Method for producing furanose derivative
An object of the present invention is to provide a industrially appropriate method for producing the β-anomers of ribofuranose derivatives in a highly selective manner at a high yield. The present invention provides a method for producing ribofuranose derivatives wherein β-anomers is precipitated from among the generated furanose derivatives by controlling the amount of a reaction reagent used and/or using a poor solvent in the acetolysis reactions of 2,3,5-tri-O-acyl-1-O-alkyl-ribofuranose and 2,3-di-O-acyl-1-O-alkyl-5-deoxy-ribofuranose.
1. A method for producing a compound represented by the following formula (4):
wherein each of X 1 and X 2 represents a protecting group of a hydroxyl group, which may be the same or different, Y represents CH 2 OX 3 or CH 3 ; X 3 represents a protecting group of a hydroxyl group; and Z represents an acyl group, which comprises allowing an acylating agent to react with a compound represented by the following formula (3) in the presence of acid:
wherein each of X 1 and X 2 represents a protecting group of a hydroxyl group, which may be the same or different; Y represents CH 2 OX 3 or CH 3 ; X 3 represents a protecting group of a hydroxyl group; and R represents a lower alkyl group, wherein 6 equivalents or less of the acylating agent, with respect to the amount of the compound of formula (3) used, is allowed to react with the compound of the formula (3), and/or the acylating agent is allowed to react with the compound of the formula (3) in the presence of a poor solvent, so that the produced compound represented by formula (4) whose configuration at 1-position is β (β-anomer) is precipitated.
2. The method according to claim 1 , wherein the ratio of the α-anomer/β-anomer (α-anomer:β-anomer) as to the configuration at 1-position of the generated compound of formula (4) is 30:70 to 0:100.
3. The method according to claim 1 , wherein the acid is a strong acid.
4. The method according to claim 1 , wherein the acid is sulfuric acid.
5. The method according to claim 1 , wherein the amount of the acid used is 5 equivalents or less with respect to the amount of the compound of formula (3) used.
6. The method according to claim 1 , which further comprises adding a base.
7. The method according to claim 6 , wherein the amount of the acid used is 3 equivalents or less with respect to the amount of the compound of formula (3) used.
8. The method according to claim 6 , wherein the base is pyridine.
9. The method according to claim 1 , wherein the acylating agent is acetic acid, acetic anhydride, or a mixture thereof.
10. The method according to claim 9 , wherein the amount of the acetic anhydride used is 3 equivalents or less with respect to the amount of the compound of formula (3) used, or the amount of the acetic acid used is 5 equivalents or less with respect to the amount of the compound of formula (3) used.
11. The method according to claim 1 , wherein the poor solvent is any one of an ether solvent, an aliphatic hydrocarbon solvent, and an aromatic hydrocarbon solvent.
12. The method according to claim 11 , wherein the amount of any one of the ether solvent, the aliphatic hydrocarbon solvent, and the aromatic hydrocarbon solvent is 20 times or less with respect to the amount of the compound of formula (3).
13. The method according to claim 1 , wherein the compound of formula (3) is used, which is obtained by allowing a compound represented by the following formula (1) to react with a lower alcohol in the presence of acid:
so as to produce a compound represented by the following formula (2):
wherein R represents a lower alkyl group, and then allowing a compound represented by X—Cl or X 2 O wherein X represents a protecting group of a hydroxyl group, to act on the thus produced compound of formula (2) to obtain the compound of formula (3).
14. The method according to claim 1 , which comprises isolating the β-anomer of the produced compound of formula (4) by further crystallizing the compound of formula (4) by further subjecting the compound of formula (4) to crystallization or to suspension and washing.
15. The method according to claim 14 , wherein the solvent used in the crystallization or the suspension and washing is an alcohol solvent, an ether solvent, water, or a mixture thereof.
16. The method according to claim 1 , which further comprises condensing the product compound of formula (4) to a nitrogen-containing heterocyclic compound, a thymine, or a 5′-fluorocytosine.