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

HRID 1963526Notes

Reaction equation

HRID 1963526 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][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[F:26][C:23]1[CH:24]=[CH:25][C:20]([CH2:19][CH2:18][C@H:10]2[CH2:9][C@@H:8]([C:6]3[O:7][NH:30][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:21][CH:22]=1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730452cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate

Product 1

HCID 68502316(2S,4S)-Methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 66%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (3.15 g, 8.30 mmol) was dissolved in MeOH (30 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.332 g, 8.30 mmol) dissolved in water (3.00 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.509 mL, 8.30 mmol) was added. The resulting solution was stirred at −40° C. for 3 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (42.9 mL, 257.36 mmol) and the mixture was stirred at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated. The compound (split into 4 runs) 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. Cis-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.9 g, 66%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.53-2.14 (m, 6H), 2.46-2.64 (m, 2H), 2.98-3.07 (m, 1H), 3.12-3.24 (m, 1H), 3.70 (s, 3H), 3.87-3.99 (m, 1H), 4.05-4.16 (m, 1H), 5.72 (s, 1H), 6.85-6.94 (m, 2H), 7.04-7.11 (m, 2H). MS m/z 349 (M+H)+

Workup

  1. additionwas added
  2. stirringThe resulting solution was stirred at −40° C. for 3 h
  3. stirringthe mixture was stirred at 80° C. for 20 min
  4. customThe phases were separated
  5. customevaporated
  6. customThe compound (split into 4 runs)
  7. customwas purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  8. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-336b1d8c0f7d407b8a3e7babb2b2994f
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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