2-Dicyclohexylphosphino-2',4',6'-triisoprophylbiphenyl → 5,7-difluoro-N-(6'-methoxy-5-morpholino-2,3'-bipyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine

HRID 1431566Notes

Reaction equation

[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([C:9]2[C:14]([NH2:15])=[CH:13][C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:32]2[C:27](=[CH:28][C:29]([F:34])=[CH:30][C:31]=2[F:33])[N:26]=[C:25]([C:35]2[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=2)[C:24]=1[CH3:42].C1(P(C2CCCCC2)C2(C(C)C)CC(C(C)C)=CC(C(C)C)=C2C2C=CC=CC=2)CCCCC1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CC(C)([O-])C.[Na+]>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].O>[F:33][C:31]1[CH:30]=[C:29]([F:34])[CH:28]=[C:27]2[C:32]=1[C:23]([NH:15][C:14]1[C:9]([C:6]3[CH:7]=[N:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=3)=[N:10][CH:11]=[C:12]([N:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH:13]=1)=[C:24]([CH3:42])[C:25]([C:35]1[CH:40]=[C:39]([CH3:41])[CH:38]=[CH:37][N:36]=1)=[N:26]2

Participants

Conditions

Temperature: 100 °C

Procedure

A mixture of 6′-methoxy-5-morpholino-2,3′-bipyridin-3-amine (51.7 mg, 0.18 mmol), 4-chloro-5,7-difluoro-3-methyl-2-(4-methylpyridin-2-yl)quinoline (45.2 mg, 0.15 mmol), 2-dicyclohexylphosphino-2,4,6,-triisopropylbiphenyl, (X-Phos) (12.6 mg, 0.026 mmol), tris(dibenzylideneacetone)dipalladium (0) (6.4 mg, 6.99 μmol), and sodium tert-butoxide (36.6 mg, 0.38 mmol) in dry toluene (1.5 mL) was degassed by nitrogen. The resulting reaction was heated to 100° C. and monitored with TLC and LC-MS. After 18 h, the reaction was cooled to rt then poured into water. After extracting twice with EtOAc and twice with DCM, the combined organic extractions were dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on basic alumina (5-50% EtOAc in hexanes) to afford an impure orange residue. The light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution). The desired fractions were cond then diluted with EtOAc. After washing twice with satd aq. sodium bicarbonate solution and once with brine, the solvent was removed under reduced pressure to yield a light yellow solid as 5,7-difluoro-N-(6′-methoxy-5-morpholino-2,3′-bipyridin-3-yl)-3-methyl-2-(4-methylpyridin-2-yl)quinolin-4-amine. 1H NMR (400 MHz, CDCl3) δ ppm 8.65 (1H, dd, J=2.4, 0.7 Hz), 8.54 (1H, dd, J=4.9, 0.6 Hz), 8.08 (2H, m), 7.71 (1H, m), 7.61 (1H, ddd, J=9.7, 2.4, 1.4 Hz), 7.20 (1H, ddd, J=5.0, 1.6, 0.8 Hz), 7.00 (3H, m), 6.53 (1H, d, J=2.5 Hz), 4.00 (3H, s), 3.92 (4H, m), 3.25 (4H, m), 2.49 (3H, s), 2.21 (3H, s). Mass Spectrum (pos.) m/e: 555.2 (M+1).

Workup

customwas degassed by nitrogen
customThe resulting reaction
temperaturethe reaction was cooled to rt
extractionAfter extracting twice with EtOAc and twice with DCM
extractionthe combined organic extractions
dry with materialwere dried over anhydrous magnesium sulfate
filtrationAfter filtration and concentration
customthe residue was purified on basic alumina (5-50% EtOAc in hexanes)
customto afford an impure orange residue
customThe light orange film was further purified with HPLC (10-90% of 0.1% TFA acetonitrile solution in 0.1% TFA water solution)
additionThe desired fractions were cond then diluted with EtOAc
washAfter washing twice with satd aq. sodium bicarbonate solution and once with brine
customthe solvent was removed under reduced pressure

Sources & evidence

ORD record: ord-d318d571ec654e25bb54da84e8b400c0
Source dataset: uspto-grants-2015_01
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US08940724B2

Reaction notes

Loading…