Acetic Acid → 1-[4-({[2-(4-Chlorophenoxy)phenyl]methyl}amino)piperidin-1-yl]ethan-1-one

HRID 1642250Notes

Reaction equation

HRID 1642250 reaction equation
[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH2:10])=[CH:4][CH:3]=1.[C:17]([N:20]1[CH2:25][CH2:24][CH2:23][CH2:22][C:21]1=O)(=[O:19])[CH3:18].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([O:6][C:7]2[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=2[CH2:9][NH:10][CH:23]2[CH2:24][CH2:25][N:20]([C:17](=[O:19])[CH3:18])[CH2:21][CH2:22]2)=[CH:4][CH:3]=1

Participants

7

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 118159051-Acetylpiperidin-2-oneHCID 19926667(2-(4-chlorophenoxy)phenyl)MethanaMine

Product 1

HCID 159522501-[4-({[2-(4-Chlorophenoxy)phenyl]methyl}amino)piperidin-1-yl]ethan-1-oneYield 81%

Reagents, catalysts & solvents 2

HCID 111,2-DichloroethaneSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
100 °C

Procedure

A solution of 2-(4-chlorophenoxy)benzylamine (AMR01073, 100 mg, 0.428 mmol), 1-acetylpiperidone (121 mg, 0.856 mmol) and acetic acid (0.13 mL, 2.14 mmol) in DCE (2 mL) was treated with NaBH(OAc)3 (227 mg, 1.07 mmol) and stirred under microwave irradiation for 15 min at 100° C. The reaction mixture was diluted with DCM (10 mL) and quenched with saturated NaHCO3 solution. The aqueous layer was washed with DCM (2×20 mL), and the combined organic layers were dried (MgSO4), filtered and evaporated to dryness. Column chromatography on silica gel of the crude product using AcOEt to AcOEt/MeOH 9:1 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}ethanone (124 mg, 81%) as a colorless oil. Rf: 0.14 (AcOEt/MeOH 9:1) LC/MS (APCI) tr=4.79 min, m/z 361.46 (35), 359.51 (M++H, 100). HPLC tr=3.04 min (97.37%) 1H NMR (270 MHz, CDCl3) δ 1.25 (2H, m, CH2), 1.68 (br s, NH), 1.79 (2H, m, CH2), 2.05 (3H, S, CH3), 2.67 (2H, m, CH2), 3.02 (1H, m, CH), 3.70 (1H, m, ½CH2), 3.82 (2H, s, CH2), 4.33 (1H, m, ½CH2), 6.84 (2H, AA′BB′, ArH), 6.86 (1H, m, ArH), 7.11 (1H, m, ArH), 7.21 (1H, m, ArH), 7.24 (2H, AA′BB′, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 21.10 (CH3), 31.49, 32.32, 39.64, 44.47, 45.05 (CH2), 53.21 (CH), 118.49, 119.04, 124.04, 127.51, 128.30, 129.36, 130.14, 131.02, 153.89, 155.80 (ArC), and 168.42 (C═O).

Workup

  1. customquenched with saturated NaHCO3 solution
  2. washThe aqueous layer was washed with DCM (2×20 mL)
  3. dry with materialthe combined organic layers were dried (MgSO4)
  4. filtrationfiltered
  5. customevaporated to dryness

Sources & evidence

ORD record
ord-e7f4bf5b379b4d9cb22976e10469f7f8
Source dataset
uspto-grants-2012_02
Patent number
US08119627B2

Reaction notes

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