1-Hydroxybenzotriazole → (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide

HRID 1362732Notes

Reaction equation

HRID 1362732 reaction equation
C1C=CC2N(O)N=NC=2C=1.C(N(C(C)C)CC)(C)C.FC(F)(F)C(O)=O.[Cl:27][CH2:28][CH2:29][CH2:30]/[C:31](=[CH:35]\[C:36]1[CH:41]=[CH:40][C:39]([N:42]2[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]2)=[C:38]([O:48][CH3:49])[CH:37]=1)/[C:32]([OH:34])=O.[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]([CH:59]([NH2:61])[CH3:60])=[CH:51]1>CN(C=O)C.O.C(OCC)(=O)C.C(Cl)CCl>[NH:50]1[C:58]2[C:53](=[CH:54][CH:55]=[CH:56][CH:57]=2)[C:52]([CH:59]([NH:61][C:32](=[O:34])/[C:31](=[CH:35]/[C:36]2[CH:41]=[CH:40][C:39]([N:42]3[CH:46]=[C:45]([CH3:47])[N:44]=[CH:43]3)=[C:38]([O:48][CH3:49])[CH:37]=2)/[CH2:30][CH2:29][CH2:28][Cl:27])[CH3:60])=[CH:51]1

Participants

9

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 30157011-(1H-indol-3-yl)ethanamineHCID 66960186(E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate

Product 1

HCID 66961554(E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amideYield 104.1%

Reagents, catalysts & solvents 4

HCID 111,2-DichloroethaneSolventHCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

EDC (384 mg), HOBT (271 mg) and IPEA (0.582 mL) were sequentially added to a solution of (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (300 mg) and 1-(1H-indol-3-yl)ethylamine (130 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 12 hours. After confirming that the raw materials disappeared, ethyl acetate and water were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and brine, and then dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (332 mg). Sodium hydride (containing mineral oil at 40%, 19.3 mg) was added to a solution of the resulting (E)-5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(1H-indol-3-yl)ethyl)amide (92 mg) in THF (3 mL) at 0° C., and the reaction solution was stirred at room temperature for 90 minutes. The reaction solution was cooled to 0° C., water and ethyl acetate were added to the reaction solution, and the organic layer was partitioned. The organic layer was washed sequentially with water and a saturated aqueous solution of sodium chloride. The organic layer was dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system) to obtain (E)-1-[1-(1H-indol-3-yl)ethyl]-3-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)piperidin-2-one as a racemate (37.3 mg). The compound (37 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: ethanol) to obtain the title optically active substance with a retention time of 10 minutes (15 mg; >99% ee) and the title optically active substance with a retention time of 14 minutes (14.2 mg; >99% ee).

Workup

  1. customthe organic layer was partitioned
  2. washThe resulting organic layer was sequentially washed with a saturated aqueous solution of ammonium chloride and brine
  3. dry with materialdried over anhydrous sodium sulfate
  4. concentrationconcentrated under reduced pressure
  5. customThe residue was purified by silica gel chromatography (Carrier: Chromatorex™ NH, elution solvent: chloroform:methanol system)

Sources & evidence

ORD record
ord-23079389a9464765a827faf2dd59550c
Source dataset
uspto-grants-2011_02
Patent number
US07880009B2

Reaction notes

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