Process for preparing adenine

Adenine is prepared by heating hydrogen chloride and hydrogen cyanide in a mixture of phosphorus oxychloride and dichlorophosphoric acid as solvent in a sealed vessel or by heating N-dichloromethylformamidine hydrochloride or triazine hydrochloride in a mixture of phosphorus oxychloride and dichlorophorphoric acid.

SUMMARY OF THE INVENTION 
This invention relates to a novel and improved method for producing 
adenine. 
Adenine is a useful intermediate for the preparation of 
6-amino-9-(substituted benzyl)purines, for example, those described in 
U.S. Pat. No. 3,846,426. Novel 6-amino-9-(substituted benzyl)purines are 
prepared by allowing an appropriately substituted benzyl halide, e.g., a 
substituted benzyl chloride, to react with adenine under the appropriate 
conditions. Oxidation of the resulting purine derivatives yields the 
corresponding N.sup.1 -oxides. These compounds, i.e., both the purine 
derivatives and the N.sup.1 -oxides thereof, have anticoccidial activity 
and are useful for controlling cecal and/or intestinal coccidiosis when 
administered in minor quantities to animals, in particular to poultry, 
usually in admixture with animal sustenance. 
Heretofore, adenine has been synthesized from pyrimidine derivatives 
obtained by the reaction between malononitrile and thiourea, or by the 
reaction between malonic diamide and formamide, or by the reaction between 
formamidine and phenylazomalononitrile, or from 6-aminopurines having a 
halogen atom or mercapto group on the purine nucleus, or from imidazole 
derivatives (e.g. 4-aminoimidazole-5-carboxamide). It has also been 
synthesized by various modifications of the above-mentioned methods. 
It has been reported that adenine was obtainable, though in very low yield, 
from hydrogen cyanide in the presence of ammonia. Recently, it has further 
been reported that adenine could be obtained in improved yields from 
hydrogen cyanide in the presence of ammonia under pressure. 
More recently, it has further been reported that adenine can be prepared by 
subjecting formamide to the action of one of the oxyacids of phosphorus or 
of sulfur or the halides thereof which comprise phosphorus trichloride, 
phosphorus pentachloride, phosphorus oxychloride, phosphorus pentoxide, 
polyphosphoric acid, pyrophosphoric acid, thionyl chloride, sulfuryl 
chloride, chlorosulfonic acid and tosyl chloride. 
However, these methods are less practical for the industrial production of 
adenine owing to the slightly more expensive starting materials and to the 
many and complicated steps as compared to the present process. 
A principal object of this invention is to obviate the defects inherent in 
the prior art methods and to provide a novel process for producing adenine 
from HCN under acidic conditions and with a simple isolation procedure. 
The aforesaid object is realized by heating hydrogen cyanide and hydrogen 
chloride in a mixture of phosphorus oxychloride and dichlorophosphoric 
acid as solvent. The novel process may be described by the following 
equation: 
##STR1## 
While the present process may be carried out in general when both starting 
materials are used in the molar ratio of 1:1, one of the starting 
materials may be employed in an excess amount if desired. The following 
molar ratios are used in carrying out this reaction: 
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HCl:HCN 1:2-10:1 
POCl.sub.3 :Cl.sub.2 PO.sub.2 H 
1:2-4.5:1 (optimum ratio) 
HCN:Cl.sub.2 PO.sub.2 H 
1:2-2:1 
______________________________________ 
The use of a mixture of phosphorus oxychloride (POCl.sub.3) and 
dichlorophosphoric acid (Cl.sub.2 PO.sub.2 H) as a solvent is critical for 
obtaining the best yields of adenine. Phosphorus oxychloride alone or 
dichlorophosphoric acid alone under these conditions yields less then 15% 
adenine. The solvent can be prepared by mixing POCl.sub.3 and Cl.sub.2 
PO.sub.2 H in the required proportion. A preferred method is to generate 
the required proportion of POCl.sub.3 and Cl.sub.2 PO.sub.2 H in situ by 
adding a calculated amount of water to POCl.sub.3. This method of 
preparing the solvent has the advantage of producing HCl which is a 
required reagent in the reaction. 
The reaction of the present invention is carried out under heating from 
about 100.degree. C. to about 170.degree. C. (preferably about 120.degree. 
C. to about 150.degree. C.) in a sealed vessel. 
According to the present invention, the HCN and HCl in the above equation 
can be replaced by one-half mole of HCN dimer i.e. 
N-dichloromethylformamidine hydrochloride or one-third mole of HCN trimer 
i.e. triazine sesquihydrochloride or a yellow polymer of HCN as its HCl 
salt as described below in Examples 5 and 6, to obtain a comparable yield 
of adenine in the same solvent system and reaction conditions and 
temperature range. 
The process can be illustrated by the following equations: 
##STR2## 
Adenine thus obtained can be separated from the reaction mixture in a 
simple manner, e.g., by concentration of the reaction system, quenching, 
filtration and recrystallization. If necessary, purification processes 
using ion-exchange resins, adsorbents or the like may concomitantly be 
employed for isolating the adenine. 
In the method of this invention, adenine is produced by a single step 
reaction and the isolation is very facile. Moreover, in the method of this 
invention, by-products which ordinarily render the separation and 
purification of adenine difficult, are largely soluble and easily removed 
by recrystallization.

The following examples set forth presently preferred illustrative, but not 
limitative embodiments of the invention. 
EXAMPLE 1 
Preparation of Mixtures Containing Phosphorus Oxychloride (POCl.sub.3) and 
Dichlorophosphoric Acid (Cl.sub.2 PO.sub.2 H) 
Mixtures of POCl.sub.3 and Cl.sub.2 PO.sub.2 H in a ratio of 1:1 are most 
conveniently prepared by carefully adding one mole of water to two moles 
of POCl.sub.3. Other ratios of these reagents may be prepared by adjusting 
the amount of water according to the amount of Cl.sub.2 PO.sub.2 H 
desired. This is in accordance with the principles set forth in J. R. Van 
Wazer and E. Flusk, J. Am. Chem. Soc., 81, 6360 (1959) which is herein 
incorporated by reference. The reaction of POCl.sub.3 with water is 
explained by the following equation: 
EQU POCl.sub.3 +H.sub.2 O.fwdarw.Cl.sub.2 PO.sub.2 H+HCl 
EXAMPLE 2 
Preparation of Adenine from HCN, HCl, POCl.sub.3 and Water 
To two moles of POCl.sub.3 (307 g., 104 ml.) was added one mole of water 
over a 45 minute period. The internal temperature was maintained at about 
20.degree. to 25.degree. C. by cooling with an ice-bath. The exothermic 
reaction temperature did not exceed 27.degree. C. To the resulting 
solution of POCl.sub.3, dichlorophosphoric acid and HCl (hydrogen 
chloride) was added one mole HCN (27 g., 39 ml.). The solution was cooled 
to 0.degree. C. and saturated with 0.4 mole anhydrous HCl (14.5 g.). 
The solution was placed in a glass lined rocking bomb with approximately 
two volumes of head space and heated at 120.degree. C. for 15 hours. The 
maximum pressure was 87 psig and the final pressure after cooling to 
25.degree. C. was 32 psig. 
At the end of the reaction period, the excess POCl.sub.3 (50 ml., 0.545 
moles) was recovered by vacuum distillation. The residue (272 g.) was 
quenched into 200 ml. of methanol at 60.degree. C. over a 30 minute 
period. The solids were collected by filtration and washed with 50 ml. 
methanol and ether (2.times.50 ml.) with slurring. The product was dried 
overnight in vacuo at 60.degree. C. to yield a dark, damp solid weighing 
45.9 g. The crude cake contained 7.6 g. of adenine. 
The crude cake was suspended in 60 ml. hot water. The dark insoluble 
material was filtered and washed with 5 ml. hot water. The filtrate and 
washings were allowed to cool to 45.degree. C. and seeded with crystals of 
adenine hydrochloride hemihydrate. The seeded solution was cooled to 
25.degree. C. over a 4 hour period and aged at 0.degree. C. for 18 hours. 
The solid was collected by filtration, washed with 15 ml. cold isopropyl 
alcohol:water (3:1) and dried in vacuo to constant weight at 75.degree. C. 
The solid weighed 7.4 g. and contained adenine.HCl1/2H.sub.2 O of about 
88% purity. 
EXAMPLE 3 
Preparation of Adenine from N-Dichloromethylformamidine Hydrochloride (HCN 
dimer) 
To a solution of 100 ml. of phosphorus oxychloride (POCl.sub.3) and 100 ml. 
of dichlorophosphoric acid (Cl.sub.2 PO.sub.2 H) was added 22.2 g. of 
N-dichloromethylformamidine hydrochloride [prepared by the process set 
forth in E. Allenstein, A. Schmidt, and V. Beylo, Chemische Berichte, 99, 
431 (1966) by treating an ethereal solution of HCN with hydrogen chloride 
at -15.degree. C.] This mixture was placed in an autoclave and heated at 
130.degree. C. for 15 hours. Assay of the cooled solution by high pressure 
liquid-liquid chromatography showed the yield of adenine to be 2.78 g. 
(38%). The isolation of the adenine is carried out as set forth in Example 
2. 
EXAMPLE 4 
Preparation of Adenine from 1,3,5-Triazine Sesquihydrochloride, POCl.sub.3 
and Water 
To two moles of POCl.sub.3 (307 g., 104 ml.) was added one pole of water 
over a 45 minute period. The internal temperature was maintained at about 
20.degree. to 25.degree. C. by cooling with an ice-bath. The exothermic 
reaction temperature did not exceed 27.degree. C. To the resulting 
solution was added 0.33 mole of triazine sesquihydrochloride (135.75 g.) 
[prepared by heating N-dichloromethylformamidine hydrochloride as 
described in C. Grundmann and A. Kreutzberger, J. Am. Chem. Soc., 76, 5646 
(1954)]. The solution was cooled to 0.degree. C. and saturated with 0.4 
mole anhydrous HCl (14.5 g.). 
The solution was placed in a glass lined rocking bomb with approximately 
two volumes of head space and heated at 120.degree. C. for 15 hours. The 
maximum pressure was 87 psig and the final pressure after cooling to 
25.degree. C. was 32 psig. 
At the end of the reaction period, the excess POCl.sub.3 (50 ml., 0.545 
moles) was recovered by vacuum distillation. The residue (272 g.) was 
quenched into 200 ml. of methanol at 60.degree. C. over a 30 minute 
period. The solids, containing adenine, were collected by filtration, 
washed with 50 ml. methanol and ether 2.times.50 ml. with slurring and 
dried overnight in vacuo at 60.degree. C. 
The crude cake was suspended in 60 ml. hot water. The dark insoluble 
material was filtered off and washed with 5 ml. hot water. The filtrate 
and washings were allowed to cool to 45.degree. C. and seeded. The seeded 
solution was cooled to 25.degree. C. over a 4 hour period and aged at 
0.degree. C. for 18 hours. The solid was collected by filtration, washed 
with 15 ml. cold isopropyl alcohol:water (3:1) and dried in vacuo to 
constant weight at 75.degree. C. The solid contained 
adenine.HCl.1/2H.sub.2 O. 
EXAMPLE 5 
Preparation of Yellow Polymer of Hydrogen Cyanide 
Phosphorus oxychloride (1.227 kg, 8 moles) was cooled to 5.degree. C. and 
over 1 hour at 5.degree. to 10.degree. C. there was added formamide (181 
g. 4 moles). The mixture was warmed to 30.degree. C. and it slowly 
exothermed to 40.degree. C. The reaction mixture was maintained at 
40.degree.-45.degree. C. with cooling until heat evolution subsided after 
45 minutes. During this time vapors of hydrogen cyanide were condensed and 
returned to the reaction. The mixture was placed in a glass-lined 
autoclave, sealed, and heated at 90.degree.-95.degree. C. for one hour. 
After cooling, the pale yellow solid was filtered, washed with 100 ml. of 
POCl.sub.3 and then with 300 ml. of diethyl ether. The product was dried 
in vacuo to a constant weight of 38.4 g. When heated this product darkens 
and partially sublimes, and the residue decomposes with vigorous gassing 
at 210.degree.-215.degree. C. This polymer is composed of approximately 
two parts of HCN and one part of HCl and a trace of phosphorus. It has the 
ratio of elements as follows: C.sub.12 H.sub.12 N.sub.12.6HCl.H.sub.3 
PO.sub.4 and is not soluble in dimethyl sulfoxide and is decomposed by 
water. The molecular weight of the polymer, exclusive of HCl and H.sub.3 
PO.sub.4, is in the range of about 324 to about 972. 
The percentage of elements found in the polymer is as follows: 
C, 20.98% 
H, 4.26% 
N, 29.08% 
Cl, 37.06% 
P, 4.0% 
EXAMPLE 6 
Preparation of Adenine from Yellow Polymer of HCN 
Yellow polymer (9.1 g.) composed of two parts of hydrogen cyanide with one 
part of hydrogen chloride was placed in a 1:1 solution (50 ml.) of 
POCl.sub.3 and Cl.sub.2 PO.sub.2 H and heated in a glass-lined autoclave 
at 130.degree. C. for 15 hours. The cooled, yellow solution was quenched 
over 400 g. of ice and diluted to a final volume of 500 ml. with water. 
This solution was assayed by quantitative high pressure liquid-liquid 
chromatography which showed the presence of 1.7 g. of adenine.