Nucleoside phosphoramidates

• US 8,642,756 B2
• Filed: 05/20/2010
• Issued: 02/04/2014
• Est. Priority Date: 05/20/2009
• Status: Active Grant

• Current Assignee: Gilead Sciences Inc.
• Original Assignee: Gilead Pharmasset LLC (Gilead Sciences Inc.)
• Inventors: Ross, Bruce, Sofia, Michael Joseph, Pamulapati, Ganapati Reddy, Rachakonda, Suguna, Zhang, Hai-Ren, Chun, Byoung-Kwon, Wang, Peiyuan
• Primary Examiner(s): OLSON, ERIC
• Application Number:
  US12/783,680
• Publication Number:
  US 20100298257A1
• Time in Patent Office: 1,356 Days
• Field of Search: 536/26.8, 536/17.4, 536/22.1, 536/28.2, 536/55.3, 536/117
• US Class Current: 536/26.8
• CPC Class Codes: A61K 31/664 Amides of phosphorus acids
• CPC Class Codes: A61K 31/7072 having two oxo groups directly attached to the pyrimidine ring, e.g. uridine, uridylic acid, thymidine, zidovudine
• CPC Class Codes: A61K 31/716 Glucans
• CPC Class Codes: A61K 45/00 Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61P 3/12 for electrolyte homeostasis
• CPC Class Codes: A61P 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/12 Antivirals
• CPC Class Codes: A61P 31/14 for RNA viruses
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: C07F 9/24 Esteramides
• CPC Class Codes: C07F 9/242 of hydroxyaryl compounds
• CPC Class Codes: C07F 9/65586 at least one of the hetero rings does not contain nitrogen as ring hetero atom
• CPC Class Codes: C07H 1/00 Processes for the preparation of sugar derivatives
• CPC Class Codes: C07H 17/02 Heterocyclic radicals containing only nitrogen as ring hetero atoms
• CPC Class Codes: C07H 19/10 with the saccharide radical esterified by phosphoric or polyphosphoric acids
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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.

Claims

1. A process for preparing a compound represented by formula (4), or a 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.

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.

13. A process for preparing a crystalline compound (Rp-4) or (Sp-4):

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).