反应详情

A suspension of 5-(piperdin-1-yl)valeric acid hydrochloride (6.6 g, 30 mmol) in 100 mL of THF was cooled in an ice bath and 100 mL of 1N lithium bis(trimethylsilyl)amide in THF was added. The ice bath was removed and the resulting solution was stirred at room temperature for 1 hour. A mixture of methyl 2-methoxy-4-amino-5-chlorobenzoate (2.15 g, 10 mmol) and chlorotrimethylsilane (2.5 mL, 20 mmol) in 25 mL of THF was cooled in an ice bath and 20 mL of lN lithium bis(trimethylsilyl)amide in THF was addled. The solution containing the 5-piperdin-1-ylvaleric acid and iN lithium bis(trimethylsilyl)amide was cooled in an ice bath and the mixture containing the methyl 2-methoxy-4-amino-5-chlorobenzoate was added over 5 minutes. The reaction mixture was removed from the ice bath and stirred at 50°-55° C. for 2 hours and then a solution of 25 mL of concentrated hydrochloric acid in 175 mL of water was added. The mixture was stirred at 50°-55° C. under a gentle stream of nitrogen and then 120 mL of ethyl acetate was added. The mixture was stirred in an ice bath for 1 hour giving a precipitate. The precipitate was isolated by filtration and washed with ethyl acetate. The precipitate was stirred in approximately 40 mL of boiling isopropanol for 30 minutes and then for 1 hour in an ice bath. The precipitate was isolated by filtration and washed with isopropanol. Drying in a vacuum oven at between 55 and 60° C. under a nitrogen gas bleed for 18 hours gave 1-(4-amino-5-chloro-2-methoxyphenyl)-5-piperidin-1-ylpentan-1-one hydrochloride (2.9 g, 8 mmol).

1. temperaturewas cooled in an ice bath
2. customThe ice bath was removed
3. temperaturewas cooled in an ice bath
4. additionwas added over 5 minutes
5. customThe reaction mixture was removed from the ice bath
6. stirringstirred at 50°-55° C. for 2 hours
7. additiona solution of 25 mL of concentrated hydrochloric acid in 175 mL of water was added
8. stirringThe mixture was stirred at 50°-55° C. under a gentle stream of nitrogen
9. addition120 mL of ethyl acetate was added
10. stirringThe mixture was stirred in an ice bath for 1 hour
11. customgiving a precipitate
12. customThe precipitate was isolated by filtration
13. washwashed with ethyl acetate
14. stirringThe precipitate was stirred in approximately 40 mL of boiling isopropanol for 30 minutes
15. waitfor 1 hour in an ice bath
16. customThe precipitate was isolated by filtration
17. washwashed with isopropanol
18. customDrying in a vacuum oven at between 55 and 60° C. under a nitrogen gas bleed for 18 hours