Hydroxylamine → Amitifadine

HRID 718120Notes

Reaction equation

HRID 718120 reaction equation
[NH2:1][CH2:2][C@:3]1([C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=2)[CH2:5][C@@H:4]1[CH2:6]O.NO.S(Cl)(Cl)=O.[OH-].[Na+]>C(OC(C)C)(=O)C>[Cl:15][C:10]1[CH:9]=[C:8]([C@@:3]23[CH2:5][C@@H:4]2[CH2:6][NH:1][CH2:2]3)[CH:13]=[CH:12][C:11]=1[Cl:14]

Participants

6

Reactant 4

HCID 787HydroxylamineHCID 14798Sodium Hydroxide2×HCID 24386Thionyl ChlorideHCID 16079683HCID 16079683, compound

Product 1

HCID 11658655AmitifadineYield 42%

Reagents, catalysts & solvents 1

HCID 7915Isopropyl AcetateSolvent3×

Procedure

Title compound 487 (4.63 g, 18.81 mmol) was dissolved in isopropyl acetate (24.5 mL). The above crude amino alcohol solution in isopropyl acetate was slowly subsurface-added to a solution of thionyl chloride (1.61 ml, 22.06 mmol) in isopropyl acetate (17.5 mL) at ambient temperature over 2 hours. After aging additional 1-5 h, 5.0 N sodium hydroxide (16.4 mL) was added over 1 hour while the batch temperature was maintained at <30° C. with external cooling. The two-phase reaction mixture was stirred for 1 hour at ambient temperature to allow pH to stabilize (usually to 8.5-9.0) with sodium hydroxide pH titration. The organic phase was washed with 40% aqueous isopropanol (21 mL) followed by water (10.5 mL). Concentrated HCl (1.69 mL) was added. The aqueous isopropyl acetate was azeotropically concentrated in vacuum to ca. 24.5 mL. Methylcyclohexane (17.5 mL) was added dropwise over 2 hours. Compound did not crystallize out. The pH was adjusted to neutral and organic layer was separated. The organic layer was washed with water and brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified by ISCO (EtOAc to 60% MeOH in EtOAc, 40 g silica column) to afford title compound 488 (1.8 g, 42%) as a thick yellow oil. 1H NMR (CD3OD) δ (ppm): 7.44 (d, J=8.4 Hz, 1H), 7.41 (d, J=2.2 Hz, 1H), 7.18 (dd, J=8.4, 2.2 Hz, 1H), 3.31-3.30 (m, 2H), 3.23-3.17 (m, 2H), 1.97-1.93 (m, 1H), 1.20-1.04 (m, 2H). MS (m/z)=228.15 (M+H)

Workup

  1. temperaturewas maintained at <30° C. with external cooling
  2. customThe two-phase reaction mixture
  3. washThe organic phase was washed with 40% aqueous isopropanol (21 mL)
  4. additionConcentrated HCl (1.69 mL) was added
  5. concentrationThe aqueous isopropyl acetate was azeotropically concentrated in vacuum to ca. 24.5 mL
  6. additionMethylcyclohexane (17.5 mL) was added dropwise over 2 hours
  7. customCompound did not crystallize out
  8. customwas separated
  9. washThe organic layer was washed with water and brine
  10. dry with materialdried over magnesium sulfate
  11. filtrationfiltered
  12. customevaporated
  13. customThe residue was purified by ISCO (EtOAc to 60% MeOH in EtOAc, 40 g silica column)

Sources & evidence

ORD record
ord-c112ca5dc9bf403898c567495f25afc9
Source dataset
uspto-grants-2015_11
Patent number
US09193749B2

Reaction notes

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