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

HRID 1963477Notes

Reaction equation

HRID 1963477 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]([C:18]2[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[F:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO>[F:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730431cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Product 1

HCID 68500585(2R,4S)-Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 76.4%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
-45 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (3 g, 7.15 mmol) was dissolved in MeOH (25 mL) and cooled to −45° C. under nitrogen. Sodium hydroxide (2.104 mL, 7.15 mmol) was added during 10 min and the yellow solution continued to stir at −45° C. for 20 min. Hydroxylamine (50% by weight in water, 0.438 mL, 7.15 mmol) was added during 8 min. The resulting solution was stirred at −45° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (36.8 mL, 221.05 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.12 g, 76%) was isolated as a colourless oil. MS m/z 389 (M+H)+

Workup

  1. stirringThe resulting solution was stirred at −45° C. for 3 h
  2. stirringto stir at 80° C. for 20 min
  3. customThe solvent was evaporated
  4. additionDCM/water added
  5. customThe phases were separated
  6. customevaporated
  7. customto yield a slightly yellow solid
  8. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  9. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-37e006df35774eaeac8f6c4555765335
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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