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

HRID 1963530Notes

Reaction equation

HRID 1963530 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 131730451trans-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate

Product 1

HCID 131730453trans-Methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 82.2%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-fluorophenethyl)piperidine-1-carboxylate (730 mg, 1.92 mmol) (from example 92, step 1) was dissolved in MeOH (7 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (77 mg, 1.92 mmol) dissolved in water (0.700 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.118 mL, 1.92 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 (9.94 mL, 59.64 mmol) and the mixture was stirred at 80° C. for 20 min. DCM and water were added. The phases were separated, the aqueous phase extracted with DCM and the combined organic layers passed through a phase separator and evaporated. The residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column. DCM:MeOH:HCOOH=50:1:0.1 over 10 CV was used as mobile phase. Trans-methyl 2-(4-fluorophenethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (550 mg, 82%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.01-2.13 (m, 6H), 2.48-2.70 (m, 2H), 2.88-3.08 (m, 2H), 3.70 (s, 3H), 3.98-4.69 (m, 2H), 5.64 (s, 1H), 6.91-7.02 (m, 2H), 7.06-7.21 (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. extractionthe aqueous phase extracted with DCM
  6. customevaporated
  7. customThe residue was purified by automated flash chromatography on a Biotage® KP-SIL 100 g column

Sources & evidence

ORD record
ord-518fc509ab264bba8baeba4e18d68b4e
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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