Hydrochloric Acid → HCID 131730447, compound

HRID 1963516Notes

Reaction equation

HRID 1963516 reaction equation
[F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@H:7]([C:9](=[O:16])[CH2:10][C:11](OCC)=[O:12])[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18].[OH-].[Na+].[NH2:24]O.Cl>CO.O.C(Cl)Cl>[F:1][CH:2]([F:21])[C@H:3]1[CH2:8][C@H:7]([C:9]2[O:16][NH:24][C:11](=[O:12])[CH:10]=2)[CH2:6][CH2:5][N:4]1[C:17]([O:19][CH3:20])=[O:18]

Participants

8

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730445HCID 131730445, compound

Product 1

HCID 131730447HCID 131730447, compoundYield 67%

Reagents, catalysts & solvents 3

HCID 887MethanolSolventHCID 962WaterSolvent2×HCID 6344DichloromethaneSolvent

Conditions

Temperature
-40 °C

Procedure

Trans-methyl 2-(difluoromethyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (203 mg, 0.66 mmol) (from example 87, step 1) was dissolved in MeOH (3 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (26.4 mg, 0.66 mmol) dissolved in water (0.300 mL) was added and the mixture was stirred at −40° C. for 15 min. Hydroxylamine (50% by weight in water, 0.040 mL, 0.66 mmol) was added. The resulting solution was stirred at −40° C. for 2 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (3.41 mL, 20.48 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 250×20 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/AcOH 95/5/0.2 buffer, over 15 minutes with a flow of 19 mL/min. Trans-methyl 2-(difluoromethyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (122 mg, 67%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.35-1.65 (m, 1H), 1.68-1.82 (m, 1H), 1.87-2.12 (m, 1H), 2.30-2.45 (m, 1H), 2.70-3.22 (m, 2H), 3.74 (s, 3H), 4.10-4.74 (m, 2H), 5.69 (s, 1H), 5.75-6.09 (m, 1H). MS m/z 275 (M−H)−

Workup

  1. additionwas added
  2. stirringThe resulting solution was stirred at −40° C. for 2 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 250×20 ID mm)
  9. waitover 15 minutes with a flow of 19 mL/min

Sources & evidence

ORD record
ord-587d030f2937464593f42a0a19e9e3cd
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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