Water → 4-{2-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic Acid Methyl Ester

HRID 730945Notes

Reaction equation

HRID 730945 reaction equation
O.NN.[CH3:4][O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]=2[CH2:26][CH2:27][N:28]2C(=O)C3[C:30](=CC=CC=3)[C:29]2=[O:38])=[CH:9][CH:8]=1.C(OC(=O)C)(=O)C.O>CC(O)C>[CH3:4][O:5][C:6](=[O:39])[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][C:16]2[C:24]3[C:19](=[CH:20][CH:21]=[C:22]([Cl:25])[CH:23]=3)[NH:18][C:17]=2[CH2:26][CH2:27][NH:28][C:29](=[O:38])[CH3:30])=[CH:9][CH:8]=1

Participants

6

Reactant 4

HCID 962WaterHCID 7918Acetic Anhydride2×HCID 24654Hydrazine hydrate (1:1)HCID 690536944-(2-{5-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic Acid Methyl Ester

Product 1

HCID 690536104-{2-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy}-benzoic Acid Methyl Ester

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent

Conditions

Temperature
70 °C

Procedure

Hydrazine hydrate (174 g, 3 mol) was added in one portion to a stirred suspension of 4-(2-{5-Chloro-2-[2-(1,3-dioxo-1,3-dihydro-isoindol-2-yl)-ethyl]-1H-indol-3-yl}-ethoxy)-benzoic acid methyl ester (503 g, 1.0 mol) in 5.7 L 2-propanol. The suspension was warmed to 82 C for 3.5 h. HPLC analysis showed remaining starting material was less than 1%. The reaction mixture was allowed to cool to 70° C. and filtered at this temperature. Pyridine (1 L) was added to the filtrate, and the 2-propanol was distilled in vacuo (40C, 50 mmHg). The concentrate was charged to a 12 L 4-neck flask equipped with mechanical stirrer. The mixture was cooled to 5° C. under stirring. Acetic anhydride (113 g, 1.1 mol) was added dropwise maintaining an internal temperature below 10 C. The mixture was stirred for 0.5 h after complete acetic anhydride addition. HPLC analysis showed less 1% of amine remaining. Water (5 L) was added and the resulting suspension was stirred for 12 h at rt. The solid was collected by filtration and washed with water (3×500 mL). The product was dried in a vacuum oven at 50C to an LOD of <1%. 1H-NMR (300 MHz, DMSO−d6): δ1.78 (s, 3H), 2.87 (t, J=7 Hz, 2H), 3.10 (t, J=7 Hz, 2H), 3.36 (t, J=7 Hz, 2H), 3.80 (s, 3H), 4.16 (t, J=7 Hz, 2H), 6.98-7.03 (m, 3H), 7.26 (d, J=9 Hz, 1H), 7.57 (d, J=2 Hz, 1H), 7.88 (d, J=9 Hz, 2H), 8.00 (t, J=6 Hz, 1H), 10.90 (s, 1H) ppm

Workup

  1. temperatureThe suspension was warmed to 82 C for 3.5 h
  2. filtrationfiltered at this temperature
  3. additionPyridine (1 L) was added to the filtrate
  4. distillationthe 2-propanol was distilled in vacuo (40C, 50 mmHg)
  5. additionThe concentrate was charged to a 12 L 4-neck flask
  6. customequipped with mechanical stirrer
  7. temperatureThe mixture was cooled to 5° C.
  8. temperaturemaintaining an internal temperature below 10 C
  9. stirringThe mixture was stirred for 0.5 h
  10. stirringthe resulting suspension was stirred for 12 h at rt
  11. filtrationThe solid was collected by filtration
  12. washwashed with water (3×500 mL)
  13. dry with materialThe product was dried in a vacuum oven at 50C to an LOD of <1%

Sources & evidence

ORD record
ord-1a4a1108022d402db8617e2a9b4edc3f
Source dataset
uspto-grants-2009_09
Patent number
US07582771B2

Reaction notes

Loading…