Nucleoside phosphoramidates
Disclosed herein are nucleoside phosphoramidates and their use as agents for treating viral diseases. These compounds are inhibitors of RNA-dependent 5 RNA viral replication and are useful as inhibitors of HCV NS5B polymerase, as inhibitors of HCV replication and for treatment of hepatitis C infection in mammals.
1. A compound represented by the structure:
wherein LG′ is tosylate, camphorsulfonate, an aryloxide, or an aryloxide substituted with at least one electron withdrawing group.
2. The compound according to claim 1 , wherein LG′ is p-nitrophenoxide, p-chlorophenoxide, o-chlorophenoxide, 2,4-dinitrophenoxide, or pentafluorophenoxide.
3. The compound according to claim 1 , wherein LG′ is p-nitrophenoxide.
4. The compound according to claim 1 , wherein LG′ is p-chlorophenoxide.
5. The compound according to claim 1 , wherein LG′ is o-chlorophenoxide.
6. The compound according to claim 1 , wherein LG′ is pentafluorophenoxide.
7. A process for preparing the compound according to claim 1 , which comprises:
reacting (LG′)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with isopropyl-alanate and a first base to obtain (LG′)P(O)(LG)(NHAla- i Pr), followed by reacting (LG′)P(O)(LG)(NHAla- i Pr) with phenol and a second base.
8. A process for preparing the compound according to claim 1 , which comprises:
reacting (LG′)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with phenol and a first base to obtain (LG′)P(O)(LG)(OPh), followed by reacting (LG′)P(O)(LG)(OPh) with isopropyl-alanate and a second base.
9. A process for preparing the compound according to claim 1 , which comprises:
reacting (LG′)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with a combination of isopropyl-alanate, phenol, and at least one base.
10. A process for preparing the compound according to claim 1 , which comprises:
reacting (PhO)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with isopropyl-alanate and a first base to obtain (PhO)P(O)(LG)(NHAla- i Pr), followed by reacting (PhO)P(O)(LG)(NHAla- i Pr) with a leaving group precursor and a second base.
11. A compound represented by the structure:
wherein LG′ is a leaving group.
12. The compound according to claim 11 , wherein LG′ is tosylate, camphorsulfonate, an aryloxide, or an aryloxide substituted with at least one electron withdrawing group.
13. The compound according to claim 11 , wherein LG′ is p-nitrophenoxide, p-chlorophenoxide, o-chlorophenoxide, 2,4-dinitrophenoxide, or pentafluorophenoxide.
14. The compound according to claim 11 , wherein the compound is represented by the structure:
15. The compound according to claim 14 , wherein LG′ is p-nitrophenoxide, 2,4-dinitrophenoxide, or pentafluorophenoxide.
16. The compound according to claim 11 , wherein the compound is represented by the structure:
17. The compound according to claim 16 , wherein LG′ is p-nitrophenoxide, 2,4-dinitrophenoxide, or pentafluorophenoxide.
18. A process for preparing the compound according to claim 11 , which comprises:
reacting (LG′)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with isopropyl-alanate and a first base to obtain (LG′)P(O)(LG)(NHAla- i Pr), followed by reacting (LG′)P(O)(LG)(NHAla- i Pr) with phenol and a second base.
19. A process for preparing the compound according to claim 11 , which comprises:
reacting (LG′)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with phenol and a first base to obtain (LG′)P(O)(LG)(OPh), followed by reacting (LG′)P(O)(LG)(OPh) with isopropyl-alanate and a second base.
20. A process for preparing the compound according to claim 11 , which comprises:
reacting (LG′)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with a combination of isopropyl-alanate, phenol, and at least one base.
21. A process for preparing the compound according to claim 11 , which comprises:
reacting (PhO)P(O)(LG) 2 , wherein LG and LG′ are independently leaving groups, with isopropyl-alanate and a first base to obtain (PhO)P(O)(LG)(NHAla- i Pr), followed by reacting (PhO)P(O)(LG)(NHAla- i Pr) with a leaving group precursor and a second base.
22. A compound represented by the following structure:
23. A compound represented by the following structure:
24. The compound according to claim 22 in crystalline form.
25. The compound according to claim 23 in crystalline form.