Hydrochloric Acid → HCID 66732123, compound

HRID 1963469Notes

Reaction equation

HRID 1963469 reaction equation
[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19](=[O:26])[CH2:20][C:21](OCC)=[O:22])[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:11])([F:10])[F:9].[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:1][C:2]1[CH:3]=[C:4]([C@H:13]2[CH2:18][C@@H:17]([C:19]3[O:26][NH:33][C:21](=[O:22])[CH:20]=3)[CH2:16][CH2:15][N:14]2[C:27]([O:29][CH3:30])=[O:28])[CH:5]=[C:6]([F:12])[C:7]=1[C:8]([F:10])([F:9])[F:11]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730427cis-Methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate

Product 1

HCID 66732123HCID 66732123, compoundYield 43%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-ethoxy-3-oxopropanoyl)-piperidine-1-carboxylate (1.489 g, 3.40 mmol) was dissolved in MeOH (15 mL) and cooled to −40° C. Sodium hydroxide (0.896 mL, 3.40 mmol) dissolved in water (1.500 mL) was added and the reaction stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.209 mL, 3.40 mmol) was added and stirring continued for 3.5 h at −40° C. The reaction mixture was then added to a prewarmed 80° C. solution of hydrogen chloride (17.59 mL, 105.54 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (100 mL) and water (100 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 20-65% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-difluoro-4-(trifluoromethyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.594 g, 42.9%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.82-1.89 (m, 1H), 2.08-2.16 (m, 1H), 2.19-2.27 (m, 1H), 2.32-2.38 (m, 1H), 3.04-3.11 (m, 1H), 3.34-3.41 (m, 1H), 3.68 (s, 3H), 4.09-4.15 (m, 1H), 5.04-5.08 (m, 1H), 5.57 (s, 1H), 6.80 (d, 2H).

Workup

  1. additionwas added
  2. stirringstirring
  3. waitcontinued for 3.5 h at −40° C
  4. stirringstirred for 20 min
  5. customThe solvent was evaporated in vacuo
  6. additionDCM (100 mL) and water (100 mL) were added
  7. stirringshaken
  8. customthe phases separated
  9. customThe organic phase was dried with a phase separator
  10. customevaporated in vacuo
  11. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  12. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-efadc58157354139be40d60923aa3484
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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