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Hydrochloric Acid → methyl(2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

HRID 1751703
Notes
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Reaction equation

HRID 1751703 reaction equation
[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12]([O:14]C(C)(C)C)=O)=[N:4][CH:3]=1.Cl.[CH3:20][O:21][C@H:22]([CH3:32])[C@H:23]([NH:27][C:28]([O:30][CH3:31])=[O:29])C(O)=O.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.[Li+].[OH-]>C(Cl)Cl.CO.CN(C=O)C>[Br:1][C:2]1[NH:6][C:5]([C@@H:7]2[CH2:11][CH2:10][CH2:9][N:8]2[C:12](=[O:14])[C@@H:23]([NH:27][C:28](=[O:29])[O:30][CH3:31])[C@H:22]([O:21][CH3:20])[CH3:32])=[N:4][CH:3]=1
ParticipantsConditionsProcedureWorkupSources & evidenceReaction notes

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 566051921,1-Dimethylethyl (2S)-2-(5-bromo-1H-imidazol-2-yl)-1-pyrrolidinecarboxylate
HCID 59540170
(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid

Product 1

HCID 86688356methyl(2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamateYield 100%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
40 °C

Procedure

To a solution of (S)-tert-butyl 2-(5-bromo-1H-imidazol-2-yl)pyrrolidine-1-carboxylate (1.00 g, 3.2 mmol) in a mixture of CH2Cl2 (30 mL) and MeOH (5 mL) was added HCl (in dioxane, 4 M, 11.5 mL, 46.0 mmol). The solution was stirred at 40° C. for 1 h, cooled to room temperature, and concentrated to dryness under reduced pressure. To the crude intermediate suspended in CH2Cl2 (30 mL) was added (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (0.67 g, 3.5 mmol), HATU (1.47 g, 3.8 mmol), and DIPEA (1.00 mL, 6.0 mmol), The resulting solution was stirred at room temperature for 24 h. DMF (2 mL) and aqueous LiOH (2.5 M, 1 mL) were added and the reaction was concentrated to dryness under reduced pressure. The crude material was diluted with EtOAc and washed with H2O and brine. The aqueous layers were back extracted with EtOAc. The combined organic layers were dried over Na2SO4 and concentrated under reduced pressure. The crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/CH2Cl2) to afford methyl (2S,3R)-1-((S)-2-(5-bromo-1H-imidazol-2-yl)pyrrolidin-1-yl)-3-methoxy-1-oxobutan-2-ylcarbamate (1.2 g, 100%).

Workup

  1. temperaturecooled to room temperature
  2. concentrationconcentrated to dryness under reduced pressure
  3. stirringThe resulting solution was stirred at room temperature for 24 h
  4. concentrationthe reaction was concentrated to dryness under reduced pressure
  5. additionThe crude material was diluted with EtOAc
  6. washwashed with H2O and brine
  7. extractionThe aqueous layers were back extracted with EtOAc
  8. dry with materialThe combined organic layers were dried over Na2SO4
  9. concentrationconcentrated under reduced pressure
  10. customThe crude residue was purified by silica column chromatography (20% to 100% EtOAc (w/5% MeOH)/CH2Cl2)

Sources & evidence

ORD record
ord-38e2c953ddd54240addb796be644bc28
Source dataset
uspto-grants-2015_10
DOI
10.6084/m9.figshare.5104873.v1
Patent number
US09156823B2

Reaction notes

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On this pageParticipantsConditionsProcedureWorkupSources & evidenceReaction notes