Reaction #3140

Reaction equation

acetic acid

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

formaldehyde

sodium cyanoborohydride

→

title compound

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

Solvents

methanol

methanol

dichloromethane

water

sodium bicarbonate

Conditions

Workup

1. 1
   Temperatureto warm to room temperature overnight
2. 2
   OtherThe phases were separated
3. 3
   Extractionthe aqueous layer was extracted with dichloromethane (10 mL)
4. 4
   WashThe combined organic phases were washed (brine)
5. 5
   Otherdried
6. 6
   Otherevaporated
7. 7
   Otherto give material which
8. 8
   Otherwas purified by chromatography with dichloro-methane:methanol (30:1) as the eluent

Procedure

To a stirred solution of 4-(4-acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine (0.30 g) in methanol (4 mL) was added aqueous formaldehyde (37% w/w, 0.027 mL). The mixture was cooled to 0° C. and acetic acid (0.038 mL) was added followed by a solution of sodium cyanoborohydride (43 mg) in methanol (1 mL). The reaction mixture was allowed to warm to room temperature overnight and was diluted with dichloromethane (5 mL), water (5 mL), and saturated sodium bicarbonate (mL). The phases were separated and the aqueous layer was extracted with dichloromethane (10 mL). The combined organic phases were washed (brine), dried, and evaporated, to give material which was purified by chromatography with dichloro-methane:methanol (30:1) as the eluent, to give the title compound as a hemihydrate (0.175 g); mp 72°-74° C.; NMR (d6 -DMSO-trifluoroacetic acid): 7.7 (m,5), 7.25 (m, 6), 3.52 (d,1, J=14.4), 3.25 (d,1, J=14.4), 3.0 (m,1), 2.7-2.45 (m,4), 2.50 (s,3), 2.35-1.95 (broad m,4), 1.85 (s,3), 1.95-1.5 (broad m,4); MS: m/z=674(M+1,100%); TLC: Rf=0.55 (10:1 dichloromethane:methanol). Analysis for C33H35Cl2F6N3O.0.50 H2O: Calculated: C, 57.98; H, 5.31; N, 6.15; Found: C, 57.95; H, 5.24; N, 6.52.

Source