Methyl Isobutyl Ketone → [4-Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-4H-indol-1-yl]acetic acid

HRID 1516984Notes

Reaction equation

HRID 1516984 reaction equation
[C:1]([NH:4][C:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]=1[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)=[C:8]([CH3:20])[N:9]2[CH2:14][C:15]([O:17]CC)=[O:16])(=[O:3])[CH3:2].[OH-].[Na+].CC(CC(C)=O)C>C(O)CC>[C:1]([NH:4][CH:5]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:6]1=[C:7]([S:21][C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=1)[CH:8]([CH3:20])[N:9]2[CH2:14][C:15]([OH:17])=[O:16])(=[O:3])[CH3:2]

Participants

5

Reactant 3

HCID 7909Methyl Isobutyl KetoneHCID 14798Sodium HydroxideHCID 11546184[4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetic acid ethyl ester

Product 1

HCID 66937643[4-Acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-4H-indol-1-yl]acetic acid

Reagents, catalysts & solvents 1

HCID 10311-PropanolSolvent

Conditions

Temperature
70 °C

Procedure

To a stirred slurry of ethyl [4-acetylamino-3-(4-chlorophenylsulfanyl)-2-methyl-1H-indol-1-yl]acetate (3.16 kg, 3.05 kg corrected for assay, 7.3 moles) in 1-propanol (15.3 L) was added aqueous NaOH (1M, 15.3 L). The mixture was then heated at 70° C. for 2 h, cooled to 40° C. then MIBK (30.5 L) was added and the mixture reheated to 80° C. Approximately 20% of the resulting biphasic mixture was removed from the reaction vessel to be processed separately. To the remainder, aqueous hydrochloric acid (1M, 13.4 L) was added to the solution over a period of 45 mins then the resulting slurry was cooled to 15° C. over 1 h and stirring continued at this temperature for a further 30 mins. The solid product was collected by filtration, washed with water (2×9.8 L) followed by EtOAc (7.3 L) then dried on the filter for 10 mins then in vacuo at 45° C. to give the title compound as a solid; 2.15 kg; assay by 1H NMR: 99.4% w/w; 2.14 kg corrected for assay (94%); purity: 99.5 area % by HPLC; m/z: 389 (MH+); 1H NMR: 1.86 (3H, s), 2.34 (3H, s), 5.11 (2H, s), 6.97-7.00 (2H, d), 7.08-7.11 (1H, m), 7.27-7.30 (3H, m), 7.47-7.50 (1H, d), 9.50 (1H, br s).

Workup

  1. temperaturecooled to 40° C.
  2. customreheated to 80° C
  3. customApproximately 20% of the resulting biphasic mixture was removed from the reaction vessel
  4. additionTo the remainder, aqueous hydrochloric acid (1M, 13.4 L) was added to the solution over a period of 45 mins
  5. temperaturethe resulting slurry was cooled to 15° C. over 1 h
  6. filtrationThe solid product was collected by filtration
  7. washwashed with water (2×9.8 L)
  8. customthen dried on the
  9. filtrationfilter for 10 mins

Sources & evidence

ORD record
ord-d91b225a43ab4deb97e2788b5f2806f4
Source dataset
uspto-grants-2012_07
Patent number
US08227622B2

Reaction notes

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