Tetrahydrofuran → 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine

HRID 323273Notes

Reaction equation

HRID 323273 reaction equation
[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[NH:33][C:32]4[CH:34]=[CH:35][CH:36]=[CH:37][C:31]=4[N:30]=3)[CH2:24][CH2:23]2)([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:9]1)=[O:7].[O:45]1[CH2:49][CH2:48][CH2:47][CH2:46]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C(OCCCl)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(N(CC)CC)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:38]=[C:39]([O:43][CH3:44])[C:40]=1[O:41][CH3:42])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][CH:25]([NH:28][C:29]3[N:30]([CH2:47][CH2:46][O:45][CH2:49][CH3:48])[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH2:24][CH2:23]2)([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH2:9]1)=[O:7]

Participants

8

Reactant 4

HCID 8028TetrahydrofuranHCID 12341Ethane, 1-chloro-2-ethoxy-2×HCID 3251421Potassium bis(trimethylsilyl)amide2×HCID 99602911-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine

Product 1

HCID 98312171-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine

Reagents, catalysts & solvents 3

HCID 74236Tetrabutylammonium BromideCatalystHCID 962WaterSolventHCID 8471TriethylamineSolvent

Conditions

Temperature
-78 °C

Procedure

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(phenylmethyl)pyrrolidine (0.56 g, 0.77 mmol) and tetrahydrofuran (10 mL). Cool to −78° C. using a dry-ice/acetone bath. Add a solution of potassium bis(trimethylsilyl)amide (1.7 mL, 0.5 M in toluene, 0.85 mmol). After 30 minutes, warm to ambient temperature. Add tetrabutylammonium bromide (0.06 g) and 2-chloroethyl ethyl ether (0.092 g 0.85 mmol). Heat to reflux. After 12 hours, potassium bis(trimethylsilyl)amide (0.5 mL, 0.5 M in toluene) and 2-chloroethyl ethyl ether (0.5 mL) and continue to reflux. After 12 hours, cool the reaction and add water. Separate the layers and extract the aqueous layer three times with ethyl acetate. Dry the combined organic layers over Na2SO4, filter, and evaporate in vacuo to give a residue. Chromatograph the residue on silica gel eluting with 2% triethylamine/5% methanol/ethyl acetate to give the title compound: Rf=0.32 (silica gel, 2% triethylamine/5% methanol/ethyl acetate).

Workup

  1. temperaturewarm to ambient temperature
  2. temperatureHeat to reflux
  3. waitAfter 12 hours
  4. temperatureto reflux
  5. waitAfter 12 hours
  6. temperaturecool
  7. customthe reaction
  8. customSeparate the layers
  9. extractionextract the aqueous layer three times with ethyl acetate
  10. dry with materialDry the combined organic layers over Na2SO4
  11. filtrationfilter
  12. customevaporate in vacuo
  13. customto give a residue

Sources & evidence

ORD record
ord-c8823596a44a4c9fbcc6f6d4df2647a2
Source dataset
uspto-grants-2001_04
Patent number
US06211199B1

Reaction notes

Loading…