Hydrochloric Acid → HCID 68500258, compound

HRID 1963605Notes

Reaction equation

HRID 1963605 reaction equation
[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730483HCID 131730483, compound

Product 1

HCID 68500258HCID 68500258, compoundYield 61.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.241 g, 5.85 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.234 g, 5.85 mmol) dissolved in water (2.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.358 mL, 5.85 mmol) was added during 8 min. 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 (30 mL, 180.00 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 yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.259 g, 61%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.88-2.13 (m, 4H), 2.63-2.83 (m, 2H), 2.99-3.10 (m, 1H), 3.23-3.34 (m, 1H), 3.45 (s, 3H), 3.88-4.00 (m, 1H), 4.35-4.46 (m, 1H), 5.85 (d, 1H), 6.88-7.06 (m, 3H). MS m/z 353 (M+H)+

Workup

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

Sources & evidence

ORD record
ord-f50d570507144c83b6f48ca00b215329
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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