Selective process for producing an anomer of a 1-phosphorylated saccharide derivative and process for producing a nucleoside

Abstract

A desired isomer is selectively prepared by phosphorolyzing and isomerizing an anomer mixture of a 1-phosphorylated saccharide derivative while crystallizing one of the isomers to displace the equilibrium. Furthermore, using the action of a nucleoside phosphorylase, a nucleoside is prepared from the 1-phosphorylated saccharide derivative obtained and a base with improved stereoselectivity and a higher yield. This process is an anomer-selective process for preparing a 1-phosphorylated saccharide derivative and a nucleoside.

Description

BACKGROUND OF THE INVENTION [0001] 1. Field of the Invention [0002] This invention relates to a process for producing a 1-phosphorylated saccharide derivative. 1-phosphorylated saccharides are widely distributed in the living world, are reaction substrates for a variety of enzymes and are utilized starting materials for preparing useful substances such as drugs and nutritional foods. Synthetic 1-phosphorylated saccharide derivatives have been expected to be used as starting materials for preparing drugs such as antiviral agents and enzyme inhibitors. [0003] This invention also relates to a process for producing a nucleoside compound used as a starting material or drug substance for medical drugs such as antiviral, anticancer and antisense drugs. [0004] 2. Description of the Prior Art [0005] There are known processes for producing a 1-phosphorylated saccharide such as: [0006] 1) condensation of a 1-bromosaccharide with a silver phosphate salt (J. Biol. Chem., Vol. 121, p. 465 (1937);...

AI Technical Summary

Benefits of technology

[0022] Another objective of this invention is to provide a highly universal process for producing a nucleoside by treating a 1-phosphorylated saccharide derivative and a nucleic-acid base with a nucleoside phosphorylase and a method for improving an inversion rate for the nucleoside in the reaction.

[0023] In other words, the ultimate objective of this invention is to provide a process for producing a highly pure nucleoside with a lower cost by achieving the first and the second objectives above.

[0024] We have intensely made attempts for achieving the first objective. Finally, we have found that a 1-phosphorylated saccharide derivative is present in an equilibrium with an anomer and a dimer of the 1-pohsphorylated saccharide derivative under certain conditions and that the conditions may be adjusted to allow only a desired anomer to be precipitated as crystals so that the equilibrium may be displaced toward the preferable direction to provide the desired anomer with good selectivity and a high yield. Thus, based on the findings, we have achieved this invention.

[0046] We have intensely attempted for achieving the second objective and thus have established a highly universal process for preparing a nucleoside by utilizing a reverse reaction of nucleoside phosphorylases widely distributed in the living world in combination with the above preparation processes for a 1-phosphorylated saccharide derivative. We have further found that a metal cation capable of forming a water-insoluble salt with a phosphate ion may be present to allow a phosphate ion as a byproduct in the reaction to be precipitated as a water-insoluble salt, resulting in displacement of the reaction equilibrium toward the direction for nucleoside production and thus improvement in a reaction yield. Thus, we have achieved this invention providing a process for preparing a highly pure nucleoside with a lower cost.

Problems solved by technology

A common problem in the chemical processes described in the above 1) to 5) is that it is difficult to establish a general synthetic method for preparing a desired isomer with a good selectivity due to variation in an anomer selectivity between α / β anomers owing to influence of a functional group adjacent to 1-position.

However, since 2-deoxysaccharide is unstable, these synthetic processes may be limited to a considerably narrow application range.

Thus, it is difficult to control anomer selectivity so that column chromatography purification is required, leading to a poor yield (Chem.

Of course, there have been no reports for chemical preparation of a 1-phosphorylated 2-deoxyfuranose which is more unstable than a 1-phosphorylated 2-deoxypyranose, resulting in more difficult selectivity control.

In terms of 6), preparation of a nucleoside itself is difficult except a quite limited type of rebonucleosides such as inosine.

In addition, since a nucleoside itself as a starting material is expensive, the process is not satisfactory in its cost.

However, as described above, an industrial process for producing a 1-phosphorylated saccharide derivative has not been established, and thus an industrial process for preparation of a universally useful nucleoside utilizing a reverse reaction of a nucleoside phosphorylase has been also not established.

Furthermore, since the reaction for forming a nucleoside from 1-phosphorylated saccharide derivative and a base utilizing the reverse reaction of the enzyme is reversible, there is a technical drawback that an inversion rate cannot be improved.

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