Hydrochloric Acid → HCID 66732055, compound

HRID 1963412Notes

Reaction equation

HRID 1963412 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])=[C:4]([F:26])[CH:3]=1.[OH-].[Na+].[NH2:29]O.Cl>CO>[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])=[C:4]([F:26])[CH:3]=1

Participants

6

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730404cis-Methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Product 1

HCID 66732055HCID 66732055, compoundYield 47.1%

Reagents, catalysts & solvents 1

HCID 887MethanolSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.31 g, 5.99 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (1.761 mL, 5.99 mmol) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.367 mL, 5.99 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30.8 mL, 185.01 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a slightly yellow solid. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-55% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(4-chloro-2-fluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1 g, 47%) was isolated after. MS m/z 355 (M+H)+

Workup

  1. stirringThe resulting solution was stirred at −40° C. for 3 h
  2. stirringto stir at 80° C. for 20 min
  3. customThe solvent was evaporated
  4. additionDCM/water added
  5. customThe phases were separated
  6. customevaporated
  7. customto yield a slightly yellow solid
  8. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  9. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-b440742cc8c14a0e9a1159ff8a3d010c
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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