Water → racemic 8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine

HRID 546695Notes

Reaction equation

HRID 546695 reaction equation
Cl[CH2:2][CH2:3][CH2:4][CH:5]([CH:10]1[CH2:12][CH2:11]1)[C:6]([NH:8][NH2:9])=O.Cl.Cl.[CH3:15][O:16][C:17]1[CH:18]=[C:19](/[CH:29]=[CH:30]/[C:31](=[NH:35])OCC)[CH:20]=[CH:21][C:22]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1.C(OCC)(=O)C.O>C(O)C>[CH:10]1([CH:5]2[CH2:4][CH2:3][CH2:2][N:8]3[N:9]=[C:31](/[CH:30]=[CH:29]/[C:19]4[CH:20]=[CH:21][C:22]([N:23]5[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]5)=[C:17]([O:16][CH3:15])[CH:18]=4)[N:35]=[C:6]23)[CH2:12][CH2:11]1

Participants

6

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 66838954ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochlorideHCID 668394715-Chloro-2-cyclopropyl-valeric acid hydrazide

Product 1

HCID 66839147racemic 8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridineYield 17.5%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
70 °C

Procedure

A solution of 5-chloro-2-cyclopropyl-valeric acid hydrazide (125 mg) in ethanol (1.5 mL) was added to a solution of ethyl (E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (259 mg) and TEA (0.46 ml) in ethanol (3 ml), and the reaction solution was stirred at 70° C. for 22 hours. The reaction solution was left to cool to room temperature. Then, ethyl acetate and water were added to the reaction solution, and the organic layer was separated. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system) and again purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system) to obtain 43 mg of racemic 8-cyclopropyl-2-{(E)-2-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]vinyl}-5,6,7,8-tetrahydro[1,2,4]triazolo[1,5-a]pyridine. Then, the racemate was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: 20% ethanol-hexane) to obtain the title optically active compound with a retention time of 28 minutes and negative optical rotation (16.4 mg; 100% ee) and the title optically active compound with a retention time of 49 minutes and positive optical rotation (16.3 mg; 99% ee).

Workup

  1. waitThe reaction solution was left
  2. temperatureto cool to room temperature
  3. customthe organic layer was separated
  4. washThe organic layer was washed with brine
  5. dry with materialdried over anhydrous magnesium sulfate
  6. concentrationconcentrated under reduced pressure
  7. customThe resulting residue was purified by silica gel column chromatography (carrier: Chromatorex™ NH; elution solvent: heptane-ethyl acetate system)
  8. customagain purified by silica gel column chromatography (elution solvent: ethyl acetate-methanol system)

Sources & evidence

ORD record
ord-38d82186bd7048638e889af43a52d9c0
Source dataset
uspto-grants-2011_05
Patent number
US07935815B2

Reaction notes

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