Hydrochloric Acid → HCID 68502775, compound

HRID 1963621Notes

Reaction equation

HRID 1963621 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12](=[O:19])[CH2:13][C:14](OCC)=[O:15])[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21].[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:24]=[C:25]([F:27])[CH:26]=1)[CH2:5][C@H:6]1[CH2:11][C@H:10]([C:12]2[O:19][NH:30][C:14](=[O:15])[CH:13]=2)[CH2:9][CH2:8][N:7]1[C:20]([O:22][CH3:23])=[O:21]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730489HCID 131730489, compound

Product 1

HCID 68502775HCID 68502775, compoundYield 76%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (0.927 g, 2.42 mmol) (from example 130, step 1) was dissolved in MeOH (8 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.097 g, 2.42 mmol) dissolved in water (0.800 mL) was added over 7 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.148 mL, 2.42 mmol) was added over 4.5 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 (12.45 mL, 74.71 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and the crude mixture redissolved in DCM and washed with 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 0-25% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Trans-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.648 g, 76%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.45-2.12 (m, 4H), 2.80-3.35 (m, 4H), 3.35-3.70 (m, 3H), 4.12 (s, br., 1H), 4.62 (s, br., 1H), 5.71 (s, 1H), 6.77 (t, 1H), 6.87 (s, br., 2H). MS m/z 353 (M+H)+

Workup

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

Sources & evidence

ORD record
ord-fb39b9b5037b47299dec3250facf4470
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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