1,2-Dichloroethane → methyl N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate

HRID 1511543Notes

Reaction equation

HRID 1511543 reaction equation
Cl.[CH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[C:9]2[C:5]=1[CH2:6][N:7]([C:13]([O:15][C@@H:16]1[CH2:20][C@@H:19]([C:21]([O:23][CH3:24])=[O:22])[NH:18][CH2:17]1)=[O:14])[CH2:8]2)=[CH2:3].[CH3:25][C:26]([CH3:43])([CH2:40][CH:41]=[CH2:42])[CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37](O)=[O:38])[C:33]([CH3:36])([CH3:35])[CH3:34])=[O:30].C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(OCC)(=O)C.C([O-])(O)=O.[Na+]>[CH3:25][C:26]([CH3:43])([CH2:40][CH:41]=[CH2:42])[CH2:27][O:28][C:29]([NH:31][C@H:32]([C:37]([N:18]1[CH2:17][C@H:16]([O:15][C:13]([N:7]2[CH2:6][C:5]3[C:9](=[CH:10][CH:11]=[CH:12][C:4]=3[CH:2]=[CH2:3])[CH2:8]2)=[O:14])[CH2:20][C@H:19]1[C:21]([O:23][CH3:24])=[O:22])=[O:38])[C:33]([CH3:34])([CH3:35])[CH3:36])=[O:30]

Participants

9

Reactant 5

HCID 111,2-DichloroethaneHCID 757711-HydroxybenzotriazoleHCID 81531DiisopropylethylamineHCID 45379932(3R,5S)-5-(Methoxycarbonyl)pyrrolidin-3-yl 4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate HydrochlorideHCID 57389288n-{[(2,2-Dimethylpent-4-en-1-yl)oxy]carbonyl}-3-methyl-l-valine

Product 1

HCID 57692675methyl N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinateYield 85.1%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolventHCID 516892Sodium BicarbonateSolvent

Procedure

To a solution of (3R,5S)-5-(methoxycarbonyl)pyrrolidin-3-yl 4-vinyl-1,3-dihydro-2H-isoindole-2-carboxylate hydrochloride (2.00 g, 5.67 mmol) and N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valine (1.54 g, 5.67 mmol) in DMF (100 mL) was added EDC (1.41 g, 7.37 mmol), HOBt (1.00 g, 7.37 mmol) and DIPEA (3.16 mL, 22.8 mmol). The reaction mixture was stirred at RT for 18 h and then diluted with ethyl acetate and aqueous NaHCO3. The layers were separated and the organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated. The crude residue was purified on silica gel (gradient elution 5% to 50% ethyl acetate in hexanes) to give methyl N-{[(2,2-dimethylpent-4-enyl)oxy]carbonyl}-3-methyl-L-valyl-(4R)-4-{[(4-vinyl-1,3-dihydro-2H-isoindol-2-yl)carbonyl]oxy}-L-prolinate (2.75 g, 85% yield) as a white foam. LRMS (ESI) m/z 570 [(M+H)+; calcd for C31H44N3O7: 570].

Workup

  1. customThe layers were separated
  2. washthe organic layer was washed with water and brine
  3. dry with materialdried over Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude residue was purified on silica gel (gradient elution 5% to 50% ethyl acetate in hexanes)

Sources & evidence

ORD record
ord-ed98a678c2fb44dd9e7201d5304308a8
Source dataset
uspto-grants-2012_07
Patent number
US08216999B2

Reaction notes

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