2-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl → 1-((2S,4R)-4-((5-fluoropyridin-2-yl)amino)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

HRID 882305Notes

Reaction equation

HRID 882305 reaction equation
[NH2:1][C@H:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([C:18]([N:20]4[CH2:25][CH2:24][O:23][CH2:22][CH2:21]4)=[O:19])=[CH:16][CH:17]=3)[CH:10]=2)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]1.Br[C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][N:32]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.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]>[F:37][C:34]1[CH:35]=[CH:36][C:31]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][C:15]([C:18]([N:20]5[CH2:25][CH2:24][O:23][CH2:22][CH2:21]5)=[O:19])=[CH:16][CH:17]=4)[CH:10]=3)[N:5]([C:26](=[O:28])[CH3:27])[C@@H:4]([CH3:29])[CH2:3]2)=[N:32][CH:33]=1

Participants

7

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenyl2×HCID 27831712-Bromo-5-fluoropyridine2×HCID 23676156Sodium t-butoxideHCID 867094251-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

Product 1

HCID 714682561-((2S,4R)-4-((5-fluoropyridin-2-yl)amino)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanoneYield 51%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalyst2×HCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

1-((2S,4R)-4-amino-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation, see Intermediate 56) (145 mg, 0.368 mmol), 2-bromo-5-fluoropyridine (129 mg, 0.735 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (29 mg, 0.074 mmol), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol) and sodium tert-butoxide (71 mg, 0.739 mmol) were combined in 1,4-dioxane (4 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 30 mins. A further portion of 2-bromo-5-fluoropyridine (129 mg, 0.735 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (29 mg, 0.074 mmol), tris(dibenzylideneacetone)dipalladium(0) (34 mg, 0.037 mmol) were added, The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 30 mins. The mixture was partitioned between water (20 mL) and DCM (3×15 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by chromatography (25 g column, (MeOH/DCM gradient) to give 1-((2S,4R)-4-((5-fluoropyridin-2-yl)amino)-2-methyl-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (91 mg, 0.186 mmol, 51% yield). LCMS: (Formate, 2 min), Rt=0.73 mins, MH+490.

Workup

  1. customThe mixture was degassed over a period of 15 mins
  2. customThe mixture was degassed over a period of 15 mins
  3. temperaturebefore being heated under microwave irradiation to 120° C. for 30 mins
  4. customThe mixture was partitioned between water (20 mL) and DCM (3×15 mL)
  5. customdried
  6. concentrationconcentrated in vacuo
  7. customThe resulting residue was purified by chromatography (25 g column, (MeOH/DCM gradient)

Sources & evidence

ORD record
ord-e660f02616b34c049961034f0e645f9e
Source dataset
uspto-grants-2015_03
Patent number
US08993554B2

Reaction notes

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