2-Bromopyridine → 1-((2S,4R)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone

HRID 882301Notes

Reaction equation

HRID 882301 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]=[CH:34][N:33]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(N(C)C)=CC=CC=2)CCCCC1.CC(C)([O-])C.[Na+]>O1CCOCC1.C(#N)C.C(=O)(O)[O-].[NH4+].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]>[CH3:30][C@H:5]1[CH2:4][C@@H:3]([NH:2][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][N:33]=2)[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]1[C:27](=[O:29])[CH3:28]

Participants

9

Reactant 4

HCID 79732-BromopyridineHCID 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 714679391-((2S,4R)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanoneYield 38%

Reagents, catalysts & solvents 4

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 6342AcetonitrileSolventHCID 14013Ammonium BicarbonateSolventHCID 312751,4-DioxaneSolvent

Conditions

Temperature
130 °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) (100 mg, 0.232 mmol), 2-bromopyridine (0.044 mL, 0.464 mmol), 2′-(dicyclohexylphosphino)-N,N-dimethyl-[1,1′-biphenyl]-2-amine (18.3 mg, 0.046 mmol), tris(dibenzylideneacetone)dipalladium(0) (21.3 mg, 0.023 mmol) and sodium tert-butoxide (66.9 mg, 0.696 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 130° C. for 25 mins. The reaction mixture was partitioned between saturated aqueous sodium bicarbonate (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 dissolved in acetonitrile (20 mL) and 0.1M aq. ammonium bicarbonate (20 mL). The mixture was filtered, and the filtrate concentrated in vacuo to give a residue which was purified by MDAP (HpH) to give 1-((2S,4R)-2-methyl-6-(5-(morpholine-4-carbonyl)pyridin-2-yl)-4-(pyridin-2-ylamino)-3,4-dihydroquinolin-1(2H)-yl)ethanone (41 mg, 0.087 mmol, 38% yield). LCMS: (Formate, 2 min), Rt=0.55 mins, MH+472

Workup

  1. customthe mixture degassed over a period of 15 mins
  2. customThe reaction mixture was partitioned between saturated aqueous sodium bicarbonate (50 mL) and DCM (3×50 mL)
  3. customdried
  4. concentrationconcentrated in vacuo
  5. customto give a residue which
  6. filtrationThe mixture was filtered
  7. concentrationthe filtrate concentrated in vacuo
  8. customto give a residue which
  9. customwas purified by MDAP (HpH)

Sources & evidence

ORD record
ord-9c0572a2e2114f84a7157c36c7b10be6
Source dataset
uspto-grants-2015_03
Patent number
US08993554B2

Reaction notes

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