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

HRID 1963551Notes

Reaction equation

HRID 1963551 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]=[CH:21][C:20]=2[F:25])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[F:25][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=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 131730464cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate

Product 1

HCID 68503458(2R,4S)-Methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 61.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluorobenzyl)piperidine-1-carboxylate (1.95 g, 5.34 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.213 g, 5.34 mmol) dissolved in water (2.000 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.327 mL, 5.34 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (25 mL, 150.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.09 g, 61%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.80-2.17 (m, 4H), 2.72-2.87 (m, 2H), 2.91-3.02 (m, 1H), 3.12-3.24 (m, 1H), 3.52 (s, 3H), 3.95-4.05 (m, 1H), 4.29-4.40 (m, 1H), 5.72 (s, 1H), 6.94-7.12 (m, 3H), 7.12-7.20 (m, 1H). MS m/z 335 (M+H)+

Workup

  1. additionwas added dropwise
  2. stirringThe resulting solution was stirred at −40° C. for 3 h
  3. stirringto stir at 80° C. for 20 min
  4. customThe solvent was evaporated
  5. additionMTBE/water added
  6. customThe phases were separated
  7. dry with materialthe organic phase dried over Na2SO4
  8. customevaporated
  9. customto yield a slightly yellow foam
  10. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  11. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-36ada6674cf94dacb44da05e93879b21
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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