Acetic Acid → 8-Chloro-5-methyl-1-(3,4,5,6-tetrahydro-2h-[1,2']bipyridinyl-4-yl)-5,6-dihydro-4h-2,3,5,10b-tetraaza-benzo[e]azulene trihydrochloride

Acetic acid (3 ml, 52 mmol) was added to a solution of the amine of example 4b (10 g, 26 mmol) in dichloromethane (100 ml) followed by formaldehyde (37% w/v aqueous, 3.2 ml, 39 mmol). In a separate vessel sodium triacetoxyborohydride (6.7 g, 31 mmol) was slurried in dichloromethane and cooled to <10° C. The imine solution was then added dropwise to the cold slurry over 15 minutes. The reaction mixture was stirred at room temperature for 0.5 hours, after which time the reaction mixture was partitioned between 2N aqueous sodium hydroxide solution and dichloromethane. The organic phase was then washed three times with a 50% aqueous solution of sodium metabisulfite, followed by a final water wash. The dichloromethane solution was distilled to half volume before adding EtOAc and further distilled to remove the remaining dichloromethane. EtOH was added and the reaction mixture heated for a further 0.5 hours, before cooling to 10° C. and isolating the product as a white solid. The solid was dried under vacuum at 50° C. for 16 hours to afford the title compound (7.48 g).

1. temperaturecooled to <10° C
2. customafter which time the reaction mixture was partitioned between 2N aqueous sodium hydroxide solution and dichloromethane
3. washThe organic phase was then washed three times with a 50% aqueous solution of sodium metabisulfite
4. washwash
5. distillationThe dichloromethane solution was distilled to half volume
6. additionbefore adding EtOAc
7. distillationfurther distilled
8. customto remove the remaining dichloromethane
9. additionEtOH was added
10. temperaturethe reaction mixture heated for a further 0.5 hours
11. temperaturebefore cooling to 10° C.

ORD record

ord-636bbc1be8d34fd6b118daf3a0c497c5

Source dataset

uspto-grants-2006_10

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US07119088B2