1-isopropyl-3-methyl-1H-1,2,4-triazole → 10-Bromo-9-fluoro-2-(1-isopropyl-3-methyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine

Temperature

-30 °C

A solution of 1-isopropyl-3-methyl-1H-[1,2,4]triazole (in a 6:4 mixture with 1-isopropyl-5-methyl-1H-[1,2,4]triazole, 0.75 g, 3.6 mmol) in THF (10 mL) was cooled to −35° C. and treated with n-butyllithium (2.5M in hexanes, 1.45 mL, 3.63 mmol). Stirring was continued for 1 h maintaining the internal temperature of between −30° C. and −20° C. The mixture was then cooled to −30° C. and a solution of zinc chloride (0.5M in THF, 4.22 mL, 2.11 mmol) was added over 5 min. The reaction mixture was stirred at −25° C. for 30 min, then slowly warmed to RT and stirred at this temperature for 1 h. A suspension of 9-bromo-8-fluoro-2-iodo-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene (1.046 g, 2.557 mmol) in THF (20 mL) was added followed by Pd(PPh3)4 (148 mg, 0.128 mmol) and the reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h. After cooling to RT, volatiles were removed in vacuo and the residue was partitioned between EtOAc (300 mL) and water. The aqueous phase was extracted with EtOAc (300 mL) and the combined organic layers were washed with water followed by brine, then dried (Na2SO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 0-8% MeOH in methyl acetate) affording 9-Bromo-8-fluoro-2-(2-isopropyl-5-methyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulene as a pale yellow solid (0.66 g, 64%). LCMS: RT 4.90 min [M+H]+ 405.9/407.9

1. temperaturemaintaining the internal temperature of between −30° C. and −20° C
2. stirringThe reaction mixture was stirred at −25° C. for 30 min
3. temperatureslowly warmed to RT
4. stirringstirred at this temperature for 1 h
5. additionwas added
6. stirringthe reaction mixture was stirred at 60° C. under a nitrogen atmosphere for 18 h
7. temperatureAfter cooling to RT
8. customvolatiles were removed in vacuo
9. customthe residue was partitioned between EtOAc (300 mL) and water
10. extractionThe aqueous phase was extracted with EtOAc (300 mL)
11. washthe combined organic layers were washed with water
12. dry with materialdried (Na2SO4)
13. concentrationconcentrated in vacuo
14. customThe resulting residue was purified by column chromatography (Si-PCC, eluent 100% EtOAc followed by gradient 0-8% MeOH in methyl acetate)

ORD record

ord-d635170fd89a4e2cadf1dcadaf8f9f08

Source dataset

uspto-grants-2015_07

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09090628B2