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

HRID 1963389Notes

Reaction equation

HRID 1963389 reaction equation
[C:1]([C:5]1[CH:6]=[C:7]([CH:11]2[CH2:16][CH:15]([C:17](=[O:24])[CH2:18][C:19](OCC)=[O:20])[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:31]O.Cl>CO.O>[C:1]([C:5]1[CH:6]=[C:7]([C@H:11]2[CH2:16][C@@H:15]([C:17]3[O:24][NH:31][C:19](=[O:20])[CH:18]=3)[CH2:14][CH2:13][N:12]2[C:25]([O:27][CH3:28])=[O:26])[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 66731921Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate

Product 1

HCID 68501687(2R,4S)-Methyl 2-(3-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 24%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Methyl 2-(3-tert-butylphenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.14 g, 8.06 mmol) was dissolved in MeOH (50 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.322 g, 8.06 mmol) dissolved in water (5.00 mL) was added during 5 min and the colourless mixture continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.494 mL, 8.06 mmol) was added during 8 min. The resulting solution was stirred at −55° C. for 6 h 30 min. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (60 mL, 360.00 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 brown oil. The crude was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 40-85% Acetonitrile in H2O/MeCN/HOAc 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-tert-butylphenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (690 mg, 24%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.29 (s, 9H), 1.81-1.88 (m, 1H), 2.14-2.21 (m, 1H), 2.22-2.31 (m, 1H), 2.35-2.42 (m, 1H), 3.03-3.10 (m, 1H), 3.37-3.44 (m, 1H), 3.66 (s, 3H), 4.16-4.22 (m, 1H), 5.12-5.16 (m, 1H), 5.48 (s, 1H), 6.97-7.01 (m, 1H), 7.17 (s, 1H), 7.21-7.25 (m, 2H). MS m/z 359 (M+H)+

Workup

  1. additionwas added during 5 min
  2. stirringThe resulting solution was stirred at −55° C. for 6 h 30 min
  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 brown oil
  9. customThe crude was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm)
  10. custombuffer over 25 minutes

Sources & evidence

ORD record
ord-f7b623220e1a4b969d56a0a08d613456
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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