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

HRID 613788Notes

Reaction equation

HRID 613788 reaction equation
[C:1]([NH:4][C:5]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:10][CH2:9][N:8]([CH:11]([CH2:24][C:25]2[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH2:15])[CH2:7][CH2:6]1)(=[O:3])[CH3:2].C=O.[C:47](O)(=O)C.C([BH3-])#N.[Na+]>CO.ClCCl.O.C(=O)(O)[O-].[Na+]>[C:1]([NH:4][C:5]1([C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH2:6][CH2:7][N:8]([CH:11]([CH2:24][C:25]2[CH:26]=[C:27]([C:35]([F:36])([F:37])[F:38])[CH:28]=[C:29]([C:31]([F:33])([F:32])[F:34])[CH:30]=2)[CH2:12][CH:13]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][NH:15][CH3:47])[CH2:9][CH2:10]1)(=[O:3])[CH3:2]

Participants

9

Reactant 4

HCID 176Acetic AcidHCID 712FormaldehydeHCID 5003444Sodium cyanoborohydrideHCID 570149314-(4-Acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-[3,5-bis(trifluoromethyl)benzyl]butylamine

Product 1

HCID 867523384-(4-Acetamido-4-phenylpiperidino)-2-(3,4-dichlorophenyl)-N-methyl-N-[3,5-bis(trifluoromethyl)benzyl]butylamine

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolventHCID 6344DichloromethaneSolventHCID 516892Sodium BicarbonateSolvent

Conditions

Temperature
0 °C

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.

Workup

  1. temperatureto warm to room temperature overnight
  2. customThe phases were separated
  3. extractionthe aqueous layer was extracted with dichloromethane (10 mL)
  4. washThe combined organic phases were washed (brine)
  5. customdried
  6. customevaporated
  7. customto give material which
  8. customwas purified by chromatography with dichloro-methane:methanol (30:1) as the eluent

Sources & evidence

ORD record
ord-545c27ffaf0c43a0b7affe2f547cde7f
Source dataset
uspto-grants-1999_12
Patent number
US06008223

Reaction notes

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