Potassium Iodide → 6-Amino-4-(3-methoxypropyl)-2H-1,4-benzoxazin-3(4H)-one

HRID 1698332Notes

Reaction equation

HRID 1698332 reaction equation
[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1)([O-])=O.[H-].[Na+].[CH3:17][O:18][CH2:19][CH2:20][CH2:21]OS(C1C=CC(C)=CC=1)(=O)=O.[I-].[K+]>CC(N(C)C)=O.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH2:11][C:10](=[O:13])[N:9]([CH2:21][CH2:20][CH2:19][O:18][CH3:17])[C:8]=2[CH:14]=1

Participants

9

Reactant 4

HCID 4875Potassium IodideHCID 24758Sodium hydrideHCID 27636836-Nitro-2H-1,4-benzoxazin-3(4H)-oneHCID 135229883-Methoxypropyl 4-methylbenzenesulfonate

Product 1

HCID 549355996-Amino-4-(3-methoxypropyl)-2H-1,4-benzoxazin-3(4H)-one

Reagents, catalysts & solvents 4

HCID 23925IronCatalystHCID 176Acetic AcidSolvent2×HCID 8857Ethyl AcetateSolventHCID 31374DimethylacetamideSolvent2×

Conditions

Temperature
5 °C

Procedure

A mixture of 6-nitro-4H-benzo[1,4]oxazin-3-one (5 g, 25.8 mmol) and NaH (˜60% moistened with oil, 911 mg, ˜23 mmol) in DMA (30 ml) is stirred at 5° C. for 30 min. Toluene-4-sulfonic acid 3-methoxy-propyl ester (6.87 g, 28.1 mmol) in DMA (10 ml) is added, followed by potassium iodide (4.67 g, 28.1 mmol). The ice-bath is removed and the mixture stirred for 3 h at 60° C. The solvent is distilled off in vacuo and the residue partitioned between H2O and ethyl acetate. The organic layer is dried (Na2SO4) and the solvent evaporated. Part of the crude product (5 g, 18.8 mmol) is dissolved in a mixture of acetic acid (50 ml) and ethyl acetate (50 ml). The solution is added dropwise to a suspension of Fe powder (6 g, 107 mmol) in 5% aqueous acetic acid (50 ml). The resultant mixture is kept at 70° C. for 5 h. After cooling to RT, the Fe powder is filtered off, and the filtrate diluted with H2O. The aqueous layer is extracted with ethyl acetate. The organic layer is washed with NaHCO3 solution, dried (Na2SO4) and evaporated. The residue is purified by column chromatography (SiO2, CH2Cl2/CH3OH 100:0-80:20) to afford 6-amino-4-(3-methoxy-propyl)-4H-benzo[1,4]oxazin-3-one as a dark brown oil. MS: 237.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 2.66 min. Part of this intermediate (1 g, 4.2 mmol) is diluted with methanol (15 ml). Acetaldehyde (166 μl, 2.94 mmol), acetic acid (480 μl, 8.4 mmol) and NaBH3CN (396 mg, 6.3 mmol) are added. The mixture is stirred for 1.5 h at RT, quenched with 5% KHSO4 solution and extracted with ethyl acetate. The organic layer is washed with NaHCO3 solution and brine, dried over Na2SO4 and evaporated in vacuo. Purification of the product by column chromatography (SiO2, CH2Cl2/CH3OH) affords the title compound as a purple oil. MS: 265.3 [M+H]+; tR (HPLC, Nucleosil C18; 5-100% CH3CN+0.1% TFA/H2O+0.1% TFA for 8 min, flow 1.5 ml/min): 3.41 min

Workup

  1. customThe ice-bath is removed
  2. stirringthe mixture stirred for 3 h at 60° C
  3. distillationThe solvent is distilled off in vacuo
  4. customthe residue partitioned between H2O and ethyl acetate
  5. dry with materialThe organic layer is dried (Na2SO4)
  6. customthe solvent evaporated
  7. temperatureAfter cooling to RT
  8. filtrationthe Fe powder is filtered off
  9. additionthe filtrate diluted with H2O
  10. extractionThe aqueous layer is extracted with ethyl acetate
  11. washThe organic layer is washed with NaHCO3 solution
  12. dry with materialdried (Na2SO4)
  13. customevaporated
  14. customThe residue is purified by column chromatography (SiO2, CH2Cl2/CH3OH 100:0-80:20)

Sources & evidence

ORD record
ord-e6d756dcec40417cbee5c84fc2300cd3
Source dataset
uspto-grants-2012_04
Patent number
US08163773B2

Reaction notes

Loading…