Water → 8-(4-fluorophenyl)-8-methoxy-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 1009404Notes

Reaction equation

HRID 1009404 reaction equation
Cl.Cl[CH2:3][CH2:4][CH2:5][C:6]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)([O:11][CH3:12])[C:7]([NH:9][NH2:10])=O.Cl.Cl.[CH3:22][O:23][C:24]1[CH:25]=[C:26](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:27]=[CH:28][C:29]=1[N:30]1[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]1.C(OCC)(=O)C.O>C(O)C>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:6]2([O:11][CH3:12])[CH2:5][CH2:4][CH2:3][N:9]3[N:10]=[C:38](/[CH:37]=[CH:36]/[C:26]4[CH:27]=[CH:28][C:29]([N:30]5[CH:34]=[C:33]([CH3:35])[N:32]=[CH:31]5)=[C:24]([O:23][CH3:22])[CH:25]=4)[N:42]=[C:7]23)=[CH:14][CH:15]=1

Participants

6

Reactant 4

HCID 962WaterHCID 8857Ethyl AcetateHCID 66838954ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochlorideHCID 670671765-Chloro-2-(4-fluorophenyl)-2-methoxyvaleric acid hydrazide monohydrochloride

Product 1

HCID 670671618-(4-fluorophenyl)-8-methoxy-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 30.1%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
75 °C

Procedure

A solution of 5-chloro-2-(4-fluorophenyl)-2-methoxyvaleric acid hydrazide monohydrochloride (81 mg) and TEA (0.16 ml) in ethanol (1 ml) was added to a solution of ethyl(E)-3-[3-methoxy-4-(4-methyl-1H-imidazol-1-yl)phenyl]acrylimidate dihydrochloride (94 mg) and TEA (0.16 ml) in ethanol (1 ml), and the reaction solution was stirred at 75° C. for 24 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 36 mg of 8-(4-fluorophenyl)-8-methoxy-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 as a racemate. Then, the racemate was separated by CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: ethanol) to obtain the title optically active compound with a retention time of 15 minutes and negative optical rotation (14.2 mg, 100% ee) and the title optically active compound with a retention time of 18 minutes and positive optical rotation (14.3 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-9e84d0e774d34d49890748d24498b3c9
Source dataset
uspto-grants-2011_07
Patent number
US07973033B2

Reaction notes

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