Acetic Acid → 1-{4-[2-(4-Chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-one

HRID 1642251Notes

Reaction equation

HRID 1642251 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.[CH3:17][CH:18]([CH3:29])[CH2:19][C:20]([N:22]1[CH2:27][CH2:26][C:25](=O)[CH2:24][CH2:23]1)=[O:21].[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C>ClCCCl>[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:25]2[CH2:26][CH2:27][N:22]([C:20](=[O:21])[CH2:19][CH:18]([CH3:17])[CH3:29])[CH2:23][CH2:24]2)=[CH:4][CH:3]=1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 5049666Sodium triacetoxyborohydrideHCID 19926667(2-(4-chlorophenoxy)phenyl)MethanaMineHCID 247015181-(3-Methylbutanoyl)piperidin-4-one

Product 1

HCID 159524451-{4-[2-(4-Chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-oneYield 66.4%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

A solution of 2-(4-chlorophenoxy)benzylamine (AMR01076, 100 mg, 0.428 mmol) and 1-(3-methylbutyryl)piperidin-4-one (78.4 mg, 0.428 mmol) in DCE (5 mL) was treated with NaBH(OAc)3 (127 mg, 0.60 mmol) and acetic acid (26 mg, 0.428 mmol). The mixture was stirred at room temperature under a N2 atmosphere until TLC showed that the reactants were consumed (30 min). Then, it was 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 DCM to DCM/MeOH 95:5 gradient as eluent gave 1-{4-[2-(4-chlorophenoxy)benzylamino]piperidin-1-yl}-3-methylbutan-1-one (114 mg, 66%) as a colorless oil. Rf: 0.4 (DCM/MeOH 9:1) LC/MS (APCI) tr=5.36 min, m/z 403.46 (35), 401.44 (M++H, 100). HPLC tr=3.39 min (96.55%) 1H NMR (270 MHz, CDCl3) δ 0.92 (6H, d, J=6.4 Hz, 2CH3), 1.23 (2H, m, CH2), 1.46 (br s, NH), 1.82 (2H, br d, J=12.9 Hz, CH2), 2.05 (1H, hept, J=6.4 Hz, CHMe2), 2.19 (2H, m, CH2), 2.65 (2H, m, CH2), 2.99 (1H, m, CHNH), 3.77 (1H, m, ½CH2), 3.79 (2H, s, CH2NH), 4.40 (1H, br d, J=13.3 Hz, ½CH2), 6.81-6.87 (3H, m, ArH), 7.11 (1H, td, ArH), 7.19-7.25 (3H, m, ArH) and 7.38 (1H, dd, J=7.2, 1.5 Hz, ArH). 13C NMR (270 MHz, CDCl3) δ 22.80 (CH2), 22.90 (CH3), 25.93 (CH), 32.30, 33.15, 40.23, 42.24, 44.44, 45.65 (CH2), 53.87 (CH), 118.93, 119.62, 124.54, 127.94, 128.71, 129.83, 130.58, 131.79, 154.34, 156.37 (ArC), and 170.91 (C═O).

Workup

  1. customwere consumed (30 min)
  2. customThen, it was quenched with saturated NaHCO3 solution
  3. washthe aqueous layer was washed with DCM (2×20 mL)
  4. dry with materialthe combined organic layers were dried (MgSO4)
  5. filtrationfiltered
  6. customevaporated to dryness

Sources & evidence

ORD record
ord-d6531674bff64c86a60a701770cb573e
Source dataset
uspto-grants-2012_02
Patent number
US08119627B2

Reaction notes

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