反应详情

To a solution of ethyl 3-(5-amino-2-(4-(2-(3-(diethoxyphosphoryl)-3,3-difluoropropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoate (6-15) (1.0 equiv.) in DCM (0.16 M) at 0° C. was added slowly TMSBr (10 equiv.). The reaction was stirred at room temperature overnight. Additional TMSBr (5.0 equiv.) was added at 0° C., and the reaction was again stirred at room temperature overnight. The solvent was removed by evaporation and the crude orange solids dried on hi-vac briefly. The solids were suspended in EtOH (0.5 M) and added 2.5 N NaOH (10.0 equiv.). The reaction was stirred at 80° C. for 3 hours. After cooling to room temperature, the mixture was adjusted to pH 9 to 10 and directly purified on RP-HPLC using a C18 column, eluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient. The fractions containing the product were combined and concentrated in vacuo. The resulting white gel was dissolved in refluxing 1:1 EtOH/water (0.04 M) with the addition of a few drops of ammonium hydroxide. While hot, the mixture was slowly poured into a stirring hot solution of acetone (0.009 M) preheated at 50° C. The acetone suspension was slowly cooled to room temperature for 15 minutes with continued stirring, and then sat in an ice bath for 10 minutes. The solids were filtered and washed successively with acetone (2×) and ether (2×). The solids were dried on hi-vac overnight to give the 3-(5-amino-2-(4-(2-(3,3-difluoro-3-phosphonopropoxy)ethoxy)-2-methylphenethyl)benzo[f][1,7]naphthyridin-8-yl)propanoic acid (19) as a solid. 1H NMR (Dimethylsulfoxide-d6): δ 9.02 (s, 1H), 8.82 (s, 1H), 8.55 (d, 1H, J=8.4 Hz), 7.58 (s, 1H), 7.48 (d, 1H, J=8.4 Hz), 7.07 (d, 1H, J=8.4 Hz), 6.75 (s, 1 H), 6.68 (d, 1H, J=8.4 Hz), 4.03-4.00 (m, 2H), 3.72-3.68 (m, 4H), 3.16-3.12 (m, 2H), 3.03-2.96 (m, 4H), 2.67-2.64 (m, 2H), 2.33-2.32 (m, 2H), 2.26 (s, 3H). LRMS [M+H]=604.2

1. stirringthe reaction was again stirred at room temperature overnight
2. customThe solvent was removed by evaporation
3. customthe crude orange solids dried on hi-vac briefly
4. stirringThe reaction was stirred at 80° C. for 3 hours
5. temperatureAfter cooling to room temperature
6. customdirectly purified on RP-HPLC
7. washeluting with 10-40% 95:5 (MeCN/5 mM NH4OAc) in 10 mM NH4OAc (pH 9) gradient
8. additionThe fractions containing the product
9. concentrationconcentrated in vacuo
10. dissolutionThe resulting white gel was dissolved
11. temperaturein refluxing 1:1 EtOH/water (0.04 M)
12. additionwith the addition of a few drops of ammonium hydroxide
13. additionWhile hot, the mixture was slowly poured into a stirring hot solution of acetone (0.009 M)
14. custompreheated at 50° C
15. temperatureThe acetone suspension was slowly cooled to room temperature for 15 minutes with continued stirring
16. waitsat in an ice bath for 10 minutes
17. filtrationThe solids were filtered
18. washwashed successively with acetone (2×) and ether (2×)
19. customThe solids were dried on hi-vac overnight