Process for the preparation of purine derivatives

A process for the preparation of a compound of formula (I) or a pharmaceutically acceptable salt thereof: ##STR1## which process comprises reacting a compound of formula (II): ##STR2## wherein the amino group is optionally protected, Y is iodo, optionally substituted benzylthio or (phenacylmethyl)thio, with a compound of formula (III): ##STR3## wherein Q is a leaving group, R.sub.x and R.sub.y are protected hydroxymethyl or acyloxymethyl, or group(s) convertible to hydroxymethyl or acyloxymethyl; and R.sub.z is hydrogen or a group convertible thereto; and thereafter converting Y to X is hydroxy by means of hydrolysis, or to X is hydrogen by means of reduction; converting R.sub.x and R.sub.y when other than hydroxymethyl or acyloxymethyl, to hydroxymethyl or acyloxymethyl, optionally converting R.sub.x /R.sub.y hydroxymethyl to acyloxymethyl or vice versa, deprotecting the 2-amino group where necessary and converting R.sub.z, (when other than hydrogen) to hydrogen; and optionally forming a pharmaceutically acceptable salt thereof.

The present invention relates to a novel process for the preparation of 
purine derivatives which have antiviral activity. EP-A-141927 and 
EP-A-182024 (Beecham Group p.l.c.) describe, inter alia, compounds of 
formula (I) and pharmaceutically acceptable salts thereof: 
##STR4## 
wherein X is hydrogen or hydroxy and R.sub.a and R.sub.b are independently 
hydrogen or a group RCO- wherein R is phenyl or C.sub.1-18 alkyl. 
The compounds of formulae (A) and (B); wherein X is OH and R.sub.a and 
R.sub.b are both hydrogen (BRL 39123); and wherein X is hydrogen and 
R.sub.a and R.sub.b are both acetyl (BRL 42810), are of particular 
interest as potential antiviral agents. 
##STR5## 
The process already described for the preparation of the above compounds 
involves the reaction of 2-amino-6-chloropurine of formula (C): 
##STR6## 
with a side chain intermediate of formula (D): 
##STR7## 
wherein R.sub.c and R.sub.d are independently acyl groups or hydroxy 
protecting groups and Z is a leaving group, such as halo, for example 
chloro, bromo, iodo; and thereafter converting the 6-chloro group to 
hydroxy by means of hydrolysis, or to hydrogen by means of reduction. 
The disadvantage with this process is that the use of the intermediate of 
formula (C) results in a mixture of products i.e. that when the side chain 
is attached at N-9 and the undesired product wherein the side chain is 
attached at N-7. This can result in low yields of the desired N-9 product. 
It has surprisingly been discovered that, if the 6-chloro group in the 
compound of formula (C) is replaced by an iodo group, a benzylthio group 
or a (phenacylmethyl)thio group, the ratio of N-9 product to N-7 product 
is increased, providing a better overall yield of the resulting compound 
of formula (I). 
Accordingly, the present invention provides a process for the preparation 
of a compound of formula (I) as hereinbefore defined, or a 
pharmaceutically acceptable salt thereof, which process comprises reacting 
a compound of formula (II): 
##STR8## 
wherein the amino group is optionally protected, Y is iodo, optionally 
substituted benzylthio or (phenacylmethyl)thio, with a compound of formula 
(III): 
##STR9## 
wherein Q is a leaving group, R.sub.x and R.sub.y are protected 
hydroxymethyl or acyloxymethyl, or group(s) convertible to hydroxymethyl 
or acyloxymethyl; and R.sub.z is hydrogen or a group convertible thereto; 
and thereafter converting Y to X is hydroxy by means of hydrolysis, or to 
X is hydrogen by means of reduction; converting R.sub.x and R.sub.y when 
other than hydroxymethyl or acyloxymethyl, to hydroxymethyl or 
acyloxymethyl, optionally converting R.sub.x /R.sub.y hydroxymethyl to 
acyloxymethyl or vice versa, deprotecting the 2-amino group where 
necessary and converting R.sub.z, (when other than hydrogen) to hydrogen; 
and optionally forming a pharmaceutically acceptable salt thereof. 
The intermediates formed in this reaction are of formula (IV): 
##STR10## 
which are novel and from an aspect of the invention. 
The reaction may be carried out in an inert solvent, for example 
dimethylformamide, dimethylsulphoxide or acetonitrile, preferably 
dimethylformamide, in the presence of an inorganic or organic base, over a 
temperature range from 0.degree. C. to the boiling point of the solvent, 
usually 30.degree.-40.degree. C. Examples of inorganic bases include 
alkali metal hydrides, alkali metal carbonates such as sodium or potassium 
carbonate and preferably potassium carbonate. Suitable organic bases are 
1,8-diazabicyclo[5 4.0]undec-7-ene and tetramethyl guanidine. 
Suitable examples of optional substituents in the phenyl group Y when 
benzylthio or (phenacylmethyl)thio, include one or two groups selected 
from C.sub.1-4 alkyl, halo and C.sub.1-4 alkoxy. Halo includes iodo, 
bromo, chloro and fluoro, and alkyl/alkoxy groups include those containing 
methyl, ethyl, n and iso-propyl. Y may also be diphenylmethylthio, 
optionally substituted in the phenyl ring(s) as defined for Y when 
benzylthio. Y is preferably iodo or benzylthio, most preferably iodo. 
Suitable examples of the leaving group Q, include halo, such as chloro, 
bromo or iodo, and tosyloxy and mesyloxy. 
Suitable examples of hydroxy protecting groups (other than acyl groups) 
include the t-butyl dimethylsilyl group removable by 80% acetic acid at 
elevated temperatures, around 90.degree. C., or by treatment with 
tetrabutyl ammonium fluoride in a solvent, such as tetrahydrofuran, at 
ambient temperature. 
Another suitable protecting group is wherein the two hydroxy groups in 
formula (III) (when R.sub.x is hydroxymethyl) are reacted with 
2,2-dimethoxypropane, forming a 1,3-dioxan ring. This group may be removed 
by acidic hydrolysis. 
Other suitable protecting groups include substituted benzyl groups such as 
p-methoxybenzyl, removable by treatment with 
2,3-dichloro-5,6-dicyanobenzoquinone. 
Other suitable protecting groups are apparent to those skilled in the art. 
R.sub.x and/or R.sub.y may be acyloxymethyl, such as a group RCO.sub.2 
CH.sub.2 wherein R is as defined in formula (I). Examples of R include 
methyl, ethyl, n- and iso-propyl, n- and iso-, sec- and tert-butyl, 
preferably methyl. 
Interconversion of R.sub.x /R.sub.y acyloxymethyl and hydroxymethyl may be 
carried out conventionally as described in EP-A-141927. 
Other suitable values of R.sub.x, R.sub.y, R.sub.z include wherein the 
compound of formula (III) is of formula (IIIA) or (IIIB): 
##STR11## 
wherein R.sub.p and R.sub.q are independently hydrogen, C.sub.1-6 alkyl or 
phenyl, or R.sub.p and R.sub.q together are C.sub.4-6 polymethylene; and 
R.sub.r is C.sub.1-6 alkyl or phenyl C.sub.1-6 alkyl, in which any phenyl 
moieties are optionally substituted, (as defined for Y hereinbefore when 
thiobenzyl). 
When the compound of formula (IIIA) is used, the resulting intermediate is 
of formula (IVA): 
##STR12## 
When the compound of formula (IIIB) is used, the resulting intermediate is 
of formula (IVB): 
##STR13## 
Values for R.sub.p and R.sub.q and R.sub.r include these values listed as 
suitable for R in formula (I), preferably methyl for R.sub.p and R.sub.q 
and ethyl for R.sub.r. In addition R.sub.p and R.sub.q may together be 
C.sub.4 or C.sub.5 polymethylene. 
The intermediates of formulae (IVA) and (IVB) are subsequently converted to 
an intermediate of formula (V): 
##STR14## 
by transesterification and hydrolysis/decarboxylation respectively, as 
described in the Examples hereinafter. 
An intermediate of formula (V) is convertible to a compound of formula 
(VI): 
##STR15## 
by reduction, under conventional conditions using, for example, sodium 
borohydride. 
It is preferred, however, that the intermediate of formula (III) is of 
formula (III)': 
##STR16## 
for the preparation of compounds of formula (A) and (B) as defined, 
because: 
(i) Compounds of formula (III)' give a particularly good N9:N7 ratio 
(regioselectivity). 
(ii) Ease of separation of N9:N7 isomers. 
(iii) The same intermediate of formula (III)' is used for the preparation 
of compounds of the formula (A) and formula (B). 
The 2-amino group may be protected, for example, using a benzyl protecting 
group, removable by hydrogenolysis. It may also be protected by an acyl 
group, for example acetyl, removable by hydrolysis, or a schiff's base, eg 
benzylidene, removable by acid hydrolysis. 
Pharmaceutically acceptable salts are formed conventionally. 
Intermediates of formula (III) wherein R.sub.x /R.sub.y are protected 
hydroxymethyl or acyloxymethyl may be prepared as described in EP-A-141927 
or by analogous methods thereto. 
Intermediates of the formula (IIIA) are known or are prepared by analogous 
methods, such as that described in Organic Syntheses Vol 60, page 66. 
Intermediates of formula (IIIB) are known or prepared by analogous methods. 
The compound of formula (IIIB) wherein Q is bromo and R.sub.r is ethyl may 
be prepared from triethyl methanetricarboxylate according to the procedure 
described by H. Rapoport et.al., J. Org. Chem., 44. 3492(1979). 
Intermediates of the formula (II) wherein Y is iodo or a thiobenzyl group 
may be prepared from the compound of formula (C). When Y is iodo, the 
preparation is by reaction with HI in a transhalogenation reaction, 
preferably using a cosolvent, such as acetone. When Y is optionally 
substituted thiobenzyl the preparation is by reaction with HY. When Y is 
(phenacylmethyl)thio the preparation is from thioguanine, by reaction with 
phenacyl bromide, as in Example 9a) hereinafter.