Reacción #163423

Ecuación de reacción

N-[3-(acetylmethylamino)-2-hydroxypropyl]-N-methylacetamide

triethylamine

1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid

oxalyl dichloride

→

acetic acid 1-[(acetylmethylamino)methyl]-2-{[1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarbonyl]methylamino}ethyl ester

Rendimiento 21.0%

Disolventes

DCM

DCM

DCM

DCM

Condiciones de reacción

Tratamiento posterior

1. 1
   OtroSolvent was evaporated
2. 2
   Otrodried under vacuum
3. 3
   Otroobtaining crude acyl chloride
4. 4
   workup.STIRRINGThe reaction was stirred at r.t. overnight
5. 5
   Temperaturaheated at 40° C. for 2 hours
6. 6
   Lavadowashed with H2O (2×)
7. 7
   SecadoThe organic layer was dried with Na2SO4
8. 8
   Filtraciónfiltered
9. 9
   Concentraciónconcentrated to dryness
10. 10
    OtroThe crude thus obtained
11. 11
    Otrowas purified by silica gel flash chromatography (DCM:methanol 99:1 v/v)

Procedimiento

To a suspension of 1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropane carboxylic acid (1630 mg, 5.012 mmol) in DCM (55 mL) containing a few drops of DMF, under nitrogen atmosphere, at 0° C., oxalyl dichloride (0.849 mL, 10.02 mmol) was added dropwise, and the reaction was stirred at room temperature for 20 minutes. Solvent was evaporated, and the residue taken up with toluene and dried under vacuum, obtaining crude acyl chloride. Acyl chloride was dissolved in DCM (10 mL) and added dropwise, at 0° C., under nitrogen atmosphere, to a solution of N-[3-(acetylmethylamino)-2-hydroxypropyl]-N-methylacetamide (I5) (676 mg, 3.342 mmol) and triethylamine (2.8 mL, 20.08 mmol) in DCM (50 mL). The reaction was stirred at r.t. overnight and then heated at 40° C. for 2 hours. The reaction mixture was diluted with DCM and washed with H2O (2×) and a saturated solution of NaHCO3 (2×). The organic layer was dried with Na2SO4, filtered and concentrated to dryness. The crude thus obtained was purified by silica gel flash chromatography (DCM:methanol 99:1 v/v) affording acetic acid 1-[(acetylmethylamino)methyl]-2-{[1-(3′,4′-dichloro-2-fluorobiphenyl-4-yl)cyclopropanecarbonyl]methylamino}ethyl ester (350 mg, 21% yield) as pale yellow foam.

Fuente