2-Methyltetrahydrofuran → HCID 118898597, compound

HRID 588396Notes

Reaction equation

HRID 588396 reaction equation
[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1I)=[O:4].C([Mg]Cl)(C)C.CC1OCCC1.Br[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[CH:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1>C1COCC1.[Cl-].[Cl-].[Zn+2]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:11])[N:7]=[CH:8][C:9]=1[C:24]1[CH:52]=[CH:51][C:27]([C:28]([N:30]([C:44]2[C:49]([CH3:50])=[CH:48][CH:47]=[CH:46][N:45]=2)[C@@H:31]2[CH2:36][CH2:35][CH2:34][N:33]([C:37]([O:39][C:40]([CH3:43])([CH3:41])[CH3:42])=[O:38])[CH2:32]2)=[O:29])=[CH:26][CH:25]=1)=[O:4]

Participants

7

Reactant 4

HCID 73012-MethyltetrahydrofuranHCID 673644Methyl 4-iodo-1-methyl-1H-pyrazole-5-carboxylateHCID 117653003HCID 117653003, compoundHCID 178418918HCID 178418918, compound

Product 1

HCID 118898597HCID 118898597, compoundYield 94.5%

Reagents, catalysts & solvents 2

HCID 3007855ZincchlorideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

To a solution of 4-iodo-2-methyl-2H-pyrazole-3-carboxylic acid methyl ester (8.1 g, 30.45 mmol) in THF (anhydrous, 60 mL) was added isopropyl magnesium chloride (16.5 mL, 16.5 mmol) at −45° C. The solution turned from clear to light green-yellowish. Stirred at this temperature for 30 min, GC-MS (sample in CD3OD) indicated all halogen-metal exchange completed. To the mixture was added 1.9 N ZnCl2 in 2-MeTHF (9.62 mL, 18.3 mmol) dropwise and the reaction was warmed to room temperature. The mixture was stirred for 2 h, over which time it turned from clear yellowish to an opaque yellowish mixture. To this reaction was added Preparation 2 tert-butyl 3-[(4-bromobenzoyl)(3-methylpyridin-2-yl)amino]piperidine-1-carboxylate (12.04 g, 25.37 mmol) as a solid in one batch. The reaction temperature was then raised to 50° C., 1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (166 mg, 0.254 mmol) was added. The reaction was then stirred at 60° C. for 2 h then cooled to room temperature. The reaction was quenched with water and extracted 3× EtOAc. The organic layer was dried and concentrated. Purification was performed by Combiflash ISCO column (220 g) 0-75% EtOAc/heptane to isolate the desired title compound (12.8 g, 78%).

Workup

  1. stirringThe mixture was stirred for 2 h, over which time it
  2. additionTo this reaction was added
  3. temperatureThe reaction temperature was then raised to 50° C.
  4. stirringThe reaction was then stirred at 60° C. for 2 h
  5. temperaturethen cooled to room temperature
  6. customThe reaction was quenched with water
  7. extractionextracted 3× EtOAc
  8. customThe organic layer was dried
  9. concentrationconcentrated
  10. customPurification

Sources & evidence

ORD record
ord-28cc2c0d79364da8a3eb45aed444335e
Source dataset
uspto-grants-2016_01
Patent number
US09227956B2

Reaction notes

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