Phosphorus oxychloride → 6-(4-Butoxyphenyl)-4-chloro-6-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

HRID 1629802Notes

Reaction equation

HRID 1629802 reaction equation
[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:22])[NH:17][C:16](=[O:18])[C:15]([C:19]#[N:20])=[C:14](O)[CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].O=P(Cl)(Cl)[Cl:25].CCN(C(C)C)C(C)C>C(Cl)CCl>[CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2([CH3:22])[NH:17][C:16](=[O:18])[C:15]([C:19]#[N:20])=[C:14]([Cl:25])[CH2:13]2)=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]

Participants

5

Reactant 3

HCID 24813Phosphorus oxychlorideHCID 81531DiisopropylethylamineHCID 866858956-(4-Butoxyphenyl)-4-hydroxy-6-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrile

Product 1

HCID 866858966-(4-Butoxyphenyl)-4-chloro-6-methyl-2-oxo-1,2,5,6-tetrahydropyridine-3-carbonitrileYield 74%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

To a stirred solution of Intermediate 107E (130 mg, 0.433 mmol) in ClCH2CH2Cl (3 mL) was added POCl3 (0.056 mL, 0.606 mmol) and Hunig's base (0.113 mL, 0.649 mmol). The reaction was stirred at rt for 30 min and then heated to 85° C. for 3 h. The reaction mixture was concentrated and the residue was diluted with EtOAc. The organic layer was washed with saturated NH4Cl, dried over MgSO4, filtered and concentrated. The crude product was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes) to yield the desired product (102 mg, 74%) as a white solid. LCMS Anal. Calc'd for C17H19ClN2O2 318.11, found [M+H] 319.2. 1H NMR (500 MHz, CDCl3) δ 7.23 (d, J=8.80 Hz, 2H), 6.90 (d, J=8.80 Hz, 2H), 3.97 (t, J=6.60 Hz, 2H), 2.05 (s, 2H), 1.74-1.82 (m, 2H), 1.69 (s, 3H), 1.46-1.55 (m, 2H), 0.99 (t, J=7.43 Hz, 3H).

Workup

  1. temperatureheated to 85° C. for 3 h
  2. concentrationThe reaction mixture was concentrated
  3. additionthe residue was diluted with EtOAc
  4. washThe organic layer was washed with saturated NH4Cl
  5. dry with materialdried over MgSO4
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customThe crude product was purified by silica gel chromatography (24 g silica gel, eluted with EtOAc in hexanes)

Sources & evidence

ORD record
ord-97f8a6af205c404a8dcb127c55fd066a
Source dataset
uspto-grants-2014_07
Patent number
US08791091B2

Reaction notes

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