Toluene → Tert-butyl 3-(2-amino-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate

HRID 1176388Notes

Reaction equation

HRID 1176388 reaction equation
Br[C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1.C(=[NH:57])(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[Na+].C1(C)C=CC=CC=1>[Cl-].[Na+].O>[NH2:57][C:2]1[CH:42]=[C:41]([CH3:43])[CH:40]=[CH:39][C:3]=1[CH2:4][O:5][CH:6]1[CH:11]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][CH2:21][O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=3[O:30][CH3:31])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:7]1

Participants

6

Reactant 4

HCID 1140TolueneHCID 136809Benzophenone imineHCID 23676156Sodium t-butoxideHCID 68504535Tert-butyl 3-(2-bromo-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate

Product 1

HCID 68504488Tert-butyl 3-(2-amino-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate

Reagents, catalysts & solvents 1

HCID 57417360Sodium chloride; waterSolvent

Conditions

Temperature
80 °C

Procedure

The mixture of 0.800 g of tert-butyl 3-(2-bromo-4-methylbenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate, 0.250 ml of benzophenone imine, 0.0037 g of dipalladiumtris(dibenzylidenacetone)-chloroform complex, 0.0051 g of (R)-(+)-2,2′-bis(diphenylphosphine)-1,1′-binaphthyl and 0.168 g of sodium tert-butoxide is admixed with 6.0 ml of toluene and stirred under argon at 80° C. over 72 hours. The reaction mixture is cooled, admixed with brine (20 ml) and extracted with ethyl acetate (2×80 ml). The organic phases are dried over sodium sulphate, filtered and concentrated by evaporation. The residue is dissolved in 6.0 ml of methanol, admixed with 0.090 g of 5% Pd/C and 1.15 g of ammonium formate, and stirred at 60° C. over 72 hours. The reaction mixture is diluted with methanol (20 ml) and clarified by filtration, and the filtrate is concentrated by evaporation. The residue is admixed with 0.1M NaOH (100 ml) and extracted with ethyl acetate (2×100 ml). The organic phases are washed successively with 0.1M NaOH (100 ml) and brine (100 ml), dried over sodium sulphate, filtered and concentrated by evaporation. The title compound is obtained as a yellowish oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.30 (1:2 EtOAc-heptane); Rt=5.32.

Workup

  1. temperatureThe reaction mixture is cooled
  2. extractionextracted with ethyl acetate (2×80 ml)
  3. dry with materialThe organic phases are dried over sodium sulphate
  4. filtrationfiltered
  5. concentrationconcentrated by evaporation
  6. dissolutionThe residue is dissolved in 6.0 ml of methanol
  7. stirringstirred at 60° C. over 72 hours
  8. additionThe reaction mixture is diluted with methanol (20 ml)
  9. filtrationclarified by filtration
  10. concentrationthe filtrate is concentrated by evaporation
  11. extractionextracted with ethyl acetate (2×100 ml)
  12. washThe organic phases are washed successively with 0.1M NaOH (100 ml) and brine (100 ml)
  13. dry with materialdried over sodium sulphate
  14. filtrationfiltered
  15. concentrationconcentrated by evaporation

Sources & evidence

ORD record
ord-5d7f9cc459344daf8fb27e3265055467
Source dataset
uspto-grants-2010_11
Patent number
US07842688B2

Reaction notes

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