Hydrochloric Acid → HCID 68502101, compound

HRID 1963433Notes

Reaction equation

HRID 1963433 reaction equation
[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17](OCC)=[O:18])[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-].[Na+].[NH2:29]O.Cl>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:29][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])[CH:5]=[C:6]([Cl:8])[CH:7]=1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730411HCID 131730411, compound

Product 1

HCID 68502101HCID 68502101, compoundYield 60.7%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(3,5-dichlorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (3.57 g, 8.87 mmol) was dissolved in MeOH (36.4 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (2.335 mL, 8.87 mmol) in water (3.64 mL) was added and the mixture stirred at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.544 mL, 8.87 mmol) was added and stirring continued at −40° C. for 3.5 h. The reaction mixture was then transferred to a preheated 80° C. solution of 6 M hydrogen chloride (45.9 mL, 275.11 mmol) and heating was continued for 20 min. The solvent was then evaporated. DCM and water 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 25-65% 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-dichlorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (2.000 g, 60.7%) was isolated as a white solid. 1H NMR (400 MHz, cd3od) δ 1.82-1.93 (m, 1H), 2.13-2.27 (m, 2H), 2.30-2.39 (m, 1H), 3.06-3.16 (m, 1H), 3.42-3.53 (m, 1H), 3.66 (s, 3H), 4.04-4.12 (m, 1H), 5.06 (dd, 1H), 5.64 (d, 1H), 7.14-7.18 (m, 2H), 7.27 (t, 1H). MS m/z 371 (M+H)+

Workup

  1. stirringstirring
  2. waitcontinued at −40° C. for 3.5 h
  3. customwas then transferred to a preheated 80° C.
  4. temperatureheating
  5. waitwas continued for 20 min
  6. customThe solvent was then evaporated
  7. additionDCM and water were added
  8. stirringshaken
  9. customthe phases separated
  10. customThe organic phase was dried with a phase separator
  11. customevaporated in vacuo
  12. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  13. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-7ac989eef0354f7cb485176543c3c11c
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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