Hydrochloric Acid → 6-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl ester

HRID 507069Notes

Reaction equation

HRID 507069 reaction equation
COC([C:5]1[C:6]([N:14]([CH2:21][CH2:22][CH2:23][C:24](OCC)=[O:25])[C:15]([O:17][CH:18]([CH3:20])[CH3:19])=[O:16])=[C:7]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8]2)=O.CC(C)([O-])C.[K+].Cl.[Cl-].[Li+]>O1CCCC1.[Cl-].[Na+].O>[CH:18]([O:17][C:15]([N:14]1[C:6]2[C:7]3[CH2:8][CH2:9][CH2:10][C:11]=3[CH:12]=[CH:13][C:5]=2[C:24](=[O:25])[CH2:23][CH2:22][CH2:21]1)=[O:16])([CH3:19])[CH3:20]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 433294Lithium ChlorideHCID 23665647Potassium tert-butoxideHCID 593791374-[(3-Ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-indan-5-carboxylic acid methyl ester

Product 1

HCID 593791336-Oxo-2,3,6,7,8,9-hexahydro-1H-10-aza-cyclohepta[e]indene-10-carboxylic acid isopropyl esterYield 81%

Reagents, catalysts & solvents 2

HCID 8028TetrahydrofuranSolvent2×HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
160 °C

Procedure

Add a solution of 4-[(3-ethoxycarbonyl-propyl)-isopropoxycarbonyl-amino]-indan-5-carboxylic acid methyl ester (510 mg, 1.30 mmol) in tetrahydrofuran (20.4 mL) to a solution of potassium tert-butoxide (2.60 mL, 2.60 mmol, 1M in tetrahydrofuran) in tetrahydrofuran (18 mL) at room temperature under an atmosphere of nitrogen. After 30 min, pour the mixture into ice/water. Treat the aqueous phase with 1M HCl to pH neutral and extract with dichloromethane. Dry the organic layer over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Dissolve the former crude in dimethyl sulfoxide (11 mL) and add water (2 drops) followed by addition of lithium chloride (134 mg, 3.2 mmol) and heat the resulting solution at 160° C. for 30 minutes. Cool the mixture to room temperature and pour into brine. Extract the mixture with ethyl acetate. Dry the organic layers over anhydrous sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate, to afford the title compound (302 mg, 81% over two steps). MS (ES+): 288 (M+H).

Workup

  1. extractionextract with dichloromethane
  2. dry with materialDry the organic layer over anhydrous sodium sulfate
  3. filtrationfilter
  4. customremove the solvent under reduced pressure
  5. dissolutionDissolve the former crude in dimethyl sulfoxide (11 mL)
  6. additionadd water (2 drops)
  7. temperatureCool the mixture to room temperature
  8. extractionExtract the mixture with ethyl acetate
  9. dry with materialDry the organic layers over anhydrous sodium sulfate
  10. filtrationfilter
  11. customremove the solvent under reduced pressure
  12. customPurify the residue by flash chromatography
  13. washeluting with hexanes/ethyl acetate

Sources & evidence

ORD record
ord-8942edd37e594a5d820fdbe41920f53f
Source dataset
uspto-grants-2010_08
Patent number
US07786108B2

Reaction notes

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