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

HRID 1963547Notes

Reaction equation

HRID 1963547 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]([F:25])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:21]1[CH:20]=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@H:8]([C:6]2[O:7][NH:29][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730460trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate

Product 1

HCID 131730462trans-Methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 35.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluorobenzyl)piperidine-1-carboxylate (0.663 g, 1.81 mmol) (from example 99, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.073 g, 1.81 mmol) dissolved in water (1 mL) was added during 20 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.111 mL, 1.81 mmol) was added during 5 min. The resulting solution was stirred at −40° C. for 4 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (9 mL, 54.00 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 brown semi-solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (214 mg, 35%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.47-1.77 (m, 2H), 1.82-2.15 (m, 2H), 2.75-3.00 (m, 2H), 3.00-3.15 (m, 2H), 3.40-3.80 (m, 3H), 4.00-4.42 (m, 1H), 4.42-4.80 (m, 1H), 5.64 (s, 1H), 6.83-7.05 (m, 3H), 7.22-7.31 (m, 1H). MS m/z 335 (M+H)+

Workup

  1. additionwas added during 20 min
  2. stirringThe resulting solution was stirred at −40° C. for 4 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 brown semi-solid
  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-1931a9f15a0e45eca1bb6448d61a736c
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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