Triethylamine → (-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazole

HRID 546762Notes

Reaction equation

HRID 546762 reaction equation
Cl.Cl[CH2:3][CH2:4][CH:5]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=1)[C:6]([NH:8][NH2:9])=O.C(N(CC)CC)C.Cl.Cl.[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38](=[NH:42])OCC)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1>C(O)C>[CH3:28][O:29][C:30]1[N:35]=[C:34](/[CH:36]=[CH:37]/[C:38]2[N:42]=[C:6]3[CH:5]([C:10]4[CH:15]=[C:14]([F:16])[C:13]([F:17])=[C:12]([F:18])[CH:11]=4)[CH2:4][CH2:3][N:8]3[N:9]=2)[CH:33]=[CH:32][C:31]=1[N:43]1[CH:47]=[C:46]([CH3:48])[N:45]=[CH:44]1

Participants

5

Reactant 3

HCID 8471Triethylamine2×HCID 66839452ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate dihydrochlorideHCID 668395654-Chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride

Product 1

HCID 66839450(-)-2-{(E)-2-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]vinyl}-7-(3,4,5-trifluorophenyl)-6,7-dihydro-5H-pyrrolo[1,2-b][1,2,4]triazoleYield 23.8%

Reagents, catalysts & solvents 1

HCID 702EthanolSolvent2×

Conditions

Temperature
80 °C

Procedure

A solution of 4 N hydrogen chloride in ethyl acetate (120 mL) was added to tert-butyl N′-[4-chloro-2-(3,4,5-trifluorophenyl)butyryl]hydrazinecarboxylate (6.6 g). The reaction solution was stirred at room temperature for one hour and then concentrated under reduced pressure to obtain 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (6.03 g). A solution of 4-chloro-2-(3,4,5-trifluorophenyl)butyric acid hydrazide hydrochloride (565 mg) and triethylamine (1.0 mL) in ethanol (10 mL) was added to a solution of ethyl (E)-3-[6-methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridin-2-yl]acrylimidate dihydrochloride (500 mg) and triethylamine (0.95 mL) in ethanol (10 mL) at room temperature. The reaction solution was stirred at 80° C. for 25 hours. The reaction solution was left to cool to room temperature and then concentrated under reduced pressure. A saturated sodium bicarbonate solution was added to the resulting residue, followed by extraction with chloroform. The resulting extract was dried over magnesium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system) to obtain 150 mg of the racemic title compound. The racemic title compound (150 mg) was separated by CHIRALPAK™ IB manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm; mobile phase: hexane:ethanol=1:1) to obtain the title optically active compound with a retention time of 13 minutes and positive optical rotation (54 mg) and the title optically active compound with a retention time of 34 minutes and negative optical rotation (51 mg).

Workup

  1. waitThe reaction solution was left
  2. temperatureto cool to room temperature
  3. concentrationconcentrated under reduced pressure
  4. additionA saturated sodium bicarbonate solution was added to the resulting residue
  5. extractionfollowed by extraction with chloroform
  6. extractionThe resulting extract
  7. dry with materialwas dried over magnesium sulfate
  8. concentrationconcentrated under reduced pressure
  9. customThe residue was purified by silica gel column chromatography (carrier: Chromatorex NH; elution solvent: heptane-ethyl acetate system)

Sources & evidence

ORD record
ord-92cb59f56aa84cae8a908ffc780c5840
Source dataset
uspto-grants-2011_05
Patent number
US07935815B2

Reaction notes

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