反应详情

温度

17 °C

Pyridinium p-toluenesulfonate (0.16 kg, 0.64 mol) was added to a solution of 5-chloromethyl-1H-tetrazole (2.37 kg, 20.0 mol) and 3,4-dihydro-3H-pyran (2.83 kg, 33.6 mol) in acetone (20 L) and the resultant solution was heated at 45° C. for 3 hours. Additional 3,4-dihydro-3H-pyran (1.46 kg, 17.4 mol) was added and heating was continued for 2 hours. 1-benzyl-2-(6-hydroxynaphthalen-2-yl)-3-pentyl-1H-indole (7.0 kg, 16.7 mol) was added and the solution was stirred at 17° C. Cesium carbonate (6.77 kg, 20.8 mol) was then added. The temperature of the suspension was adjusted to 60° C. and heating was continued for 3 hours, at which time HPLC analysis showed 100% conversion. Toluene (55 L) was added and acetone was removed by atmospheric distillation. The mixture was heated to 100° C. to provide 35 L of residual volume. After cooling the residue to 20° C., a solution of 1 N hydrochloric acid (28.6 L) was added, the mixture was stirred for 30 minutes, and the layers were separated. The upper organic layer was treated with a mixture of concentrated hydrochloric acid (8.3 kg, 84.2 mol) and methanol (28 L) at 20° C. for 30 minutes, the time necessary to complete hydrolysis, followed by dilution with toluene (58 L). A 1 N sodium hydroxide solution (35 L) was added, which changed the pH to 4. The layers were separated and the upper organic layer was washed with a 17% sodium chloride solution (35 L) at 40° C. The toluene layer was slowly cooled to −3° C. (crystallization begins at 21° C.) while being stirred for 1 hour. The suspension was then filtered, and the cake was washed with cold toluene (−3° C., 40 L) to yield, after drying, 6.4 kg (76.4% yield) of the title compound as an off-white solid with 99.26% ar. HPLC purity.

1. temperatureheating
2. customwas adjusted to 60° C.
3. temperatureheating
4. waitwas continued for 3 hours, at which time HPLC analysis
5. customacetone was removed by atmospheric distillation
6. temperatureThe mixture was heated to 100° C.
7. customto provide 35 L of residual volume
8. temperatureAfter cooling the residue to 20° C.
9. stirringthe mixture was stirred for 30 minutes
10. customthe layers were separated
11. customhydrolysis
12. customThe layers were separated
13. washthe upper organic layer was washed with a 17% sodium chloride solution (35 L) at 40° C
14. temperatureThe toluene layer was slowly cooled to −3° C.
15. custom(crystallization begins at 21° C.)
16. stirringwhile being stirred for 1 hour
17. filtrationThe suspension was then filtered
18. washthe cake was washed with cold toluene (−3° C., 40 L)
19. customto yield
20. customafter drying