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

HRID 1963541Notes

Reaction equation

HRID 1963541 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 131730457trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate

Product 1

HCID 131730459trans-Methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 64.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorobenzyl)piperidine-1-carboxylate (0.454 g, 1.24 mmol) (from example 97, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.050 g, 1.24 mmol) dissolved in water (1 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, 0.076 mL, 1.24 mmol) was added during 5 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 (6 mL, 36.00 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 slightly yellow oil. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(4-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.268 g, 64.5%) was isolated as a white solid. 1H NMR (400 MHz, cdcl3) δ 1.47-1.75 (m, 2H), 1.85-2.14 (m, 2H), 2.71-3.00 (m, 2H), 3.02-3.16 (m, 2H), 3.40-3.76 (m, 3H), 4.22 (d, br., 1H), 4.59 (d, br., 1H), 5.64 (s, 1H), 6.95-7.03 (m, 2H), 7.15 (s, br., 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 slightly yellow oil
  9. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  10. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-4292080029534808b61f9b85b80adc71
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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