Hexane → 5-(2,4-Dimethoxy-benzyl)-8-isopropyl-6-oxo-5,6-dihydro-4H-2,5,10b-triaza-benzo[e]azulene-3-carboxylic Acid Ethyl Ester

Temperature

-70 °C

Hexamethyldisilazane (2.8 mL, 13.4 mmol) was dissolved in TBF (25 mL), cooled under Argon to −70° C., and treated slowly with a 1.6 M solution of n-BuLi in hexane (8.4 mL, 13.4 mmol). After stirring for 1 h at −70° C., a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (1.28 g, 8.1 mmol) in THF (5 mL) was added, and stirring continued for 1 h at −70° C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-isopropyl-3,4-dihydro-benzo[e][1,4]diazepin-5-one (1.59 g, 4.1 mmol) (prepared as described above) was added at −70° C., and subsequently allowed to warm up to at 10° C. over 1 h, then cooled again to −30° C. After 30 min, acetic acid (3.0 mL) was added at −30° C. and the suspension was allowed to warm up to room temperature and water (3.0 mL) added and the resulting mixture heated under reflux for 14 h. After cooling, the mixture was evaporated and then dissolved in DCM (30 mL). This solution was then washed with HCl (1 M, 2×15 mL) and sodium hydrogen carbonate (sat., 10 ml), dried (Na2SO4) and evaporated. Chromatography on silica gel eluting with EtOAc:Hexane (19:1). Yield: 1.9 g (99%). m/z 464 (MH+).

1. stirringstirring
2. waitcontinued for 1 h at −70° C
3. temperatureto warm up to at 10° C. over 1 h
4. temperaturecooled again to −30° C
5. waitAfter 30 min
6. temperatureto warm up to room temperature
7. temperaturethe resulting mixture heated
8. temperatureunder reflux for 14 h
9. temperatureAfter cooling
10. customthe mixture was evaporated
11. dissolutiondissolved in DCM (30 mL)
12. washThis solution was then washed with HCl (1 M, 2×15 mL) and sodium hydrogen carbonate (sat., 10 ml)
13. dry with materialdried (Na2SO4)
14. customevaporated

ORD record

ord-4da70ca667014d6bacab8ebc6b834048

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06743789B2