Ethanol → (+/-)-[10-(4-Chlorophenyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetic acid

HRID 857317Notes

Reaction equation

HRID 857317 reaction equation
Br[C:2]1[CH:8]=[C:7](Br)[C:6]([S:10][CH3:11])=[CH:5][C:3]=1[NH2:4].N([O-])=O.[Na+].[CH3:16][C:17]([O-:19])=[O:18].[Na+].[Cl:21][C:22]1[CH:37]=[CH:36][C:25]([CH2:26][CH:27]([C:33](=O)[CH3:34])C(OCC)=O)=[CH:24][CH:23]=1.[OH-:38].[K+].[CH3:40][CH2:41]O>O.Cl>[Cl:21][C:22]1[CH:23]=[CH:24][C:25]([C:26]2[C:5]3[C:3](=[CH:2][CH:8]=[CH:7][C:6]=3[S:10]([CH3:11])=[O:38])[N:4]3[CH2:40][CH2:41][CH2:34][CH:33]([CH2:16][C:17]([OH:19])=[O:18])[C:27]=23)=[CH:36][CH:37]=1

Participants

9

Reactant 6

HCID 702EthanolHCID 14797Potassium HydroxideHCID 517045Sodium Acetate2×HCID 2757404Ethyl 2-(4-chlorobenzyl)acetoacetateHCID 218675112,4-Dibromo-5-(methylsulfanyl)anilineHCID 23668193Sodium Nitrite

Product 1

HCID 21867520(+/-)-[10-(4-Chlorophenyl)-1-(methylsulfinyl)-6,7,8,9-tetrahydropyrido[1,2-a]indol-9-yl]acetic acid

Reagents, catalysts & solvents 2

HCID 313Hydrochloric AcidSolventHCID 962WaterSolvent

Conditions

Temperature
0 °C

Procedure

To a suspension of the aniline of Step 2 (5.95 g, 20 mmol) in 13 mL of water and 8 mL of concentrated HCl at 0° was added a NaNO2 solution (1.52 g in 3 mL of water). The mixture was stirred for 15 minutes at 0° C. and was adjusted to pH 3 with the addition of NaOAc. In a separate flask, a solution of the ester of Step 1 (5.1 g, 20 mmol) in 27 mL of EtOH was treated with an aqueous solution of KOH (1.12 g in 3 mL of water). The solution was then cooled to −5° C. and the diazonium salt was added to the alkaline solution. The pH was adjusted to 5 with NaOAc and the mixture was stirred at 0° C. for 16 hours. The reaction mixture was extracted with EtOAc and the combined organic layers were dried over MgSO4 and concentrated. The residue was added slowly to a 3N HCl solution in EtOH and was stirred at 70° C. for 2 hours. EtOH was removed by evaporation and water was added. The aqueous layer was extracted with CH2Cl2 and the combined organic layers were dried over Na2SO4 and concentrated. The residue was purified by silica gel chromatography eluted with 25% EtOAc in Hexanes to provide 2.1 g of the title compound as an orange solid.

Workup

  1. temperatureThe solution was then cooled to −5° C.
  2. stirringthe mixture was stirred at 0° C. for 16 hours
  3. extractionThe reaction mixture was extracted with EtOAc
  4. dry with materialthe combined organic layers were dried over MgSO4
  5. concentrationconcentrated
  6. additionThe residue was added slowly to a 3N HCl solution in EtOH
  7. stirringwas stirred at 70° C. for 2 hours
  8. customEtOH was removed by evaporation and water
  9. additionwas added
  10. extractionThe aqueous layer was extracted with CH2Cl2
  11. dry with materialthe combined organic layers were dried over Na2SO4
  12. concentrationconcentrated
  13. customThe residue was purified by silica gel chromatography
  14. washeluted with 25% EtOAc in Hexanes

Sources & evidence

ORD record
ord-0256bdec7ced40479bfc8ead41426de8
Source dataset
uspto-grants-2006_12
Patent number
US07144913B2

Reaction notes

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