Process for preparing a synthetic intermediate for preparation of branched nucleosides

• US 7,781,576 B2
• Filed: 12/22/2006
• Issued: 08/24/2010
• Est. Priority Date: 12/23/2005
• Status: Active Grant

• Current Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Original Assignee: Idenix Pharmaceuticals (Merck & Co., Inc.)
• Inventors: Moussa, Adel, Mayes, Benjamin Alexander
• Primary Examiner(s): Jiang; Shaojia Anna
• Assistant Examiner(s): Krishnan; Ganapathy
• Application Number:
  US11/644,304
• Publication Number:
  US 20070203334A1
• Time in Patent Office: 1,341 Days
• Field of Search: 536/27.1, 536/28.1, 536/55.3
• US Class Current: 536/27.1
• CPC Class Codes: C07D 307/33 in position 2, the oxygen atom being in its keto or unsubstituted enol form
• CPC Class Codes: C07D 309/30 Oxygen atoms, e.g. delta-lactones
• CPC Class Codes: C07H 15/24 Condensed ring systems having three or more rings
• CPC Class Codes: C07H 19/048 Pyridine radicals
• CPC Class Codes: C07H 19/22 Pteridine radicals

Abstract

A process is provided for the preparation of a key intermediate in the preparation of 2′-branched nucleoside compounds. The process includes contacting a protected precursor 3,4-O-isopropylidene-2-C-substituted-D-arabinono-1,5-lactone with a fluorinating agent under anhydrous conditions and converting the precursor into a protected 2-deoxy-2-halo-2-C-disubstituted ribono-1,5-lactone and optionally into a 2-deoxy-2-halo-2-C-disubstituted ribono-1,4-lactone.

Claims

1. A process of preparing a compound of Formula II

2. The process of claim 1 wherein the fluorinating agent is tris(dimethylamino)sulfonium difluorotrimethyl silicate (TASF).

3. The process of claim 1 wherein a compound of Formula (II) is produced in at least 40% or more yields.

4. The process of claim 1 wherein R′

is methyl.

5. The process of claim 1 wherein R¹ is ethyl.

6. The process of claim 1 wherein R¹ is vinyl.

7. The process of claim 1 wherein R¹ is —

C≡

CH.

8. The process of claim 1 wherein OR is selected from the group consisting of triflate, mesylate, and tosylate.

9. The process of claim 1 wherein X in Formula (II) is bromine, chlorine or iodine.

10. The process of claim 8 wherein OR is triflate.

11. The process of claim 1 wherein the reaction contains less than 1% water.

12. The process of claim 1 wherein the reaction contains less than 0.1% water.

13. The process of claim 1 wherein the reaction contains less than 0.01% water.

14. The process of claim 1 further comprising converting a compound of Formula (II) to a 1,4-lactone compound by contacting the product from step (b) with an organic acid in an organic solvent.

15. The process of claim 14 wherein the acid is trifluoroacetic acid.

16. The process of claim 14 wherein the acid is an aryl or alkyl sulfonic acid.

17. The process of claim 16 wherein the acid is methanesulfonic acid.

18. The process of claim 16 wherein the acid is p-toluenesulfonic acid.

19. The process of claim 14 wherein the solvent is 1,4-dioxane.

20. The process of claim 14 wherein 1,4-lactone compound is a compound of Formula (B)

21. The process of claim 14 wherein the 1,4-lactone compound is a 2-deoxy-2-fluoro-2-C-methyl-D-ribono-1,4-lactone.

22. The process of claim 20 wherein R¹ is acetylene.

23. The process of claim 20 wherein R¹ is vinyl.

24. The process of claim 14 further comprising:

d) reducing the 1,5-lactone product of step c) to a hemiacetal, e) derivatizing the hydroxyl from step d) to a suitable leaving group; and

f) contacting the product of step e) with a purine or pyrimidine base to provide a 2′

-branched nucleoside compound.

25. The process of claim 1, wherein the compound of Formula (i) is 3,4-O-isopropylidene-2-C-methyl-2-O-trifluoromethanesulfonyl-D-arabinono-1,5-lactone.

26. The process of claim 1 wherein a 2-deoxy-2-fluoro-3,4-O-isopropylidene-2-C-methyl-D-ribono-1,5-lactone is produced.

27. The process of claim 1 wherein step (b) is carried out at a temperature below 0°

C.

28. The process of claim 1 wherein step (b) is carried out at a temperature below −

5°

C.

34. The process of claim 29, step d) wherein benzoyl is the protecting group on one or more hydroxy groups on either of one of the products from claim 1, step c).

29. A process for preparing a 2-deoxy-2-alkyl-2-halo-lactone compound comprising:

a) reacting the 2-position of an isopropylidene, 2-alkyl-substituted arabinono-1,5-lactone compound with a leaving group reagent, to provide a 2-deoxy-2-alkyl-substituted-3,4-isopropylidene arabinono-1,5-lactone substituted with a leaving group at the 2-position selected from the group consisting of p-toluene sulfonate, methanesulfonate, trifluoromethanesulfonate, allylsulfonate, 4-nitrobenzenesulfonate, 4-bromobenzenesulfonate, acetate, trifluoroacetate, arylsulfate and alkylsulfonate;

b) reacting the product from step a) with a fluorinating agent, a chlorinating agent, a brominating agent or an iodinating reagent to provide a 2-deoxy-2-halo-2-alkyl-substituted-3,4-isopropylidene ribono-1,5-lactone;

c) deprotecting the product from step b) with an acid to provide a 2-deoxy-2-halo-2-alkyl-substituted ribono-1,4-lactone as a major product and a 2-deoxy-2-halo-2-alkyl-substituted ribono-1,5-lactone as a minor product; and

d) optionally protecting one or more hydroxy groups on either one of the products from step c.

30. The process of claim 29, step a) wherein the 2-deoxy-2-alkyl-substituted isopropylidene arabinono-1,5-lactone substituted with a leaving group at the 2-position is 3,4-O-isopropylidene-2-C-methyl-2-O-trifluoromethanesulfonyl-D-arabinono-1,5-lactone.

31. The process of claim 29, step b) wherein the 2-deoxy-2-halo-2-alkyl-substituted-3,4-isopropylidene ribono-1,5-lactone is 2-deoxy-2-fluoro-3,4-O-isopropylidene-2-C-methyl-D-ribono-1,5-lactone.

32. The process of claim 29, step c) wherein the 2-deoxy-2-halo-2-alkyl-substituted ribono-1,4-lactone major product is 2-deoxy-2-fluoro-2-C-methyl-D-ribono-1,4-lactone.

33. The process of claim 29, step c) wherein the 2-deoxy-2-halo-2-alkyl-substituted ribono-1,4-lactone minor product is 2-deoxy-2-fluoro-2-C-methyl-D-ribono-1,5-lactone.

35. The process of claim 29 wherein the fluorinating agent is TASF.

36. The process of claim 29, step c) wherein the deprotecting reagent is trifluoroacetic acid (TFA).

37. The process of claim 29, step a) wherein the leaving group is selected from the group consisting of triflate, mesylate.

38. The process of claim 37 wherein the leaving group is triflate.