Process for preparing nucleosides with unprotected sugars

Details Process for preparing nucleosides with unprotected sugars Process for preparing nucleosides with unprotected sugars

1997-04-04

1998-05-12

Kunz, Gary L.

Organic compounds -- part of the class 532-570 series

Organic compounds

Carbohydrates or derivatives

536 2671, C07H 100, C07H 106, C07H 19067, C07H 19167

Patent

active

057506760

DESCRIPTION:

BRIEF SUMMARY
The invention relates to a novel process for preparing nucleosides.
German Patent DBP 1919307 describes a process for preparing nucleosides, in which process O-acylated 1-O-acyl, 1-O-alkyl and 1-halo sugars are converted into the corresponding O-acylated nucleosides using silylated heterocyclic bases, such as uracil or 6-azauracil, in the presence of Friedel-Crafts catalysts such as SnCI.sub.4.
This process, involving the separate, prior silylation of the heterocyclic bases and their subsequent condensation with the abovementioned O-acylated 1-O-alkyl or 1-O-acyl sugars can, according to DOS 25 08 312, be simplified by carrying out the silylation of the heterocyclic bases and their condensation with O-acylated 1-O-alkyl or 1-O-acyl sugars in one step.
However, all these previous processes, which have been used widely in practice, employ O-acylated sugar derivatives which, like the very frequently used 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose, have to be prepared from D-ribose by a multistep synthesis.
It has now been found, surprisingly, that this multistep and elaborate conversion of the free sugars, such as D-ribose, into the corresponding O-acylated 1-O-alkyl or 1-O-acyl sugars, such as the already mentioned 1-O-acetyl-2,3,5-tri-O-benzoyl-.beta.-D-ribofuranose, no longer applies, or becomes superfluous, if the free sugars, such as D-ribose or D-glucose, are persilylated, in the presence of the free bases, such as uracil, 6-azauracil, N.sup.6 -benzoyladenine or N.sup.2 -acetylguanine, in an inert solvent, with silylating agents, such as hexamethyldisilazane (HMDS) and trimethylchlorosilane (TCS), and a Lewis acid, such as trimethylsilyl triflate, trifluoromethanesulfonic acid, trimethylsilyl nonaflate, perfluorobutanesulfonic acid or SnCl.sub.4, is added either simultaneously or subsequently, resulting in the corresponding persilylated nucleosides being produced. These persilylated nucleosides can be converted into the desired free nucleosides by means of transsilylation using boiling methanol.
The invention consequently relates to a novel process for nucleoside synthesis, which process comprises reacting the free sugar with heterocyclic bases in the presence of silylating agents in an inert solvent containing a Lewis acid.
Following neutralization of the Lewis acid, the persilylated nucleosides which have been obtained are converted into the corresponding free nucleosides by means of transsilylation using excess methanol.
When the free sugars and the heterocyclic bases are persilylated with equivalent quantities of hexamethyldisilazane (HMDS) and trimethylchlorosilane (TCS) in boiling absolute acetonitrile, the ammonium chloride which forms sublimes in the reflux condenser and in this way is removed from the reaction mixture.
However, it is often expedient to silylate the mixture of sugar and heterocyclic base only with the calculated quantity of HMDS in the presence of catalytic quantities of TCS, with only ammonia being produced and escaping during heating in acetonitrile. When the reaction is conducted in this manner, the reaction mixture is not contaminated with NH.sub.4 Cl, and the Lewis acid can be added after the silylation is completed, with a clear solution being formed.
However, any other silylating agent, such as N,O-bis(trimethylsilyl)-acetamide or N,O-bis(trimethylsilyl)acetamide, can be used instead of HDMS/TCS. ##STR1##
Suitable free sugars are the sugars, such as D-ribose, D-xylose, D-glucose and D-galactose, inter alia, which are customarily used for nucleoside synthesis.
When free D-ribose reacts, the primary 5-hydroxyl group of the furanose form is first of all silylated selectively so that the persilylation results in virtually only persilylated D-ribofuranose, which, together with silylated heterocyclic bases, only gives rise to the corresponding natural D-ribofuranosyl nucleosides.
In individual cases, it can be advantageous, prior to the actual nucleoside synthesis, to selectively react the free primary hydroxyl groups of the sugars, such as the 5-hydroxyl group of D-r

REFERENCES:
Bennua-Skalmowski et al. Tetrahedron Letters vol. 36, No. 43, pp. 7845-7848, 1995.
Derwent Abstract No. 78-77591A, JP53108986 A 780922.

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