Hydrochloric Acid → (1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester

HRID 71989Notes

Reaction equation

HRID 71989 reaction equation
C(OC([N:8]1[CH2:12][CH:11]([CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:10][CH:9]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=O)(C)(C)C.Cl.[CH3:31][O:32][C:33]([NH:35][CH:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C.CCOC(C)=O>[CH3:31][O:32][C:33](=[O:34])[NH:35][CH:36]([C:37]([N:8]1[CH2:12][CH:11]([CH2:13][O:14][CH:15]([F:17])[F:16])[CH2:10][CH:9]1[C:18]1[NH:19][C:20]([C:23]2[CH:28]=[CH:27][C:26]([Br:29])=[CH:25][CH:24]=2)=[CH:21][N:22]=1)=[O:38])[CH:40]([CH3:42])[CH3:41]

Participants

9

Reactant 5

HCID 313Hydrochloric AcidHCID 8471TriethylamineHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 138211012-((Methoxycarbonyl)amino)-3-methylbutanoic acidHCID 666207862-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 66620824(1-{2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterYield 61%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Procedure

2-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-4-difluoromethoxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester was dissolved in DCM (4 mL) and treated with HCl (4.0M in dioxane, 1 mL, 4 mmol). After 2.5 h, the solution was concentrated and the residue was treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (55 mg, 0.315 mmol) and HATU (120 mg, 0.315 mmol). The solids were suspended in DMF (3 mL) and the reaction mixture was cooled to 0° C. before triethylamine (0.25 mL, 1.43 mmol) was added in a dropwise fashion. After 30 min, the mixture was warmed to RT. After another 1 h, it was diluted with EtOAc and washed with saturated aqueous NaHCO3 and brine. Then it was dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (60% to 100% EtOAc/Hex) to afford the title compound (92 mg, 61%).

Workup

  1. concentrationthe solution was concentrated
  2. additionwas added in a dropwise fashion
  3. waitAfter 30 min
  4. waitAfter another 1 h
  5. washwashed with saturated aqueous NaHCO3 and brine
  6. dry with materialThen it was dried over MgSO4
  7. filtrationfiltered
  8. concentrationconcentrated
  9. customThe crude residue was purified by silica column chromatography (60% to 100% EtOAc/Hex)

Sources & evidence

ORD record
ord-fa17410b1fe24e069f24840e6ac7aed8
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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