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

HRID 1965163Notes

Reaction equation

HRID 1965163 reaction equation
[C:1]([N:11]([CH3:17])[C@H:12]([C:14]([OH:16])=O)[CH3:13])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].[C:18]([O:22][C:23]([N:25]1[CH2:29][CH:28]([O:30][C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:27]2[N:37]([C:40](=[O:46])[CH:41]([NH2:45])[CH:42]([CH3:44])[CH3:43])[CH2:38][CH2:39][CH:26]12)=[O:24])([CH3:21])([CH3:20])[CH3:19].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:18]([O:22][C:23]([N:25]1[CH2:29][CH:28]([O:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:27]2[N:37]([C:40](=[O:46])[CH:41]([NH:45][C:14](=[O:16])[CH:12]([N:11]([C:1]([O:3][CH2:4][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=3)=[O:2])[CH3:17])[CH3:13])[CH:42]([CH3:43])[CH3:44])[CH2:38][CH2:39][CH:26]12)=[O:24])([CH3:20])([CH3:19])[CH3:21]

Participants

8

Reactant 4

HCID 81531DiisopropylethylamineHCID 7016365Z-N-Me-Ala-OHHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 676088584-(2-Amino-3-methyl-butyryl)-3-phenoxy-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester

Product 1

HCID 676088904-{2-[2-(Benzyloxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-3-phenoxy-hexahydro-pyrrolo[3,2-b]pyrrole-1-carboxylic acid tert-butyl ester

Reagents, catalysts & solvents 3

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

Conditions

Temperature
0 °C

Procedure

To a solution containing Cbz-N(Me)Ala-OH (196 mg, 0.83 mmol) and crude 15 (307 mg, 0.76 mmol) in anhydrous NMP (3 mL) was cooled to 0° C. HATU (315 mg, 0.83 mmol) and DIPEA (118 mg, 0.91 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 to afford 420 mg (88%) of crude 16 which was used without further purification. 1H NMR (CDCl3, 300 MHz), mixture of rotomers: δ7.37-7.25 (m, 9H), 6.96 (m, 1H), 6.69 (br s, 1H), 5.19 (m, 2H), 4.91 (m, 1H), 4.81 (m, 1H), 4.58-4.46 (m, 2H), 4.04 (m, 2H), 3.97 (app d, J=12.6 Hz, 0.5H), 3.84 (app d, J=12.6 Hz, 0.5H), 3.40-3.25 (m, 2H), 2.88 (s, 3H), 2.48 (dd, J=5.7, 13.5 Hz, 0.5H), 2.33 (dd, J=5.4, 12.9 Hz, 0.5H), 2.06-1.82 (m, 2H), 1.51 (s, 4.5H), 1.49 (s, 4.5H), 1.36 (d, J=6.9 Hz, 3H), 0.91 (dd, J=2.7, 6.6 Hz, 3H), 0.83 (dd, J=1.8, 6.9 Hz, 3H) 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. customto afford 420 mg (88%) of crude 16 which
  7. customwas used without further purification

Sources & evidence

ORD record
ord-8fcbd0b57dfd47fb9f62009c700e3587
Source dataset
uspto-grants-2013_04
Patent number
US08415486B2

Reaction notes

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