Hydrochloric Acid → {1-[2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester

HRID 417555Notes

Reaction equation

HRID 417555 reaction equation
C(OC([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:28])[NH:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.[CH3:30][O:31][C:32]([NH:34][CH:35]([CH:39]([CH3:41])[CH3:40])[C:36](O)=[O:37])=[O:33].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>CO.C(OCC)(=O)C.CN(C=O)C>[CH3:30][O:31][C:32](=[O:33])[NH:34][CH:35]([C:36]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13](=[O:28])[NH:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=2)=[CH:19][CH:20]=1)=[O:37])[CH:39]([CH3:41])[CH3:40]

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 138211012-((Methoxycarbonyl)amino)-3-methylbutanoic acidHCID 666213242-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester

Product 1

HCID 66620562{1-[2-(4'-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl esterYield 93.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
60 °C

Procedure

2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (496 mg, 1.11 mmol) was dissolved in methanol and concentrated HCl (2 mL) was added. The solution was stirred at 60° C. for 30 min then concentrated. The resulting residue was treated with 2-methoxycarbonylamino-3-methyl-butyric acid (233 mg, 1.33 mmol), HATU (549 mg, 1.44 mmol) and DMF (10 mL). After cooling this mixture to 0° C., DIPEA (0.970 mL, 5.55 mmol) was added. The reaction mixture was Stirred for 5 hours then diluted with ethyl acetate (150 mL) and washed with water and brine. The organic phase was dried over magnesium sulfate and concentrated. The resulting residue was purified by silica column chromatography (70% to 90% EtOAc/hexanes) to afford {1-[2-(4′-Bromo-biphenyl-4-ylcarbamoyl)-pyrrolidine-1-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (520 mg, 93% over 2 steps).

Workup

  1. concentrationthen concentrated
  2. temperatureAfter cooling this mixture to 0° C.
  3. stirringThe reaction mixture was Stirred for 5 hours
  4. washwashed with water and brine
  5. dry with materialThe organic phase was dried over magnesium sulfate
  6. concentrationconcentrated
  7. customThe resulting residue was purified by silica column chromatography (70% to 90% EtOAc/hexanes)

Sources & evidence

ORD record
ord-99f5f805035e4adcb6a164d8a5b423de
Source dataset
uspto-grants-2012_01
Patent number
US08088368B2

Reaction notes

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