Hydrochloric Acid → HCID 68500326, compound

HRID 1963617Notes

Reaction equation

HRID 1963617 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 131730488HCID 131730488, compound

Product 1

HCID 68500326HCID 68500326, compoundYield 65.6%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(3,5-difluorobenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.662 g, 6.94 mmol) was dissolved in MeOH (24 mL) and cooled to −40° C. under nitrogen atmosphere. Sodium hydroxide (0.278 g, 6.94 mmol) dissolved in water (2.400 mL) was added over 13 min. After 20 min with stirring, hydroxylamine (50% by weight in water, 0.425 mL, 6.94 mmol) was added over 9 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 (35.8 mL, 214.55 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 in 2 injections 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. Cis-methyl 2-(3,5-difluorobenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.604 g, 65.6%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.91-2.07 (m, 4H), 2.62-2.80 (m, 2H), 2.97-3.04 (m, 1H), 3.23-3.34 (m, 1H), 3.54 (s, 3H), 3.89-3.99 (m, 1H), 4.26-4.36 (m, 1H), 5.73 (s, 1H), 6.69-6.79 (m, 3H). MS m/z 353 (M+H)+

Workup

  1. additionwas added over 13 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 in 2 injections on a XBridge C18 column (10 μm 250×50 ID mm)
  9. custombuffer over 20 minutes

Sources & evidence

ORD record
ord-71fd1fd2df914b759352e2982a7db36b
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

Loading…