Sodium Iodide → [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid ethyl ester

HRID 1516981Notes

Reaction equation

HRID 1516981 reaction equation
[I-].[Na+].[C:3](OC(=O)C)(=[O:5])[CH3:4].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][C:18]2[C:26]3[C:25](=[N:27]O)[CH2:24][CH2:23][CH2:22][C:21]=3[N:20]([CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:19]=2[CH3:35])=[CH:13][CH:12]=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C1(C)C(C)=CC=CC=1.C(O)(=O)C.O>[C:3]([NH:27][C:25]1[CH:24]=[CH:23][CH:22]=[C:21]2[C:26]=1[C:18]([S:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][CH:13]=1)=[C:19]([CH3:35])[N:20]2[CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])(=[O:5])[CH3:4]

Participants

8

Reactant 4

HCID 5238Sodium IodideHCID 7918Acetic Anhydride2×HCID 24477Sodium ThiosulfateHCID 76689533HCID 76689533, compound

Product 1

HCID 11546184[4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid ethyl esterYield 77%

Reagents, catalysts & solvents 3

HCID 176Acetic AcidSolvent2×HCID 962WaterSolventHCID 7237O-XyleneSolvent2×

Conditions

Temperature
100 °C

Procedure

A mixture of sodium iodide (0.05 mol equiv) in xylene (1.0 rel vol), acetic acid (1.0 rel vol) and acetic anhydride (1.2 mole equiv) was heated to 97-103° C. in vessel 1 with stirring. In vessel 2, acetic anhydride (1.3 mole equiv) was added to a stirred slurry of ethyl [3-(4-chlorophenylsulfanyl)-4-(hydroxyimino)-2-methyl-4,5,6,7-tetrahydro-1H-indol-1-yl]acetate (1 mole equiv, limiting reagent) in xylene (1.0 rel vol) and acetic acid (1.0 rel vol) at 19-25° C. After stirring at this temperature for 2 h, this mixture was added to the solution in reaction vessel 1 over 2.5 h, maintaining the temperature at between 98 and 102° C. Vessel 2 was rinsed with a mixture of xylene (0.25 rel vol) and acetic acid (0.25 rel vol) which was added to vessel 1. The reaction was held at 98 to 102° C. for a further 1.5 h then cooled to 60° C. Xylene (0.9 rel vol) was added followed by a warm (60° C.) solution of sodium chloride (0.19 rel wt) in water (1.5 rel vol) and the temperature adjusted to 60° C. The aqueous layer was separated and discarded. A warm (60° C.) solution of sodium thiosulfate (0.1 mole equiv) in water (0.5 rel vol) was added and after mixing, the aqueous layer was separated and discarded. The product was precipitated by the is addition of heptanes (3 rel vol) to the organic layer, whilst maintaining the temperature at between 57 and 63° C. The resulting slurry was cooled to 20° C. over 1 h then the solid product was collected by centrifugation, washed with ethanol (3.0 rel vol) and dried to afford crude ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate as a solid in 77% yield; purity by UHPLC 97.4 area %.

Workup

  1. stirringAfter stirring at this temperature for 2 h
  2. additionthis mixture was added to the solution in reaction vessel 1 over 2.5 h
  3. temperaturemaintaining the temperature at between 98 and 102° C
  4. washVessel 2 was rinsed with a mixture of xylene (0.25 rel vol) and acetic acid (0.25 rel vol) which
  5. additionwas added to vessel 1
  6. temperaturethen cooled to 60° C
  7. additionXylene (0.9 rel vol) was added
  8. temperaturea warm (60° C.) solution of sodium chloride (0.19 rel wt) in water (1.5 rel vol)
  9. customadjusted to 60° C
  10. customThe aqueous layer was separated
  11. additionwas added
  12. additionafter mixing
  13. customthe aqueous layer was separated
  14. customThe product was precipitated by the is addition of heptanes (3 rel vol) to the organic layer
  15. temperaturewhilst maintaining the temperature at between 57 and 63° C
  16. temperatureThe resulting slurry was cooled to 20° C. over 1 h
  17. customthe solid product was collected by centrifugation
  18. washwashed with ethanol (3.0 rel vol)
  19. customdried

Sources & evidence

ORD record
ord-7c0ce9900c2a466e9b4e4df84b6f3758
Source dataset
uspto-grants-2012_07
Patent number
US08227622B2

Reaction notes

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