2-Bromo-5-chloropyridine → 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

HRID 628959Notes

Reaction equation

HRID 628959 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][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=3)[CH:10]=2)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]1.Br[C:26]1[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][N:27]=1.CN(C1C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=CC=CC=1)C.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:32][C:29]1[CH:30]=[CH:31][C:26]([NH:1][C@H:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([C:12]4[CH:13]=[N:14][N:15]([CH2:17][CH2:18][O:19][CH3:20])[CH:16]=4)[CH:10]=3)[N:5]([C:21](=[O:23])[CH3:22])[C@@H:4]([CH3:24])[CH2:3]2)=[N:27][CH:28]=1

Participants

7

Reactant 4

HCID 8170982-Bromo-5-chloropyridineHCID 27342172-(Dicyclohexylphosphino)-2'-(dimethylamino)biphenylHCID 23676156Sodium t-butoxideHCID 709775541-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone

Product 1

HCID 709778061-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanoneYield 38%

Reagents, catalysts & solvents 2

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

Conditions

Temperature
120 °C

Procedure

1-((2S,4R)-4-amino-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (for a preparation see Intermediate 11) (100 mg, 0.304 mmol), 2-bromo-5-chloropyridine (117 mg, 0.609 mmol), Davephos (23.97 mg, 0.061 mmol), Pd2(dba)3 (27.9 mg, 0.030 mmol) and sodium tert-butoxide (58.5 mg, 0.609 mmol) were combined in 1,4-dioxane (3 ml) and the mixture degassed over a period of 20 min before being heated at 120° C. for 25 min (microwave). The reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml). The organics were combined, dried (hydrophobic frit) and evaporated under vacuum. The residual brown oil was dissolved in DMSO (2×1 ml) and purified by MDAP (HpH ×2). The solvent was evaporated under vacuum to give 1-((2S,4R)-4-((5-chloropyridin-2-yl)amino)-6-(1-(2-methoxyethyl)-1H-pyrazol-4-yl)-2-methyl-3,4-dihydroquinolin-1(2H)-yl)ethanone (51 mg, 0.116 mmol, 38% yield) as a yellow glass. LCMS (formate), Rt 0.87 min, MH+ 440.

Workup

  1. customthe mixture degassed over a period of 20 min
  2. customThe reaction mixture was partitioned between water (100 ml) and DCM (3×100 ml)
  3. customdried (hydrophobic frit)
  4. customevaporated under vacuum
  5. dissolutionThe residual brown oil was dissolved in DMSO (2×1 ml)
  6. custompurified by MDAP (HpH ×2)
  7. customThe solvent was evaporated under vacuum

Sources & evidence

ORD record
ord-83156206d9584d77947269d0dcb2ff5f
Source dataset
uspto-grants-2016_04
Patent number
US09315487B2

Reaction notes

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