Chlorosuccinimide → Ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate

HRID 2423419Notes

Reaction equation

HRID 2423419 reaction equation
[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:11])[C:7]=1[CH:8]=[N:9][OH:10].ClN1C(=O)CCC1=O.[CH:20]1([C:24](=O)[CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:23][CH2:22][CH2:21]1.[O-]CC.[Na+]>CN(C)C=O.O1CCCC1.O>[CH:20]1([C:24]2[O:10][N:9]=[C:8]([C:7]3[C:6]([Cl:11])=[CH:5][N:4]=[CH:3][C:2]=3[Cl:1])[C:25]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:21][CH2:22][CH2:23]1

Participants

8

Reactant 4

HCID 31398ChlorosuccinimideHCID 2723922Sodium ethoxideHCID 21846412Ethyl 3-cyclobutyl-3-oxopropanoateHCID 1363488123,5-Dichloro-4-pyridinecarbaldehyde oxime

Product 1

HCID 59321470Ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylateYield 53%

Reagents, catalysts & solvents 3

HCID 962WaterSolventHCID 6228DimethylformamideSolventHCID 8028TetrahydrofuranSolvent2×

Conditions

Temperature
65 °C

Procedure

To a solution of 3,5-dichloro-4-pyridinecarbaldehyde oxime (3.15 g, 16.5 mmol) in N,N-dimethylformamide (13 mL) was added N-chlorosuccinimide (2.20 g, 16.5 mmol). The mixture was heated to 65° C. and all solids dissolved. The solution was stirred at 65° C. for approximately 1.5 hours, poured into water and extracted with ether. The ether layer containing the crude imidoyl chloride was washed with brine, dried over magnesium sulfate and concentrated. To a separate solution of ethyl 3-cyclobutyl-3-oxopropanoate (3.37 g, 19.8 mmol) in tetrahydrofuran (4 mL) at 0° C. was added sodium ethoxide (25 wt % in ethanol, 6.21 mL, 19.8 mmol) and the mixture was stirred for approximately 7 minutes. Then the above imidoyl chloride was added in tetrahydrofuran (13 mL) at a slow rate. A solid precipitated and the mixture was allowed to warm to ambient temperature and stir overnight. The mixture was concentrated and taken up with ethyl acetate and washed with water. The aqueous layer was back-extracted with ethyl acetate and the combined organic layers were washed with brine, dried over magnesium sulfate and purified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution) to afford ethyl 5-cyclobutyl-3-(3,5-dichloro-4-pyridinyl)-4-isoxazolecarboxylate (2.98 g, 53%). 1H-NMR (400 MHz, DMSO-d6) δ 8.64 (s, 2H), 4.35-4.20 (m, 1H), 4.05 (q, J=7 Hz, 2H), 2.45-2.30 (m, 4H), 2.14-2.04 (m, 1H), 2.00-1.89 (m, 1H), 0.96 (t, J=7 Hz, 3H). LRMS (APCI) m/z 341 (M+H)+.

Workup

  1. dissolutionall solids dissolved
  2. extractionextracted with ether
  3. additionThe ether layer containing the crude imidoyl chloride
  4. washwas washed with brine
  5. dry with materialdried over magnesium sulfate
  6. concentrationconcentrated
  7. stirringthe mixture was stirred for approximately 7 minutes
  8. customA solid precipitated
  9. temperatureto warm to ambient temperature
  10. stirringstir overnight
  11. concentrationThe mixture was concentrated
  12. washwashed with water
  13. extractionThe aqueous layer was back-extracted with ethyl acetate
  14. washthe combined organic layers were washed with brine
  15. dry with materialdried over magnesium sulfate
  16. custompurified by chromatography (silica gel, 0-10% ethyl acetate in hexanes gradient elution)

Sources & evidence

ORD record
ord-d2f0faf7818d4a48bfef9cc39965be36
Source dataset
uspto-grants-2011_06
Patent number
US07960552B2

Reaction notes

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