Water → HCID 86596762, compound

HRID 730947Notes

Reaction equation

HRID 730947 reaction equation
Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[NH:29][C:28]=1[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41].CC(C)([O-])C.[K+].O>C(#N)C.C(OC(=O)C)C>[CH3:15][O:16][C:17](=[O:43])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[O:24][CH2:25][CH2:26][C:27]1[C:35]2[C:30](=[CH:31][CH:32]=[C:33]([Cl:36])[CH:34]=2)[N:29]([CH:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:28]=1[CH2:37][CH2:38][NH:39][C:40](=[O:42])[CH3:41]

Participants

7

Reactant 4

HCID 962WaterHCID 236603BromodiphenylmethaneHCID 23665647Potassium tert-butoxideHCID 86596763HCID 86596763, compound

Product 1

HCID 86596762HCID 86596762, compoundYield 50.6%

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 8857Ethyl AcetateSolvent2×

Procedure

Bromodiphenylmethane (208.3 g 0.843 mol) and 4-{2-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-ethoxy-benzoic acid methyl ester (250.0 g, 0.603 mol) were suspended in acetonitrile (10 L). The suspension was stirred and cooled to −1 C and potassium tert. butoxide (94.6 g 0.843 mol) was added in one portion. the reaction was complete by HPLC analysis after stirring for 2.5 h at −1 C. Water (125 mL) was added to the reaction mixture. The suspension was heated to 50 C and then 8.3 L solvent was removed by vacuum distillation (180 mmHg). Aqueous Potassium hydroxide (84.4 g KOH (87%) in 300 mL of water) was added and the reaction mixture was refluxed for 3 h. The solution was cooled to 35 C and acidified (pH=3) with 4N hydrochloric acid (435 mL). The suspension was stirred for 20 min. at 5 C and the precipitate was collected by filtration. The cake was washed with water (250 mL×3) and ethyl acetate (250 mL) and the wet cake was dried at 70 C/30 mmHg for 36 h to yield 253 g crude product. The solid was suspended with 1 L ethylacetate and stirred and warmed at refluxed for 4 h. This ethylacetate slurry was repeated two times. The wet product was collected by filtration and dried for 16 h at 60 C/30 mmHg to obtain 177.3 g (50%) product. The structure was determined by 1H-NMR. δ(300 MHz, DMSOd6) 1.78 (s, 3H), 2.97 (m, 2H), 3.15-3.25 (m, 4H), 4.22 (t, J=6 Hz, 2H), 6.48 (d, J=9 Hz, 1H), 6.80 (dd, J=2 Hz, J=9 Hz, 1H), 6.87 (d, J=8 Hz, 2H), 7.10-7.13 (m, 4H), 7.26 (s, 1H), 7.31-7.40 (m, 6H), 7.66 (d, J=2 Hz, 1H), 7.85 (d, J=8 Hz, 2H), 8.15 (t, J=5 Hz, 1H) ppm.

Workup

  1. additionwas added in one portion
  2. stirringafter stirring for 2.5 h at −1 C
  3. temperatureThe suspension was heated to 50 C
  4. custom8.3 L solvent was removed by vacuum distillation (180 mmHg)
  5. additionAqueous Potassium hydroxide (84.4 g KOH (87%) in 300 mL of water) was added
  6. temperaturethe reaction mixture was refluxed for 3 h
  7. temperatureThe solution was cooled to 35 C
  8. stirringThe suspension was stirred for 20 min. at 5 C
  9. filtrationthe precipitate was collected by filtration
  10. washThe cake was washed with water (250 mL×3) and ethyl acetate (250 mL)
  11. customthe wet cake was dried at 70 C/30 mmHg for 36 h
  12. customto yield 253 g crude product
  13. stirringstirred
  14. temperaturewarmed
  15. temperatureat refluxed for 4 h
  16. filtrationThe wet product was collected by filtration
  17. customdried for 16 h at 60 C/30 mmHg

Sources & evidence

ORD record
ord-18c1e222d8114a8e927c24ce26ccc976
Source dataset
uspto-grants-2009_09
Patent number
US07582771B2

Reaction notes

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