 mmol, 0.2 eq) and Cs2CO3 (606.0 mg, 1.86 mmol, 2.0 eq). The reaction mixture was degassed with bubbling nitrogen for 10 minutes and stirred at 105° C. under N2 for 17 h. The reaction mixture was cooled to room temperature and diluted with ethyl acetate (150 ml). The mixture was then filtered through a pad of Celite®. The celite pad was rinsed with EtOAc (2×50 mL), and the filtrate was concentrated under reduced pressure. The crude residue was then purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane) to afford the title compound as a yellow foam (265 mg, 71.7%). 1H-NMR (400 MHz, DMSO-d6) δ ppm 8.52 (s, 1H), 8.33 (d, J=6.0 Hz, 1H), 7.86 (s, 1H), 7.55 (d, J=6.0 Hz, 1H), 7.29 (d, J=11.6 Hz, 1H), 7.13 (d, J=7.9 Hz, 1H), 6.90 (s, 1H), 3.82 (s, 3H), 3.57-3.46 (m, 1H), 1.27-1.03 (m, 2H), 0.96-0.71 (m, 2H), 0.23 (s, 9H); LC-MS (method D): [M+H]+=398.2, RT=2.69 min.

Workup

  1. customThe reaction mixture was degassed with bubbling nitrogen for 10 minutes
  2. temperatureThe reaction mixture was cooled to room temperature
  3. additiondiluted with ethyl acetate (150 ml)
  4. filtrationThe mixture was then filtered through a pad of Celite®
  5. washThe celite pad was rinsed with EtOAc (2×50 mL)
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. customThe crude residue was then purified by flash column chromatography (silica, ISCO, 45 mL/min, 25 to 100% EtOAc in hexane)

Sources & evidence

ORD record
ord-bc88cab3d4b84e3dbdb362c7817d3605
Source dataset
uspto-grants-2010_12
Patent number
US07855216B2

Reaction notes

Loading…