Cesium carbonate → 4-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one

HRID 2103307Notes

Reaction equation

HRID 2103307 reaction equation
[CH3:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.Cl[CH2:14][CH2:15][CH2:16]I.C([O-])([O-])=O.[Cs+].[Cs+].C([O-])([O-])=O.[K+].[K+].[CH2:30]([CH:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33].[N-]=C=O>C(#N)C.ClCCl>[CH2:30]([CH:34]1[CH2:39][CH2:38][N:37]([CH2:14][CH2:15][CH2:16][N:7]2[C:6]3[CH:12]=[C:2]([CH3:1])[CH:3]=[CH:4][C:5]=3[O:10][CH2:9][C:8]2=[O:11])[CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]

Participants

9

Reactant 6

HCID 10796Cesium carbonateHCID 11430Potassium CarbonateHCID 813631-Chloro-3-iodopropaneHCID 105034IsocyanateHCID 27638392H-1,4-Benzoxazine-3(4H)-one, 6-methyl-HCID 132838674-Butylpiperidine

Product 1

HCID 102369054-[3-(4-Butyl-piperidin-1-yl)-propyl]-6-methyl-4H-benzo[1,4]oxazin-3-one

Reagents, catalysts & solvents 2

HCID 6342AcetonitrileSolventHCID 6344DichloromethaneSolvent

Conditions

Temperature
60 °C

Procedure

6-Methyl-4H-benzo[1,4]oxazin-3-one (82 mg, 0.5 mmol), 1-chloro-3-iodopropane (50 μl, 0.5 mmol) and Cs2CO3 (163 mg, 0.5 mmol) in acetonitrile (2 mL) were shaken at 50° C. for 24 h then the reaction mixture was concentrated in vacuo. The product (4-[3-chloropropyl]-6-methyl-4H-benzo[1,4]-oxazin-3-one) was purified on an Isco CombiFlash Sq 16× (4 g silica column, eluting 0-20% ethyl acetate in heptanes) then dissolved in acetonitrile (2 mL). K2CO3 (85 mg, 0.5 mmol) and 4-butylpiperidine (80 μl, 0.5 mmol) were added. The reaction mixture was shaken at 60° C. for 16 h then cooled to room temperature. Dichloromethane (2 mL) and PS-isocyanate (loading 1.47 mmol/g, 100 mg) were added. The mixture was filtered after 5 h and the organic layer was loaded onto a Varian SCX ion exchange column. The column was washed with methanol (2×5 mL) then the product was eluted off the column using 10% ammonium hydroxide in methanol (6 mL). The solute was concentrated in vacuo to give the title product. Yield: 100 mg, 58%. HPLC-MS: M+1+=345.5 (UV/MS(%)=99/99). 1H NMR (400 MHz, CDCl3): δ=0.89 (3H, t), 1.15-1.30 (9H, m), 1.65 (2H, broad d), 1.81-1.89 (4H, m), 2.30 (3H, s), 2.36 (2H, t), 2.86 (2H, broad d), 3.94 (2H, dd), 4.51 (2H, s), 6.76 (1H, dd), 6.84 (1H, d), 6.86 (1H, d). 13C NMR (CDCl3): δ 14.3, 21.3, 23.1, 25.1, 29.2, 32.8 (2C), 36.0, 36.5, 39.8, 54.4 (2C), 56.1, 67.9, 115.8, 116.9, 124.3, 128.6, 132.5, 143.4, 164.6.

Workup

  1. concentrationthe reaction mixture was concentrated in vacuo
  2. customThe product (4-[3-chloropropyl]-6-methyl-4H-benzo[1,4]-oxazin-3-one) was purified on an Isco CombiFlash Sq 16× (4 g silica column, eluting 0-20% ethyl acetate in heptanes)
  3. dissolutionthen dissolved in acetonitrile (2 mL)
  4. temperaturethen cooled to room temperature
  5. filtrationThe mixture was filtered after 5 h
  6. washThe column was washed with methanol (2×5 mL)
  7. washthe product was eluted off the column
  8. concentrationThe solute was concentrated in vacuo

Sources & evidence

ORD record
ord-baadc000eb434aeca85f0160238a1316
Source dataset
uspto-grants-2009_08
Patent number
US07576100B2

Reaction notes

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