Heptane → HCID 44124594, compound

A stirred solution of (R)-6-methoxy-2-(3-(piperidin-1-yl)pyrrolidin-1-yl)benzo[d]thiazole (Example 46, 920 mg, 2.90 mmol) in dichloromethane (70 mL) was chilled to −78° C. with a dry ice/acetone bath under a dry nitrogen atmosphere. Boron tribromide, 1.0 M solution in heptane (11.600 mL, 11.60 mmol) was then added via syringe. The reaction mixture was stirred overnight while slowly warming to ambient temperature. A large quantity of precipitate had formed. The reaction mix was cooled to 0° C., then ice water containing 5 equivalents of sodium carbonate was added. The mixture was vigorously stirred for 30 minutes. The mixture was filtered free of an insoluble solid. The filtrate was extracted with CHCl3. The solid was dissolved in 3 N aqueous sodium hydroxide. This basic aqueous solution was brought to ˜pH 7 with aqueous citric acid, then extracted with CHCl3. The two organic extracts were compared by TLC (1:1 dichloromethane/90% acetonitrile and 10% methanol). The second extract contained product, meaning the insoluble material that was collected by filtration was actually the product. That aqueous layer was adjusted to ˜pH 7 again, saturated with sodium chloride and extracted again with CHCl3. The combined organic extracts were dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure to give a solid. The solid was purified by column chromatography on an Analogix IF-280 (Analogix SF15-12 g, 100% dichloromethane to 50:50 dichloromethane/90% acetonitrile and 10% methanol). Fractions containing product were combined and concentrated under reduced pressure to give a solid that was dissolved in hot 1:1 CHCl3/tetrahydrofuran. This solution was dried (MgSO4) and filtered. The filtrate was concentrated under reduced pressure. The resulting solid was dissolved in hot methanol and the resulting solution was filtered and then concentrated under reduced pressure. The concentrated methanol solution was scratched with a spatula inducing crystallization. The first crystal batch was dried overnight in a vacuum oven at 60° C. to provide the title compound as crystals. Additional title compound was obtained from the crystallization filtrate and other column fractions. 1H NMR (300 MHz, CD3OD) δ ppm 7.30 (d, J=8.7 Hz, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.78 (dd, J=2.5, 8.7 Hz, 1H), 3.85-3.74 (m, 1H), 3.74-3.63 (m, 1H), 3.56-3.43 (m, 1H), 3.41-3.33 (m, 1H), 3.16-3.01 (m, 1H), 2.67-2.45 (m, 4H), 2.40-2.28 (m, 1H), 2.07-1.91 (m, 1H), 1.72-1.60 (m, 4H), 1.57-1.45 (m, 2H); MS (DCI/NH3) m/z 304 (M+H)+.

1. customA large quantity of precipitate had formed
2. additionThe reaction mix
3. temperaturewas cooled to 0° C.
4. stirringThe mixture was vigorously stirred for 30 minutes
5. filtrationThe mixture was filtered free of an insoluble solid
6. extractionThe filtrate was extracted with CHCl3
7. dissolutionThe solid was dissolved in 3 N aqueous sodium hydroxide
8. extractionextracted with CHCl3
9. extractionThe second extract
10. filtrationwas collected by filtration
11. extractionsaturated with sodium chloride and extracted again with CHCl3
12. dry with materialThe combined organic extracts were dried (MgSO4)
13. filtrationfiltered
14. concentrationThe filtrate was concentrated under reduced pressure
15. customto give a solid
16. customThe solid was purified by column chromatography on an Analogix IF-280 (Analogix SF15-12 g, 100% dichloromethane to 50:50 dichloromethane/90% acetonitrile and 10% methanol)
17. additionFractions containing product
18. concentrationconcentrated under reduced pressure
19. customto give a solid
20. dry with materialThis solution was dried (MgSO4)
21. filtrationfiltered
22. concentrationThe filtrate was concentrated under reduced pressure
23. dissolutionThe resulting solid was dissolved in hot methanol
24. filtrationthe resulting solution was filtered
25. concentrationconcentrated under reduced pressure
26. customThe concentrated methanol solution was scratched with a spatula inducing crystallization
27. customThe first crystal batch was dried overnight in a vacuum oven at 60° C.

ORD record

ord-7f2c54bb2dd5447396be69c51cff5415

Source dataset

uspto-grants-2013_11

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US08580968B2