Epichlorohydrin → (r,s)-4-[2-Hydroxy-3-(3-pentylbicyclo[3.2.1]oct-8-yl)-propyl]-4h-benzo[1,4]oxazin-3-one

HRID 1986746Notes

Reaction equation

HRID 1986746 reaction equation
[CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[C:6]([O-])([O-])=O.[Cs+].[Cs+].[O:12]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[NH:15][C:14](=[O:22])[CH2:13]1.[CH2:23]([CH:28]1[CH2:34][CH:33]2N[CH:30]([CH2:31][CH2:32]2)[CH2:29]1)[CH2:24][CH2:25][CH2:26][CH3:27]>CCOCC.CN(C=O)C>[OH:5][C@H:3]([CH2:1][CH:6]1[CH:33]2[CH2:32][CH2:31][C@H:30]1[CH2:29][CH:28]([CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:34]2)[CH2:4][N:15]1[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:12][CH2:13][C:14]1=[O:22]

Participants

7

Reactant 4

HCID 7835EpichlorohydrinHCID 10796Cesium carbonate2×HCID 727572H-1,4-benzoxazin-3(4H)-oneHCID 219898523-Pentyl-8-azabicyclo[3.2.1]octane

Product 1

HCID 68912783(r,s)-4-[2-Hydroxy-3-(3-pentylbicyclo[3.2.1]oct-8-yl)-propyl]-4h-benzo[1,4]oxazin-3-oneYield 47.2%

Reagents, catalysts & solvents 2

HCID 3283Diethyl EtherSolvent2×HCID 6228DimethylformamideSolvent2×

Conditions

Temperature
65 °C

Procedure

Epichlorohydrin (0.48 g, 5.2 mmol), Cs2CO3 (2.3 g, 7.0 mmol), 4H-benzo[1,4]oxazin-3-one (0.52 g, 3.5 mmol) were stirred with dry DMF (7 mL) for 22 h. Thereafter the mixture was diluted with ether (50 mL) washed with water (10 mL) and then brine (10 mL). The organic phase was dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by flash CC (SiO2; CH2Cl2/acetone/MeOH 95:3:2). Of the resulting oil (0.060 g, 0.29 mmol) was dissolved in DMF (1.5 mL), 3-pentyl-8-azabicyclo[3.2.1]octane (0.060 g, 0.33 mmol) and Cs2CO3 (0.30 g, 0.81 mmol) were added and the mixture was shaken at 65° C. for 72 h. The mixture was then poured into ether (25 mL) washed with water (10 mL) and the water phase was extracted with ether (20 mL). The combined organic phase was washed with brine (10 mL), dried over Na2SO4, filtered, concentrated under reduced pressure and the residue was purified by cation exchange CC, followed by flash CC (SiO2; CH2Cl2:acetone:MeOH 85/10/5) to yield the title compound (0.060 g, 33% (from 4H-benzo[1,4]oxazin-3-one)). 1H NMR (CDCl3) δ 7.42 (dm, J=7.2 Hz, 1H), 7.05-6.94 (m, 3H), 4.60 (ABq, J=14.8, 16.8 Hz, 2H), 4.15 (dd, J=3.2, 14.0 Hz, 1H), 3.86-3.78 (m, 3H), 3.14 (m, 2H), 2.54 (dd, J=4.8, 12.5 Hz, 1H), 2.22 (dd, J=9.2, 12.4 Hz), 2.16-1.98 (m, 2H), 1.98-1.83 (m, 2H), 1.72-1.55 (m, 3H), 1.43-1.34 (m, 2H), 1.42-1.15 (m, 8H), 0.87 (t, J=7.2 Hz). 13C NMR (CDCl3) δ 165.3, 145.5, 129.7, 124.2, 122.9, 117.0, 116.6, 67.9, 67.4, 60.9, 58.6, 56.7, 46.7, 38.3, 36.7, 36.5, 28.5, 28.3, 28.2, 27.1, 22.9, 14.3. HPLC-MS (ammonium acetate) [M+H]+=387.3.

Workup

  1. washwashed with water (10 mL)
  2. dry with materialThe organic phase was dried over Na2SO4
  3. filtrationfiltered
  4. concentrationconcentrated under reduced pressure
  5. customthe residue was purified by flash CC (SiO2; CH2Cl2/acetone/MeOH 95:3:2)
  6. washwashed with water (10 mL)
  7. extractionthe water phase was extracted with ether (20 mL)
  8. washThe combined organic phase was washed with brine (10 mL)
  9. dry with materialdried over Na2SO4
  10. filtrationfiltered
  11. concentrationconcentrated under reduced pressure
  12. customthe residue was purified by cation exchange CC

Sources & evidence

ORD record
ord-b0162d5dcd4d4bc9b2ead94f3a07064a
Source dataset
uspto-grants-2009_06
Patent number
US07550459B2

Reaction notes

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