反应详情

温度

62.5 °C

A 3-necked flask was charged with 6-chloronicotinic acid (53.0 g, 336 mmol), 4-(dimethylamino)-pyridine (3.03 g, 24.6 mmol), and tetrahydrofuran (350 mL). The contents of the flask was heated to 62.5° C. and a solution of di-tert-butyl dicarbonate (200.2 g, 917 mmol) in tetrahydrofuran (240 mL) was slowly added over a period of 4.6 h. The contents of the flask were maintained at 62.5° C. for approximately 1 h and then cooled to 21° C. A portion of the solution (219 mL), which contained tert-butyl 6-chloronicotinate (16.4 g, 76.8 mmol), was mixed with 1 N NaOH (150 mL) and methyl tert-butyl ether (150 mL) at 21° C. To this mixture was charged 4-[(5S,9R)-3-(3,5-Dichlorophenyl)-1-methyl-2,4-dioxo-1,3,7-triazaspiro[4.4]non-9-yl]-benzonitrile semi (+)-DTTA salt (37.4 mmol, 61.5 mmol). After mixing for 10 minutes, a phase split was performed, the aqueous layer was discarded and the organic layer was distilled under atmospheric pressure. After 220 mL of distillate was collected, 220 mL of methyl tert-butyl ether was charged back and the distillation was resumed. After an additional 250 mL of distillate was collected, 100 mL of n-methyl-2-pyrrolidinone was charged and the distillation was continued until the pot temperature rose to 90° C. Diisopropylethyl amine (27 mL, 155 mmol) was then charged and the mixture was heated at 110° C. for approximately 17 h. A portion of the crude reaction mixture (48 mL) was transferred into a separate funnel and was extracted twice with 3.4:1 heptane:cyclohexane (31 mL). The top layers were discarded and the bottom layer was extracted three times with a mixture of methyl tert-butyl ether (36 mL) and H2O (24 mL). The bottom aqueous layers were discarded. To the top layer was added methyl tert-butyl ether (40 mL) and was filtered back to a distillation flask. After most of methyl tert-butyl ether was distilled off, the mixture was diluted to a total volume of 169 mL with 1:1 methyl tert-butyl ether:isopropyl alcohol. p-Toluenesulfonic acid (0.358 g) was then added to this solution and was dissolved upon gently heating. The solution was then cooled and stirred until crystals appeared. A second charge of p-toluenesulfonic acid (0.424 g) was added and the slurry was further stirred at 21° C. for 30 minutes before it was filtered and washed twice with 25 mL of 1:1 methyl tert-butyl ether:isopropyl alcohol. The product (3.34 g, 86% yield) was isolated as white crystals and was dried in a vacuum oven at 40° C.

1. temperatureThe contents of the flask were maintained at 62.5° C. for approximately 1 h
2. temperaturecooled to 21° C
3. additionAfter mixing for 10 minutes
4. customa phase split
5. distillationthe organic layer was distilled under atmospheric pressure
6. distillationAfter 220 mL of distillate was collected
7. addition220 mL of methyl tert-butyl ether was charged back
8. distillationthe distillation
9. distillationAfter an additional 250 mL of distillate was collected
10. addition100 mL of n-methyl-2-pyrrolidinone was charged
11. distillationthe distillation
12. customrose to 90° C
13. temperaturethe mixture was heated at 110° C. for approximately 17 h
14. customwas transferred into a separate funnel
15. extractionwas extracted twice with 3.4:1 heptane
16. extractionthe bottom layer was extracted three times
17. additionwith a mixture of methyl tert-butyl ether (36 mL) and H2O (24 mL)
18. additionTo the top layer was added methyl tert-butyl ether (40 mL)
19. filtrationwas filtered back to a distillation flask
20. distillationAfter most of methyl tert-butyl ether was distilled off
21. additionthe mixture was diluted to a total volume of 169 mL with 1:1 methyl tert-butyl ether
22. additionp-Toluenesulfonic acid (0.358 g) was then added to this solution
23. dissolutionwas dissolved
24. temperatureupon gently heating
25. temperatureThe solution was then cooled
26. additionA second charge of p-toluenesulfonic acid (0.424 g)
27. additionwas added
28. stirringthe slurry was further stirred at 21° C. for 30 minutes before it
29. filtrationwas filtered
30. washwashed twice with 25 mL of 1:1 methyl tert-butyl ether