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

HRID 632093ノート

反応式

HRID 632093 の反応式
[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]

参加物

7

反応物 4

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

生成物 1

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

試薬・触媒・溶媒 2

HCID 9811564Bis(dibenzylideneacetone)palladium触媒HCID 1140Toluene溶媒

反応条件

温度
110 °C

実験手順

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]+.

後処理

  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)

出典と根拠

ORDレコード
ord-fa6657a7af8a49a18a2e33883a690641
出典データセット
uspto-grants-2016_04
特許番号
US09321727B2

反応ノート

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