Hydrochloric Acid → HCID 68507161, compound

HRID 1963457Notes

Reaction equation

HRID 1963457 reaction equation
[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([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:4][C:3]=1[F:27].[OH-].[Na+].[NH2:30]O.Cl>CO.O.C(Cl)Cl>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C@H:9]2[CH2:14][C@@H:13]([C:15]3[O:22][NH:30][C:17](=[O:18])[CH:16]=3)[CH2:12][CH2:11][N:10]2[C:23]([O:25][CH3:26])=[O:24])=[CH:4][C:3]=1[F:27]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730421HCID 131730421, compound

Product 1

HCID 68507161HCID 68507161, compoundYield 62.3%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (1.445 g, 3.58 mmol) was dissolved in MeOH (14 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.150 g, 3.76 mmol) dissolved in water (1.4 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.230 mL, 3.76 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 (18.49 mL, 110.93 mmol) and the mixture was stirred at 80° C. for 20 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 (10 μm 250×50 ID mm) using a gradient of 15-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. The compounds were detected by UV at 220 nm. Cis-methyl 2-(4-chloro-3,5-difluorophenyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (0.831 g, 62.3%) was yielded as colorless solid. 1H NMR (600 MHz, cdcl3) δ 1.80-1.87 (m, 1H), 2.04-2.15 (m, 1H), 2.19-2.28 (m, 1H), 2.30-2.36 (m, 1H), 3.00-3.09 (m, 1H), 3.30-3.39 (m, 1H), 3.66 (s, 3H), 4.07-4.16 (m, 1H), 4.98-5.05 (m, 1H), 5.59 (s, br., 1H), 6.80 (d, 2H). MS m/z 273 (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 20 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 (10 μm 250×50 ID mm)
  9. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-d7517e62128345ff9678de6fcadaef8f
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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