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

HRID 1963539Notes

Reaction equation

HRID 1963539 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][C:22]([F:25])=[CH:21][CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:29][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:20][CH:21]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730458cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate

Product 1

HCID 68504226(2R,4S)-Methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 65.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (2.53 g, 6.92 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.277 g, 6.92 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.424 mL, 6.92 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 2 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 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 yellow solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.516 g, 65.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.83-2.14 (m, 4H), 2.55-2.65 (m, 1H), 2.72-2.81 (m, 1H), 2.93-3.03 (m, 1H), 3.08-3.19 (m, 1H), 3.61 (s, 3H), 3.95-4.05 (m, 1H), 4.20-4.30 (m, 1H), 5.73 (s, 1H), 6.91-6.99 (m, 2H), 7.02-7.09 (m, 2H). MS m/z 335 (M+H)+

Workup

  1. additionwas added during 10 min
  2. stirringThe resulting solution was stirred at −40° C. for 2 h
  3. stirringto stir at 80° C. for 20 min
  4. customThe solvent was evaporated
  5. additionDCM/water added
  6. customThe phases were separated
  7. customevaporated
  8. customto yield a yellow solid
  9. customThe compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm)
  10. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-d92513c84d4742d783b088183c1de8fc
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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