Reacción #795015

Ecuación de reacción

diisopropylethylamine

isopropylhydrazine hydrochloride

NaOH

sodium bicarbonate

NaOCl

8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid

diisopropylethylamine

HATU

1-benzyloxycarbonyl-2-methyl-isothiourea

→

[5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid benzyl ester

Rendimiento 57.0%

Disolventes

THF

Condiciones de reacción

Tratamiento posterior

1. 1
   workup.ADDITIONwas added
2. 2
   Extracciónthe mixture extracted with 1:1 EtOAc/THF solution (×2)
3. 3
   Lavadowashed with brine
4. 4
   Secadodried (Na2SO4)
5. 5
   Concentraciónconcentrated in vacuo
6. 6
   workup.ADDITIONThe resulting solid was added to DMF (50 mL)
7. 7
   Temperaturato cool to RT
8. 8
   Extracciónextracted with EtOAc
9. 9
   Lavadowashed with water
10. 10
    SecadoThe organic layer was dried (Na2SO4)
11. 11
    Concentraciónconcentrated in vacuo
12. 12
    OtroThe resultant residue was purified by flash chromatography (SiO2, gradient 0-50% EtOAc in cyclohexane)

Procedimiento

To a suspension of 8-bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulene-2-carboxylic acid (1.86 g, 5.70 mmol) in anhydrous THF (75 mL) was added diisopropylethylamine (2 mL, 11.4 mmol), HATU (2.39 g, 6.27 mmol) and 1-benzyloxycarbonyl-2-methyl-isothiourea (1.47 g, 6.56 mmol) at RT. After stirring for 24 hours an aqueous saturated sodium bicarbonate solution was added and the mixture extracted with 1:1 EtOAc/THF solution (×2). The organic layers were combined, washed with brine, dried (Na2SO4) and concentrated in vacuo. The resulting solid was added to DMF (50 mL) and treated with diisopropylethylamine (4 mL, 22.8 mmol) and isopropylhydrazine hydrochloride (941 mg, 8.55 mmol). The mixture was heated to 95° C. and scrubbed with 1N NaOH solution and NaOCl solution. After 2 hours the mixture was allowed to cool to RT, extracted with EtOAc and washed with water. The organic layer was dried (Na2SO4) and concentrated in vacuo. The resultant residue was purified by flash chromatography (SiO2, gradient 0-50% EtOAc in cyclohexane) to afford [5-(8-Bromo-4,5-dihydro-6-oxa-3-thia-1-aza-benzo[e]azulen-2-yl)-1-isopropyl-1H-[1,2,4]triazol-3-yl]-carbamic acid benzyl ester (1.75 g, 57%). LCMS: RT=5.11 min, [M+H]+=540/542

Fuente