Hydrochloric Acid → HCID 68502958, compound

HRID 1963421Notes

Reaction equation

HRID 1963421 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 131730407HCID 131730407, compound

Product 1

HCID 68502958HCID 68502958, compoundYield 57.9%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.731 g, 4.49 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.181 mL, 4.49 mmol) dissolved in water (2 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.247 mL, 4.49 mmol) was added dropwise and stirring continued for 3 h. The mixture was then transferred to a prewarmed 80° C. solution of 6 M hydrogen chloride (23.18 mL, 139.09 mmol) and stirring was continued at 80° C. for 20 min. The solvent was evaporated and DCM (200 mL) and water (200 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 250×50 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 100 mL/min. Cis-methyl 2-(4-chloro-3-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylate (0.921 g, 57.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.79-1.87 (m, 1H), 2.06-2.15 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.37 (m, 1H), 3.00-3.09 (m, 1H), 3.31-3.40 (m, 1H), 3.66 (s, 3H), 4.07-4.16 (m, 1H), 5.00-5.07 (m, 1H), 5.56 (s, 1H), 6.87-6.91 (m, 1H), 6.95 (dd, 1H), 7.29 (t, 1H). MS m/z 355 (M+H)+

Workup

  1. additionwas added
  2. stirringstirring
  3. waitcontinued for 3 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
  8. additionDCM (200 mL) and water (200 mL) were 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 250×50 ID mm)
  14. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-fd84bf56ade546bd98b499246cb492ee
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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