反应详情

温度

0 °C

2′-deoxycytidine monohydrochloride (13.18 g, 52 mmol) that had been subjected to azeotropic dehydration with pyridine (2×20 ml) under an argon gas stream was suspended in anhydrous pyridine (120 ml) and cooled to 0° C. Chlorotrimethylsilane (19.0 ml, 150 mmol) was added and the mixture was stirred for 15 minutes. The benzoyl chloride-monomethoxypolyethylene glycol; CH3O(CH2CH2O)kC6H4COCl {34.9 mmol, mPEG portion Mn=350; 1H-NMR (400 MHz, CDCl3, TMS) δ68.07 (d, J=8.8Hz,2H,ArH), 6.99 (d, J=8.8 Hz,2H,ArH), 4.23 (t, J=4.8 Hz,2H,ArOCH2), 3.89 (t, J=4.8 Hz,2H,OCH2), 3.79-3.51 (m), 3.38(s,3H,OCH3) ppm} prepared by the reaction of benzoic acid-monomethoxypolyethylene glycol (C. J. van Staveren, et al., J. Am. Chem. Soc., 110, 4994 (1988)) with thionyl chloride, was dissolved in anhydrous pyridine (80 ml) under an argon gas stream, and was added to the previously prepared reaction solution and stirred at room temperature for 2 hours. After cooling to 0° C., distilled water ((10 ml) was added to the reaction mixture , and after concentration to approximately 1/2, concentrated ammonium hydroxide (20 ml) was added at 0° C. and the mixture was stirred for 20 minutes. The solvent was removed under reduced pressure, a saturated sodium bicarbonate aqueous solution (200 ml) was added, and extraction was performed with chloroform (3×100 ml). The organic layer was washed with water a (2×200 ml) and dried over anhydrous sodium sulfate. After filtration, the filtrate was condensed under reduced pressure and the residue was purified by silica gel column chromatography (chloroform/methanol=100/5) to obtain the target PEG-modified 2′-deoxycytidine represented by the formula (3′-1) (18.85 g, 82.4% yield). The 1H-NMR of the obtained compound (400 MHz, CDCl3, TMS) was δ=9.30 (brs,1H,NH), 8.41 (d, J=7.2 Hz,1H,H6), 7.83 (d, J=7.6 Hz,2H,ArH), 7.48 (br,1H,H5), 6.92 (d, J=7.6 Hz,2H,ArH), 6.29-6.10 (m,1H,H1′), 5.07 (brs,1H), 4.74-4.40 (br,2H), 4.27-4.00 (m,3H), 4.00-3.42 (m), 3.36 (s,3H,OCH3), 2.70-2.50 (m,1H,H2″), 2.35-2.18 (m,1H,H2′) ppm.

1. additionwas added to the previously prepared reaction solution
2. stirringstirred at room temperature for 2 hours
3. temperatureAfter cooling to 0° C.
4. distillationdistilled water ((10 ml)
5. additionwas added to the reaction mixture
6. concentrationafter concentration to approximately 1/2, concentrated ammonium hydroxide (20 ml)
7. additionwas added at 0° C.
8. stirringthe mixture was stirred for 20 minutes
9. customThe solvent was removed under reduced pressure
10. additiona saturated sodium bicarbonate aqueous solution (200 ml) was added
11. extractionextraction
12. washThe organic layer was washed with water a (2×200 ml)
13. dry with materialdried over anhydrous sodium sulfate
14. filtrationAfter filtration
15. customcondensed under reduced pressure
16. customthe residue was purified by silica gel column chromatography (chloroform/methanol=100/5)