Triethylamine → (2R,5R)-4-[2-(6-Chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-2-oxo-ethyl]-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester

HRID 1475278Notes

Reaction equation

Cl[CH2:2][C:3]([N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=2)[C:7]([CH3:16])([CH3:15])[CH2:6]1)=[O:4].C(N(CC)CC)C.[C:24]([O:28][C:29]([N:31]1[CH2:36][C@H:35]([CH2:37][OH:38])[NH:34][CH2:33][C@H:32]1[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]>C1COCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][C@H:35]([CH2:37][OH:38])[N:34]([CH2:2][C:3]([N:5]2[C:13]3[C:8](=[CH:9][CH:10]=[C:11]([Cl:14])[CH:12]=3)[C:7]([CH3:16])([CH3:15])[CH2:6]2)=[O:4])[CH2:33][C@H:32]1[CH3:39])=[O:30])([CH3:27])([CH3:26])[CH3:25]

Participants

Conditions

Temperature: 65 °C

Procedure

To 2-chloro-1-(6-chloro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (397 mg, 1.31 mmol) in anhydrous THF (1.23 mL) was added triethylamine (366 μL, 2.60 mmol) and a solution of (2R,5R)-5-hydroxymethyl-2-methyl-piperazine-1-carboxylic acid tert-butyl ester (380 mg, 1.6 mmol) in anhydrous THF (730 μL). The reaction was heated to 65° C. for 3 h, cooled to ambient temperature and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel (gradient elution, 0-80%, EtOAc/petrol), to give the title compound (447 mg, 75%) as a colourless solid. 1H NMR (Me-d3-OD): 8.15 (1H, d), 7.20 (1H, d), 7.09 (1H, dd), 5.51 (2H, s), 4.23-4.13 (1H, m), 4.09-3.96 (3H, m), 3.81-3.65 (2H, m), 3.64-3.47 (2H, m), 2.97-2.82 (2H, m), 2.67 (1H, dd), 1.48 (9H, s), 1.37 (6H, s), 1.26-1.22 (3H, m).

Workup

temperaturecooled to ambient temperature
customthe solvent removed in vacuo
customThe residue was purified by column chromatography on silica gel (gradient elution, 0-80%, EtOAc/petrol)

Sources & evidence

ORD record: ord-bc890b535fbd48ecb54545e86fbcb047
Source dataset: uspto-grants-2015_04
DOI: 10.6084/m9.figshare.5104873.v1
Patent number: US09018214B2

Reaction notes

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