Hydroxyamine hydrochloride → tert-butyl 1-(4-(N'-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate

HRID 1804519Notes

Reaction equation

HRID 1804519 reaction equation
[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:11][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])#[N:2].Cl.[NH2:26][OH:27].C(=O)(O)[O-].[Na+]>C(O)(C)C>[OH:27][N:26]=[C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[CH2:9][CH:10]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:11]2)=[CH:5][C:4]=1[C:21]([F:24])([F:23])[F:22])[NH2:2]

Participants

5

Reactant 3

HCID 443297Hydroxyamine hydrochloride2×HCID 516892Sodium Bicarbonate2×HCID 67456438Tert-butyl 1-(4-cyano-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate

Product 1

HCID 86659948tert-butyl 1-(4-(N'-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylateYield 88%

Reagents, catalysts & solvents 1

HCID 3776IsopropanolSolvent2×

Procedure

A solution of tert-butyl 1-(4-cyano-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.268 g, 0.787 mmol), hydroxylamine hydrochloride (0.109 g, 1.57 mmol), and sodium bicarbonate (0.265 g, 3.15 mmol) in isopropanol (2.2 mL) was stirred at 90° C. for 6.0 hrs. HPLC and LCMS indicated that the reaction was 69% complete. Additional hydroxylamine hydrochloride (0.109 g), sodium bicarbonate (0.265 g), and isopropanol (2.2 mL) were added, and heating was continued for 16 hrs. The isopropanol was removed under reduced pressure, and the reaction mixture was diluted with ethyl acetate and washed with water (2×), washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure afforded tert-butyl 1-(4-(N′-hydroxycarbamimidoyl)-3-(trifluoromethyl)benzyl)azetidine-3-carboxylate (0.258 g, 0.690 mmol, 88% yield) of a colorless, viscous oil. The compound had an HPLC ret. time=0.880 min.−Column: PHENOMENEX® S5 4.6×30 mm (2 min.); Solvent A=10% MeOH, 90% H2O, 0.1% TFA; Solvent B=90% MeOH, 10% H2O, 0.1% TFA. MS M+1=374.10.

Workup

  1. temperatureheating
  2. customThe isopropanol was removed under reduced pressure
  3. additionthe reaction mixture was diluted with ethyl acetate
  4. washwashed with water (2×)
  5. washwashed with brine
  6. dry with materialdried over anhydrous sodium sulfate
  7. concentrationConcentration under reduced pressure

Sources & evidence

ORD record
ord-2def0f3048b142a5ac81580f513f332a
Source dataset
uspto-grants-2013_01
Patent number
US08354398B2

Reaction notes

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