Water → 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester

HRID 730946Notes

Reaction equation

HRID 730946 reaction equation
[CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:10]=[CH:9][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][N:26]2C(=O)C3[C:28](=CC=CC=3)[C:27]2=[O:36])=[CH:7][CH:6]=1)[CH3:2].NN.C(OC(=O)C)(=O)C.O>CC(O)C>[CH2:1]([O:3][C:4](=[O:37])[C:5]1[CH:6]=[CH:7][C:8]([CH2:11][CH2:12][CH2:13][C:14]2[C:22]3[C:17](=[CH:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][C:15]=2[CH2:24][CH2:25][NH:26][C:27](=[O:36])[CH3:28])=[CH:9][CH:10]=1)[CH3:2]

Participants

6

Reactant 4

HCID 962WaterHCID 7918Acetic AnhydrideHCID 9321HydrazineHCID 117204684-(3-{5-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-propyl)-benzoic Acid Ethyl Ester

Product 1

HCID 113623414-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl esterYield 87.6%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
80 °C

Procedure

A stirred mixture of 4-(3-{5-chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-propyl)-benzoic acid ethyl ester (415 g, 0.81 mol) and 55% hydrazine solution (141 g, 2.42 mol) in 2-propanol (4 L) is warmed to 80° C. for 3 h-4 h. The reaction is complete when the product/starting material ratio is greater than 99/1 by HPLC. The reaction mixture is cooled to room temperature. The byproduct is removed by filtration. The cake is washed with 2-propanol (400 mL×3). The filtrate and wash are combined and distilled to about half volume. Pyridine (830 mL×2) is added and the remainder of the 2-propanol is removed under reduced pressure. The stirred mixture is cooled to 5° C.-10° C. Acetic anhydride (90.4 g, 1.10 mol) is added dropwise to the reaction mixture at 5° C.-10° C. The reaction is complete when the product/starting material ratio is >99/1 by HPLC analysis. Water (5.0 L) is added to the reaction mixture, maintaining the temperature below 25° C. The reaction mixture is stirred at room temperature for 12 hours. The solid product is collected by filtration, washed with water (500 mL×3) and dried in vacuum oven (70° C.) to give 303 g (87.6%, 95.4% by HPLC) of 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester.

Workup

  1. temperatureThe reaction mixture is cooled to room temperature
  2. customThe byproduct is removed by filtration
  3. washThe cake is washed with 2-propanol (400 mL×3)
  4. washThe filtrate and wash
  5. distillationdistilled to about half volume
  6. additionPyridine (830 mL×2) is added
  7. customthe remainder of the 2-propanol is removed under reduced pressure
  8. temperatureThe stirred mixture is cooled to 5° C.-10° C
  9. temperaturemaintaining the temperature below 25° C
  10. filtrationThe solid product is collected by filtration
  11. washwashed with water (500 mL×3)
  12. customdried in vacuum oven (70° C.)

Sources & evidence

ORD record
ord-74a03d5a08f24de384e81de9d6d8e975
Source dataset
uspto-grants-2009_09
Patent number
US07582771B2

Reaction notes

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