1,2-Dichloroethane → {1-Cyclohexyl-2-[4-cyclopropanecarbonyl-6-(1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester

HRID 446982Notes

Reaction equation

HRID 446982 reaction equation
[C:1]([O:5][C:6]([NH:8][CH:9]([CH:28]1[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]1)[C:10]([N:12]1[CH:19]2[CH:15]([N:16]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:17][CH:18]2[C:20]([OH:22])=O)[CH2:14][CH2:13]1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:34](Cl)[CH2:35]Cl.[CH:38]1[CH:39]=[CH:40][C:41]2N(O)N=[N:44][C:42]=2[CH:43]=1.[CH3:48][CH2:49]N(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([CH:28]1[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1)[C:10]([N:12]1[CH2:13][CH2:14][CH:15]2[N:16]([C:23]([CH:25]3[CH2:27][CH2:26]3)=[O:24])[CH2:17][CH:18]([C:20](=[O:22])[NH:44][CH:42]3[C:41]4[C:40](=[CH:48][CH:49]=[CH:34][CH:35]=4)[CH2:39][CH2:38][CH2:43]3)[CH:19]12)=[O:11])([CH3:2])([CH3:4])[CH3:3]

Participants

6

Reactant 4

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 672806544-(2-tert-Butoxycarbonylamino-2-cyclohexyl-acetyl)-1-cyclopropanecarbonyl-octahydro-pyrrolo[3,2-b]pyrrole-3-carboxylic acid

Product 1

HCID 67280896{1-Cyclohexyl-2-[4-cyclopropanecarbonyl-6-(1,2,3,4-tetrahydro-naphthalen-1-ylcarbamoyl)-hexahydro-pyrrolo[3,2-b]pyrrol-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl esterYield 60%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent2×

Procedure

A solution of 45 (563 mg, 1.21 mmol) in DCM (15 mL) was cooled to 0° C. and treated with R-(−)-tetrahydronaphthylamine (0.17 mL, 1.21 mmol), EDC (279 mg, 1.46 mmol), HOBt (197 mg, 1.46 mmol) and DIPEA (0.66 mL, 3.76 mmol), respectively. After 18 h, the solution was diluted with DCM, washed successively with 1M HCl, saturated aqueous NaHCO3, and brine, dried over anhydrous Na2SO4, filtered and concentrated. Purification by reverse phase HPLC (2″ Dynamax® C18, 20-100% ACN in H2O with 0.1% HOAc over 30 min) afforded 46 (430 mg) as a white foam. 1H NMR (CDCl3, 300 MHz), ˜1:1 mixture of rotomers: δ8.36 (d, J=8.4 Hz, 0.25H), 8.09 (d, J=8.7 Hz, 0.25H), 7.35 (d, J=9 Hz, 0.5H), 7.28-7.20 (m, 0.5H), 7.18-7.05 (m, 3.5H), 6.52 (d, J=8.4 Hz, 0.25H) 5.25-5.02 (m, 2H), 4.91-4.84 (m, 0.5H), 4.72-4.44 (m, 2H), 4.33-4.19 (m, 1.5H), 4.05-3.93 (m, 1H), 3.67-3.58 (m, 0.5H), 3.49-3.31 (m 1H), 3.15-2.98 (m, 1H), 2.86-2.71 (m, 2H), 2.44-2.35 (m, 1H), 1.98-1.54 (m, 10H), 1.44 (s, 5.5H), 1.17-0.75 (m, 15H) ppm. Mass spectrum, m/z [593.8] (M+H)+.

Workup

  1. washwashed successively with 1M HCl, saturated aqueous NaHCO3, and brine
  2. dry with materialdried over anhydrous Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. customPurification by reverse phase HPLC (2″ Dynamax® C18, 20-100% ACN in H2O with 0.1% HOAc over 30 min)

Sources & evidence

ORD record
ord-8f8d63b448d142ff9ce62e85170eebac
Source dataset
uspto-grants-2013_07
Patent number
US08481495B2

Reaction notes

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