Toluene → 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

HRID 323485Notes

Reaction equation

HRID 323485 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)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.[N:62]1[CH:67]=[CH:66][CH:65]=[CH:64][C:63]=1[CH2:68]Cl>O1CCCC1.C(OCC)(=O)C.ClCCl.C(OCC)(=O)C.CCCCCC>[CH3:44][O:43][C:39]1[CH:38]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[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]([CH2:68][C:63]4[CH:64]=[CH:65][CH:66]=[CH:67][N:62]=4)[C:31]4[CH:37]=[CH:36][CH:35]=[CH:34][C:32]=4[N:33]=3)[CH2:24][CH2:23]2)([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:9]1)=[O:7]

Participants

9

Reactant 4

HCID 1140TolueneHCID 23393Picolyl chloride2×HCID 3251421Potassium bis(trimethylsilyl)amideHCID 99167631-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl) pyrrolidine

Product 1

HCID 98530431-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(pyrid-2-ylmethyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine

Reagents, catalysts & solvents 4

HCID 6344DichloromethaneSolventHCID 8028TetrahydrofuranSolvent2×HCID 8857Ethyl AcetateSolventHCID 21226206Ethyl acetate hexaneSolvent

Conditions

Temperature
-65 °C

Procedure

Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-(4-fluorophenyl)pyrrolidine (0.52 g, 0.87 mmol) and tetrahydrofuran (20 mL). Cool to about −65° C. using a dry-ice/acetone bath. Add dropwise a solution of potassium bis(trimethylsilyl)amide in toluene (2.1 mL, 0.5 M, 1.05 mmol) at such a rate that the temperature of the reaction mixture does not rise above about 60° C. After 1.5 hours, add a solution of 2-picolyl chloride (prepared as described in Example 37.2) (0.13 g, 1.05 mmol) in tetrahydrofuran (5 mL). When the addition of 2-picolyl chloride is complete, warm the reaction mixture to ambient temperature. After 18 hours, dilute the reaction mixture with ethyl acetate, extract twice with a saturated aqueous sodium bicarbonate solution. Dry the organic layer over Na2SO4, filter, and concentrate in vacuo to obtain a residue. Chromatograph the residue on silica gel eluting with methanol/ethyl acetate 1/1. Evaporate the product containing fractions to give a residue, dissolve the residue in dichloromethane, filter through a fine filter, and evaporate the filtrate in vacuo to give the title compound.

Workup

  1. customdoes not rise above about 60° C
  2. temperaturewarm the reaction mixture to ambient temperature
  3. waitAfter 18 hours
  4. extractionextract twice with a saturated aqueous sodium bicarbonate solution
  5. dry with materialDry the organic layer over Na2SO4
  6. filtrationfilter
  7. concentrationconcentrate in vacuo
  8. customto obtain a residue
  9. customEvaporate the product
  10. additioncontaining fractions
  11. customto give a residue
  12. filtrationfilter through a fine filter
  13. customevaporate the filtrate in vacuo

Sources & evidence

ORD record
ord-3b2eead9c5e7480bb7c99e469756e37e
Source dataset
uspto-grants-2001_04
Patent number
US06211199B1

Reaction notes

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