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

HRID 624837Notes

Reaction equation

HRID 624837 reaction equation
[CH3:1][O:2][C:3]([C:5]1[C:10](C)=[CH:9][C:8](Br)=[C:7]([Cl:13])[N:6]=1)=[O:4].Cl.[F:15][C:16]1([F:20])[CH2:19][NH:18][CH2:17]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:18]2[CH2:19][C:16]([F:20])([F:15])[CH2:17]2)=[C:7]([Cl:13])[N:6]=1)=[O:4]

Participants

7

Reactant 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 86674738Methyl 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester

Product 1

HCID 866747536-Chloro-5-(3,3-difluoroazetidin-1-yl)-pyridine-2-carboxylic acid methyl esterYield 21%

Reagents, catalysts & solvents 2

HCID 9811564Bis(dibenzylideneacetone)palladiumCatalystHCID 1140TolueneSolvent

Conditions

Temperature
110 °C

Procedure

Under a nitrogen atmosphere a mixture of methyl 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 3 a, 2 g, 8 mmol), 3,3-difluoroazetidine hydrochloride (CAN 288315-03-7, 1 g, 8 mmol), tris(dibenzylideneacetone)dipalladium (CAN 51364-51-3, 0.16 g, 0.16 mmol), (R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (CAN 76189-55-4, 0.19 g, 0.32 mmol) and cesium carbonate (3.9 g, 12 mmol) in toluene (50 mL) was stirred at 110° C. overnight. After concentration, the residue was partitioned between water (50 mL) and ethyl acetate (40 mL), the aqueous phase was extracted with ethyl acetate (2×40 mL). The combined organic phase was washed with brine (40 mL), dried over anhydrous sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether) to give the target compound (0.44 g, 21%) as light-yellow solid; MS (EI): m/e=263.0 [MH+].

Workup

  1. concentrationAfter concentration
  2. customthe residue was partitioned between water (50 mL) and ethyl acetate (40 mL)
  3. extractionthe aqueous phase was extracted with ethyl acetate (2×40 mL)
  4. washThe combined organic phase was washed with brine (40 mL)
  5. dry with materialdried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto give a residue
  9. customThe residue was purified by column chromatography (silica gel, 20 g, 10% ethyl acetate in petroleum ether)

Sources & evidence

ORD record
ord-c2d58bd685d743b8b17d80376dbf23bc
Source dataset
uspto-grants-2016_04
Patent number
US09303012B2

Reaction notes

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