Hydrochloric Acid → (4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylic acid

HRID 470666Notes

Reaction equation

HRID 470666 reaction equation
[OH-].[Na+].[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C@@:8]3([C:21]4([CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]4)[N:20]4[C@@H:15]([C:16](=[O:41])[O:17][C@@H](C5C=CC=CC=5)[C@H]4C4C=CC=CC=4)[C@@H:14]3[C:42]3[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=3[F:49])[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1.Cl.[N+]([O-])([O-])=O.[NH4+].[NH4+].[Ce+4].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:3][C:4]1[CH:12]=[C:11]2[C:7]([C:8]3([C@@H:14]([C:42]4[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[C:43]=4[F:49])[C@H:15]([C:16]([OH:41])=[O:17])[NH:20][C:21]43[CH2:26][CH2:25][C:24]([CH3:28])([CH3:27])[CH2:23][CH2:22]4)[C:9](=[O:13])[NH:10]2)=[CH:6][CH:5]=1

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 180504Ceric ammonium nitrateHCID 70872025(3'S,4'R,7'S,8'S,8a'R)-6''-chloro-8'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-3',4'-diphenyl-3',4',8',8a'-tetrahydro-1'H-dispiro[cyclohexane-1,6'-pyrrolo[2,1-c][1,4]oxazine-7',3''-indole]-1',2''(1''H)-dione

Product 1

HCID 68310034(4'S,5'R)-6''-chloro-4'-(3-chloro-2-fluorophenyl)-4,4-dimethyl-2''-oxo-1'',2''-dihydrodispiro[cyclohexane-1,2'-pyrrolidine-3',3''-indole]-5'-carboxylic acidYield 57%

Reagents, catalysts & solvents 2

HCID 887MethanolSolvent2×HCID 962WaterSolvent

Procedure

1N sodium hydroxide solution (50 ml, 50 mmol) was added to a methanol (250 ml) solution of the compound (15.7 g, 23.4 mmol) obtained in Step 1 of Example 1 and the resulting mixture was heated to reflux overnight. After cooling, methanol (500 ml) and water (200 ml) were added to the reaction mixture and then the resulting mixture was neutralized by addition of 1N hydrochloric acid (50 ml) under ice cooling. Cerium (IV) diammonium nitrate (26.9 g, 49.1 mmol) was added under ice cooling, the resulting mixture was stirred for 20 minutes, then potassium carbonate (13.6 g, 98.3 mmol) was added and the resulting mixture was further stirred for 30 minutes. Insoluble matter was removed by filtration through celite and the filtrate was concentrated under reduced pressure. The residue was diluted with water, followed by extraction with ethyl acetate. The aqueous layer was further subjected to extraction with chloroform:methanol [5:1 (v/v)], the organic layers were combined and dried over anhydrous sodium sulfate, then the solvent was evaporated under reduced pressure and the residue was dried to give 6.54 g (57%) of the title compound as a pale yellow solid.

Workup

  1. temperaturethe resulting mixture was heated
  2. temperatureto reflux overnight
  3. temperatureAfter cooling
  4. stirringthe resulting mixture was further stirred for 30 minutes
  5. customInsoluble matter was removed by filtration through celite
  6. concentrationthe filtrate was concentrated under reduced pressure
  7. additionThe residue was diluted with water
  8. extractionfollowed by extraction with ethyl acetate
  9. extractionThe aqueous layer was further subjected to extraction with chloroform
  10. dry with materialdried over anhydrous sodium sulfate
  11. customthe solvent was evaporated under reduced pressure
  12. customthe residue was dried

Sources & evidence

ORD record
ord-fa6527aa59984eb1b7e7a211dd446f40
Source dataset
uspto-grants-2014_01
Patent number
US08629133B2

Reaction notes

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