Process for preparing 2-chloro-1,7-dihydropurin-6-one and a process for its purification

A process for the preparation of 2-chloro-1,7-dihydropurin-6-one which comprises the steps of: PA0 a) suspending 2-thioxanthine in concentrated hydrocloric acid, to produce a suspension; and PA0 b) contacting the suspension with chlorine, to produce 2-chloro-1,7-dihydropurin-6-one.

The invention relates to a process for the preparation and purification of 
2-chloro-1,7-dihydropurin-6-one (2-chloro-hypoxanthine). 
##STR1## 
2-chlorohypoxanthine (I) is derived from the base-structure 9H-purine 
(which, when unsubstituted in the 7and 9-positions, is in equilibrium with 
its tautomer 7H-purine [H. Beyer and W. Walter, Lehrbuch der organischen 
Chemie, S. Hirzel Verlag, Stuttgart 1988, p. 797]). 
In past years, derivatives of the purines have undergone a stormy period of 
development in terms of their use as therapeutic agents [T. W. Stone Ed., 
Purines - Pharmacology and Physiological Roles, VCH Verlagsgesellschaft, 
Weinheim 1985]. 
Thus, a large number of nucleosides having a purine partial structure have 
antimetabolic properties. Some nucleoside derivatives have been found 
which are capable of restricting the replication of the HIV virus 
responsible for AIDS. 
This group of effective nucleosides includes, in particular, nucleosides in 
which the so-called nucleoside base has a naturally occurring or 
derivatised purine system. The use of purine derivatives which are 
derivatised at the nitrogen atom in the 9-position and functionalised in 
the 2-position appear particularly promising [see also European Patent 
Application 343 133 and 291 917]. 2-Chlorohypoxanthine (I) would appear to 
be a suitable starting material for derivatised purines of this kind, 
being already suitably functionalised in the 2-position. 
The processes hitherto known from the literature for preparing this 
attractive intermediate compound do, however, suffer from the defect that 
industrial production is only possible at high cost, or that the necessary 
educts are not commercially available. 
Thus, J. A. Montgomery and L. B. Holum [J. Am. Chem. Soc. 79 (1957) 2185] 
describe a method of synthesis starting from 2,6-dichloropurine. A similar 
process is described by Y. Yamada et al. [Chemical Abstracts 66 (1967) 
9536 8a]. The disadvantages of both methods are, in particular, the fact 
that the partial hydrolysis of the dichloro compound requires considerable 
dilution of the starting material and the 2-chlorohypoxanthine can only be 
isolated in a yield of 66% (crude product). Furthermore, 
2,6-dichloropurine is expensive, not commercial available in large 
quantities and represents--because of its critical irritant, its 
allergenic and potential cancerogenic, character--a substance, the 
handling of which raises important problems with regard to safety 
engineering and working hygiene. These disadvantageous aspects indicate 
that this type of synthesis would be impractical for the industrial 
production of 2-chlorohypoxanthine. 
The second method described in the literature starts from 
2,8-dichloro-6-hydroxypurine [E. Fischer, Chem. Ber. 30 (1897) 2208; ibid. 
30 (1897) 2226] which is not, however, commercially available and 
accordingly has first to be produced from uric acid and 
phosphorusoxychloride. 
The 2,8-dichloro-6-hydroxypurine synthesised in this way has to be 
partially dehalogenated in another reaction step either with hydrogen 
iodide or by selective catalytic hydrogenolysis [H. Ballweg, Liebigs Ann. 
Chem. 649 (1961) 114]. Whereas dehalogenation with hydrogen iodide is very 
complex and impractical for industrial application, in catalytic 
hydrogenolysis the reaction product has to be recrystallised several times 
from water and is then obtained in a yield of only 77%, which means that 
this process is also unsuitable for adoption on an industrial scale. 
In addition, very high standards have to be imposed on the purity criteria 
of intermediate products used in manufacturing methods for synthesising 
pharmaceuticals. 
The aim of the present invention is to provide a process for preparing 
2-chlorohypoxanthine (I) (2-chloro-1, 7-dihydropurin-6-one) which allows 
this purine derivative to be produced easily and in good yields. 
A further objective of the present invention is to provide a method of 
synthesis in which the reaction products or intermediate products are 
obtained in a crystalline form which permits trouble-free further 
processing--centrifugation, drying, etc.--even of industrial-scale 
batches. 
A further aim of the present invention is to provide a method of 
purification in which the 2-chlorohypoxanthine (I) is obtained in a degree 
of purity which allows the product to be used directly as a starting 
material in other processes for preparing pharmaceutically active 
substances. 
In its broadest aspect, the invention provides a process for preparing 
2-chlorohypoxanthine, which may be obtained in the form of a salt or a 
hydrate, the process comprising reacting 2-thioxanthine suspended in a 
concentrated hydrochloride acid, with chlorine. 
Preparation of the 2-chlorohypoxanthine-hydrochloride monohydrate 
##STR2## 
According to the invention, the objectives outlined above are achieved by 
first preparing the monohydrate of 2-chlorohypoxanthine-hydrochloride 
starting from commercial 2-thioxanthine by chlorination in the presence of 
concentrated hydrochloric acid. To do this, the 2-thioxanthine is first 
suspended in concentrated hydrochloric acid and chlorine is introduced 
into the reaction mixture over a period of 3 to 7 hours--preferably about 
5 hours--at a temperature of 0.degree. C. to 10.degree. C.--preferably 
2.degree. C. to 7.degree. C. and especially 3.degree. C. to 5.degree. C. 
Then some of the hydrochloric acid is distilled off and the reaction 
mixture is cooled to a temperature in the range from -5.degree. C. to 
+10.degree. C.--preferably 0.degree. C. to 5.degree. C.--to cause 
precipitation of the required 2-chlorohypoxanthine in the form of the 
monohydrate of its hydrochloric salt. The reaction mixture is then suction 
filtered and the crystalline residue is washed first with saline solution 
and then with an organic solvent, preferably an alcohol, especially 
isopropanol, and dried. 
Preparation of the 2-chlorohypoxanthine 
##STR3## 
In a subsequent reaction step the 2-chlorohypoxanthine hydrochloride 
monohydrate is suspended in an aqueous solution at a pH ranging from 6 to 
7 and, preferably, a pH of 6.5, which is adjusted with an aqueous solution 
of an alkali or alkaline earth metal hydroxide, preferably an alkali metal 
hydroxide and especially concentrated sodium hydroxide solution. After the 
suspension is heated to a temperature in the range from 50.degree. C. to 
70.degree. C.--preferably 55.degree. C. to 65.degree. C. and more 
especially to a temperature of 60.degree. C. The resulting solution is, if 
necessary, treated with decolorising charcoal and filtered. An aqueous 
solution of an acid is admixed with the solution to adjust the pH to a 
value in the range from 2 to 4 and, preferably, 3.0. The acid is 
preferably an inorganic acid and especially hydrochloric acid. 
The resulting solution is cooled to a temperature in the range from 
-5.degree. C. to +15.degree. C.--preferably 5.degree. C. to 10.degree. C. 
to precipitate 2-chloro-hypoxanthine. The precipitate is washed with water 
and then with an organic solvent, preferably an alcohol, more particularly 
isopropanol, and dried. 
Preparation of sodium 2-chlorohypoxanthine hydrate 
##STR4## 
In order to prepare the sodium salt of 2-chlorohypoxanthine in highly pure 
form, 2-chloro-hypoxanthine-hydrochloride-monohydrate is suspended in 
water. Whilst cooling, the pH is adjusted to a value in the range from 9 
to 10, preferably, 9.5 to 10, and more preferably, 9.7, using an aqueous 
solution of an inorganic base, preferably a solution of an alkali metal 
hydroxide and more preferably using concentrated sodium hydroxide 
solution. 
The reaction mixture is then cooled to a temperature below ambient 
temperature, preferably to a temperature in the range from -2.degree. C. 
to +10.degree. C., more preferably 2.degree. C. to 5.degree. C. to 
precipitate the hydrate of the desired sodium salt. The crystalline 
precipitate is suction filtered and washed first with cooled brine and 
then with an organic solvent, preferably an alcohol and more especially 
isopropanol, and dried. 
Preparation of high purity 2-chlorohypoxanthine (I) 
##STR5## 
The pH of a suspension of sodium 2-chloro-hypoxanthine hydrate in water is 
adjusted to a value in the range of 6.5, using acid, preferably an 
inorganic acid and more especially dilute hydrochloric acid. The 
suspension is then heated to a temperature in the range from 55.degree. C. 
to 65.degree. C., preferably 60.degree. C. 
The resulting solution is filtered, optionally after treatment with 
decolorising charcoal. The pH of the filtrate is adjusted to a value in 
the range from 2 to 4, preferably a pH of 3.0, using an aqueous solution 
of an acid, preferably an inorganic acid and more particularly 1 N 
hydrochloric acid. The resulting suspension is then cooled to a 
temperature below ambient temperature, preferably to a temperature in the 
range from -2.degree. C. to +15.degree. C., more especially from 5 to 
10.degree. C., to precipitate the desired 2-chloro-hypoxanthine. The 
resulting precipitate is suction filtered and washed with water and then 
with an organic solvent, preferably an alcohol and more especially 
isopropanol. 
The crystalline residue is dried. The 2-chloro-hypoxanthine obtained in 
this way has a purity of more than 99%, according to HPLC analysis. 
The process steps explained above are described more accurately by the 
reaction sequence mentioned in the Examples. Various alternative 
embodiments of the process and the like will become apparent to anyone 
skilled in the art from the description. However, it is expressly pointed 
out that the Examples and the related specification are provided solely 
for the purpose of explanation and description and should not be regarded 
as a restriction of the invention.

EXAMPLES 
1) Preparation of 2-chlorohypoxanthine-hydrochloride-monohydrate 
230 g (3.24 mol) of chlorine are introduced into a suspension of 168.2 g 
(1.0 mol) of 2-thioxanthine in 68 liters of conc. hydrochloric acid in the 
course of about 5 hours at 3.degree.-5.degree. C. Then about 1 liter of 
hydrochloric acid is distilled off in a water jet vacuum, the residue is 
cooled to 0.degree.to +5.degree. C., suction filtered and washed with 0.5 
liters of saturated, ice-cold brine and finally with 300 ml of 
isopropanol. After drying at 50.degree. C. over a period of about 12 
hours, 93 g (85.7% of theory) of colourless crystal powder are obtained. 
By preparing the free base and again converting it into the hydrochloride 
the title compound is obtained in analytically pure form. Elemental 
analysis corresponds to the composition C.sub.5 H.sub.4 Cl.sub.2 N.sub.4 
O.times.H.sub.2 O. 
2) Preparation of 2-chlorohypoxanthine 
180 g (0.80 mol) of 2-chlorohypoxanthine-hydrochloride-monohydrate are 
suspended in 3.6 liters of water and the pH is adjusted to 6.5 by the 
dropwise addition of concentrated sodium hydroxide solution. After heating 
to 60.degree. C. the solution is treated with 18 g of decolorising 
charcoal and filtered. The filtrate is added dropwise to 300 ml of water, 
whilst a pH of 3.0 +/- 0.5 is maintained in the aqueous solution using 1N 
hydrochloric acid. The resulting suspension is cooled to 
5.degree.-10.degree. C., suction filtered and the precipitate is washed 
with 0.5 liters of water at a temperature of +5.degree. C. and with 300 ml 
of isopropanol. After drying at 50.degree. C., 117 g (85.8% of theory) of 
the title compound are obtained in the form of a colourless crystal 
powder. By purifying via the sodium salt and re-liberation of the base, 
analytically pure material is obtained which is identical to the substance 
prepared from 2,6-dichloropurine according to J. A. Montgomery and L. B. 
Holum [J. Am. Chem. Soc. 79 (957) 2185]. 
3) Preparation of sodium 2-chlorohypoxanthine hydrate 
80 g (0.3mol) of 2-chlorohypoxanthine-hydrochloride-monohydrate are 
suspended in 1.6 liters of water. Whilst cooling, a pH of 9.7 is adjusted 
using concentrated sodium hydroxide solution. After cooling to +5.degree. 
C. the precipitate is suction filtered, then washed with 250 ml of 20% 
brine (previously cooled to +5.degree. C.) and 250 ml of isopropanol. 
After drying at 50.degree. C., 65.7 g (77.6% of theory) of the title 
compound are obtained in the form of a colourless crystal powder. By 
suspending in cold water and again suction filtering, washing with cold 
water and methanol and drying, an analytically pure product is obtained, 
the composition of which corresponds to the formula C.sub.5 H.sub.2 
ClN.sub.4 ONa.times.2.5H.sub.2 O, according to elemental analysis. 
4) Preparation of highly pure 2-chlorohypoxanthine 
20 g of sodium 2-chlorohypoxanthine-hydrate are suspended in 400 ml of 
water, the pH is adjusted to 6.5 in the reaction solution using dilute 
hydrochloric acid and the mixture is heated to about 60.degree. C. After 
treatment with 2 g of decolorising charcoal and filtration, the 
2-chlorohypoxanthine is precipitated and isolated in the same way as 
described in Example 2 (at pH 3.0 +/- 0.5 and at ambient temperature). 
11.6 g (8% of theory) of the title compound are obtained in the form of 
colourless crystals. According to HPLC analysis the product has a degree 
of purity of more than 99%.