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 process for preparing a compound represented by formula (4), or a phosphorous-based diastereomer thereof:
wherein P* represents a chiral phosphorus atom, and wherein said phosphorous-based diastereomer is represented by formula (Rp-4) or (Sp-4):
which comprises:
a) reacting a mixture comprising an isopropyl-alanate (A), a di-X′-phenylphosphate (B), 2′-deoxy-2′-fluoro-2′-C-methyluridine (3), and a base to obtain a first mixture comprising (4), or the phosphorous-based diastereomer thereof:
wherein X is a conjugate base of an acid, n is 0 or 1, and X′ is a halogen;
b) reacting the first mixture with a protecting compound to obtain a second mixture comprising protected (4), or the phosphorous-based diastereomer thereof; and
c) optionally subjecting the second mixture to crystallization, chromatography, or extraction in order to obtain (4), or the phosphorous-based diastereomer thereof.
2. The process according to claim 1 , wherein X is chloride and n is 1.
3. The process according to claim 2 , wherein (A) is substantially anhydrous.
4. The process according to claim 1 , wherein the base is N-methylimidazole.
5. The process according to claim 1 , wherein the mole ratio of (A):(B):(3) is about 1.6:1.3:1.
6. The process according to claim 1 , wherein the protecting compound is tert-butyldimethylsilyl chloride.
7. The process according to claim 1 wherein the compound is (R P -4):
8. The process according to claim 7 , wherein X is chloride and n is 1.
9. The process according to claim 8 , wherein (A) is substantially anhydrous.
10. The process according to claim 7 , wherein the base is N-methylimidazole.
11. The process according to claim 7 , wherein the mole ratio of (A):(B):(3) is about 1.6:1.3:1.
12. The process according to claim 7 , wherein the protecting compound is tert-butyldimethylsilyl chloride.
13. A process for preparing a crystalline compound (Rp-4) or (Sp-4):
which comprises: a) reacting a mixture comprising an isopropyl-alanate (A), a di-X′-phenylphosphate (B), 2′-deoxy-2′-fluoro-2′-C-methyluridine (3), and a base to obtain a first mixture comprising (Rp-4) or (Sp-4):
wherein X is a conjugate base of an acid, n is 0 or 1, and X′ is a halogen;
b) reacting the first mixture with a protecting compound to obtain a second mixture; and
c) optionally subjecting the second mixture to crystallization, chromatography, or extraction in order to obtain a third mixture.
14. The process according to claim 1 wherein the compound is (S P -4):
15. The process according to claim 14 , wherein X is chloride and n is 1.
16. The process according to claim 15 , wherein (A) is substantially anhydrous.
17. The process according to claim 14 , wherein the base is N-methylimidazole.
18. The process according to claim 14 , wherein the mole ratio of (A):(B):(3) is about 1.6:1.3:1.
19. The process according to claim 14 , wherein the protecting compound is tert-butyldimethylsilyl chloride.
20. The process according to claim 13 wherein the compound is crystalline (S P -4), further comprising:
d) dissolving or suspending the second mixture or the third mixture in a solvent followed by seeding with crystalline (S P -4) at about room temperature;
e) collecting a first solid the majority of which comprises (S P -4);
f) dissolving or suspending the first solid in a solvent at its reflux temperature; and
g) cooling or adding an anti-solvent to obtain a second solid comprising crystalline (S P -4).
21. The process according to claim 13 wherein the compound is crystalline (S P -4), further comprising:
d) dissolving or suspending the second mixture or the third mixture in a first solvent followed by adding an anti-solvent so as to obtain a first composition in which the residual solvent/anti-solvent is removed by decanting to obtain a residue;
e) treating the residue with a solution containing the first solvent and anti-solvent to yield a second composition whereby upon reducing the pressure affords a first solid;
f) dissolving or suspending the first solid using a second solvent so as to obtain a third composition;
g) adding seed crystals of (S P -4) to the third composition;
h) collecting a second solid;
i) dissolving or suspending the second solid in a third solvent, optionally heated to the reflux temperature of the third solvent to obtain a fourth composition; and
j) optionally cooling the fourth composition to obtain a third solid comprising crystalline (S P -4), which is collected by filtration.
22. The process according to claim 13 wherein the compound is crystalline (S P -4), further comprising:
d) adding silica gel to the second mixture or the third mixture followed by solvent evaporation to afford a dry slurry;
e) stirring the dry slurry in a first solvent/anti-solvent combination to obtain a first wet slurry;
f) decanting the first solvent/anti-solvent combination from the first wet slurry to obtain a second wet slurry and a first composition;
g) adding to the second wet slurry a second solvent/anti-solvent combination followed by stirring;
h) decanting the second solvent/anti-solvent combination from the second wet slurry to obtain a third wet slurry and a second composition;
i) optionally repeating steps g)-h) on the third wet slurry or additional wet slurries;
j) evaporating the solvent from the second composition, and optionally any additional composition obtained from optional step i) to obtain a first solid;
k) dissolving or suspending the first solid in a solution containing a third solvent and optionally a fourth solvent to obtain a third composition;
l) optionally adding seed crystals of (S P -4) to the third composition;
m) obtaining from the third composition a second solid comprising (S P -4); and
n) optionally recrystallizing the second solid using a third solvent to obtain a third solid comprising crystalline (S P -4).
23. The process according to claim 13 , wherein the compound is crystalline (R P -4), further comprising:
d) dissolving or suspending the second mixture or the third mixture in a solvent;
e) optionally followed by seeding with crystalline (R P -4); and
f) adding sufficient anti-solvent to obtain crystalline (R P -4).