Dimethylamine → (6-Dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester

HRID 216665ノート

反応式

HRID 216665 の反応式
[C:1]([O:5][C:6](=[O:20])[CH2:7][C:8]1[N:16]2[C:11]([CH:12]=[CH:13][C:14]([C:17]#N)=[CH:15]2)=[CH:10][C:9]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2].O.[PH2]([O-])=O.[Na+].[CH3:26]NC.[C:29]([BH3-])#[N:30].[Na+].C([O-])(O)=O.[Na+]>O.N1C=CC=CC=1.C(O)(=O)C.[Ni].CO>[C:1]([O:5][C:6](=[O:20])[CH2:7][C:8]1[N:16]2[C:11]([CH:12]=[CH:13][C:14]([CH2:17][N:30]([CH3:29])[CH3:26])=[CH:15]2)=[CH:10][C:9]=1[CH3:19])([CH3:4])([CH3:3])[CH3:2]

参加物

11

反応物 5

HCID 674DimethylamineHCID 516892Sodium BicarbonateHCID 5003444Sodium cyanoborohydrideHCID 68708411(6-Cyano-2-methyl-indolizin-3-yl)-acetic acid tert-butyl esterHCID 178418950HCID 178418950、化合物

生成物 1

HCID 68712027(6-Dimethylaminomethyl-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester収率 23%

試薬・触媒・溶媒 5

HCID 935Nickel触媒HCID 176Acetic Acid溶媒2 回HCID 887Methanol溶媒HCID 962Water溶媒2 回HCID 1049Pyridine溶媒

反応条件

温度
75 °C

実験手順

(6-Cyano-2-methyl-indolizin-3-yl)-acetic acid tert-butyl ester (500 mg, 1.76 mmol) is dissolved in a mixture of water (5.0 ml), pyridine (10 ml) and glacial acetic acid (5.0 ml). Sodium hypophosphite monohydrate (1.51 g, 14.1 mmol, 8 equiv) and Raney nickel (approx. 210 mg) are added at room temperature. The reaction mixture is heated to 75° C. for 1 h, cooled to room temperature, filtered through Celite and concentrated in vacuo. The residue is taken up in THF (5.0 ml) and treated with dimethylamine (5.3 M solution in EtOH, 1.66 ml, 8.8 mmol, 5.0 equiv). The mixture is stirred at room temperature for 18 hours. A solution of sodium cyanoborohydride (128 mg, 1.94 mmol, 1.1 equiv) in MeOH (0.5 ml) and glacial acetic acid (5.0 ml) are added, and the solution is stirred at room temperature for 2 hours. The reaction mixture is diluted with water and adjusted to pH 8-9 by the addition of concentrated aqueous NaHCO3 solution. Extraction with EtOAc, washing with brine, drying over Na2SO4 and removal of solvent affords the crude reaction product. Purification via flash chromatography (EtOAc/hexane 4:1, +0.2% NEt3) yields the title compound (122 mg, 23%). 1H NMR (400 MHz, CDCl3): δ=7.62 (s, 1H), 7.20 (d, J=9.0 Hz, 1H), 7.00 (s, 1H), 6.56 (dd, J=9.3/1.5 Hz. 1H), 3.52 (s, 2H), 3.22 (s, 2H), 2.19 (s, 6H), 1.35 (s, 9H). MS (ES+): 303 (M+H)+.

後処理

  1. temperaturecooled to room temperature
  2. filtrationfiltered through Celite
  3. concentrationconcentrated in vacuo
  4. stirringthe solution is stirred at room temperature for 2 hours
  5. extractionExtraction with EtOAc
  6. washwashing with brine
  7. dry with materialdrying over Na2SO4 and removal of solvent
  8. customaffords the crude
  9. customreaction product
  10. customPurification via flash chromatography (EtOAc/hexane 4:1, +0.2% NEt3)

出典と根拠

ORDレコード
ord-24a4512c3b1f4ecb87ba0e116f8fc82c
出典データセット
uspto-grants-2012_06
特許番号
US08193236B2

反応ノート

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