Hydrochloric Acid → (2R,4S)-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate

HRID 1963612Notes

Reaction equation

HRID 1963612 reaction equation
[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11](=[O:18])[CH2:12][C:13](OCC)=[O:14])[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[C:3]=1[CH2:4][C@H:5]1[CH2:10][C@@H:9]([C:11]2[O:18][NH:30][C:13](=[O:14])[CH:12]=2)[CH2:8][CH2:7][N:6]1[C:19]([O:21][CH3:22])=[O:20]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730486cis-Methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate

Product 1

HCID 66732352(2R,4S)-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylateYield 55.8%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.404 g, 6.27 mmol) was dissolved in MeOH (21 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.251 g, 6.27 mmol) dissolved in water (2.100 mL) was added over 8 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.384 mL, 6.27 mmol) was added over 6 minutes and the solution was stirred for 3.5 hours at −40° C. The reaction mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (32.3 mL, 193.76 mmol) and the mixture continued to stir at 80° C. for 25 min. The solvent was evaporated and the crude mixture was redissolved in DCM/water. The organic phase was dried and concentrated. The compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-20% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(2,6-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.232 g, 55.8%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.94-2.04 (m, 2H), 2.08-2.16 (m, 2H), 2.63-2.73 (m, 1H), 2.81-2.91 (m, 1H), 2.98-3.09 (m, 1H), 3.24-3.37 (m, 4H), 3.88-3.99 (m, 1H), 4.41-4.54 (m, 1H), 5.81 (s, 1H), 6.82-6.92 (m, 2H), 7.16-7.26 (m, 1H). MS m/z 353 (M+H)+

Workup

  1. additionwas added over 8 min
  2. stirringthe solution was stirred for 3.5 hours at −40° C
  3. stirringto stir at 80° C. for 25 min
  4. customThe solvent was evaporated
  5. dissolutionthe crude mixture was redissolved in DCM/water
  6. customThe organic phase was dried
  7. concentrationconcentrated
  8. customThe compound was purified by preparative HPLC on a XBridge C18 column (10 μm 250×50 ID mm)
  9. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-03b58da40f0946b081f6dea4ca3a5183
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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