1-Bromo-3-chlorobenzene → 1-((2S,4R)-4-((3-chlorophenyl)amino)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone

HRID 882303Notes

Reaction equation

HRID 882303 reaction equation
Cl.[NH2:2][C@H:3]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]3[CH:18]=[CH:17][C:16]([C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:20])=[CH:15][N:14]=3)[CH:11]=2)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]1.Br[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([Cl:38])[CH:33]=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]>[Cl:38][C:34]1[CH:33]=[C:32]([NH:2][C@H:3]2[C:12]3[C:7](=[CH:8][CH:9]=[C:10]([C:13]4[CH:18]=[CH:17][C:16]([C:19]([N:21]5[CH2:26][CH2:25][O:24][CH2:23][CH2:22]5)=[O:20])=[CH:15][N:14]=4)[CH:11]=3)[N:6]([C:27](=[O:29])[CH3:28])[C@@H:5]([CH3:30])[CH2:4]2)[CH:37]=[CH:36][CH:35]=1

Participants

7

Reactant 4

HCID 79281-Bromo-3-chlorobenzeneHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 867094321-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride

Product 1

HCID 714681401-((2S,4R)-4-((3-chlorophenyl)amino)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanoneYield 9.2%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 312751,4-DioxaneSolvent

Conditions

Temperature
120 °C

Procedure

1-((2S,4R)-4-amino-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone hydrochloride (for a preparation see Intermediate 65) (120 mg, 0.278 mmol), 1-bromo-3-chlorobenzene (0.065 mL, 0.557 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (21.9 mg, 0.056 mmol), tris(dibenzylideneacetone)dipalladium(0) (25.5 mg, 0.028 mmol) and sodium tert-butoxide (37.5 mg, 0.390 mmol) were combined in 1,4-dioxane (2 mL) and the mixture degassed over a period of 15 mins, before being heated under microwave irradiation to 120° C. for 25 mins. The reaction mixture was partitioned between water (50 mL) and DCM (3×50 mL). The organics were combined, dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-4-((3-chlorophenyl)amino)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-3,4-dihydroquinolin-1(2H)-yl)ethanone (13 mg, 0.026 mmol, 9.2% yield).

Workup

  1. customthe mixture degassed over a period of 15 mins
  2. customThe reaction mixture was partitioned between water (50 mL) and DCM (3×50 mL)
  3. customdried
  4. concentrationconcentrated in vacuo
  5. customto give a residue which
  6. customwas purified by MDAP (HpH)

Sources & evidence

ORD record
ord-0316751964d34c3ca54f0047eab1dcfb
Source dataset
uspto-grants-2015_03
Patent number
US08993554B2

Reaction notes

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