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

HRID 730948Notes

Reaction equation

HRID 730948 reaction equation
C([O:3][C:4](=[O:30])[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][NH:26][C:27](=[O:29])[CH3:28])=[CH:7][CH:6]=1)C.Br[CH:32]([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.CC(C)([O-])C.[OH-].[K+].Cl>C(#N)C.O>[C:27]([NH:26][CH2:25][CH2:24][C:15]1[N:16]([CH:32]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[C:17]2[C:22]([C:14]=1[CH2:13][CH2:12][CH2:11][C:8]1[CH:7]=[CH:6][C:5]([C:4]([OH:3])=[O:30])=[CH:10][CH:9]=1)=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)(=[O:29])[CH3:28]

Participants

8

Reactant 5

HCID 313Hydrochloric AcidHCID 14797Potassium HydroxideHCID 236603BromodiphenylmethaneHCID 45749132-Methylpropan-2-olateHCID 113623414-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester

Product 1

HCID 113874774-{3-[2-(2-Acetylamino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acidYield 54%

Reagents, catalysts & solvents 2

HCID 962WaterSolventHCID 6342AcetonitrileSolvent

Conditions

Temperature
3 °C

Procedure

To a suspension of the 4-{3-[2-(2-Acetylamino-ethyl)-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid ethyl ester (250.0 g, 0.585 mol, WAY-185133) and bromodiphenylmethane (203.0 g, 0.82 mol) in acetonitrile (10.0 L) at 3° C. was added potasssium tert.butoxide (92.0 g, 0.82 mol). The reaction mixture was stirred for 7 hours at 3° C. Water (125 ml) was added to the reaction mixture and then 7.5 L of solvent was distilled off. To the concentrated reaction mixture, potassium hydroxide (82.1 g, 1.46 mol) was added followed by 2 hours of reflux. To the cooled reaction mixture at 35° C., dil. HCl was added to bring pH to 4-5. The reaction mixture suspension was then cooled to 3° C. It was then filtered, washed with water (250 mL×2). The wet cake was slurried in ethyl acetate (750 ml) at reflux for 2 h. The suspension was cooled to ambient temperature, filtered and washed with ethyl acetate (85 mL×2). Drying the product in vacuo at 50° C. provided 177.5 g (yield 54%, HPLC 93%, SLI 1.4%) of 4-{3-[2-(2-Acetylamino-ethyl)-1-benzhydryl-5-chloro-1H-indol-3-yl]-propyl}-benzoic acid (WAY-185008). Mass spectrum (electrospray, m/e): M+H 565. 1H NMR (DMSO−d6): δ12.30 (br.s, 1H), 8.06 (m,1H), 7.86 (m, 2H), 7.45 (d, 1H, J=3 Hz), 7.34 (m, 6H), 7.21 (s, 1H), 7.12 (m, 4H), 6.77 (dd, 1H, J=9 Hz& 3 Hz), 6.45 (d,1H, J=9 Hz), 3.28 (m, 2H), 2.87 (m, 2H), 2.72 (m, 4H), 1.90 (m, 2H).

Workup

  1. distillation7.5 L of solvent was distilled off
  2. additionwas added
  3. waitfollowed by 2 hours
  4. temperatureof reflux
  5. customTo the cooled reaction mixture at 35° C.
  6. temperatureThe reaction mixture suspension was then cooled to 3° C
  7. filtrationIt was then filtered
  8. washwashed with water (250 mL×2)
  9. temperatureat reflux for 2 h
  10. temperatureThe suspension was cooled to ambient temperature
  11. filtrationfiltered
  12. washwashed with ethyl acetate (85 mL×2)
  13. customDrying the product in vacuo at 50° C.

Sources & evidence

ORD record
ord-3e1dc9cd0bc549fe8388e5c2f3fb237f
Source dataset
uspto-grants-2009_09
Patent number
US07582771B2

Reaction notes

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