Dimethyl Sulfide → 3-Bromo-4-cyclopropyl-5-fluoro-4H-pyridine-1-carboxylic acid phenyl ester

HRID 530012Notes

Reaction equation

HRID 530012 reaction equation
Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].CSC.[Br:14][C:15]1[CH:16]=[N:17][CH:18]=[C:19]([F:21])[CH:20]=1.[CH:22]1([Mg]Br)[CH2:24][CH2:23]1>O1CCCC1.[Cu](I)I>[Br:14][C:15]1[CH:20]([CH:22]2[CH2:24][CH2:23]2)[C:19]([F:21])=[CH:18][N:17]([C:2]([O:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[O:3])[CH:16]=1

Participants

7

Reactant 4

HCID 1068Dimethyl SulfideHCID 15891Phenyl chloroformateHCID 8202063-Bromo-5-fluoropyridineHCID 178418630HCID 178418630, compound

Product 1

HCID 867296503-Bromo-4-cyclopropyl-5-fluoro-4H-pyridine-1-carboxylic acid phenyl ester

Reagents, catalysts & solvents 2

HCID 83717Copper iodideCatalystHCID 8028TetrahydrofuranSolvent

Procedure

Phenyl chloroformate (0.764 mL, 0.0060 mol) was added to a mixture of copper iodide (1.082 g, 0.0056 mol), dimethylsulphide (2.78 mL, 0.0380 mol) and 3-bromo-5-fluoropyridine (1.0 g, 0.0056 mol) in anhydrous tetrahydofuran (25 mL) at room temperature and the mixture was stirred for 40-50 min. To this suspension cyclopropyl magnesium bromide (12.13 mL, 0.0060 mol, 0.5M solution in tetrahydofuran) was added at −25 to −20° C. over 30-40 min. The mixture was stirred at this temperature for 30 min, and then warmed slowly to room temperature over 1.0-1.5 h. The reaction mixture was quenched with 20% ammonium chloride (25 mL), followed by extraction of the aqueous layer with ethyl acetate (50 mL). The organic layer was washed with 20% ammonium chloride (25 mL), then saturated sodium chloride (25 mL), and dried over anhydrous sodium sulphate. Silica gel chromatography using 0-5% ethyl acetate-hexane gradient yielded crude phenyl 3-bromo-4-cyclopropyl-5-fluoropyridine-1 (4H)-carboxylate MS (M+1): 339.7.

Workup

  1. stirringThe mixture was stirred at this temperature for 30 min
  2. customThe reaction mixture was quenched with 20% ammonium chloride (25 mL)
  3. extractionfollowed by extraction of the aqueous layer with ethyl acetate (50 mL)
  4. washThe organic layer was washed with 20% ammonium chloride (25 mL)
  5. dry with materialsaturated sodium chloride (25 mL), and dried over anhydrous sodium sulphate

Sources & evidence

ORD record
ord-336bbd6a248a4d26b14683310d2eb33b
Source dataset
uspto-grants-2016_05
Patent number
US09351973B2

Reaction notes

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