Bromide ion → methyl 4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxylate

HRID 1172610Notes

Reaction equation

HRID 1172610 reaction equation
Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)=[N:15][N:14]2[CH2:24][CH2:25][CH2:26][C:13]=12.[C:27]([O-:30])(=[O:29])C.[Na+].Cl[CH2:33]Cl.[C]=O.[Br-]>[Pd].CO.C1(C)C=CC=CC=1.CC(C)=O>[CH3:33][O:30][C:27]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[C:12]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)=[N:15][N:14]2[CH2:24][CH2:25][CH2:26][C:13]=12)=[O:29]

Participants

9

Reactant 5

HCID 259Bromide ionHCID 6344DichloromethaneHCID 517045Sodium AcetateHCID 219927086-bromo-4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinolineHCID 178418416HCID 178418416, compound3×

Product 1

HCID 24776250methyl 4-(2-(6-methylpyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl)quinoline-6-carboxylateYield 4,702.3%

Reagents, catalysts & solvents 3

HCID 23938PalladiumCatalystHCID 887MethanolSolventHCID 20247278Toluene acetoneSolvent

Conditions

Temperature
90 °C

Procedure

Add 6-bromo-4-[2-(6-methyl-pyridin-2-yl)-5,6-dihydro-4H-pyrrolo[1,2-b]pyrazol-3-yl]-quinoline (22.7 g, 45 mmol) to a mixture of sodium acetate (19 g, 230 mmol) and the palladium catalyst [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane (1:1) (850 mg, 1.04 mmol) in 130 mL methanol. Place the mixture under 50 psi carbon monoxide atmosphere and stir while warming to 90° C. over 1 hour and with constant charging with additional carbon monoxide. Allow the mixture to cool over 8 hours, recharge again with carbon monoxide and heat to 90° C. The pressure may rise to about 75 PSI. The reaction is complete in about an hour when the pressure is stable and the (1:1 toluene/acetone) shows no remaining bromide. Partition the mixture between methylene chloride (600 mL) and water (1 L). Extract the aqueous portion with an additional portion of methylene chloride (400 mL). Filter the organic solution through a 300 mL silica plug and wash with 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone. Discard the acetone portion. Combine appropriate fractions and concentrate to yield 18.8 g (87.4%) of the desired subtitled intermediate as a pink powder. MS ES+=385 (M+1).

Workup

  1. temperatureAllow the mixture to cool over 8 hours
  2. waitThe reaction is complete in about an hour
  3. customPartition the mixture between methylene chloride (600 mL) and water (1 L)
  4. extractionExtract the aqueous portion with an additional portion of methylene chloride (400 mL)
  5. filtrationFilter the organic solution through a 300 mL silica plug
  6. washwash with 500 mL methylene chloride, 1200 mL ethyl acetate and 1500 mL acetone
  7. concentrationCombine appropriate fractions and concentrate

Sources & evidence

ORD record
ord-0829bcdd9d0a4a33acbf7768c5900fe2
Source dataset
uspto-grants-2010_11
Patent number
US07834029B2

Reaction notes

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