2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → 3-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridine

HRID 872067Notes

Reaction equation

HRID 872067 reaction equation
Br[C:2]1[C:3]([O:12][CH2:13][C@H:14]2[CH2:16][C@@H:15]2[C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=2)=[N:4][C:5]2[C:10]([CH:11]=1)=[N:9][CH:8]=[CH:7][CH:6]=2.[N:25]1[C:34]2[CH2:33][CH2:32][NH:31][CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1.CC(C)([O-])C.[Na+].CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C>C1(C)C=CC=CC=1.CCOC(C)=O.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]>[N:25]1[C:34]2[CH2:33][CH2:32][N:31]([C:2]3[C:3]([O:12][CH2:13][C@H:14]4[CH2:16][C@@H:15]4[C:17]4[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][N:18]=4)=[N:4][C:5]4[C:10]([CH:11]=3)=[N:9][CH:8]=[CH:7][CH:6]=4)[CH2:30][C:29]=2[CH:28]=[CH:27][CH:26]=1

Participants

8

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 131938825,6,7,8-Tetrahydro-1,6-naphthyridineHCID 23676156Sodium t-butoxideHCID 1176891283-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]-methoxy}-1,5-naphthyridine

Product 1

HCID 1176891403-(7,8-dihydro-1,6-naphthyridin-6(5H)-yl)-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridine

Reagents, catalysts & solvents 3

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

Conditions

Temperature
100 °C

Procedure

A mixture of 3-bromo-2-{[(1S,2S)-2-(5-methoxypyridin-2-yl)cyclopropyl]methoxy}-1,5-naphthyridine (LL1) (25 mg, 0.07 mmol), 5,6,7,8-tetrahydro-1,6-naphthyridine (16.1 mg, 0.08 mmol), sodium t-butoxide (21.8 mg, 0.23 mmol), DavePhos (3.8 mg, 0.009 mmol) and tris(dibenzylideneacetone)dipalladium(0) (4.5 mg, 0.005 mol) in toluene (0.3 mL) was heated at 100° C. for 14 hours. The reaction mixture was allowed to cool to room temperature. The mixture was then diluted with EtOAc (5 mL), washed with sodium bicarbonate (1 mL) and brine (1 mL), dried over MgSO4, filtered and concentrated. The crude residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier) to afford the title compound. 1H NMR (500 MHz, DMSO): δ 8.69 (d, J=4.3 Hz, 1 H), 8.38 (d, J=4.8 Hz, 1 H), 8.14 (s, 1 H), 8.06 (d, J=8.3 Hz, 1 H), 7.61-7.53 (m, 2 H), 7.49 (dd, J=8.4, 4.4 Hz, 1 H), 7.27 (s, 2 H), 7.20 (dd, J=7.9, 4.9 Hz, 1 H), 4.63 (dd, J=11.2, 6.4 Hz, 1 H), 4.47-4.36 (m, 3 H), 3.79 (s, 3 H), 3.70-3.59 (m, 2 H), 2.93 (s, 2 H), 2.27-2.23 (m, 1 H), 1.85 (s, 1 H), 1.24 (m, 1 H), 1.12 (dd, J=8.7, 5.4 Hz, 1 H); LRMS m/z (M+H) 440.3 found, 440.2 required.

Workup

  1. temperatureto cool to room temperature
  2. washwashed with sodium bicarbonate (1 mL) and brine (1 mL)
  3. dry with materialdried over MgSO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified by reverse phase chromatography (Waters Sunfire Prep C18 OBD, 5-60% acetonitrile in water with 0.1% TFA modifier)

Sources & evidence

ORD record
ord-70cb3eaee8eb4fd59beef8b93e0c836e
Source dataset
uspto-grants-2015_03
Patent number
US08975261B2

Reaction notes

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