Reaction #3137

Reaction equation

acetic acid

4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylamine

3,5-bis(trifluoromethyl)benzaldehyde

sodium cyanoborohydride

→

title compound

4-(4-Acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine

Solvents

methanol

methanol

dichloromethane

water

hydrochloric acid

Conditions

Workup

1. 1
   Temperatureto slowly warm to room temperature overnight
2. 2
   OtherThe layers were separated
3. 3
   Extractionthe aqueous layer was extracted three times with dichloromethane (10 mL)
4. 4
   Extractionextracted with 5:1 dichloromethane
5. 5
   WashThe combined organic layers were washed (brine)
6. 6
   Otherdried
7. 7
   Filtrationfiltered
8. 8
   Otherevaporated
9. 9
   Otherto afford an oil which
10. 10
    Otherwas purified by chromatography, with dichloromethane:methanol (40:1) as eluent
11. 11
    OtherEvaporation of the appropriate fractions

Procedure

To a solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)butylamine (0.30 g) in methanol (3 mL) was added 3,5-bis(trifluoromethyl)benzaldehyde (0.088 mL) and the mixture cooled to 0° C. To this stirred mixture was sequentially added acetic acid (0.046 mL) and a solution of sodium cyanoborohydride (0.50 g) in methanol (1 mL). The mixture was allowed to slowly warm to room temperature overnight and was diluted with dichloromethane (5 mL), water (5 mL), and hydrochloric acid (1N, 5 mL). The layers were separated, and the aqueous layer was extracted three times with dichloromethane (10 mL). The acidic aqueous layer was made basic with aqueous sodium hydroxide (1N, 5 mL) and then extracted with 5:1 dichloromethane:methanol (3×10 mL). The combined organic layers were washed (brine), dried, filtered and evaporated to afford an oil which was purified by chromatography, with dichloromethane:methanol (40:1) as eluent. Evaporation of the appropriate fractions afforded a partial hydrate of the title compound as a white solid (0.154 g); mp 66°-68° C.; NMR: 7.82 (s,3), 7.75 (s,1), 7.50 (m,2), 7.35-5.15 (m,6), 2.75 (m,1), 2.65-2.55 (m,2), 2.32-1.95 (m,6), 1.85 (s,3), 1.95-1.55 (m,6); MS: m/z=660(M+1, 100%); Rf =0.51 (10:1, dichloromethane:methanol). Analysis for C32H33Cl2F6N3O.0.25 H2O: Calculated: C, 57.79; H, 5.08; N, 6.32; Found: C, 57.68; H, 5.07; N, 6.30.

Source