Diisopropylethylamine → 4-(2-Benzyloxycarbonylamino-3-methyl-butyryl)-3-phenoxy-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester

HRID 1965161Notes

Reaction equation

HRID 1965161 reaction equation
[NH:1]([C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10])[C@H:2]([C:6]([OH:8])=O)[CH:3]([CH3:5])[CH3:4].[C:19]([O:23][C:24]([N:26]1[CH2:30][CH:29]([O:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:28]2[NH:38][CH2:39][CH2:40][CH:27]12)=[O:25])([CH3:22])([CH3:21])[CH3:20].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN1C(=O)CCC1.C(OCC)C.CCOC(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:30][CH:29]([O:31][C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)[CH:28]2[N:38]([C:6](=[O:8])[CH:2]([NH:1][C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[O:10])[CH:3]([CH3:4])[CH3:5])[CH2:39][CH2:40][CH:27]12)=[O:25])([CH3:22])([CH3:20])[CH3:21]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 726987N-Carbobenzoxy-L-valineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 675137713-Phenoxy-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester

Product 1

HCID 676063944-(2-Benzyloxycarbonylamino-3-methyl-butyryl)-3-phenoxy-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl esterYield 90.8%

Reagents, catalysts & solvents 3

HCID 3283Diethyl EtherSolventHCID 8857Ethyl AcetateSolventHCID 13387N-methyl-2-pyrrolidoneSolvent

Conditions

Temperature
0 °C

Procedure

To a solution containing Cbz-Val-OH (233 mg, 0.92 mmol) and crude 13 (256 mg, 0.84 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (352 mg, 0.93 mmol) and DIPEA (125 mg, 1.01 mmol) were added and the reaction mixture was slowly warmed to ambient temperature. After 16 h, the reaction mixture was diluted with diethyl ether and EtOAc (1:4) and washed successively with 1M HCl, aqueous NaHCO3, water, and brine, dried over anhydrous Na2SO4, filtered, and concentrated. The crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc) to afford 410 mg (90%) of 14 as a white solid. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.31 (m, 9H), 6.96 (m, 1H), 5.79 (m, 1H). 5.07 (m, 2H), 4.91 (d, J=2.7 Hz, 1H), 4.51-4.43 (m, 2H), 4.35 (t, J=7.5 Hz, 1H), 4.07-3.99 (m, 2H), 3.90 (app d, J=26.4 Hz, 0.5H), 3.77 (app d, J=27.3 Hz, 0.5H), 3.31 (m, 2H), 2.49 (m, 0.5H), 2.35 (m, 0.5H), 1.92 (m, 1H), 1.51 (m, 9H), 0.95 (m, 6H) ppm.

Workup

  1. temperaturethe reaction mixture was slowly warmed to ambient temperature
  2. washwashed successively with 1M HCl, aqueous NaHCO3, water, and brine
  3. dry with materialdried over anhydrous Na2SO4
  4. filtrationfiltered
  5. concentrationconcentrated
  6. customThe crude product was purified by flash silica gel chromatography (4:1 hexanes/EtOAc)

Sources & evidence

ORD record
ord-567e39736ad2456ba7a415d72fa5e3d7
Source dataset
uspto-grants-2013_04
Patent number
US08415486B2

Reaction notes

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