US 5,688,948 AGranted

Process for isomerizing acyclic nucleosides and process for separating purine nucleosides

AssigneeAjinomoto Co., Inc.

InventorsKunisuke Izawa, Yoshihito Koguchi, Hiroshi Shiragami, Yumiko Uchida, Satoshi Takamatsu

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Abstract

Herein is disclosed a novel and industrially advantageous process for synthesizing acyclic nucleosides such as acyclovir and ganciclovir from ribonucleosides, which process comprises adding an acid catalyst and an acid anhydride to a solution of a ribonucleoside such as guanosine and an ester derivative of an acyclic sugar, and heating the mixture, whereby a transglycosilation reaction takes place between the ribose moiety of the ribonucleoside and the ester derivative of the acyclic sugar. Herein is also disclosed an industrially favorable method for the separation of 9-substituted purine nucleosides which are important intermediates for the synthesis of acyclic nucleosides such as acyclovir, ganciclovir, and the like from ribonucleosides, which method comprises crystallizing only the 9-isomer from a solution or suspension containing both a 9-substituted purine nucleoside and a 7-substituted purine nucleoside by cooling the solution or/and by adding a crystallizing solvent thereto.

A process for producing an acyclic nucleoside derivative represented by the formula (I):

##STR19## wherein R.sup.1 represents a methylene group, R.sup.2 represents an alkylene group with 1 to 4 carbon atoms which may be substituted with hydroxyl group(s), amino group(s), alkoxyl group(s) with 1 to 12 carbon atoms, alkoxycarbonyl group(s), phosphono group(s), dialkoxyphosphoryl group(s), acyloxyl group(s) with 1 to 12 carbon atoms, acylamino group(s) with 1 to 12 carbon atoms, halogen atom(s) and/or silyloxyl group(s) represented by the formula (Ib):
##STR20## wherein R.sup.5, R.sup.6 and R.sup.7 which may be identical with, or different from, one another represent an alkyl group with 1 to 4 carbon atoms, a phenyl group or a benzyl group,
R.sup.3 and R.sup.4 each represent independently a hydrogen atom, a halogen atom, a hydroxyl group, an amino group or a mercapto group, said hydroxyl group, amino group and mercapto group being one which may be substituted with an alkyl group with 1 to 12 carbon atoms, an acyl group with 1 to 12 carbon atoms or a silyl group represented by the formula (Ia):
##STR21## wherein R.sup.5, R.sup.6 and R.sup.7 are the same as those in the formula (Ib),
X represents an oxygen atoms, a sulfur atom, or an amino group, and
Y represents a hydroxyl group, an amino group, an alkoxyl group with 1 to 12 carbon atoms, a phosphono group, a dialkoxyphosphoryl group, an alkoxycarbonyl group with 1 to 12 carbon atoms, an acylamino group with 1 to 12 carbon atoms, a halogen atom, or a silyoxyl group represented by the above-mentioned formula (Ib), wherein acyl is a hydrocarbon carboxylic acid acyl having 1 to 12 carbons, and wherein said process comprises:
(1) heating a solution or suspension containing a 9-substituted purine nucleoside represented by the formula (I) and a 7-substituted purine nucleoside represented by the formula (II) at a temperature within the range from 50.degree. C. to the reflux temperature:
##STR22## where R.sup.1, R.sup.2, R.sup.3, R.sup.4, X and Y are respectively the same as in the above-mentioned formula (I), and
(2) crystallizing selectively the 9-substituted purine nucleoside from said solution or suspension.

6 more elements

Facts

Application

08/454,567Filed 30 May 1995 · division

Priority

JP 3-23824718 Sep 1991

Granted

18 Nov 1997

Term ends

Not estimatedThe source records don’t support an estimate.

Classification5 codes

C07D 473/00
Heterocyclic compounds containing purine ring systems
C07D 473/18
With oxygen, sulphur, or nitrogen atoms directly attached in positions 2 and 6: one oxygen and one nitrogen atom, e.g. guanine
C07H 19/16
Heterocyclic radicals containing only nitrogen atoms as ring hetero atom: purine radicals
C07D
Heterocyclic compounds

Abstract

Claims6