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

HRID 1963569Notes

Reaction equation

HRID 1963569 reaction equation
C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].Cl.[NH2:33]O.Cl>CO.CO.O.O.C(OCC)(=O)C>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[CH:20]=3)[CH2:9]2)[O:7][NH:33]1

Participants

9

Reactant 4

HCID 313Hydrochloric AcidHCID 14798Sodium Hydroxide2×HCID 443297Hydroxyamine hydrochlorideHCID 131730467HCID 131730467, compound

Product 1

HCID 131730469trans-Methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate

Reagents, catalysts & solvents 4

HCID 887MethanolSolvent2×HCID 962WaterSolvent2×HCID 8857Ethyl AcetateSolventHCID 22242641Methanol--water (1/1)Solvent

Procedure

A solution of trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (1.8 g, 4.33 mmol) (from example 107, step 1) in MeOH (7 mL) was added to a solution of NaOH (225 mg, 5.63 mmol) in MeOH/H2O (8 mL/0.5 mL) at −30° C. After 10 min hydroxylamine hydrochloride (0.602 g, 8.67 mmol) and NaOH (347 mg, 8.67 mmol) were added in MeOH (7 mL) and H2O (7 mL). Stirring was continued at −30° C. for 30 min. The reaction solution was poured into 6 M HCl (60 mL) at 80° C. and heated for 30 min. The reaction mixture was dissolved between water and ethyl acetate. The organic phase was isolated, dried with Na2SO4, filtered through celite and the solvent was evaporated. Purification using prepLC (pH=3, large column 25-55% MeCN over 20 min) Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.06 g, 63.6%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.49-2.17 (m, 4H), 2.80-3.22 (m, 4H), 3.34-3.76 (m, 3H), 4.07-4.40 (m, 1H), 4.52-4.84 (m, 1H), 5.65 (s, 1H), 7.28-7.54 (m, 4H). MS m/z 385 (M+H)+

Workup

  1. temperatureheated for 30 min
  2. customThe organic phase was isolated
  3. dry with materialdried with Na2SO4
  4. filtrationfiltered through celite
  5. customthe solvent was evaporated
  6. customPurification
  7. custom(pH=3, large column 25-55% MeCN over 20 min) Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.06 g, 63.6%)
  8. customwas isolated

Sources & evidence

ORD record
ord-50363cb597fe4dadace2a7e15dfec980
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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