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Details for Patent: 8,642,756

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Details for Patent: 8,642,756

Title:Nucleoside phosphoramidates
Abstract: 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.
Inventor(s): Ross; Bruce (Plainsboro, NJ), Sofia; Michael Joseph (Doylestown, PA), Pamulapati; Ganapati Reddy (Plainsboro, NJ), Rachakonda; Suguna (Twinsburg, OH), Zhang; Hai-Ren (Ellicott City, MD), Chun; Byoung-Kwon (Robbinsville, NJ), Wang; Peiyuan (Glen Rock, NJ)
Assignee: Gilead Pharmasset LLC (Foster City, CA)
Filing Date:May 20, 2010
Application Number:12/783,680
Claims:1. A process for preparing a compound represented by formula (4), or a phosphorous-based diastereomer thereof: ##STR00037## wherein P* represents a chiral phosphorus atom, and wherein said phosphorous-based diastereomer is represented by formula (Rp-4) or (Sp-4): ##STR00038## ##STR00039## 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: ##STR00040## 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.sub.P-4): ##STR00041##

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): ##STR00042## ##STR00043## 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): ##STR00044## 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.sub.P-4): ##STR00045##

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.sub.P-4), further comprising: d) dissolving or suspending the second mixture or the third mixture in a solvent followed by seeding with crystalline (S.sub.P-4) at about room temperature; e) collecting a first solid the majority of which comprises (S.sub.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.sub.P-4).

21. The process according to claim 13 wherein the compound is crystalline (S.sub.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.sub.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.sub.P-4), which is collected by filtration.

22. The process according to claim 13 wherein the compound is crystalline (S.sub.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.sub.P-4) to the third composition; m) obtaining from the third composition a second solid comprising (S.sub.P-4); and n) optionally recrystallizing the second solid using a third solvent to obtain a third solid comprising crystalline (S.sub.P-4).

23. The process according to claim 13, wherein the compound is crystalline (R.sub.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.sub.P-4); and f) adding sufficient anti-solvent to obtain crystalline (R.sub.P-4).
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