CS269077B1 - Method of 5-azacytosines preparation - Google Patents

Abstract

The invention relates to the production of antisecretory compounds. The method of production according to the invention enables the production of large quantities of a substance of general formula I, where R represents hydrogen, C. to C. alkyl or phenyl, in high yields and in very good quality. The method of production according to the invention consists in heating salts of amidinoureas with esters of orthoacids in a medium of H,H-dialkylamides.

Description

The invention relates to methods for the preparation of 5-azacytosines, i.e. 4-amino-1,3,5-triazin-2(1H)-ones of the general formula I

' II I ^/J/ '

H · where R represents hydrogen, alkyl with 1-6 carbon atoms or phenyl.

Some compounds of the general formula X exhibit antisecretory effects in mammals and at the same time significantly reduce the incidence and extent of gastric ulcers in doses that are non-toxic to the organism. Thus, unsubstituted 5-azacytosine alone at a dose of 30 mg/kg body weight prevents almost 100% of the formation of experimental gastric ulcers [čihák, Pískala, Korbová, Čížková, Kučerová: Experientia 42, 32 (1986)]'. Some 6-aryl-5-azacytosines inhibit the formation of experimental gastric ulcers by 41 to 86%. ^Hurai, Oochata, Aoyagi, Ueda: Jap. pat. vykl, spis no. 7 670 780 (1976); Chem. Abstr. 86, 29889 h (1977)]. 5-Azacytosine is also an important intermediate for the production of cytostatically highly effective 5-azacytosine nucleosides (5-azacytidine, 2*-deoxy-5-azacytidine and 1-^-D-arabinofuranosyl-5-azacytosine), 5-azacytosines can be prepared by partial hydrolysis of 2,4-diamino-1,3,5-triazines, cyclization of acylamidoureas, condensation of cyanoguanidines with acid anhydrides, further oxidation of 2-amino-4-mercapto-1,3,5-triazines or, reaction of acylurethanes with guanidine (Smolin, Rapoport: s-Triazines and Derivatives, Interscience, New York 1959). 5-Azacytosines can be further prepared by ammonolysis of 4-methoxy-1,3,5-triazin-2(1H)-ones [Pískala, Gut: Collect. Czech. Chem. Commun. 28, 1681, 1963)] or cyclocondensations of amidinoureas with various carboxylic acid derivatives [ Pískala: Collect. Czech. Chem. Commun 32, 3966 (1967)]. The best results were achieved using dimethylformamide dimethylacetal or orthoacid esters. Due to the high price of dimethylformamide dimethylacetals and the difficult availability of dialkylacetals of other dialkylenes, it is more advantageous from a production point of view to use orthoacid esters, which are significantly cheaper and generally readily available. The disadvantage of orthoacid esters is their lower reactivity, which requires the use of higher temperatures (around 150 °C). Since free amidinoureas are unstable at the above temperatures, by-products are formed, which reduces the overall yield and quality of the products obtained.

Further study of this approach to the preparation of 5-azacytosines revealed that the above-mentioned shortcomings can be eliminated by using amidinourea salts with mineral or carboxylic acids. The reaction of these salts with orthoacid esters proceeds surprisingly easily even at lower temperatures, in high yields, and the products obtained are of very good quality. The best course of the reaction was when using Ν,Ν-dialkylamides as solvents. The reaction was carried out by heating to 100 to 120 °C (bath temperature), but it proceeds more slowly even at lower temperatures. Alkyl esters of orthoacids, preferably ethyl esters of orthoacids, were used for cyclocondensations. The advantage of the presented procedure is that the preparation of free amidinourea is eliminated here and the starting salts of amidinoureas are easily available by hydrolysis of very cheap dicyandiamide.

The essence of the invention of the method for preparing 5-azacytosines of general formula I consists in reacting the amidinourea salt of general formula II nh ₂ nh ₂ -co-n=Í-nh ₂ .hk /11/, where X is the anion of a hydrohalic acid or a carboxylic acid with 1 to 4 carbon atoms, with an ester of an orthoacid of general formula III

CS 269 077 B1 ^/OR ¹ RC—--OR ¹ /111/, •^or' where R means the same as in formula I and R ¹ is alkyl with 1 to 4 carbon atoms, in the environment of an N,K-dialkylamide of general formula IV •2 ?

r^-c-r//IV/ \r3.

where R is hydrogen or alkyl of 1 to 4 carbon atoms and R ^J is alkyl of 1 to 4 carbon atoms.

The readily available salts of amidinourea with formic or hydrochloric acid proved to be suitable as starting materials. The reaction proceeded rapidly when the bath was heated to a temperature of 100 to 120 °C, but slowly at room temperature. An excess of ethyl esters of orthoacids was preferably used for the cyclocondensation. N,N-dimethylformamide or N,H-dimethylacetamide was preferably used as the solvent. In other solvents the reaction proceeded slowly.

The invention is further explained in the examples without being limited thereto.

Example 1

Preparation of 5-azacytosine

A mixture of 2.94 g of amidinourea formate, 20 ml of ethyl orthoformate and 30 ml of H,H-dimethylphoxamide is heated for 1 h at 100 to 120 °C (bath temperature). After cooling, the precipitated product is filtered off with suction, washed with methanol and dried at 110 °C in a water pump vacuum. 1.75 g (79%) of 5-azacytosine is obtained; mp > 350 °C (decomposition); UV:^ _max 0.1N-HCl 248 nm (log£ 3.80). '

Example 2

A mixture of 2.75 amidinourea hydrochloride, 20 ml ethyl orthoformate and 30 ml H,R-dimethylformamide is heated for 1.5 h at 100-120 °C (bath temperature). After cooling, the precipitated product is filtered off with suction and worked up as in Example 1. 1.62 g (73%) of 5-azacytosine are obtained, mp >350 °C (decomposition); nV:A _max 0.1 K-H01 248 nm (log £ 3.80).

Example 3

Preparation of 6-methyl-5-azacytosine

A mixture of 2.94 formate amidinourea, 20 ml ethyl orthoacetate and 30 ml N,K-dimethylformamide is heated for 30 min. at 100 to 120 °C (bath temperature). After cooling, the precipitated product is filtered off with suction, washed with methanol and dried at 110 °C in a water pump vacuum. 2.10 g (83%) of 6-methyl-5-azacytosine are obtained; mp >350 °C (decomposition); UV- _{A ax} 0.1 N-HCl 245 nm (log 6 3.93).

Example 4

Using 2.75 g of amidinourea hydrochloride, 2.02 g (80%) of 6-methyl-5-azacytosine were obtained by the procedure of Example 3, mp <350°C (decomposition); UV:A _Bax 0.1 N-HCl 245 nm (log ε 3.93).

Example 5

By the procedure of Example 3, using N,K-dimethylacetamide (30 ml) instead of N,N-dimethylformamide, 2.15 g (85 ¢) of 6-methyl-5-azacytosine is obtained; mp)>-350 °C (decomposition); UV: Amax ⁰ »' ^{H-HCl 245 m} 3.93).

Example 6

Preparation of 6-phenyl-5-azacytosine

CS 269 077 Bl 3

A mixture of 2.75 amidinourea hydrochloride, 20 ml ethyl orthobenzoate and 30 ml N,N-dimethylformamide is heated for 1.5 h at 100 to 120 °C (bath temperature). After cooling, the precipitated product is filtered off with suction, washed with methanol and dried at 110 °C in a water pump vacuum. 1.95 g (52 $) of 6-phenyl-5-azacytosine is obtained; mp 332 to 335 °C (decomposition); UV:A _max pH6.9 248 nm (log£ 4.28). ^m '

Claims (4)

SUBJECT OF THE INVENTION 1. Method for preparing 5-azacytosines of general formula I /1/, where R denotes hydrogen, alkyl with 1 to 6 carbon atoms or phenyl, characterized in that the salt of the amidino compound of general formula II nh ₂ NH ₂ -CO-N=C-NH ₂ .HX /11/, where X is the anion of a hydrohalic acid or a carboxylic acid with 1 to 4 carbon atoms, is reacted with an orthoacid ester of the general formula III ^OR ¹ where R means the same as in formula I and R ¹ is an alkyl-dialkylamide of general formula IV η where R is hydrogen or alkyl of 1 to 4 carbon atoms /111/, with 1 to 4 carbon atoms, in the N,N/IV/ environment, and R^ is alkyl of 1 to 4 carbon atoms. 2. The method according to item 1, characterized in that formate or amidino urea hydrochloride is used as starting materials. 3. The method according to item 1, characterized in that ethyl esters of ortho acids are used for the cyclocondensation. 4. The method according to item 1, characterized in that the reaction is carried out in an environment of N,N-dimethylformamide or N,N-dimethylacetamide at a bath temperature of 100 to 120 °C.