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

HRID 2392425Notes

Reaction equation

HRID 2392425 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.CC[N:26]([CH2:29][CH3:30])CC.BrCC([C:35]1[CH:44]=[CH:43][C:42]2[C:37](=[CH:38][CH:39]=[C:40]([Br:45])[CH:41]=2)[CH:36]=1)=O.C([O:50]C(N1C(C2NC(C3C=CC(Br)=CC=3)=CN=2)C2CC1CC2)=O)(C)(C)C.C(OC(N1C(C(=O)NCC(C2C=CC(Br)=CC=2)=O)C2CC1CC2)=O)(C)(C)C.COC(=O)NC(C(N1C(C2NC(C3C=CC4C(=CC=C(Br)C=4)C=3)=CN=2)CC2(CC2)C1)=O)C(C)C.COC(=O)NC(C(N1C(C2NC(C3C=CC(Br)=CC=3)=CN=2)CC2(CC2)C1)=O)C(C)C.C(OC(N1CCC2(CC2)C1)=O)C1C=CC=CC=1>CO.CC#N>[CH2:1]([O:8][C:9]([N:11]1[CH:17]([C:18](=[O:20])[NH:26][CH2:29][C:30]([C:35]2[CH:44]=[CH:43][C:42]3[C:37](=[CH:38][CH:39]=[C:40]([Br:45])[CH:41]=3)[CH:36]=2)=[O:50])[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

13

Reactant 10

HCID 313Hydrochloric AcidHCID 3939Lithium HydroxideHCID 8471TriethylamineHCID 126988982-Bromo-1-(6-bromonaphthalen-2-yl)ethanoneHCID 596105415-[(Benzyloxy)carbonyl]-5-azaspiro[2.4]heptane-6-carboxylic acidHCID 596106863-[2-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 596109073-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl esterHCID 66620752(1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 66620764(1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl esterHCID 68030140HCID 68030140, compound

Product 1

HCID 666203866-[2-(6-Bromo-naphthalen-2-yl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 6342AcetonitrileSolvent

Procedure

5-Aza-spiro[2.4]heptane-5,6-dicarboxylic acid 5-benzyl ester (2.217 g, 7.66 mmol) was dissolved in MeOH (30 mL) and LiOH (1 M in H2O, 15 mL, 15 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 MeCN (40 mL), Et3N (1.2 mL, 8.4 mmol) and 2-Bromo-1-(6-bromo-naphthalen-2-yl)-ethanone and the mixture was stirred at room temperature for 20 hours before being filtered over CELITE and concentrated. The resulting oil was dissolved in the minimum amount of DCM and EtOAc (30 mL) was added causing the product to precipitate. The mixture was cooled to 0° C. then the solid was filtered off and rinsed with EtOAc giving clean product (4.00 g, 100%). 6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester: Title compound was prepared according to the method employed to prepare 3-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (Example AS), substituting 6-[2-(6-Bromo-naphthalen-2-yl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 3-[2-(4-bromo-phenyl)-2-oxo-ethylcarbamoyl]-2-aza-bicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester. (1-{6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester: Title compound was prepared according to the method employed to prepare (1-{6-[5-(4-Bromo-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester, substituting 6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester for 642-(4-Bromo-phenyl)-2-oxo-ethylcarbamoyl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester according to example FJ.

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. stirringthe mixture was stirred at room temperature for 20 hours
  6. filtrationbefore being filtered over CELITE
  7. concentrationconcentrated
  8. dissolutionThe resulting oil was dissolved in the minimum amount of DCM and EtOAc (30 mL)
  9. additionwas added
  10. customto precipitate
  11. temperatureThe mixture was cooled to 0° C.
  12. filtrationthe solid was filtered off
  13. washrinsed with EtOAc giving clean product (4.00 g, 100%)
  14. custom6-[5-(6-Bromo-naphthalen-2-yl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carboxylic acid benzyl ester: Title compound was prepared

Sources & evidence

ORD record
ord-79f38c0cfc324fa3906b7de5b293f91d
Source dataset
uspto-grants-2012_09
Patent number
US08273341B2

Reaction notes

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