4-Ethoxyaniline → (R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrile

HRID 1782570Notes

Reaction equation

HRID 1782570 reaction equation
[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)[CH3:2].O=[C:12]1[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+].[OH-].[Na+]>C(Cl)Cl.CC(O)=O>[CH2:1]([O:3][C:4]1[CH:10]=[CH:9][C:7]([NH:8][CH:12]2[CH2:17][CH2:16][N:15]([C@H:18]([CH3:22])[CH2:19][C:20]#[N:21])[CH2:14][CH2:13]2)=[CH:6][CH:5]=1)[CH3:2]

Participants

8

Reactant 5

HCID 90764-EthoxyanilineHCID 14798Sodium HydroxideHCID 516892Sodium BicarbonateHCID 5049666Sodium triacetoxyborohydrideHCID 68972438(betaR)-beta-Methyl-4-oxo-1-piperidinepropanenitrile

Product 1

HCID 68971325(R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrileYield 90%

Reagents, catalysts & solvents 2

HCID 176Acetic AcidCatalystHCID 6344DichloromethaneSolvent

Procedure

Following General Procedure A, a solution of 4-ethoxyaniline (0.48 g, 3.5 mmol) and (R)-3-(4-oxo-piperidin-1-yl)butyronitrile (0.49 g, 3.0 mmol) in CH2Cl2 (10 mL), was treated with glacial AcOH (3 drops) and NaBH(OAc)3 (0.93 g, 4.4 mmol), stirring for 16 h at room temperature. Saturated aqueous NaHCO3 solution (15 mL) and 1N NaOH (2 mL) was added and the phases were separated and the aqueous extracted with CH2Cl2 (2×15 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated under reduced pressure. The crude material was then purified by flash column chromatography on silica gel (1:1 EtOAc/CH2Cl2) to afford (R)-3-[4-(4-ethoxy-phenylamino)-piperidin-1-yl]-butyronitrile as a pale brown solid (90%). 1H NMR (CDCl3) δ 1.20 (d, 3H, J=6.6 Hz), 1.37 (t, 2H, J=7.2 Hz), 1.39 (m, 2H), 2.05 (br d, 2H), 2.36 (m, 3H), 2.47 (m, 1H), 2.81 (m, 2H), 3.07 (sex, 1H, J=7.2 Hz), 3.28 (m, 2H), 3.96 (q, 2H, J=7.5 Hz), 6.55 (d, 2H, J=9.0 Hz), 6.76 (d, 2H, J=9.0 Hz).

Workup

  1. customthe phases were separated
  2. extractionthe aqueous extracted with CH2Cl2 (2×15 mL)
  3. dry with materialThe combined organic extracts were dried (Na2SO4)
  4. filtrationfiltered
  5. concentrationconcentrated under reduced pressure
  6. customThe crude material was then purified by flash column chromatography on silica gel (1:1 EtOAc/CH2Cl2)

Sources & evidence

ORD record
ord-6008e08859864474be49f332de1a7652
Source dataset
uspto-grants-2009_03
Patent number
US07498346B2

Reaction notes

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