Hydrochloric Acid → Methyl (2S,3R)-1-((1R,4S)-3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamate

HRID 1751438Notes

Reaction equation

HRID 1751438 reaction equation
[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[C@@H:18]4[CH2:19][C@@H:15]([CH2:16][CH2:17]4)[N:14]3[C:20](OC(C)(C)C)=[O:21])=[N:10][CH:9]=2)=[C:4]([F:27])[CH:3]=1.Cl.[CH3:29][O:30][C@H:31]([CH3:41])[C@H:32]([NH:36][C:37]([O:39][CH3:40])=[O:38])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>C(Cl)Cl.CCOC(C)=O.CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]([CH:13]3[C@@H:18]4[CH2:19][C@@H:15]([CH2:16][CH2:17]4)[N:14]3[C:20](=[O:21])[C@@H:32]([NH:36][C:37](=[O:38])[O:39][CH3:40])[C@H:31]([O:30][CH3:29])[CH3:41])=[N:10][CH:9]=2)=[C:4]([F:27])[CH:3]=1

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 81531DiisopropylethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 59540170(2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acidHCID 67681771(1R,4S)-tert-butyl 3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate

Product 1

HCID 67681773Methyl (2S,3R)-1-((1R,4S)-3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptan-2-yl)-3-methoxy-1-oxobutan-2-ylcarbamateYield 78%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

(1R,4S)-tert-butyl 3-(5-(4-bromo-2-fluorophenyl)-1H-imidazol-2-yl)-2-azabicyclo[2.2.1]heptane-2-carboxylate was dissolved in DCM (5 mL) and treated with HCl (4M in dioxane, 1 mL). After 1 h, the reaction mixture was concentrated. The residue was treated (2S,3R)-3-methoxy-2-(methoxycarbonylamino)butanoic acid (76 mg, 0.406 mmol), HATU (154 mg, 0.406 mmol) and DMF (4 mL). The stirred reaction mixture was cooled to 0° C., DIPEA (0.35 mL, 2.03 mmol) was added dropwise and the reaction mixture was warmed to RT. After 20 min, it was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine, dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc) to afford the title compound (162 mg, 78%).

Workup

  1. concentrationthe reaction mixture was concentrated
  2. customThe stirred reaction mixture
  3. temperaturethe reaction mixture was warmed to RT
  4. waitAfter 20 min
  5. washwashed with saturated aqueous NaHCO3 and brine
  6. dry with materialdried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude residue was purified by silica column chromatography (0% to 33% MeOH/EtOAc)

Sources & evidence

ORD record
ord-a126249876e64a159fa77a3c70673c44
Source dataset
uspto-grants-2015_10
Patent number
US09156823B2

Reaction notes

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