反应详情

温度

10 °C

Method A Toluene (85L) was azeotropically dried in an argon purged reactor, cooled to 10° C. and a solution of trimethylaluminum in toluene (18.57 kg, 16.7% w/w, 43 mole) added. To this at 20 to 24° C. was added a solution of 1-n-butyl-4-piperidinylmethylamine (7.39 kg, 99.4% pure, 42.7 mole) in toluene (22 L) over 43 minutes. Methyl 3,4-dihydro-2H-[1,3]-oxazino[3,2-a]indole-10-carboxylate (9.65 kg, 98.9% pure, 41.3 mole) was added in one portion and the reaction heated to reflux at 112° C. for 4 hours 10 minutes after which time the reaction was judged to be complete by HPLC analysis. 10% Sodium hydroxide solution (52.2 L), prepared from 32% ww sodium hydroxide (24 L) and water (80 L), was added cautiously over 16 minutes at about 60 to 70° C. The resulting mixture was heated to 70 to 80° C. and the aqueous layer separated. The toluene layer was washed with 10% sodium hydroxide (52.2 L) followed twice by water (29 L each wash). The toluene layer was cooled and diluted with hexane fraction (133 L) to crystallise the product. After cooling to about 2° C. overnight the product was collected by filtration, washed on the filter with hexane (21 L) and dried in vacuo at 40° C. overnight to give SB-207266 batch 207266-HP8 (12.26 kg, 94.5% pure, 75.9%).

1. dry with materialMethod A Toluene (85L) was azeotropically dried in an argon purged reactor
2. temperaturethe reaction heated
3. temperatureto reflux at 112° C. for 4 hours 10 minutes after which time the reaction
4. additionwas added cautiously over 16 minutes at about 60 to 70° C
5. temperatureThe resulting mixture was heated to 70 to 80° C.
6. customthe aqueous layer separated
7. washThe toluene layer was washed with 10% sodium hydroxide (52.2 L)
8. temperatureThe toluene layer was cooled
9. additiondiluted with hexane fraction (133 L)
10. customto crystallise the product
11. temperatureAfter cooling to about 2° C. overnight the product
12. filtrationwas collected by filtration
13. washwashed on the
14. filtrationfilter with hexane (21 L)
15. customdried in vacuo at 40° C. overnight