1,2-Dichloroethane → 1,1-Dimethylethyl (1S,4S)-5-[N-(1H-indol-2-ylcarbonyl)-3-methyl-L-valyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

HRID 2098446Notes

Reaction equation

HRID 2098446 reaction equation
[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([OH:12])=O.[CH3:13][C:14]([CH3:34])([CH3:33])[C@@H:15]([C:17]([N:19]1[CH2:24][C@@H:23]2[CH2:25][C@H:20]1[CH2:21][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[NH2:16].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CN1CCOCC1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([NH:16][C@H:15]([C:17]([N:19]1[CH2:24][C@@H:23]2[CH2:25][C@H:20]1[CH2:21][N:22]2[C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[O:18])[C:14]([CH3:34])([CH3:33])[CH3:13])=[O:12]

Participants

7

Reactant 5

HCID 111,2-DichloroethaneHCID 79724-MethylmorpholineHCID 72899Indole-2-carboxylic acidHCID 757711-HydroxybenzotriazoleHCID 582864131,1-Dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate

Product 1

HCID 672151111,1-Dimethylethyl (1S,4S)-5-[N-(1H-indol-2-ylcarbonyl)-3-methyl-L-valyl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylateYield 97.9%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

To a solution of 1H-indole-2-carboxylic acid (14.6 g, 91 mmol) in CH2Cl2 (300 mL) was added 1,1-dimethylethyl (1S,4S)-5-(3-methyl-L-valyl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (28.1 g, 91 mmol), EDC (20.9 g, 109 mmol), HOBt (2.45 g, 18 mmol), and NMM (25.2 g, 249 mmol). The reaction mixture was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with sat. NaHCO3 (150 mL), 1N HCl (150 mL), sat. NaHCO3 (150 mL) and brine (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated to give the crude product which was purified by column chromatography (petroleum ether/ethyl acetate, 2:1). Concentration of the desired fractions afforded the title compound (40.5 g) as a yellow solid. LCMS (m/z): 455.3 (M+H).

Workup

  1. washwashed with sat. NaHCO3 (150 mL), 1N HCl (150 mL), sat. NaHCO3 (150 mL) and brine (200 mL)
  2. dry with materialThe organic layer was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customto give the crude product which
  6. customwas purified by column chromatography (petroleum ether/ethyl acetate, 2:1)

Sources & evidence

ORD record
ord-d607aecd6b924a1aaf7cd0b7c782ed73
Source dataset
uspto-grants-2013_05
Patent number
US08450484B2

Reaction notes

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