Hydrochloric Acid → 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester

HRID 71939Notes

Reaction equation

HRID 71939 reaction equation
[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18]([OH:20])=O)[CH2:16][C:13]2([CH2:15][CH2:14]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl.Cl.[NH2:25][CH2:26][C:27]([C:29]1[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=1)=[O:28].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.CCOC(C)=O.CN(C=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18](=[O:20])[NH:25][CH2:26][C:27]([C:29]2[CH:34]=[CH:33][C:32]([Br:35])=[CH:31][CH:30]=2)=[O:28])[CH2:16][C:13]2([CH2:14][CH2:15]2)[CH2:12]1)=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1

Participants

10

Reactant 6

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 81531DiisopropylethylamineHCID 27982162-Amino-1-(4-bromophenyl)ethan-1-one hydrochlorideHCID 9886157Methanaminium, N-((dimethylamino)(3H-1,2,3-triazolo(4,5-b)pyridin-3-yloxy)methylene)-N-methyl-, hexafluorophosphate(1-) (1:1)HCID 596105415-[(Benzyloxy)carbonyl]-5-azaspiro[2.4]heptane-6-carboxylic acid

Product 1

HCID 666210666-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl esterYield 100%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 6228DimethylformamideSolventHCID 8857Ethyl AcetateSolvent

Procedure

5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (361 mg, 1.25 mmol) was dissolved in MeOH (10 mL) and LiOH (1 M in H2O, 5 mL, 5 mmol) was added. After stirring for 15 hours at room temperature, the reaction mixture was poured into 10% HCl and the aqueous phase was extracted 3× with DCM. The combined organics were dried over MgSO4, filtered and concentrated. The residue was treated with 2-Amino-1-(4-bromo-phenyl)-ethanone hydrochloride (344 mg, 1.38 mmol), HATU (525 mg, 1.38 mmol) and DMF (14 mL). The suspension was stirred at 0° C. for 21 minutes before DIPEA (0.72 mL, 4.1 mmol) was added dropwise. Immediately after addition, the reaction mixture was warmed to room temperature. 40 minutes later the mixture was diluted with EtOAc. The organic layer was washed with saturated aqueous NaHCO3 and brine, then dried over MgSO4, filtered and concentrated. The crude residue was purified by silica column chromatography (30% to 50% EtOAc/hexane) to afford 6-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester (589 mg, 100%).

Workup

  1. extractionthe aqueous phase was extracted 3× with DCM
  2. dry with materialThe combined organics were dried over MgSO4
  3. filtrationfiltered
  4. concentrationconcentrated
  5. additionwas added dropwise
  6. additionImmediately after addition
  7. temperaturethe reaction mixture was warmed to room temperature
  8. washThe organic layer was washed with saturated aqueous NaHCO3 and brine
  9. dry with materialdried over MgSO4
  10. filtrationfiltered
  11. concentrationconcentrated
  12. customThe crude residue was purified by silica column chromatography (30% to 50% EtOAc/hexane)

Sources & evidence

ORD record
ord-e1c2ec28f0ac46ad9f50512cee37f8f9
Source dataset
uspto-grants-2014_09
Patent number
US08822430B2

Reaction notes

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