Hydrochloric Acid → trans-Methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

HRID 1963630Notes

Reaction equation

HRID 1963630 reaction equation
[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730490trans-Methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Product 1

HCID 131730492trans-Methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 101.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 2-(2,4-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.18 g, 3.08 mmol) (from example 134, step 1) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.123 g, 3.08 mmol) dissolved in water (1.7 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.2 mL, 3.26 mmol) was added over 1 min and stirring continued at −40° C. for 2 h. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. Crude trans-methyl 2-(2,4-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.1 g, 101%) was isolated as a pale orange foam. 1H NMR (500 MHz, cdcl3) δ 1.43-2.15 (m, 4H), 2.66-3.23 (m, 4H), 3.39-3.79 (m, 3H), 4.04-4.41 (m, 1H), 4.45-4.78 (m, 1H), 5.67 (s, 1H), 6.73-6.90 (m, 2H), 7.03-7.37 (m, 1H). MS m/z 353 (M+H)+

Workup

  1. additionwas added over 1 min
  2. stirringstirring
  3. waitcontinued at −40° C. for 2 h
  4. stirringto be stirred at 80° C. for 1 h
  5. temperatureThen cooled to room temperature
  6. customMethanol was evaporated
  7. additionwater was added
  8. extractionExtracted three times with DCM
  9. dry with materialCombined organic layers dried over MgSO4
  10. customevaporated

Sources & evidence

ORD record
ord-e4a798d3e62e4d51bb1deb1eb36b0b69
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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