Hydrochloric Acid → HCID 131730409, compound

HRID 1963423Notes

Reaction equation

HRID 1963423 reaction equation
[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14](=[O:21])[CH2:15][C:16](OCC)=[O:17])[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26].[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:13][C@H:12]([C:14]3[O:21][NH:29][C:16](=[O:17])[CH:15]=3)[CH2:11][CH2:10][N:9]2[C:22]([O:24][CH3:25])=[O:23])=[CH:4][C:3]=1[F:26]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730408HCID 131730408, compound

Product 1

HCID 131730409HCID 131730409, compound

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (171 mg, 0.44 mmol) (from example 49, step 1) was dissolved in MeOH (2 mL) and cooled to −40° C. Sodium hydroxide (0.117 mL, 0.44 mmol) dissolved in water (0.200 mL) was added dropwise and the solution stirred for 20 min. Hydroxylamine (50% by weight in water, 0.024 mL, 0.44 mmol) was then added and stirring was continued for 3.5 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (2.290 mL, 13.74 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated in vacuo and DCM (50 mL) and water (50 mL) were added. The phases were shaken, separated and the organic phase dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 10-60% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 19 mL/min. (2S,4S)-Methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (49.0 mg, 31.2%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.58-1.70 (m, 1H), 1.85-2.06 (m, 2H), 2.60 (d, 1H), 2.73-2.96 (m, 2H), 3.73 (s, 3H), 4.04-4.44 (m, 1H), 5.42-5.78 (m, 2H), 6.92-7.05 (m, 2H), 7.38 (t, 1H). MS m/z 355 (M+H)+

Workup

  1. additionwas added dropwise
  2. stirringstirring
  3. waitwas continued for 3.5 h
  4. customwas then transferred to a prewarmed 80° C.
  5. stirringstirring
  6. waitwas continued at 80° C. for 20 min
  7. customThe solvent was evaporated in vacuo and DCM (50 mL) and water (50 mL)
  8. additionwere added
  9. stirringThe phases were shaken
  10. customseparated
  11. customthe organic phase dried with a phase separator
  12. customevaporated in vacuo
  13. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm)
  14. custombuffer over 30 minutes
  15. customwas isolated as a white solid

Sources & evidence

ORD record
ord-60ace68b7ef340b987f6160ca77d9aae
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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