Acetic Acid → 6-Cyclopropylamino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

HRID 1698342Notes

Reaction equation

HRID 1698342 reaction equation
[NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]=2[CH:19]=1.[CH3:20][C:21](O)=O.[BH3-][C:25]#N.[Na+].[OH-].[Na+]>C(Cl)Cl>[CH:21]1([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:10][C:9]([CH3:12])([CH3:11])[C:8](=[O:13])[N:7]([CH2:14][CH2:15][CH2:16][O:17][CH3:18])[C:6]=3[CH:19]=2)[CH2:20][CH2:25]1

Participants

6

Reactant 4

HCID 176Acetic AcidHCID 14798Sodium HydroxideHCID 5003444Sodium cyanoborohydrideHCID 577911746-amino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one

Product 1

HCID 577903556-Cyclopropylamino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-oneYield 64%

Reagents, catalysts & solvents 1

HCID 6344DichloromethaneSolvent

Conditions

Temperature
70 °C

Procedure

At room temperature, a methanolic solution (33 ml) of 6-amino-4-(3-methoxy-propyl)-2,2-dimethyl-4H-benzo[1,4]oxazin-3-one (4.13 g, 15.6 mmol) is treated with AcOH (8.3 ml) and [(1-ethoxycycopropyl)-oxy]trimethylsilane (3.1 ml, 15.6 mmol), warmed to 70° C., stirred for 1.5 h under reflux. At the same temperature, to this mixture is added dropwise a methanolic solution (5.5 ml) of NaBH3CN (1.10 g, 17.5 mmol) over 5 min, and the resulting mixture is stirred at 70° C. under reflux for 2 h, and treated with CH2Cl2 (100 ml) and 5N NaOH (50 ml). After the separation of the both layers, the aq. layer is extracted with CH2Cl2 (3×30 ml). The combined org. layer is washed with brine (50 ml), dried (Na2SO4), and evaporated. A SiO2 flash chromatography (200 g, hexane/EtOAc 3:2) gives the title compound (3.03 g, 64%) as light yellow solid. Rf(hexane/EtOAc 3:2) 0.48. 1H-NMR (400 MHz, CDCl3) 0.47-0.54 (m, 2 H), 0.68-0.73 (m, 2 H), 1.55 (s), 1.88-1.96 (m, 2 H), 2.36-2.43 (m, 1 H), 3.34 (s), 3.44 (t, J=6.0), 3.97 (t, J=9.0), 4.09 (br. s), 6.45 (dd, J=9.0, 0.4), 6.53 (d, J=0.4), 6.80 (d, J=9.0). 13C-NMR (100 MHz, CDCl3) 169.2 (s), 144.3 (s), 135.5 (s), 129.6 (s), 118.1 (d), 107.9 (d), 99.9 (d), 77.2 (s), 70.1 (t), 58.7 (q), 39.2 (t), 27.6 (t), 25.7 (d), 23.6 (2q), 7.3 (2t).

Workup

  1. temperatureunder reflux
  2. stirringthe resulting mixture is stirred at 70° C.
  3. temperatureunder reflux for 2 h
  4. customAfter the separation of the both layers
  5. extractionthe aq. layer is extracted with CH2Cl2 (3×30 ml)
  6. washlayer is washed with brine (50 ml)
  7. dry with materialdried (Na2SO4)
  8. customevaporated

Sources & evidence

ORD record
ord-1dd507a1f2f4401b9606f2c72c02b17f
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

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