反应详情

温度

55 °C

The organic layer from the naphthyridine formation containing N-(tert-butoxycarbonyl)-3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine (34.2 kg total weight containing 989 g of BOC naphthyridine) was concentrated to an oil. The residue was diluted with methanol (6 L) and the solution was concentrated to an oil. Methanol (6 L) was added to the residue and this solution was concentrated to 2.3 L. The solution was diluted with methanol to a volume of 7.3 L and 4.58 M HCl in IPA (3.6 L) was added. The solution was heated to 55° C. and aged for 1 h. After cooling to room temperature water (5 L) was added. A solution of K2CO3 (2.28 kg) in water (5 L) was then carefully added (pH=10). The mixture was extracted with IPAc (3×10 L). The organic extractions contained 601 g (91%) of deprotected naphthyridine. The combined organic layers were concentrated and the residue was diluted with IPA (6 L) and reconcentrated. The resulting oil was diluted with EPA (6 L) and the solution was concentrated to a total volume of ˜2 L. The solution was filtered through a sintered glass funnel, which was washed with EPA (3×1 L). The combined filtrate and rinses were concentrated to ˜0.5 L and then diluted with IPA (1.95 L). The solution was heated to 60° C. and HCl in IPA (790 mL, 4.33 M by titration) was added over 40 min. During the addition the formation of solids became evident. Heptane (2.75 L) was added over 30 min after which heating was discontinued and the slurry was allowed to cool to room temperature overnight. Additional HCl/IPA (80 mL) and heptane (2×1.38 L) were added. The solids were filtered, washed with 2:1 heptane/IPA (3×550 mL), and dried under vacuum with a nitrogen stream to afford 678.8 g of 3-(trifluoromethyl)-5,6,7,8-tetrahydro-1,6-naphthyridine in 75% yield from BOC naphthyridine (497 g, 73.2 weight percent as free base).

1. concentrationwas concentrated to an oil
2. additionThe residue was diluted with methanol (6 L)
3. concentrationthe solution was concentrated to an oil
4. additionMethanol (6 L) was added to the residue
5. concentrationthis solution was concentrated to 2.3 L
6. additionThe solution was diluted with methanol to a volume of 7.3 L and 4.58 M HCl in IPA (3.6 L)
7. additionwas added
8. temperatureAfter cooling to room temperature water (5 L)
9. additionwas added
10. additionA solution of K2CO3 (2.28 kg) in water (5 L) was then carefully added (pH=10)
11. extractionThe mixture was extracted with IPAc (3×10 L)
12. extractionThe organic extractions
13. concentrationThe combined organic layers were concentrated
14. additionthe residue was diluted with IPA (6 L)
15. additionThe resulting oil was diluted with EPA (6 L)
16. concentrationthe solution was concentrated to a total volume of ˜2 L
17. filtrationThe solution was filtered through a sintered glass funnel
18. washwhich was washed with EPA (3×1 L)
19. concentrationThe combined filtrate and rinses were concentrated to ˜0.5 L
20. additiondiluted with IPA (1.95 L)
21. temperatureThe solution was heated to 60° C.
22. additionHCl in IPA (790 mL, 4.33 M by titration) was added over 40 min
23. additionDuring the addition the formation of solids
24. additionHeptane (2.75 L) was added over 30 min after which
25. temperatureheating
26. temperatureto cool to room temperature overnight
27. additionAdditional HCl/IPA (80 mL) and heptane (2×1.38 L) were added
28. filtrationThe solids were filtered
29. washwashed with 2:1 heptane/IPA (3×550 mL)
30. customdried under vacuum with a nitrogen stream