Hydrogen Bromide → {1-[6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl]-carbamic acid methyl ester

HRID 71946Notes

Reaction equation

HRID 71946 reaction equation
C(OC([N:11]1[CH:17]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:20]=3[N:19]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=O)C1C=CC=CC=1.Br.[CH3:29][O:30][C:31]([NH:33][CH:34]([CH:38]([CH3:40])[CH3:39])[C:35](O)=[O:36])=[O:32].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>[CH3:29][O:30][C:31](=[O:32])[NH:33][CH:34]([C:35]([N:11]1[CH:17]([C:18]2[NH:22][C:21]3[CH:23]=[C:24]([Br:27])[CH:25]=[CH:26][C:20]=3[N:19]=2)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:36])[CH:38]([CH3:40])[CH3:39]

Participants

9

Reactant 5

HCID 260Hydrogen BromideHCID 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 666203746-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester

Product 1

HCID 66621073{1-[6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl]-carbamic acid methyl esterYield 75%

Reagents, catalysts & solvents 3

HCID 6228DimethylformamideSolventHCID 6344DichloromethaneSolventHCID 8857Ethyl AcetateSolvent

Conditions

Temperature
0 °C

Procedure

6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (301 mg, 0.706 mmol) was dissolved in DCM (10 mL) and HBr (33 wt % in AcOH, 5 mL) was added. After 2 h the reaction mixture was concentrated and placed under hi-vac. The residue was co-evaporated with PhMe, MeOH, then again with PhMe and MeOH and placed under hi-vac. The residue was treated with 2-Methoxycarbonylamino-3-methyl-butyric acid (130 mg, 0.741 mmol, HATU (282 mg, 0.741 mmol) and DMF (7 mL). The reaction mixture was cooled to 0° C. then DIPEA (0.615 mL, 3.53 mmol) was added before warming to room temperature. After 30 minutes, the reaction mixture was diluted with EtOAc and the organic phase was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (50% to 80% EtOAc/hexane) to afford {1-[6-(6-Bromo-1H-benzoimidazol-2-yl)-5-aza-spiro[2.4]heptane-5-carbonyl]-2-methyl-propyl}-carbamic acid methyl ester (238 mg, 75%).

Workup

  1. concentrationAfter 2 h the reaction mixture was concentrated
  2. temperaturebefore warming to room temperature
  3. washthe organic phase was washed with saturated aqueous NaHCO3 and brine
  4. dry with materialdried over MgSO4
  5. filtrationfiltered
  6. concentrationconcentrated
  7. customThe crude residue was purified by silica column chromatography (50% to 80% EtOAc/hexane)

Sources & evidence

ORD record
ord-97aeb605b3d64916b944c9a43a3c256e
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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