2-Bromopyridine → ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate

HRID 882257Notes

Reaction equation

HRID 882257 reaction equation
CC(C)([O-])C.[Na+].[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH2:31])[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8].Br[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1>C1(C)C=CC=CC=1>[C:7]([N:10]1[C:19]2[C:14](=[CH:15][C:16]([C:20]3[CH:30]=[CH:29][C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:22][CH:21]=3)=[CH:17][CH:18]=2)[C@H:13]([NH:31][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=2)[CH2:12][C@@H:11]1[CH3:32])(=[O:9])[CH3:8]

Participants

6

Reactant 4

HCID 79732-BromopyridineHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 67205707ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate

Product 1

HCID 86709426ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoateYield 39%

Reagents, catalysts & solvents 1

HCID 1140TolueneSolvent

Conditions

Temperature
120 °C

Procedure

Sodium tert-butoxide (135 mg, 1.41 mmol)) was added to a suspension of ethyl 4-((2S,4R)-1-acetyl-4-amino-2-methyl-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (for a preparation see Intermediate 16) (450 mg, 1.28 mmol), 2-bromopyridine (403 mg, 2.55 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (40 mg, 0.102 mmol) and tris(dibenzyldieneacetone)dipalladium(0) (47 mg, 0.051 mmol) in anhydrous toluene (4.5 mL). The mixture was heated under microwave irradiation to 120° C. for 1 h in a sealed vial. The mixture was partitioned between EtOAc and water, the aqueous layer was extracted twice with EtOAc, the combined organic phases were dried by passing through a hydrophobic frit and concentrated in vacuo to give a residue. The residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient) to give ethyl 4-((2S,4R)-1-acetyl-2-methyl-4-(pyridin-2-ylamino)-1,2,3,4-tetrahydroquinolin-6-yl)benzoate (216 mg, 0.503 mmol, 39% yield) as a brown gum. LCMS: (Formate, 2 min), Rt=0.84 min, MH+430.

Workup

  1. customThe mixture was partitioned between EtOAc and water
  2. extractionthe aqueous layer was extracted twice with EtOAc
  3. customthe combined organic phases were dried
  4. concentrationconcentrated in vacuo
  5. customto give a residue
  6. customThe residue was purified by chromatography (10 g column, EtOAc/cyclohexane gradient followed by MeOH/EtOAc gradient)

Sources & evidence

ORD record
ord-88325e161bcd4fc3ab5e4e5de68fc8f6
Source dataset
uspto-grants-2015_03
Patent number
US08993554B2

Reaction notes

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