Hydrazine → tert-Butyl ((6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methyl)carbamate

A 2-L round bottom flask flask equipped with a magnetic stirbar was charged with di(1H-imidazol-1-yl)methanone (121 g, 749 mmol) and acetonitrile (500 mL). The stirred slurry was cooled by immersing the flask in an ice bath. A solution of N-Boc glycine (125 g, 714 mmol) in acetonitrile (500 mL) was added via a 500-mL addition funnel over the course of 30-45 min. The mixture was aged for 1 h while a 5-L, 3-neck, round bottom flask equipped with a mechanical overhead stirrer and a thermocouple w/adapter was charged with 1-(6-chloropyridazin-3-yl)hydrazine (108 g, 749 mmol) and acetonitrile (900 mL) and cooled to <5 deg C. in an ice bath. The cold solution of the acylimidazole was then transferred via a polyethylene cannula into the thick suspension of the hydrazine over a period of 30-45 min). The ice bath was removed, and the mixture was allowed to warm. After 2.5 h of stirring, 4-methylbenzenesulfonic acid hydrate (143 g, 749 mmol) was added. The flask was then equipped with a heating mantle and a reflux condenser and was heated to reflux (82 deg C.) for 13 h, then cooled back to about 60 deg C. At this point, the warm solution was vacuum filtered through paper. The brown filtrate was then concentrated by rotary evaporation. The resulting thick yellow-brown slurry was stirred in an ice bath and diluted with ACN (about 100 mL). After stirring for 1 h, the solids were isolated by vacuum filtration, washed with ice-cold 1:1 ACN/H2O (2×150 mL) and air-dried on the filter until a freely flowing solid was obtained (159 g, 78.5% yield).

1. customA 2-L round bottom flask flask equipped with a magnetic stirbar
2. temperatureThe stirred slurry was cooled
3. custom3-neck, round bottom flask equipped with a mechanical overhead stirrer and a thermocouple w/adapter
4. temperaturecooled to <5 deg C
5. customThe ice bath was removed
6. temperatureto warm
7. customThe flask was then equipped with a heating mantle and a reflux condenser
8. temperaturewas heated
9. temperatureto reflux (82 deg C.) for 13 h
10. temperaturecooled back to about 60 deg C
11. filtrationfiltered through paper
12. concentrationThe brown filtrate was then concentrated by rotary evaporation
13. stirringThe resulting thick yellow-brown slurry was stirred in an ice bath
14. additiondiluted with ACN (about 100 mL)
15. stirringAfter stirring for 1 h
16. customthe solids were isolated by vacuum filtration
17. washwashed with ice-cold 1:1 ACN/H2O (2×150 mL)
18. customair-dried on the
19. filtrationfilter until
20. customwas obtained (159 g, 78.5% yield)

ORDレコード

ord-ecfd4c82fabc48ae80830d3f7f2887ce

出典データセット

uspto-grants-2013_09

DOI

10.6084/m9.figshare.5104873.v1

特許番号

US08524900B2