反应详情

To a mixture of 2-[(R)-5-(6-methyl-pyrimidin-4-yl)-indan-1-yl]-2,7-diaza-spiro[3.5]nonane dihydrochloride (3-1g, 800 g, 1.87 mol), (2-(2-methylimidazo[2,1-b][1,3,4]thiadiazol-6-yl)acetic acid (SM-1ae, 406.4 g, 2.06 mol), and triethylamine (1.31 L, 9.37 mol) in dichloromethane (8 L) was added T3P (2150 g, 3.37 mol) dropwise over 45 min and stirred for 1 h maintaining a temperature between 20 and 30° C. Water was added dropwise (4 L) and the reaction was stirred at 30° C. for 15 min. The layers were separated and the aqueous layer was concentrated to remove residual solvent under partial vacuum at 20° C. The aqueous layer was treated with activated charcoal (20 wt %), stirred for 30 min and filtered through Celite® washing with water. The filtrate was adjusted to pH 7.5-8.0 with 1N NaOH. The resulting slurry was extracted with dichloromethane (12 L) and stirred for 10 min at room temperature. The layers were separated and the organic layer was concentrated under reduced pressure to approximately 4 L. Isopropyl acetate (12 L) was added and the solution was concentrated under reduced pressure at 78° C. to 8 L. The solution was cooled slowly over 4 hours to 20° C. The resulting slurry was stirred for 1 h, filtered and washed with isopropyl acetate (2.4 L). The resulting solid was further dried under vacuum at 45° C. for 8 hours to give the title compound 3Z as a white crystalline solid (883 g, 92%). MS (ES+) 514.0 (M+H)+. 1H NMR (CDCl3) δ 1.69-1.72 (m, 4H), 1.88-1.96 (m, 1H), 2.11-2.22 (m, 1H), 2.57 (s, 3H), 2.66 (s, 3H), 2.82-2.88 (m, 1H), 3.03-3.20 (m, 5H), 3.49-3.55 (m, 4H), 3.77 (s, 2H), 3.93-3.97 (m, 1H), 7.36 (d, 1H), 7.53 (s, 1H), 7.61 (s, 1H), 7.84 (d, 1H), 7.93 (s, 1H), 9.10 (s, 1H).

1. temperaturemaintaining a temperature between 20 and 30° C
2. stirringthe reaction was stirred at 30° C. for 15 min
3. customThe layers were separated
4. concentrationthe aqueous layer was concentrated
5. customto remove residual solvent under partial vacuum at 20° C
6. additionThe aqueous layer was treated with activated charcoal (20 wt %)
7. stirringstirred for 30 min
8. filtrationfiltered through Celite®
9. washwashing with water
10. extractionThe resulting slurry was extracted with dichloromethane (12 L)
11. stirringstirred for 10 min at room temperature
12. customThe layers were separated
13. concentrationthe organic layer was concentrated under reduced pressure to approximately 4 L
14. additionIsopropyl acetate (12 L) was added
15. concentrationthe solution was concentrated under reduced pressure at 78° C. to 8 L
16. temperatureThe solution was cooled slowly over 4 hours to 20° C
17. stirringThe resulting slurry was stirred for 1 h
18. filtrationfiltered
19. washwashed with isopropyl acetate (2.4 L)
20. customThe resulting solid was further dried under vacuum at 45° C. for 8 hours