Hydrochloric Acid → (2R,4S)-Methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

HRID 1963507Notes

Reaction equation

HRID 1963507 reaction equation
[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].[NH2:29]O.Cl>CO.O.C(Cl)Cl>[CH:1]1([O:7][CH2:8][C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730443cis-Methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Product 1

HCID 68502091(2R,4S)-Methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 41%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.13 g, 3.06 mmol) was dissolved in MeOH (14 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.128 g, 3.21 mmol) dissolved in water (1.400 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.197 mL, 3.21 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (15.80 mL, 94.82 mmol) and the mixture was stirred at 80° C. for 20 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(cyclohexyloxymethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (423 mg, 41%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.12-2.15 (m, 14H), 2.93-3.04 (m, 1H), 3.10-3.31 (m, 2H), 3.35-3.50 (m, 2H), 3.70 (s, 3H), 3.83-3.94 (m, 1H), 4.05-4.15 (m, 1H), 5.75 (s, 1H). MS m/z 339 (M+H)+

Workup

  1. additionwas added
  2. stirringThe resulting solution was stirred at −40° C. for 1 h
  3. stirringthe mixture was stirred at 80° C. for 20 min
  4. customthe phases separated
  5. extractionThe aqueous phase was extracted with DCM
  6. filtrationthe combined organic layers were filtered through a phase separator
  7. customevaporated
  8. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  9. custombuffer over 25 minutes

Sources & evidence

ORD record
ord-a0682de1aeb141f6af12ddd1d321645b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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