Ammonia → HCID 15894274, compound

2.01 g of 1-O-acetyl-5-O-t-butyldiphenylsilyl-3-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinose was dissolved in 27 ml of acetonitrile in the presence of molecular sieves 4A (3.30 g). To this solution were added 1.07 g of 2,6-diaminopurine and 2.70 ml of trimethylsilyl-trifluoromethanesulfonate (TMSOTf), and the mixture was stirred at 0° C. for 30 minutes, and at room temperature for 2 hours. To this mixture was added a saturated aqueous solution of sodium hydrogencarbonate. After removing insolubles by filtration, the mixture was extracted twice with chloroform. The organic layer was dried. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography. The fractions eluted with 2% methanol/chloroform were collected, and concentrated to obtain 687 mg of 9-(3-O-benzyl-5-O-t-butyldiphenylsilyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)-2,6-diaminopurine. This product was dissolved in 24 ml of DMF. To this solution was added 756 mg of ammonium fluoride, and the mixture was stirred at room temperature overnight. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The crystals obtained were suspended in 21 ml of acetonitrile. To this suspension were added 0.19 ml of acetic anhydride and 0.30 ml of triethylamine, and the mixture was stirred at room temperature overnight. 5.0 ml of methanol was added to the reaction solution, and the mixture was stirred for 30 minutes. Thereafter, the solvent was distilled off, and the residue was purified by silica gel column chromatography to obtain 393 mg of 9-(5-O-acetyl-3-O-benzyl-2-deoxy-2-fluoro 4-thio-D-arabinofuranosyl)-2,6-diaminopurine. 9-(5-O-Acetyl-3-O-benzyl-2-deoxy-2-fluoro-4-thio-D-arabinofuranosyl)-2,6-diaminopurine was dissolved in 4.30 ml of a 60% hydrogen fluoride/pyridine solution. To this solution, 0.13 ml of t-butylnitrite was added dropwise at 0° C. After the mixture was stirred for 30 minutes, ice water was added to the reaction solution. This mixture was extracted twice with chloroform. The organic layer was dried, and the solvent was distilled off. The residue was purified by silica gel column chromatography. The fractions eluted with 2% methanol/chloroform were collected, and concentrated to obtain 276 mg (yield 14%) of the desired protected product. 206 mg of this protected product was suspended in 7.0 ml of methanol. To this suspension was added 5.0 ml of concentrated aqueous ammonia, and the mixture was stirred at room temperature for 4 hours. The solvent was distilled off under reduced pressure, and the residue was separated into the alpha-anomer and the beta-anomer by ODS reverse phase column chromatography. Thus, 84 mg of the beta-anomer was obtained. This anomer was suspended in 4.0 ml of methylene chloride, and 0.90 ml of chlorotrimethylsilane was added to the suspension. The mixture was stirred at room temperature for 10 minutes. To this was added dropwise 1.03 ml of 1 M trichloroboran at -78° C. under a stream of argon. The temperature of the mixture was then raised to room temperature, and the mixture was stirred for 1 hour. 2.0 ml of methanol was added to the mixture at -78° C., and the resulting mixture was stirred for a further 30 minutes. The mixture was allowed to warm up to room temperature, and concentrated aqueous ammonia was added to the mixture. The solvent was distilled off, and the residue was purified by silica gel column chromatography. The fractions eluted with 20% methanol/chloroform were collected, and concentrated to obtain 36 mg (yield 26%) of the title compound.

1. extractionThis mixture was extracted twice with chloroform
2. customThe organic layer was dried
3. distillationthe solvent was distilled off
4. customThe residue was purified by silica gel column chromatography
5. washThe fractions eluted with 2% methanol/chloroform
6. customwere collected
7. concentrationconcentrated
8. customto obtain 276 mg (yield 14%) of the
9. stirringthe mixture was stirred at room temperature for 4 hours
10. distillationThe solvent was distilled off under reduced pressure
11. customthe residue was separated into the alpha-anomer
12. customThus, 84 mg of the beta-anomer was obtained
13. stirringThe mixture was stirred at room temperature for 10 minutes
14. stirringthe mixture was stirred for 1 hour
15. stirringthe resulting mixture was stirred for a further 30 minutes
16. temperatureto warm up to room temperature
17. distillationThe solvent was distilled off
18. customthe residue was purified by silica gel column chromatography
19. washThe fractions eluted with 20% methanol/chloroform
20. customwere collected
21. concentrationconcentrated

ORD record

ord-04802ed79f494ceda5b0245af7eefe33

Source dataset

uspto-grants-2000_08

DOI

10.6084/m9.figshare.5104873.v1

Patent number

US06103707