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

HRID 882295Notes

Reaction equation

HRID 882295 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]=[N:35][C:34]([CH3:37])=[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]>[CH3:29][C@H:4]1[CH2:3][C@@H:2]([NH:1][C:31]2[CH:36]=[N:35][C:34]([CH3:37])=[CH:33][N:32]=2)[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]1[C:26](=[O:28])[CH3:27]

Participants

7

Reactant 4

HCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 224193462-Bromo-5-methylpyrazineHCID 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 709767771-((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanoneYield 26%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 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) (80 mg, 0.203 mmol), 2-bromo-5-methylpyrazine (70.2 mg, 0.406 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1-biphenyl]-2-amine (16.0 mg, 0.041 mmol), tris(dibenzylideneacetone)dipalladium(0) (18.6 mg, 0.020 mmol) and sodium tert-butoxide (27.3 mg, 0.284 mmol) were combined in 1,4-dioxane (2 mL). The mixture was degassed over a period of 15 mins before being heated under microwave irradiation to 120° C. for 25 mins. The mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3×50 mL). The organic layers were combined, dried by passing through a hydrophobic frit and concentrated in vacuo. The resulting residue was purified by MDAP (HpH) followed by further purification by MDAP (Formate) to give 1-((2S,4R)-2-methyl-4-((5-methylpyrazin-2-yl)amino)-6-(6-(morpholine-4-carbonyl)pyridin-3-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (26 mg, 0.053 mmol, 26% yield).

Workup

  1. customThe mixture was degassed over a period of 15 mins
  2. customThe mixture was partitioned between saturated aq. sodium bicarbonate (50 mL) and DCM (3×50 mL)
  3. customdried
  4. concentrationconcentrated in vacuo
  5. customThe resulting residue was purified by MDAP (HpH)
  6. customfollowed by further purification by MDAP (Formate)

Sources & evidence

ORD record
ord-8c8cf7a89bd541da92c1d76830c85396
Source dataset
uspto-grants-2015_03
Patent number
US08993554B2

Reaction notes

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