Hydrochloric Acid → HCID 68503455, compound

HRID 1963493Notes

Reaction equation

HRID 1963493 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 131730438HCID 131730438, compound

Product 1

HCID 68503455HCID 68503455, compoundYield 55%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-cyclohexyl-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.644 g, 4.84 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.194 g, 4.84 mmol) dissolved in water (1.500 mL) was added dropwise and the colourless solution continued to stir at −40° C. for 30 min. Hydroxylamine (50% by weight in water, 0.297 mL, 4.84 mmol) was added dropwise. 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 (21 mL, 126.00 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 dried over Na2SO4 and evaporated to yield a slightly yellow foam. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using two injections with 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. Cis-methyl 2-cyclohexyl-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (814 mg, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 0.83-0.98 (m, 2H), 1.01-1.16 (m, 3H), 1.25-1.40 (m, 1H), 1.50-1.88 (m, 6H), 1.95-2.13 (m, 3H), 2.88-3.07 (m, 2H), 3.70 (s, 3H), 3.79-3.89 (m, 1H), 3.95-4.07 (m, 1H), 5.70 (s, 1H). MS m/z 309 (M+H)+

Workup

  1. additionwas added dropwise
  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. additionMTBE/water added
  6. customThe phases were separated
  7. dry with materialthe organic phase dried over Na2SO4
  8. customevaporated
  9. customto yield a slightly yellow foam
  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-97d566aa71fe4275b70af6f9a1b0cffd
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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