Hydrochloric Acid → HCID 66731837, compound

HRID 1963417Notes

Reaction equation

HRID 1963417 reaction equation
[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24].[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][CH:13]([C:15]2[O:22][NH:29][C:17](=[O:18])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 66731881Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Product 1

HCID 66731837HCID 66731837, compoundYield 65.4%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.655 g, 4.29 mmol) was dissolved in MeOH (22 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.180 g, 4.50 mmol) dissolved in water (2.200 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.276 mL, 4.50 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred with a pipette into a prewarmed (80° C.) solution of 6 M hydrogen chloride (22.16 mL, 132.98 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min (3 runs). Methyl 2-(2-chloro-4-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.995 g, 65.4%) was yielded as a white solid. MS m/z 355 (M+H)+

Workup

  1. additionwas added
  2. stirringThe resulting solution was stirred at −40° C. for 1 h
  3. stirringthe mixture was stirred at 80° C. for 15 min
  4. customthe phases separated
  5. extractionThe aqueous phase was extracted with DCM
  6. filtrationthe combined organic layers were filtered through a phase separator
  7. customevaporated
  8. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  9. custombuffer over 25 minutes

Sources & evidence

ORD record
ord-470f58135ec745239de0649afdf87c7a
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…