Hydrochloric Acid → HCID 46844020, compound

To a dry 5 L three-necked round flask fitted with a mechanical stirrer and an addition funnel was loaded (2R,3R,4R,5R)-5-(2-amino-6-chloro-9H-purin-9-yl)-2-(((4-chlorobenzoyl)oxy)methyl)-4-fluoro-4-methyltetrahydrofuran-3-yl 4-chlorobenzoate (6b, 313.2 g, 526.5 mmol). The solid was suspended in anhydrous methanol (2.1 L) and cooled in an ice-water bath under an atmosphere of nitrogen. A solution of sodium 25 wt. % methoxide in methanol (361 mL, 1.58 mol) was added via an additional funnel over 20 min to give a clear solution. The reaction was allowed to warm to room temperature for 6 hours to form a turbid solution. The completion of the reaction was confirmed by LC/MS by the lack of any remaining 6-chloro deprotected nucleoside. The reaction solution was acidified with con. HCl (132 mL, 1.58 mol). After standing at room temperature (1 h), the solution was filtered to remove a white precipitate. The precipitate was washed with methanol (3×50 mL). The combined filtrate was concentrated under reduced pressure to afford a sticky solid residue. The residue was mixed with 420 mL of 2 N HCl (420 mL) and dichloromethane (1 L). The organic layer was separated and the aqueous layer was extracted with additional dichloromethane (3×500 mL). To the aqueous layer, ethyl acetate (1.4 L) was added and solid sodium carbonate (86 g) was added portion-wise to neutralize the aqueous layer to ca pH 8 (caution: foaming). After separation of the organic layer, the solid in aqueous layer was dissolved by adding more water (200 mL). The aqueous layer was extracted with ethyl acetate (3×700 mL and 400 mL). The combined organic layer was dried over sodium sulfate and concentrated under reduced pressure to a light yellow color solid that was redissolved in acetone (820 mL) at 50° C. and stirred until new solid formation initiated. The saturated solution was cooled in a freezer and product was collected by filtration. The white solid was rinsed with acetone (2×150 mL) and ethyl ether (3×80 mL) and dried (0.2 mm Hg, 50° C., 4H) to a white crystalline solid, 151.6 g (92%) of material with NMR and HPLC matching material purified by chromatography.

1. customTo a dry 5 L three-necked round flask fitted with a mechanical stirrer and an addition funnel
2. temperaturecooled in an ice-water bath under an atmosphere of nitrogen
3. customto give a clear solution
4. customto form a turbid solution
5. customAfter standing at room temperature
6. custom(1 h)
7. filtrationthe solution was filtered
8. customto remove a white precipitate
9. washThe precipitate was washed with methanol (3×50 mL)
10. concentrationThe combined filtrate was concentrated under reduced pressure
11. customto afford a sticky solid residue
12. customThe organic layer was separated
13. extractionthe aqueous layer was extracted with additional dichloromethane (3×500 mL)
14. additionTo the aqueous layer, ethyl acetate (1.4 L) was added
15. additionsolid sodium carbonate (86 g) was added portion-wise
16. customAfter separation of the organic layer
17. dissolutionthe solid in aqueous layer was dissolved
18. additionby adding more water (200 mL)
19. extractionThe aqueous layer was extracted with ethyl acetate (3×700 mL and 400 mL)
20. dry with materialThe combined organic layer was dried over sodium sulfate
21. concentrationconcentrated under reduced pressure to a light yellow color solid
22. dissolutionthat was redissolved in acetone (820 mL) at 50° C.
23. temperatureThe saturated solution was cooled in a freezer and product
24. filtrationwas collected by filtration
25. washThe white solid was rinsed with acetone (2×150 mL) and ethyl ether (3×80 mL)
26. dry with materialdried (0.2 mm Hg, 50° C., 4H) to a white crystalline solid, 151.6 g (92%) of material with NMR and HPLC
27. custompurified by chromatography

ORD record

ord-d73ef42b31e844c3b002d189b2282287

Source dataset

uspto-grants-2015_06

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US09045520B2