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

Temperature

-70 °C

Hexamethyldisilazane (48.5 mL, 66 mmol) was dissolved in TBF (150 mL), cooled under argon to −70° C., and treated slowly with a 1.6 M solution of n-butyllithium in hexane (145 ml, 233 mmol). After stirring for 1 h at −70° C., a solution of (E)-(dimethylamino-methyleneamino)-acetic acid ethyl ester (21 g, 133 mmol) in THF (50 mL) was added, and stirring continued for 1 h at −70° C. Then a solution of 2-chloro-4-(2,4-dimethoxy-benzyl)-7-methoxy-3,4-dihydro-benzo[e][1,4]diazepin-5-one (24.9 g, 66 mmol) in TBF (150 mL) was added at −70° C., and subsequently allowed to warm to 10° C. over ca. 1 h, then cooled again to −30° C. Neat acetic acid (38 mL, 664 mmol) was added slowly at −30° C. with cooling, the muddy suspension was allowed to warm to 0° C., water (40 mL) added, and the resulting solution was refluxed for 1 h, leading to the formation of a thick precipitate. The hot suspension was diluted with water (450 mL), cooled to 30° C., filtered, and the white crystals washed with THF/water 1:1 (400 mL), and dried at 25 mbar/60° C. Yield: 16.7 g (56%). mp 204° C. m/z 451 (M).

1. stirringstirring
2. waitcontinued for 1 h at −70° C
3. temperatureto warm to 10° C. over ca. 1 h
4. temperaturecooled again to −30° C
5. temperaturewith cooling
6. temperatureto warm to 0° C.
7. temperaturethe resulting solution was refluxed for 1 h
8. temperaturecooled to 30° C.
9. filtrationfiltered
10. washthe white crystals washed with THF/water 1:1 (400 mL)
11. customdried at 25 mbar/60° C

ORD record

ord-2cf37f75ad9e449d9d2d7aeb5b497dc9

Source dataset

uspto-grants-2004_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06743789B2