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

HRID 402884Notes

Reaction equation

HRID 402884 reaction equation
[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]

Participants

11

Reactant 5

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

Product 1

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

Reagents, catalysts & solvents 5

HCID 935NickelCatalystHCID 176Acetic AcidSolvent2×HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 1049PyridineSolvent

Conditions

Temperature
75 °C

Procedure

(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)+.

Workup

  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)

Sources & evidence

ORD record
ord-1f8013b89d1b4cb0832769edbfb6a911
Source dataset
uspto-grants-2014_06
Patent number
US08742132B2

Reaction notes

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