2-Fluoroaniline → 5-cyclopropyl-2-{4-[(2-fluorophenyl)amino]phenyl}-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamide

HRID 1037540Notes

Reaction equation

HRID 1037540 reaction equation
Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([C:17]([NH:19][CH3:20])=[O:18])=[C:15]3[C:10]([CH:11]=[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])[C:13]([CH:21]4[CH2:23][CH2:22]4)=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[F:33][C:34]1[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=1[NH2:36].C1(P(C2C=CC=CC=2)C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.CCOC(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH:21]1([C:13]2[C:12]([N:24]([CH2:29][CH2:30][CH2:31][OH:32])[S:25]([CH3:28])(=[O:27])=[O:26])=[CH:11][C:10]3[C:15](=[C:16]([C:17]([NH:19][CH3:20])=[O:18])[N:8]([C:5]4[CH:6]=[CH:7][C:2]([NH:36][C:35]5[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=5[F:33])=[CH:3][CH:4]=4)[N:9]=3)[CH:14]=2)[CH2:23][CH2:22]1

Participants

8

Reactant 4

HCID 95842-FluoroanilineHCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 569627692-(4-bromophenyl)-5-cyclopropyl-6-[3-hydroxypropyl(methylsulfonyl)amino]-N-methyl-indazole-3-carboxamide

Product 1

HCID 569627705-cyclopropyl-2-{4-[(2-fluorophenyl)amino]phenyl}-6-[(3-hydroxypropyl)(methylsulfonyl)amino]-N-methyl-2H-indazole-3-carboxamideYield 22%

Reagents, catalysts & solvents 3

HCID 167845palladium(II) acetateCatalystHCID 1140TolueneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
100 °C

Procedure

A mixture of Compound (4) (16 mg, 31 μmol), 2-fluoroaniline (4.4 μL, 46 μmol), 2,2′-bis(diphenylphosphino)-1,1′-binaphthalene (4 mg, 6 μmol) and cesium carbonate (30 mg, 92 μmol) in toluene (0.5 mL) and 1,2-dimethoethane (0.2 mL) was placed in a high pressure vial. Nitrogen was bubbled through the mixture for ˜20 min. Palladium acetate (0.7 mg, 3 μmol) was then added and the vial was sealed. The mixture was heated to 100° C. and stirred for 16 h. After cooling to RT, the mixture was diluted with EtOAc (10 mL) and filtered through a pad of Celite®. The filtrate was concentrated in vacuo to give a crude mixture which was purified by flash column chromatography eluting with MeOH/DCM (0-20%). Further purification was done by preparative HPLC to give Compound (5) (3.68 mg, 22%) as a pale yellow solid. ESI-MS m/z calculated for [M+H]+: 552.21; found: 552.14. 1H NMR (400 MHz, CDCl3) δ 7.73 (s, 1H), 7.52 (s, 1H), 7.49-7.43 (m, 2H), 7.41 (dt, J=8.2, 1.5 Hz, 1H), 7.20-7.07 (m, 4H), 7.04-6.93 (m, 1H), 6.01 (brd, J=1.8 Hz, 1H), 5.71 (brd, J=4.6 Hz, 1H), 4.02-3.63 (m, 4H), 3.07 (s, 3H), 2.95 (d, J=4.9 Hz, 3H), 2.51-2.25 (m, 1H), 1.87-1.74 (m, 2H), 1.13-0.94 (m, 3H), 0.74-0.55 (m, 1H).

Workup

  1. customNitrogen was bubbled through the mixture for ˜20 min
  2. customthe vial was sealed
  3. temperatureAfter cooling to RT
  4. filtrationfiltered through a pad of Celite®
  5. concentrationThe filtrate was concentrated in vacuo
  6. customto give a crude mixture which
  7. customwas purified by flash column chromatography
  8. washeluting with MeOH/DCM (0-20%)
  9. customFurther purification

Sources & evidence

ORD record
ord-05bcc35ea1344e2dbc492f5201f44c32
Source dataset
uspto-grants-2013_10
Patent number
US08546389B2

Reaction notes

Loading…