Hydrochloric Acid → HCID 68501466, compound

HRID 1963440Notes

Reaction equation

HRID 1963440 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]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][C:19]=2[F:29])[CH2:9]1)=[O:7])C.[OH-].[Na+].[NH2:33]O.Cl>CO.O.C(Cl)Cl>[F:29][C:19]1[CH:20]=[C:21]([O:24][C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:23][C:18]=1[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

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730413cis-Methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate

Product 1

HCID 68501466HCID 68501466, compoundYield 61%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 4-(3-ethoxy-3-oxopropanoyl)-2-(2-fluoro-4-(trifluoromethoxy)phenyl)piperidine-1-carboxylate (3.22 g, 7.40 mmol) was dissolved in MeOH (30 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.311 g, 7.77 mmol) dissolved in water (3.00 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.476 mL, 7.77 mmol) was added. The resulting solution was stirred at −40° C. for 1 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (38.2 mL, 229.28 mmol) and the mixture was stirred at 80° C. for 15 min. Water and DCM were added and the phases separated. The aqueous phase was extracted with DCM and the combined organic layers were filtered through a phase separator and evaporated. The compound was purified by preparative HPLC on a Kromasil C8 column (4 runs) (10 μm 250×50 ID mm) using a gradient of 25-65% Acetonitrile in H2O/MeCN/HOAc 95/5/0.2 buffer over 25 minutes with a flow of 100 mL/min. Cis-methyl 2-(2-fluoro-4-(trifluoromethoxy)phenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.82 g, 61%) was isolated. 1H NMR (600 MHz, cdcl3) δ 1.82-1.91 (m, 1H), 2.03-2.13 (m, 1H), 2.22-2.41 (m, 2H), 3.01-3.10 (m, 1H), 3.43-3.53 (m, 1H), 3.63 (s, 3H), 4.11-4.21 (m, 1H), 5.19 (dd, 1H), 5.59 (s, 1H), 6.89-6.95 (m, 2H), 7.14 (t, 1H). MS m/z 405 (M+H)+

Workup

  1. additionwas added
  2. stirringThe resulting solution was stirred at −40° C. for 1 h
  3. stirringthe mixture was stirred at 80° C. for 15 min
  4. customthe phases separated
  5. extractionThe aqueous phase was extracted with DCM
  6. filtrationthe combined organic layers were filtered through a phase separator
  7. customevaporated
  8. customThe compound was purified by preparative HPLC on a Kromasil C8 column (4 runs) (10 μm 250×50 ID mm)
  9. custombuffer over 25 minutes

Sources & evidence

ORD record
ord-87b0a2674fc544c482cdc0ab73fb0f0e
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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