Allyl bromide → 4-[(1-Allyl-3-methyl-piperidin-4-yl)-phenyl-amino]-N,N-diethyl-benzamide

HRID 1358108Notes

Reaction equation

HRID 1358108 reaction equation
[CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:4]([CH3:28])[CH2:3]1.ClC(O[C:33]1C=CC=C[CH:34]=1)=O.[OH-].[Na+].C(C1C=C(OC)C=C(C(C)(C)C)C=1C1C=C(N(C2C=CC=CC=2)C2CCN(C)CC2C)C=CC=1C([O-])=O)(C)(C)C.C(Br)C=C.C([O-])([O-])=O.[K+].[K+]>ClCCCl.C(O)C.C(N(CC)CC)C.C(O)C.C(O)(C)C.O.CO>[CH2:1]([N:2]1[CH2:7][CH2:6][CH:5]([N:8]([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:9]2[CH:21]=[CH:20][C:12]([C:13]([N:15]([CH2:18][CH3:19])[CH2:16][CH3:17])=[O:14])=[CH:11][CH:10]=2)[CH:4]([CH3:28])[CH2:3]1)[CH:33]=[CH2:34]

Participants

13

Reactant 6

HCID 7841Allyl bromideHCID 11430Potassium CarbonateHCID 14798Sodium HydroxideHCID 15891Phenyl chloroformateHCID 22475287(+/-)-4-[N-{(3RS,4RS)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethylbenzamideHCID 86586382HCID 86586382, compound

Product 1

HCID 224752724-[(1-Allyl-3-methyl-piperidin-4-yl)-phenyl-amino]-N,N-diethyl-benzamideYield 93%

Reagents, catalysts & solvents 6

HCID 111,2-DichloroethaneSolventHCID 702EthanolSolventHCID 887MethanolSolventHCID 962WaterSolventHCID 3776IsopropanolSolventHCID 22663003EtOH triethylamineSolvent

Procedure

(±)-4-[N-{(3RS,4SR)-N,3-Dimethyl-4-piperidinyl}phenylamino]-N,N-diethyl-benzamide (7a) (4.1 g, 10.82 mmol) was treated with phenyl chloroformate (1.25 mL, 11.13 mmol) in 1,2-dichloroethane (35 mL) at room temperature for 24 h. The reaction was quenched with water and NaOH 30% then extracted with CHCl3. After drying over Na2SO4 and evaporation of the solvents under reduced pressure, the crude product was chromatographed on silica gel to give a mixture of starting material and product which was then treated with methanol (100 mL), water (60 mL), isopropanol (50 mL), and NaOH 50% (30 mL) at reflux for 5 h. The alcohols were evaporated under reduced pressure, and the aqueous layer was extracted with CHCl3/THF (3:1). After drying with Na2SO4, the solvents were evaporated under reduced pressure. Chromatography on silica gel using hexanes/ethyl acetate/ethanol/triethylamine (50:50:3:3) afforded starting material (6a), (548 mg, 13%), as a yellow oil followed by the N-demethylated material (924 mg, 30%) as a yellow oil using ethanol/triethylamine (80:20) as eluent. The latter material was dissolved in ethanol (40 mL) and treated with allyl bromide (220 μL, 2.54 mmol) and K2CO3 (1.0 g, 7.24 mmol) at room temperature for 24 h. After evaporation of the ethanol under reduced pressure, the residue was chromatographed on silica gel using hexanes/ethyl acetate/ethanol/triethylamine (50:50:3:3) to give 3a (950 mg, 93%) as a yellow oil. This was converted to the hydrochloride as previously described: 1H NMR (δ4-MeOH) 1.18 (m, 6H), 1.23 (d, 3H, J=7.4 Hz), 1.54 (d, 1H, J=13.0 Hz), 1.81 (ddd, 1H, J=13.0 Hz, 13.0 Hz, 11.0 Hz), 2.91 (m, 1H), 3.09 (dd, 1H, J=13.0 Hz, 13.0 Hz), 3.44 (m, 7H), 3.75 (d, 1H, 7.4 Hz), 4.38 (d, 1H, J=13.5 Hz), 5.59 (d, 1H, J=9.9 Hz), 5.60 (d, 1H, J=17.0 Hz), 6.00 (ddd, 1H, J=17.0 Hz, 17.0 Hz, 7.4 Hz), 6.79 (d, 2H, J=8.5 Hz), 7.14 (d, 2H J=8.0 Hz), 7.23 (d, 2H, J=8.5 Hz), 7.28 (dd, 1H, J=8.0 Hz, 8.0 Hz), 7.40 (dd, 2H, J=8.0 Hz, 8.0Hz). 13C NMR (d4-MeOH) 11.3, 13.2 (broad), 24.5, 29.3, 45.0 (broad), 52.4, 55.2, 56.7, 59.6, 118.3, 125.9, 126.4, 126.6, 127.7, 129.7, 145.0, 149.8, 172.7. Anal. (C26H36ClN3O.0.25H2O): C, H, N.

Workup

  1. customThe reaction was quenched with water and NaOH 30%
  2. extractionthen extracted with CHCl3
  3. dry with materialAfter drying over Na2SO4 and evaporation of the solvents under reduced pressure
  4. customthe crude product was chromatographed on silica gel
  5. customto give
  6. additiona mixture of starting material and product which
  7. temperatureat reflux for 5 h
  8. customThe alcohols were evaporated under reduced pressure
  9. extractionthe aqueous layer was extracted with CHCl3/THF (3:1)
  10. dry with materialAfter drying with Na2SO4
  11. customthe solvents were evaporated under reduced pressure
  12. customafforded
  13. customAfter evaporation of the ethanol under reduced pressure
  14. customthe residue was chromatographed on silica gel

Sources & evidence

ORD record
ord-9fe5df6b760146c8b75591b7fb492834
Source dataset
uspto-grants-2003_07
Patent number
US06593348B2

Reaction notes

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