Hydrochloric Acid → HCID 66742254, compound

HRID 1963519Notes

Reaction equation

HRID 1963519 reaction equation
[F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][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])[CH2:4][CH2:3]1.[OH-].[Na+].[NH2:30]O.Cl>CO.O>[F:1][C:2]1([F:27])[CH2:7][CH2:6][CH:5]([CH2:8][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])[CH2:4][CH2:3]1

Participants

7

Reactant 4

HCID 313Hydrochloric AcidHCID 787HydroxylamineHCID 14798Sodium HydroxideHCID 131730449HCID 131730449, compound

Product 1

HCID 66742254HCID 66742254, compoundYield 65.4%

Reagents, catalysts & solvents 2

HCID 887MethanolSolventHCID 962WaterSolvent

Conditions

Temperature
-40 °C

Procedure

Cis-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.66 g, 6.83 mmol) was dissolved in MeOH (20 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (2.009 mL, 6.83 mmol) dissolved in water (2.000 mL) was added during 10 min and the yellow solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.419 mL, 6.83 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3 h. The mixture was then rapidly poured into a prewarmed (80° C.) solution of 6 M hydrogen chloride (30 mL, 180.00 mmol) and the mixture continued to stir at 80° C. for 20 min. The solvent was evaporated and DCM/water added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a white solid. The compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm) using a gradient of 5-55% Acetonitrile in H2O/MeCN/FA 95/5/0.2 buffer over 30 minutes with a flow of 100 mL/min. Cis-methyl 2-((4,4-difluorocyclohexyl)methyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.6 g, 65%) was isolated. 1H NMR (400 MHz, cdcl3) δ 1.10-2.12 (m, 15H), 2.96-3.05 (m, 1H), 3.08-3.19 (m, 1H), 3.71 (s, 3H), 3.87-4.00 (m, 1H), 4.14-4.24 (m, 1H), 5.72 (s, 1H). MS m/z 357 (M−H)−

Workup

  1. additionwas added during 10 min
  2. stirringThe resulting solution was stirred at −40° C. for 3 h
  3. stirringto stir at 80° C. for 20 min
  4. customThe solvent was evaporated
  5. additionDCM/water added
  6. customThe phases were separated
  7. customevaporated
  8. customto yield a white solid
  9. customThe compound was purified by preparative HPLC on a Kromasil C8 column (10 μm 250×50 ID mm)
  10. custombuffer over 30 minutes

Sources & evidence

ORD record
ord-3804b405b97344daa7c76cbce89a59db
Source dataset
uspto-grants-2013_04
Patent number
US08415378B2

Reaction notes

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