Dimethylformamide → 2-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamide

HRID 1486444Notes

Reaction equation

HRID 1486444 reaction equation
Cl.CN[O:4][CH3:5].O.O[N:8]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2N=N1.[CH2:17](N(CC)CC)C.[C:24]([OH:30])([C:26](F)(F)F)=O.[CH3:31][N:32]([CH:34]=[O:35])C>O.CO>[NH2:8][C:12]1[C:11]([O:30][CH:24]2[CH2:17][CH2:26]2)=[CH:16][CH:15]=[CH:14][C:13]=1[C:34]([N:32]([O:4][CH3:5])[CH3:31])=[O:35]

Participants

7

Reactant 5

HCID 6228DimethylformamideHCID 6422Trifluoroacetic acidHCID 8471TriethylamineHCID 81138Methanamine, N-methoxy-, hydrochloride (1:1)HCID 27960291-Hydroxybenzotriazole hydrate

Product 1

HCID 900798402-amino-3-cyclopropoxy-N-methoxy-N-methylbenzamideYield 64.3%

Reagents, catalysts & solvents 1

HCID 22242641Methanol--water (1/1)Solvent

Conditions

Temperature
60 °C

Procedure

In a flask, at room temperature, was added Intermediate A-1D (6.61 g, 34.2 mmol), N,O-dimethylhydroxylamine hydrochloride (10.01 g, 103 mmol), N-Ethyl-N″-(3-Dimethylaminopropyl)carbodiimide hydrochloride (7.87 g, 41.1 mmol) and 1-hydroxybenzotriazole hydrate (6.29 g, 41.1 mmol) in 50 mL of DMF. To the solution was added triethylamine (19.07 mL, 137 mmol). The reaction solution was stirred at 60° C. overnight and then cooled to room temperature. The reaction mixture was partitioned between water and ethyl acetate and transferred to a separatory funnel and the organic layer was washed with 10% LiCl, water, and brine. The organic phase was dried over anhydrous sodium sulfate, filtered and concentrated to provide a dark oil. The crude product mixture was purified via silica gel chromatography (0%-50% of EtOAc/DCM over 15 minutes, 120 g column) to give Intermediate A-1E (5.2 g, 22.01 mmol, 64.3% yield). HPLC: RT=1.975 min (H2O/MeOH with TFA, SunFire C18 3.5 μm, 2.1×30 mm, gradient=4 min, wavelength=220 nm); MS(ES):m/z=237.12 [M+H]+; 1H NMR (400 MHz, chloroform-d) δ 7.17 (dd, J=8.0, 1.2 Hz, 1H), 7.02 (dd, J=7.9, 1.3 Hz, 1H), 6.67 (t, J=7.9 Hz, 1H), 4.78 (br. s., 2H), 3.88-3.73 (m, 1H), 3.69-3.56 (m, 3H), 3.36 (s, 3H), 0.92-0.72 (m, 4H).

Workup

  1. temperaturecooled to room temperature
  2. customThe reaction mixture was partitioned between water and ethyl acetate
  3. customtransferred to a separatory funnel
  4. washthe organic layer was washed with 10% LiCl, water, and brine
  5. dry with materialThe organic phase was dried over anhydrous sodium sulfate
  6. filtrationfiltered
  7. concentrationconcentrated
  8. customto provide a dark oil
  9. customThe crude product mixture was purified via silica gel chromatography (0%-50% of EtOAc/DCM over 15 minutes, 120 g column)
  10. customto give Intermediate A-1E (5.2 g, 22.01 mmol, 64.3% yield)

Sources & evidence

ORD record
ord-c70802fb4f944236a70c688cdf7bda1c
Source dataset
uspto-grants-2016_08
Patent number
US09427442B2

Reaction notes

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