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

HRID 216665노트

반응식

HRID 216665 반응식
[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]

참가 물질

11

반응물 5

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

생성물 1

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

시약·촉매·용매 5

HCID 935Nickel촉매HCID 176Acetic Acid용매2회HCID 887Methanol용매HCID 962Water용매2회HCID 1049Pyridine용매

반응 조건

온도
75 °C

실험 절차

(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)+.

후처리

  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)

출처 및 근거

ORD 기록
ord-24a4512c3b1f4ecb87ba0e116f8fc82c
출처 데이터셋
uspto-grants-2012_06
특허 번호
US08193236B2

반응 노트

불러오는 중…