Реакция #795015

Уравнение реакции

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

Выход 57.0%

Растворители

THF

Условия реакции

Обработка

1. 1
   workup.ADDITIONwas added
2. 2
   Экстракцияthe mixture extracted with 1:1 EtOAc/THF solution (×2)
3. 3
   Промывкаwashed with brine
4. 4
   Сушкаdried (Na2SO4)
5. 5
   Концентрированиеconcentrated in vacuo
6. 6
   workup.ADDITIONThe resulting solid was added to DMF (50 mL)
7. 7
   Температураto cool to RT
8. 8
   Экстракцияextracted with EtOAc
9. 9
   Промывкаwashed with water
10. 10
    СушкаThe organic layer was dried (Na2SO4)
11. 11
    Концентрированиеconcentrated in vacuo
12. 12
    ДругоеThe resultant residue was purified by flash chromatography (SiO2, gradient 0-50% EtOAc in cyclohexane)

Методика

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

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