Hydroxylamine → Methyl 2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate

HRID 1365718Notes

Reaction equation

HRID 1365718 reaction equation
Cl[CH2:2][CH2:3][O:4][C:5]([CH3:9])([CH3:8])[C:6]#[N:7].[NH2:10][OH:11].C(=O)([O-])[O-].[Na+].[Na+].[C:18]([C:24]([O:26][CH3:27])=[O:25])#[C:19][C:20]([O:22][CH3:23])=[O:21]>CO.O.C(OCC)(=O)C>[CH3:23][O:22][C:20](=[O:21])[CH2:19][C:18]1([C:24]([O:26][CH3:27])=[O:25])[O:11][N:10]2[C:6]([C:5]([CH3:9])([CH3:8])[O:4][CH2:3][CH2:2]2)=[N:7]1

Participants

8

Reactant 4

HCID 787HydroxylamineHCID 10340Sodium CarbonateHCID 12980Dimethyl acetylenedicarboxylate2×HCID 210697862-(2-Chloroethoxy)-2-methylpropanenitrile

Product 1

HCID 21069965Methyl 2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolvent

Conditions

Temperature
22.5 °C

Procedure

Alternate procedure. To a solution of 2-(2-chloroethoxy)-2-methylpropanenitrile (5.00 g, 33.87 mmol) in methanol (30 mL) was added at 20-22° C. a 50% aqueous solution of hydroxylamine (2.21 mL, 40.58 mmol). Sodium carbonate (1.44 g, 13.59 mmol) and finally water (5 mL) were added. The suspension was stirred at 20-25° C. for 18 h. The reaction mixture was heated at reflux (65-66° C.) for 3 h. The resulting solution was cooled to 20-25° C. The pH (7.5) required no adjustment. The mixture was cooled to −5° C. and dimethyl acetylenedicarboxylate (3.75 mL, 30.56 mmoles) was added slowly over about 18 min keeping the temperature between −5° C. to 0° C. The mixture was stirred for 60 min. Additional dimethyl acetylenedicarboxylate (0.4 mL, 3.26 mmoles) was added and mixture was stirred another 10 min at 0° C. to complete the reaction as confirmed by HPLC. Ethyl acetate (50 mL) and water (25 mL) were added to the reaction mixture. The phases were separated and the aqueous phase was extracted again with ethyl acetate (25 mL). The combined ethyl acetate extracts were washed with about 14% aq. NaCl (2×25 mL). The solvent was removed under vacuum to afford methyl 2-(2-methoxy-2-oxoethyl)-8,8-dimethyl-2,5,6,8-tetrahydro-[1,2,4]oxadiazolo[3,2-c][1,4]oxazine-2-carboxylate as a crude oil (9.4 g, 96.9% yield) with a purity of71% by HPLC. A sample (0.80 g) was purified by reverse-phase chromatography giving an oil (0.48 g) of 97% purity by HPLC, which crystallized on standing; mp 68-69° C.

Workup

  1. temperatureThe reaction mixture was heated
  2. temperatureat reflux (65-66° C.) for 3 h
  3. temperatureThe resulting solution was cooled to 20-25° C
  4. temperatureThe mixture was cooled to −5° C.
  5. custombetween −5° C. to 0° C
  6. stirringThe mixture was stirred for 60 min
  7. stirringmixture was stirred another 10 min at 0° C.
  8. customthe reaction
  9. customThe phases were separated
  10. extractionthe aqueous phase was extracted again with ethyl acetate (25 mL)
  11. washThe combined ethyl acetate extracts were washed with about 14% aq. NaCl (2×25 mL)
  12. customThe solvent was removed under vacuum

Sources & evidence

ORD record
ord-d75ccb7126e942eab3009488be9bb934
Source dataset
uspto-grants-2011_02
Patent number
US07893055B2

Reaction notes

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