Potassium Phosphate, Tribasic → 1-Cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester

HRID 2264951Notes

Reaction equation

HRID 2264951 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]([S:25][CH3:26])[CH:22]=[CH:21][C:20]=1N.C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.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]([S:25][CH3:26])=[CH:24][C:19]=1[F:18])=[O:4]

Participants

8

Reactant 4

HCID 62657Potassium Phosphate, TribasicHCID 6360441,1'-(9,9-Dimethyl-9H-xanthene-4,5-diyl)bis(1,1-diphenylphosphine)HCID 220256172-Fluoro-4-(methylsulfanyl)anilineHCID 595965463-Amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester

Product 1

HCID 595965861-Cyclopropyl-3-(2-fluoro-4-methylsulfanyl-phenylamino)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl esterYield 68.7%

Reagents, catalysts & solvents 3

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

In a high-pressure tube was placed 3-amino-1-cyclopropyl-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (307.6 mg, 1.33 mmol), 2-fluoro-4-methylsulfanyl-phenylamine (500.0 mg, 2.26 mmol, 1.7 eq), 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene (115.5 mg, 0.20 mmol, 1.5 eq), tris(dibenzylideneacetone)di-palladium(0) (91.4 mg, 0.10 mmol, 0.75 eq), and potassium phosphate (564.7 mg, 2.6 mmol, 2.0 eq) in degassed anhydrous toluene (21 mL). The tube was sealed tightly and the reaction mixture was heated to 100° C. for 17 h and cooled to room temperature. The reaction mixture was diluted with ethyl acetate (100 ml) and 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 an orange glassy solid (339.6 mg, 68.7%). 1H-NMR (500 MHz, MeOD) δ ppm 8.36 (s, 1H), 8.24 (d, J=6.13 Hz, 1H), 7.59 (d, J=6.14 Hz, 1H), 7.14 (d, J=11.72 Hz, 1H), 7.08-6.93 (m, 2H), 3.95 (s, 3H), 3.59-3.47 (m, 1H), 2.47 (s, 3H), 1.25-1.21 (m, 2H), 0.92-0.89 (m, 2H); LC-MS (method C): [M+H]+=371.8, RT=0.80 min.

Workup

  1. customIn a high-pressure tube was placed
  2. customThe tube was sealed tightly
  3. temperaturecooled to room temperature
  4. filtrationfiltered 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-82bd72d2da344a3f9f3303176c4ba92b
Source dataset
uspto-grants-2010_12
Patent number
US07855216B2

Reaction notes

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