Hydrochloric Acid → HCID 131730397, compound

HRID 1963397Notes

Reaction equation

HRID 1963397 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]([C:18]2[CH:23]=[CH:22][C:21]([S:24]([CH3:27])(=[O:26])=[O:25])=[CH:20][CH:19]=2)[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:31]O.Cl>CO.O>[CH3:27][S:24]([C:21]1[CH:22]=[CH:23][C:18]([C@H:10]2[CH2:9][C@H:8]([C:6]3[O:7][NH:31][C:4](=[O:3])[CH:5]=3)[CH2:13][CH2:12][N:11]2[C:14]([O:16][CH3:17])=[O:15])=[CH:19][CH:20]=1)(=[O:26])=[O:25]

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730396HCID 131730396, compound

Product 1

HCID 131730397HCID 131730397, compoundYield 64.5%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(4-(methylsulfonyl)phenyl)piperidine-1-carboxylate (505 mg, 1.23 mmol) (from example 38, step 1) was suspended in MeOH (5 mL) and cooled to −40° C. 3.8 M sodium hydroxide (0.323 mL, 1.23 mmol) in water was added. After 20 min, hydroxylamine (50% in water, 0.075 mL, 1.23 mmol) was added and stirring continued at −40° C. for 3 h. The reaction mixture was then added to a prewarmed 80° C. solution of 6 M hydrogen chloride (6.14 mL, 36.82 mmol) and stirred for 20 min. The solvent was evaporated in vacuo. DCM (50 mL) and water (50 mL) were added, shaken and the phases separated. The organic phase was dried with a phase separator and evaporated in vacuo. The residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm) using a gradient of 15-40% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 25 minutes with a flow of 19 mL/min. Trans-methyl 2-(4-(methylsulfonyl)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (301 mg, 64.5%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.61-1.73 (m, 1H), 1.91-1.99 (m, 1H), 2.05-2.14 (m, 1H), 2.66-2.82 (m, 2H), 2.91 (t, 1H), 3.05 (s, 3H), 3.77 (s, 3H), 4.12-4.46 (m, 1H), 5.60-5.80 (m, 2H), 7.44 (d, 2H), 7.95 (d, 2H). MS m/z 381 (M+H)+

Workup

  1. waitcontinued at −40° C. for 3 h
  2. stirringstirred for 20 min
  3. customThe solvent was evaporated in vacuo
  4. additionDCM (50 mL) and water (50 mL) were added
  5. stirringshaken
  6. customthe phases separated
  7. customThe organic phase was dried with a phase separator
  8. customevaporated in vacuo
  9. customThe residue was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×20 ID mm)
  10. waitover 25 minutes with a flow of 19 mL/min

Sources & evidence

ORD record
ord-68a5697cb5654fdaa89ae0ef675c62c2
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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