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

HRID 1963566Notes

Reaction equation

HRID 1963566 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 131730468HCID 131730468, compound

Product 1

HCID 68504649(2R,4S)-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 Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-(trifluoromethyl)benzyl)-piperidine-1-carboxylate (2.45 g, 5.90 mmol) in MeOH (7 mL) was added to a solution of NaOH (307 mg, 7.67 mmol) in MeOH/H2O (8 ml/0.5 mL) at −30° C. After 10 min hydroxylamine hydrochloride (0.82 g, 11.80 mmol) and NaOH (472 mg, 11.80 mmol) were added in MeOH (8 mL) and H2O (8 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 40-55% MeCN over 20 min) Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.27 g, 56%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.86-2.15 (m, 4H), 2.68 (dd, 1H), 2.86 (dd, 1H), 2.96-3.06 (m, 1H), 3.12-3.25 (m, 1H), 3.58 (s, 3H), 3.95-4.08 (m, 1H), 4.25-4.37 (m, 1H), 5.75 (s, 1H), 7.23-7.32 (m, 1H), 7.35-7.41 (m, 2H), 7.43-4.49 (m, 1H). 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 40-55% MeCN over 20 min) Cis-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-(3-(trifluoromethyl)benzyl)piperidine-1-carboxylate (1.27 g, 56%)
  8. customwas isolated

Sources & evidence

ORD record
ord-1c17d60641ff4cd2b6c069baf78eba3b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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