Hydrochloric Acid → HCID 68499998, compound

HRID 1963633Notes

Reaction equation

HRID 1963633 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]([CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([F:29])[CH:20]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O>[F:29][C:21]1[CH:20]=[C:19]([CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=1)[CH2:18][C@H:10]1[CH2:9][C@@H:8]([C:6]2[O:7][NH:33][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 131730494HCID 131730494, compound

Product 1

HCID 68499998HCID 68499998, compoundYield 65%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1-carboxylate (2.52 g, 5.81 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. Sodium hydroxide (0.246 g, 6.15 mmol) dissolved in water (2.2 mL) was added over 1 min and the resulting solution was stirred at −40° C. for 20 min. Then hydroxylamine (50% by weight in water, 0.38 mL, 6.20 mmol) was added over 1 min and stirring continued at −40° C. for 2 h 20 min. The reaction mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (40 mL, 240.00 mmol) and the mixture was continued to be stirred at 80° C. for 1 h. Then cooled to room temperature. Methanol was evaporated, then water was added. Extracted three times with DCM. Combined organic layers dried over MgSO4 and evaporated. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 0-35% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.52 g, 65%) was isolated as a colorless foam. 1H NMR (600 MHz, cdcl3) δ 1.87-2.10 (m, 4H), 2.61-2.67 (m, 1H), 2.80-2.87 (m, 1H), 2.97-3.04 (m, 1H), 3.13-3.21 (m, 1H), 3.60 (s, 3H), 3.96-4.04 (m, 1H), 4.26-4.32 (m, 1H), 5.74 (s, 1H), 7.00 (d, 1H), 7.11-7.16 (m, 2H). MS m/z 403 (M+H)+

Workup

  1. additionwas added over 1 min
  2. stirringstirring
  3. waitcontinued at −40° C. for 2 h 20 min
  4. stirringto be stirred at 80° C. for 1 h
  5. temperatureThen cooled to room temperature
  6. customMethanol was evaporated
  7. additionwater was added
  8. extractionExtracted three times with DCM
  9. dry with materialCombined organic layers dried over MgSO4
  10. customevaporated
  11. customThe compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm)
  12. custombuffer over 25 minutes

Sources & evidence

ORD record
ord-e8a26ec0fdac46088ed422f3deb0ba83
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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