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

HRID 632093

Reaktionsgleichung

Reaktionsgleichung von HRID 632093
[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]

Komponenten

7

Edukt 4

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

Produkt 1

HCID 866747576-Chloro-5-(3,3-difluoro-pyrrolidin-1-yl)-pyridine-2-carboxylic acid methyl esterAusbeute 30,1 %

Reagenzien, Katalysatoren, Lösungsmittel 2

HCID 9811564Bis(dibenzylideneacetone)palladiumKatalysatorHCID 1140TolueneLösungsmittel

Reaktionsbedingungen

Temperatur
110 °C

Versuchsvorschrift

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]+.

Aufarbeitung

  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)

Quellen und Nachweise

ORD-Eintrag
ord-fa6657a7af8a49a18a2e33883a690641
Quelldatensatz
uspto-grants-2016_04
Patentnummer
US09321727B2

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