Hydrochloric Acid → HCID 131730436, compound

HRID 1963489Notes

Reaction equation

HRID 1963489 reaction equation
C([O:3][C:4](=O)[CH2:5][C:6]([C@@H:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[O:3]=[C:4]1[CH:5]=[C:6]([C@@H:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][CH3:17])=[O:15])[C@@H:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH2:9]2)[O:7][NH:27]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730434HCID 131730434, compound

Product 1

HCID 131730436HCID 131730436, compoundYield 72.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-phenylpiperidine-1-carboxylate (1.104 g, 3.31 mmol) (from example 77, step 1) was dissolved in MeOH (10 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.132 g, 3.31 mmol) dissolved in water (1.000 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.203 mL, 3.31 mmol) was added during 6 min. The resulting solution was stirred at −40° C. for 2 h 30 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (14 mL, 84.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water was added. The phases were separated and the organic phase evaporated to yield a brown oil. The residue was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-30% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 4-(3-oxo-2,3-dihydroisoxazol-5-yl)-2-phenylpiperidine-1-carboxylate (722 mg, 72%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.66 (dq, 1H), 1.86-2.09 (m, 2H), 2.72 (d, 1H), 2.79-3.03 (m, 2H), 3.78 (s, 3H), 4.26 (br. s, 1H), 5.68 (br. s, 2H), 7.20-7.32 (m, 3H), 7.34-7.43 (m, 2H). MS m/z 303 (M+H)+

Workup

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

Sources & evidence

ORD record
ord-0480154048714af78e54bdfd3ee8a796
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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