Acrylonitrile → 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine

HRID 323328Notes

Reaction equation

HRID 323328 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:39]=[C:40]([O:44][CH3:45])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[NH:34][C:33]4[CH:35]=[CH:36][CH:37]=[CH:38][C:32]=4[N:31]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7].O1CCCC1.C([Li])(CC)C.[C:56](#[N:59])[CH:57]=[CH2:58]>CO.O>[CH3:45][O:44][C:40]1[CH:39]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:41]=1[O:42][CH3:43])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:21][CH2:22][N:23]2[CH2:28][CH2:27][CH:26]([NH:29][C:30]3[N:31]([CH2:58][CH2:57][C:56]#[N:59])[C:32]4[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=4[N:34]=3)[CH2:25][CH2:24]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[C:15]([F:20])[CH:14]=2)[CH2:9]1)=[O:7]

Participants

7

Reactant 4

HCID 7855AcrylonitrileHCID 8028TetrahydrofuranHCID 220092161-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidineHCID 178418400CID 53628100

Product 1

HCID 98099991-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-cyanoethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-78 °C

Procedure

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(3,4-difluorophenyl)pyrrolidine (0.145 g, 0.23 mmol) and tetrahydrofuran (5 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of s-butyl lithium (0.22 mL, 1.3 M in hexane, 0.28 mmol). After 30 minutes, add acrylonitrile (0.015 g, 0.28 mmol). Allow to warm to ambient temperature and then heat to reflux. After 12 hours, add water and separate the layers. Extract the aqueous layer three times with ethyl acetate. Combine the organic layers, dry over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 3/0.5/96.5 methanol/concentrated ammonium hydroxide/dichloromethane to give the title compound: Rf=0.61 (silica gel, 5/0.5/94.5 methanol/concentrated ammonium hydroxide/dichloromethane).

Workup

  1. temperatureAllow to warm to ambient temperature
  2. temperatureheat to reflux
  3. waitAfter 12 hours
  4. customseparate the layers
  5. extractionExtract the aqueous layer three times with ethyl acetate
  6. dry with materialdry over Na2SO4
  7. filtrationfilter
  8. customevaporate in vacuo
  9. customto give a residue

Sources & evidence

ORD record
ord-7453ee5c13154ae9b93ce2ed57f056c2
Source dataset
uspto-grants-2001_04
Patent number
US06211199B1

Reaction notes

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