Hydrochloric Acid → HCID 131730439, compound

HRID 1963495Notes

Reaction equation

HRID 1963495 reaction equation
[CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13](=[O:20])[CH2:14][C:15](OCC)=[O:16])[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:27]O.Cl>CO.O>[CH:1]1([C@H:7]2[CH2:12][C@H:11]([C:13]3[O:20][NH:27][C:15](=[O:16])[CH:14]=3)[CH2:10][CH2:9][N:8]2[C:21]([O:23][CH3:24])=[O:22])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730437HCID 131730437, compound

Product 1

HCID 131730439HCID 131730439, compoundYield 53.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (349 mg, 1.03 mmol) (from example 79, step 1) was dissolved in MeOH (5 mL) and cooled to −40° C. Sodium hydroxide (41.1 mg, 1.03 mmol) dissolved in water (0.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.063 mL, 1.03 mmol) was added dropwise. The resulting solution was stirred at −40° C. for 2 h 20 min. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (5 mL, 30.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and MTBE/water added. The phases were separated and the organic phase was dried over Na2SO4 and evaporated to yield a yellow oil. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-75% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Trans-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (170 mg, 53%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.82-1.08 (m, 2H), 1.08-1.32 (m, 3H), 1.45-1.83 (m, 8H), 1.89-2.02 (m, 1H), 2.12-2.23 (m, 1H), 2.79-3.04 (m, 2H), 3.70 (s, 3H), 3.87-4.83 (m, 2H), 5.64 (s, 1H). MS m/z 309 (M+H)+

Workup

  1. additionwas added dropwise
  2. stirringThe resulting solution was stirred at −40° C. for 2 h 20 min
  3. stirringto stir at 80° C. for 20 min
  4. customThe solvent was evaporated
  5. additionMTBE/water added
  6. customThe phases were separated
  7. dry with materialthe organic phase was dried over Na2SO4
  8. customevaporated
  9. customto yield a yellow oil
  10. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  11. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-619bb698c3464ecd8eb50579b1f64781
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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