Cesium carbonate → 6-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid methyl ester

HRID 927479Notes

Reaction equation

HRID 927479 reaction equation
[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8](Br)=[C:7]([Cl:12])[N:6]=1)=[O:4].Cl.[F:14][C:15]1([F:20])[CH2:19][CH2:18][NH:17][CH2:16]1.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([N:17]2[CH2:18][CH2:19][C:15]([F:20])([F:14])[CH2:16]2)=[C:7]([Cl:12])[N:6]=1)=[O:4]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 249034823,3-Difluoropyrrolidine hydrochlorideHCID 46311197Methyl 5-bromo-6-chloropicolinate

Product 1

HCID 866747576-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid methyl esterYield 30.1%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

Under nitrogen atmosphere, a suspension of 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9 c, 1.5 g, 6 mmol), 3,3-difluoropyrrolidine hydrochloride (CAN 163457-23-6, 0.64 g, 6 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 120 mg, 0.12 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 150 mg, 0.24 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (30 mL) was stirred at 110° C. overnight. After concentration, the residue was partitioned between water (30 mL) and ethyl acetate (30 mL). The aqueous phase was extracted with ethyl acetate (2×30 mL). The combined organic phase was washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give the crude product. The crude product was purified by column chromatography (silica gel, 15 g, 10% ethyl acetate in petroleum ether) to give the target compound (0.5 g, 30%) as light-yellow solid; MS (EI): m/e=277.0 [M+H]+.

Workup

  1. concentrationAfter concentration
  2. customthe residue was partitioned between water (30 mL) and ethyl acetate (30 mL)
  3. extractionThe aqueous phase was extracted with ethyl acetate (2×30 mL)
  4. washThe combined organic phase was washed with brine (30 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give the crude product
  9. customThe crude product was purified by column chromatography (silica gel, 15 g, 10% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-44f4e1c09605440681f54cffff4b3fc4
Source dataset
uspto-grants-2016_03
Patent number
US09290451B2

Reaction notes

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