Methyl iodide → (-)-1-(2-Methyl-pyridin-4-yl)-3-[4-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenyl]-3-o-tolyl-propan-1-one

HRID 1618023Notes

Reaction equation

HRID 1618023 reaction equation
[C:1]([C:3]1[CH:8]=[CH:7][C:6]([C@H:9]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH2:10][C:11]([C:13]2[CH:18]=[CH:17][N:16]=[C:15]([CH3:19])[CH:14]=2)=[O:12])=[CH:5][CH:4]=1)#[CH:2].I[CH3:28].[N-:29]=[N+:30]=[N-:31].[Na+]>C(OCC)(=O)C.O.[Cu]>[CH3:19][C:15]1[CH:14]=[C:13]([C:11](=[O:12])[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([C:1]3[N:29]=[N:30][N:31]([CH3:28])[CH:2]=3)=[CH:8][CH:7]=2)[C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=2[CH3:26])[CH:18]=[CH:17][N:16]=1

Participants

7

Reactant 3

HCID 6328Methyl iodideHCID 33557Sodium AzideHCID 86661100(R)-3-(4-Ethynyl-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one

Product 1

HCID 66668840(-)-1-(2-Methyl-pyridin-4-yl)-3-[4-(1-methyl-1H-[1,2,3]triazol-4-yl)-phenyl]-3-o-tolyl-propan-1-one

Reagents, catalysts & solvents 3

HCID 23978CopperCatalystHCID 962WaterSolventHCID 8857Ethyl AcetateSolvent

Procedure

Synthesis conducted in flow using a FlowSyn (Uniqsis) flow system equipped with a home-made copper coil reactor, a standard T-piece mixer and 250 psi back-pressure regulator: A stream of a solution containing (−)-3-(4-ethynyl-phenyl)-1-(2-methyl-pyridin-4-yl)-3-o-tolyl-propan-1-one (150 mg in 5 mL, c=0.088 mol/L; example 287, step 2) and iodomethane (125 mg in 5 mL, c=0.177 mol/L) in ethyl acetate was combined with a second stream of sodium azide (58 mg in 5 mL, c=0.177 mol/L) in water and directed through a copper coil (volume=21 mL) at 150° C. Both channels were running at a flow rate of 0.4 mL/min, which equals to a residence time of 26 min. The product stream was collected in a 25% solution of ammonium hydroxide and extracted with ethyl acetate (3×50 mL). The combined organic phases were dried over sodium sulfate and the crude reaction product purified by silica gel chromatography using a MPLC system (CombiFlash Companion, Isco Inc.) eluting with a gradient of n-heptane/ethyl acetate (1:1 to 2:1) to provide the title compound as a colorless solid. MS (ESI+): m/z=397.3 ([M+H]+).

Workup

  1. customSynthesis
  2. customequipped with a home-made copper coil reactor
  3. customequals to a residence time of 26 min
  4. customThe product stream was collected in a 25% solution of ammonium hydroxide
  5. extractionextracted with ethyl acetate (3×50 mL)
  6. dry with materialThe combined organic phases were dried over sodium sulfate
  7. customthe crude reaction product
  8. custompurified by silica gel chromatography
  9. washeluting with a gradient of n-heptane/ethyl acetate (1:1 to 2:1)

Sources & evidence

ORD record
ord-e7efbd96ea824894877fa9a98f9bcaa3
Source dataset
uspto-grants-2014_07
Patent number
US08765730B2

Reaction notes

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