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

HRID 632075Notizen

Reaktionsgleichung

Reaktionsgleichung von HRID 632075
COC(=O)C(N[C:8]([C:10]1[CH:15]=[CH:14][C:13](C2CCOCC2)=[C:12](OCC2CC2)[N:11]=1)=[O:9])(C)C.[ClH:28].[F:29][C:30]1([F:34])[CH2:33][NH:32][CH2:31]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:81](=[O:84])([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]>[CH3:81][O:84][C:8]([C:10]1[CH:15]=[CH:14][C:13]([N:32]2[CH2:33][C:30]([F:34])([F:29])[CH2:31]2)=[C:12]([Cl:28])[N:11]=1)=[O:9]

Komponenten

7

Edukt 4

HCID 10796Cesium carbonateHCID 634876Binap, (A+-)-HCID 27582473,3-Difluoroazetidine hydrochlorideHCID 710873402-{[6-Cyclopropylmethoxy-5-(tetrahydro-pyran-4-yl)-pyridine-2-carbonyl]-amino}-2-methyl-propionic acid methyl ester

Produkt 1

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

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

Under a nitrogen atmosphere a mixture of methyl 5-bromo-6-chloro-pyridine-2-carboxylic acid methyl ester (Example 9 c, 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 [M+H]+.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-1493ca2c6bd24454bcf0ed62d6fc3ed2
Quelldatensatz
uspto-grants-2016_04
Patentnummer
US09321727B2

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