METHOD FOR SYNTHESIZING NUCLEIC ACID

• US 20120108800A1
• Filed: 06/22/2010
• Published: 05/03/2012
• Est. Priority Date: 06/23/2009
• Status: Abandoned Application

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Murata, Shumpei, Umemoto, Tadashi, Miyata, Kenichi, Hayase, Yoji
• Application Number:
  US13/379,485
• Publication Number:
  US 20120108800A1
• Time in Patent Office: Days
• US Class Current: 536/18.1
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 9/04 Cyclic acetals
• CPC Class Codes: Y02P 20/55 Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

Provided is a new production method for the synthesis of an NC type nucleoside efficiently and conveniently in a high yield without unnecessary protecting group conversion steps. It relates to a step of producing a compound represented by the formula (II):

or a salt thereof, by inverting a compound represented by the formula (I):

and a method of producing a compound represented by the formula (III):

or a salt thereof (wherein each symbol is as defined in the specification), which includes the step.

Claims

1. A method of producing a compound represented by the formula (II):

3. The method according to claim 1, wherein B is a purine ring group optionally having substituent(s), which is bonded at the 9-position of the purine ring.

4. The method according to claim 1, wherein B is a purin-9-yl group optionally having substituent(s) selected from the following group α

[group α

;

a hydroxyl group,

a hydroxyl group protected by a protecting group for nucleic acid synthesis,

an alkoxy group having a carbon number of 1-5,

a mercapto group,

a mercapto group protected by a protecting group for nucleic acid synthesis,

an alkylthio group having a carbon number of 1-5,

an amino group,

an amino group protected by a protecting group for nucleic acid synthesis,

an amino group substituted by an alkyl group having a carbon number of 1-5,

an alkyl group having a carbon number of 1-5 and a halogen atom].

5. The method according to claim 1, wherein B is

a 6-aminopurin-9-yl group,

a 6-aminopurin-9-yl group wherein the amino group is protected by a protecting group for nucleic acid synthesis,

a 2,6-diaminopurin-9-yl group,

a 2-amino-6-chloropurin-9-yl group,

a 2-amino-6-chloropurin-9-yl group wherein the amino group is protected by a protecting group for nucleic acid synthesis,

a 2-amino-6-fluoropurin-9-yl group,

a 2-amino-6-fluoropurin-9-yl group wherein the amino group is protected by a protecting group for nucleic acid synthesis,

a 2-amino-6-bromopurin-9-yl group,

a 2-amino-6-bromopurin-9-yl group wherein the amino group is protected by a protecting group for nucleic acid synthesis,

a 2-amino-6-hydroxypurin-9-yl group,

a 2-amino-6-hydroxypurin-9-yl group wherein the amino group is protected by a protecting group for nucleic acid synthesis,

a 6-amino-2-methoxypurin-9-yl group,

a 6-amino-2-chloropurin-9-yl group,

a 6-amino-2-fluoropurin-9-yl group,

a 2,6-dimethoxypurin-9-yl group,

a 2,6-dichloropurin-9-yl group or

a 6-mercaptopurin-9-yl group.

6. The method according to claim 1, wherein B is a 6-aminopurin-9-yl group.

7. The method according to claim 1, wherein R₁ is

(1) an aliphatic acyl group optionally having substituent(s),

(2) an aromatic acyl group optionally having substituent(s),

(3) an aliphatic sulfonyl group optionally having substituent(s),

(4) an aromatic sulfonyl group optionally having substituent(s),

(5) a methyl group substituted by 1 to 3 aryl groups optionally having 1 to 3 substituents, or

(6) —

Si(R₈)(R₉)(R₁₀)

wherein R₈, R₉ and R₁₀ are the same or different and each is

(i) a lower alkyl group or

(ii) an aryl group optionally having substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyano group.

8. The method according to claim 1, wherein R₁ is

an acetyl group,

a benzoyl group,

a methanesulfonyl group,

a p-toluenesulfonyl group,

a benzyl group,

a p-methoxybenzyl group,

a trityl group,

a dimethoxytrityl group,

a monomethoxytrityl group or

a tert-butyldiphenylsilyl group.

9. The method according to claim 1, wherein R₁ is a tert-butyldiphenylsilyl group.

14. The method according to claim 1, wherein R₄ is a lower alkylsulfonyl group optionally substituted by a halogen atom.

15. The method according to claim 1, wherein R₄ is a trifluoromethanesulfonyl group.

16. The method according to claim 1, wherein R_4′

is an alkyl having a carbon number of 1-6-carbonyl group optionally having substituent(s).

17. The method according to claim 1, wherein R_4′

is an acetyl group.

18. The method according to claim 1, wherein R₅ is an aromatic sulfonyl group optionally having substituent(s).

19. The method according to claim 1, wherein R₅ is a phenylsulfonyl group optionally having substituent(s).

20. The method according to claim 1, wherein R₅ is a p-toluenesulfonyl group.

21. The method according to claim 1, wherein the reaction is performed in a solvent in the presence of an organic acid salt of an alkali metal.

22. The method according to claim 21, wherein the solvent is a sulfoxide solvent.

23. The method according to claim 21, wherein the solvent is dimethyl sulfoxide.

24. The method according to claim 21, wherein the organic acid salt of alkali metal is alkali metal acetate.

25. The method according to claim 21, wherein the organic acid salt of alkali metal is cesium acetate.

26. The method according to claim 21, wherein the reaction temperature is room temperature.

2. A method of producing a compound represented by the formula (III):

10. The method according to claim 2, wherein R₃ is

a hydrogen atom,

a phenoxyacetyl group,

an alkyl group having a carbon number of 1-5,

an alkenyl group having a carbon number of 2-5,

an aryl group having a carbon number of 6-14 and optionally having substituent(s),

a methyl group substituted by 1 to 3 aryl groups optionally having substituent(s),

a lower aliphatic sulfonyl group optionally having substituent(s),

an aromatic sulfonyl group optionally having substituent(s),

an aliphatic acyl group having a carbon number of 1-5 and optionally having substituent(s), or

an aromatic acyl group optionally having substituent(s).

11. The method according to claim 2, wherein R₃ is

a hydrogen atom,

an alkyl group having a carbon number of 1-5,

a p-toluenesulfonyl group,

a methanesulfonyl group, or

a trifluoromethanesulfonyl group.

12. The method according to claim 2, wherein R₃ is an alkyl group having a carbon number of 1-5.

13. The method according to claim 2, wherein the functional molecular unit substituent for R₃ is a fluorescence·

luminescence-labeling molecule or chemical luminescence-labeling molecule, a functional group having nucleic acid cleavage activity, or an intracellular or nuclear localization signal peptide.

27. A compound represented by the formula:

28. The compound according to claim 27, wherein R_1A is —

Si(R_8A)(R_9A)(R_10A)

wherein R_8A, R_9A and R_10A are the same or different and each is

(i) a lower alkyl group, or

(ii) an aryl group optionally having substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyano group,

or a salt thereof.

29. A compound represented by the formula:

30. The compound according to claim 29, wherein R_1A is —

Si(R_8A)(R_9A)(R_10A)

wherein R_8A, R_9A and R_10A are the same or different and each is

(i) a lower alkyl group, or

(ii) an aryl group optionally having substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyano group, or a salt thereof.

31. The compound according to claim 29, wherein R_A is a hydrogen atom, and

R_B is a hydroxyl group optionally having substituent(s), or a salt thereof.

32. The compound according to claim 29, wherein R_A is a hydrogen atom, and

R_B is a hydroxyl group optionally having substituent(s) selected from

(1) an acyl group optionally having substituent(s);

(2) a sulfonyl group optionally having substituent(s); and

(3) —

NR_11AR_12A

(R_11A and R_12A are the same or different and each is

(i) a hydrogen atom,

(ii) a hydrocarbon group optionally having substituent(s),

(iii) a heterocyclic group optionally having substituent(s),

(iv) an acyl group optionally having substituent(s), or

(v) a sulfonyl group optionally having substituent(s), or

R_11A and R_12A form, together with the adjacent nitrogen atom, a cyclic group optionally having substituent(s)),

or a salt thereof.

33. The compound according to claim 29, wherein R_A is a hydroxyl group optionally having substituent(s), and

R_B is a hydrogen atom, or a salt thereof.

34. The compound according to claim 29, wherein R_A is a hydroxyl group optionally having substituent(s) selected from

(1) an acyl group optionally having substituent(s);

and

(2) a sulfonyl group optionally having substituent(s), and

R_B is a hydrogen atom, or a salt thereof.

39. The compound according to claim 29, wherein R_5A is a p-toluenesulfonyl group, or a salt thereof.

35. A compound represented by the formula:

36. The compound according to claim 35, wherein R_1A is —

Si(R_8A)(R_9A)(R_10A)

(R_8A, R_9A and R_10A are the same or different and each is

(i) a lower alkyl group, or

(ii) an aryl group optionally having substituent(s) selected from the group consisting of a lower alkyl group, a lower alkoxy group, a halogen atom and a cyano group),

or a salt thereof.

37. The compound according to claim 35, wherein R_3A is a hydrogen atom or an alkyl group having a carbon number of 1-5, or a salt thereof.

38. The compound according to claim 35, wherein B is a 6-aminopurin-9-yl group wherein the amino group is optionally protected by a protecting group for nucleic acid synthesis, or a salt thereof.