Ethyl chloroformate → 4-(2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-3-(6-fluoro-1H-indol-3-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid methyl ester

HRID 1949634Notes

Reaction equation

HRID 1949634 reaction equation
[C:1]([O:5][C:6](=[O:35])[NH:7][CH:8]([CH:29]1[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1)[C:9]([N:11]1[CH2:15][CH2:14][CH:13]2[NH:16][CH2:17][CH:18]([C:19]3[C:27]4[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=4)[NH:21][CH:20]=3)[CH:12]12)=[O:10])([CH3:4])([CH3:3])[CH3:2].Cl[C:37]([O:39][CH2:40]C)=[O:38]>C(Cl)Cl>[CH3:40][O:39][C:37]([N:16]1[CH2:17][CH:18]([C:19]2[C:27]3[C:22](=[CH:23][C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:12]2[N:11]([C:9](=[O:10])[CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:35])[CH:29]3[CH2:30][CH2:31][CH2:32][CH2:33][CH2:34]3)[CH2:15][CH2:14][CH:13]12)=[O:38]

Participants

4

Reactant 2

HCID 10928Ethyl chloroformateHCID 67410158HCID 67410158, compound

Product 1

HCID 674097574-(2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-3-(6-fluoro-1H-indol-3-yl)-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid methyl esterYield 88.6%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Conditions

Temperature
0 °C

Procedure

A solution containing crude 49 (229 mg, 0.47 mmol) in DCM (5 mL) was cooled to 0° C. TEA (73 mg, 0.72 mmol) was added followed by ethyl chloroformate (73 mg, 0.78 mmol). After 30 min, the reaction mixture was diluted with DCM and washed successively with 1M HCl and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (2:1 hexanes/EtOAc to 1:1 hexanes/EtOAc) to afford 226 mg (88%) of 50 as an off-white-colored foam. 1H NMR (300 MHz, CDCl3): δ8.25-8.14 (m, 1H), 8.10 (s, 1H), 7.03-6.97 (m, 1H), 6.95-6.83 (m, 1H), 5.36-5.32 (m, 1H), 4.63 (dd, J=5.4, 19.8 Hz, 1H), 4.39-4.34 (m, 1H), 4.26-4.22 (m, 1H), 4.09-4.04 (m, 2H), 3.95 (app t, J=5.7 Hz, 1H), 3.80 (s, 3H), 3.53-3.48 (m, 2H), 2.49-2.43 (m, 0.5H), 2.31-2.24 (m, 0.5H), 1.94-1.88 (m, 1H), 1.77-1.65 (m, 6H), 1.44 (s, 9H), 1.29-1.10 (m, 5H) ppm. Mass spectrum, m/z [543.4] (M+H)+.

Workup

  1. washwashed successively with 1M HCl and brine
  2. dry with materialdried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customThe crude product was purified by flash silica gel chromatography (2:1 hexanes/EtOAc to 1:1 hexanes/EtOAc)

Sources & evidence

ORD record
ord-a97bcd6bf263452dac440da416546d28
Source dataset
uspto-grants-2013_03
Patent number
US08399683B2

Reaction notes

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