Process for producing nucleoside

• US 8,653,254 B2
• Filed: 03/30/2010
• Issued: 02/18/2014
• Est. Priority Date: 03/31/2009
• Status: Active Grant

• Current Assignee: Takeda Pharmaceutical Company Limited
• Original Assignee: Takeda Pharmaceutical Company Limited
• Inventors: Umemoto, Tadashi, Hayase, Yoji, Murata, Shumpei, Miyata, Kenichi
• Primary Examiner(s): LEWIS, PATRICK T
• Application Number:
  US13/260,096
• Publication Number:
  US 20120071646A1
• Time in Patent Office: 1,421 Days
• Field of Search: None
• US Class Current: 536/25.3
• CPC Class Codes: C07H 19/06 Pyrimidine radicals
• CPC Class Codes: C07H 19/16 Purine radicals
• CPC Class Codes: C07H 23/00 Compounds containing boron, silicon, or a metal, e.g. chelates, vitamin B12 esters with inorganic acids C07H11/00; metal salts, see parent compounds

Abstract

There is a demand for a convenient production method of an NC type purine nucleoside.

The present invention relates to a method of producing a purine nucleoside represented the formula (I′)

or a salt thereof, which comprising reacting a pyrimidine nucleoside represented by the formula (I)

or a salt thereof with a purine nucleobase represented by the formula B′H in the presence of a Lewis acid.

Claims

1. A method of producing a purine nucleoside represented by the formula (I′

)

2. The method of claim 1, wherein B is a residue derived from a pyrimidine nucleobase optionally having substituent(s), and is bonded at the N1-position on the pyrimidine ring, and B′

is a residue derived from a purine nucleobase optionally having substituent(s), and is bonded at the N9-position on the purine ring.

3. The method of claim 1 or 2, wherein B is a residue derived from a pyrimidine nucleobase protected by an amino-protecting group, and is bonded at the N1-position on the pyrimidine ring.

4. The method of claim 1 or 2, wherein B is a residue derived from a thymine nucleobase wherein the nitrogen atom at the N3-position is protected by a benzoyl group, which is bonded at the N1-position on the pyrimidine ring.

5. The method of claim 1 or 2, wherein B′

is a residue derived from a purine nucleobase having a bulky substituent at the C6-position on the purine ring and optionally having additional substituent(s), and is bonded at the N9-position on the purine ring.

6. The method of claim 1 or 2 wherein B′

is a residue derived from a purine nucleobase having an amino group optionally protected by a benzoyl group at the C6-position, and is bonded at the N9-position on the purine ring.

7. The method of claim 1 or 2, wherein B′

is a residue derived from a purine nucleobase having a hydroxyl group optionally protected by a diphenyicarbamoyl group at the C6-position, and optionally having an amino group protected by an amino-protecting group, and is bonded at the N9-position on the purine ring.

8. The method of claim 1 or 2 wherein B′

is a residue derived from a purine nucleobase having an oxo group at the C6-position, and optionally having an amino group protected by an amino-protecting group, and is bonded at the N9-position on the purine ring.

9. The method of claim 1 or 2 wherein the eaction is performed in the presence of a silylating agent.

10. The method of claim 1 or 2 wherein the reaction is performed at 80 to 120°

C.

11. The method of claim 1 or 2 wherein the solvent is toluene.

12. The method of claim 1 or 2, wherein the reaction is performed by reacting the pyrimidine nucleoside represented by the formula (I)

13. The method of claim 1 or 2, wherein R₁ and R₁′

are each independently a hydrogen atom;

an acyl group;

an aliphatic or aromatic sulfonyl group;

a methyl group substituted by 1 to 3 aryl groups;

a methyl group substituted by 1 to 3 aryl groups optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, a halogen atom, and cyano;

or a silyl group.

14. The method of claim 1 or 2, wherein R₁ and R₁′

are each independently a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a benzyl group, a p-methoxybenzyl group, or a tert-butyldiphenylsilyl group.

15. The method of claim 1 or 2, wherein R₂ and R₂′

are each independently a hydrogen atom;

an acyl group;

an aliphatic or aromatic sulfonyl group;

a methyl group substituted by 1 to 3 aryl groups;

a methyl group substituted by 1 to 3 aryl groups optionally substituted by 1 to 3 substituents selected from the group consisting of alkyl, alkoxy, a halogen atom, and cyano;

or a silyl group.

16. The method of claim 1 or 2, wherein R₂ and R₂′

are each independently a hydrogen atom, an acetyl group, a benzoyl group, a methanesulfonyl group, a p-toluenesulfonyl group, a benzyl group, a p-methoxybenzyl group, or a tert-butyldiphenylsilyl group.

17. The method of claim 1 or 2, wherein R₁ and R₂ in combination or R₁′

and R₂′

in combination form a group represented by the formula

18. The method of claim 1 or 2, wherein R₃ is a hydrogen atom, an alkyl group, an alkenyl group, an aryl group, a methyl group substituted by 1 to 3 aryl groups, an aliphatic or aromatic sulfonyl group, or a phenoxyacetyl group.

19. The method of claim 1 or 2, wherein R₃ is a C_1-6 alkyl group.

20. The method of claims 1 or 2, wherein m is 0 and n is 1.

21. The method of claim 1 or 2,

wherein

B′

is a residue derived from a purine nucleobase optionally having substituent(s), and is bonded at the N9-position on the purine ring.

22. A method of producing a purine nucleoside represented by the formula (I′

)