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

HRID 1362711Notes

Reaction equation

HRID 1362711 reaction equation
[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH2:11])[CH3:10].C(N(C(C)C)CC)(C)C.C1C=CC2N(O)N=NC=2C=1.FC(F)(F)C(O)=O.[Cl:38][CH2:39][CH2:40][CH2:41][C:42](=[CH:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([O:59][CH3:60])[CH:48]=1)[C:43](O)=[O:44]>CN(C=O)C.C(OCC)(=O)C.O.C(Cl)CCl>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([NH:11][C:43](=[O:44])[C:42](=[CH:46][C:47]1[CH:52]=[CH:51][C:50]([N:53]2[CH:57]=[C:56]([CH3:58])[N:55]=[CH:54]2)=[C:49]([O:59][CH3:60])[CH:48]=1)[CH2:41][CH2:40][CH2:39][Cl:38])[CH3:10]

Participants

9

Reactant 4

HCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 183470502,3-Difluoro-α-methylbenzenemethanamineHCID 669601895-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate

Product 1

HCID 669602285-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,3-difluorophenyl)ethyl)amide

Reagents, catalysts & solvents 4

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

Procedure

1-(2,3-difluorophenyl)ethylamine (purity: 72 wt %, 195 mg), IPEA (1 mL), EDC (257 mg) and HOBT (181 mg) were added to a solution of 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid trifluoroacetate (200 mg) in DMF (5 mL), and the reaction solution was stirred at room temperature for 1 hour. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,3-difluorophenyl)ethyl)amide. Sodium hydride (containing mineral oil at 40%, 30 mg) was added to a solution of the resulting 5-chloro-2-(3-methoxy-4-(4-methyl-1H-imidazol-1-yl)benzylidene)valeric acid (1-(2,3-difluorophenyl)ethyl)amide in DMF (5 mL), and the reaction solution was stirred at room temperature for 5 minutes. Water and ethyl acetate were added to the reaction solution and the organic layer was partitioned. The resulting organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system) to obtain 95 mg of the title compound as a racemate. The compound (18 mg) was fractionated using CHIRALPAK™ AD-H manufactured by Daicel Chemical Industries, Ltd. (2 cm×25 cm: mobile phase: hexane:ethanol=5:5) to obtain the title optically active substance with a retention time of 28 minutes (7.5 mg; >99% ee) and the title optically active substance with a retention time of 37 minutes (7.5 mg; >90% ee). The physical properties of the compounds are as follows.

Workup

  1. customthe organic layer was partitioned
  2. dry with materialThe resulting organic layer was dried over anhydrous magnesium sulfate
  3. customthe solvent was evaporated under reduced pressure
  4. customThe residue was purified by silica gel column chromatography (Carrier: Chromatorex™ NH, elution solvent: heptane-ethyl acetate system->ethyl acetate-methanol system)

Sources & evidence

ORD record
ord-636cf499858f4e668a36a4cf34f10038
Source dataset
uspto-grants-2011_02
Patent number
US07880009B2

Reaction notes

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