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

HRID 1963474Notes

Reaction equation

HRID 1963474 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][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][C:19]=2[CH3:28])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:32]O.Cl>CO.O>[CH3:28][C:19]1[CH:20]=[C:21]([C:24]([F:27])([F:26])[F:25])[CH:22]=[CH:23][C:18]=1[C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:32][C:4](=[O:3])[CH:5]=2)[CH2:13][CH2:12][N:11]1[C:14]([O:16][CH3:17])=[O:15]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730430cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate

Product 1

HCID 86646612(2R,4S)-Methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)-piperidine-1-carboxylateYield 55.1%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-methyl-4-(trifluoromethyl)phenyl)piperidine-1-carboxylate (6.28 g, 15.12 mmol) was dissolved in MeOH (60 mL) and cooled to −40° C. 3.8 M NaOH (3.98 mL, 15.12 mmol) was dissolved in water (6 mL) and added to the mixture and the reaction stirred at −40° C. for 40 min. Hydroxylamine (50% by weight in water, 0.926 mL, 15.12 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a preheated 80° C. warm solution of 6 M HCl (76 mL, 453.53 mmol) and stirred for 20 min. The reaction mixture was partitioned between water and DCM. The aqueous phase was extracted twice with DCM and the combined organic phase was dried and evaporated. The compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 35-75% acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-methyl-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (3.2 g, 55%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.81-1.93 (m, 2H), 2.21-2.42 (m, 2H), 2.44 (s, 3H), 3.03-3.13 (m, 1H), 3.59 (s, 3H), 3.63-3.75 (m, 1H), 4.12-4.20 (m, 1H), 5.02 (dd, 1H), 5.65 (s, 1H), 7.30 (d, 1H), 7.37-7.44 (m, 2H). MS m/z 383 (M−H)−

Workup

  1. additionadded to the mixture
  2. stirringstirring
  3. waitcontinued for 3.5 h at −40° C
  4. additionThe reaction mixture was then added to a preheated 80° C.
  5. stirringstirred for 20 min
  6. customThe reaction mixture was partitioned between water and DCM
  7. extractionThe aqueous phase was extracted twice with DCM
  8. customthe combined organic phase was dried
  9. customevaporated
  10. customThe compound was purified in two runs by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  11. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-c1eeb03b5b6f4af98dc92972b60d694f
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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