1,3,5-Triazines biguanides

Aromatic biguanides such as proguanil (181) have been found useful as antimalarial agents. Investigation of the metabolism of this class of drugs revealed that the active compound was in fact the triazine produced by oxidative cyclization onto the terminal alkyl group. The very rapid excretion of the active entity means that it cannot be used as such in therapy. Consequently, treatment usually consists in administration of either the metabolic precursor or, alternately, the triazine as some very insoluble salt to provide slow but continual release of drug. 

Biguanides are also formed by the breakdown of certain triazines. Thus alcoholic hydrochloric acid converts 2-dichloromethyl-6-phenylguanamine (LIV) into phenylbiguanide (LVI, R=Ph) 443), and aqueous ethanol... 

The conversion of biguanides into guanamines under the influence of acylating agents is well known (see also Section VII 12). Acetic anhydride or benzoyl chloride in conjunction with alkali react with the parent compound, gelding 2-methyl- 519) or 2-phenyl-4,6-diamino-s-triazine 17) (LXXXI R = Me or Ph) respectively. 

The reaction of biguanides with esters was first studied in detail by Rackmann 518) who showed that ethyl formate and arylbiguanides gave 2,4-diaraino-6-substituted s-triazines (LXXXIII, where R, R and R" may vary widely). 

The condensation of biguanide with acrylate esters [e.g. methyl acrylate in presence of sodium methoxide 484)1 was expected to afford a vinyl-triazine (LXXXIV, R = R = H), but gave in fact 2-( 3-methoxy-ethyl)guanamine (LXXXVI) (51%). The desired vinyl-triazine was finally synthesised 486) from phenylbiguanide and acrylyl chloride in aqueous acetonitrile and its structure proved by its hydrogenation to 2-ethyl-6-phenylguanamine. 

Methyl acetoacetate is reported (696) to yield the triazine (XCV R = H) as main product (85%), the pyrimidine being the by-product, of probable structure (XCIX) rather than (XCIV R = H). However, in view of the opposite conclusion in the case of the condensation of ethyl acetoacetate and substituted biguanides (see above), this formulation requires careful confirmation. 

The interaction of biguanide and ethyl 4-ketopentanoate affords the triazine (C) and pyrimidine (CII ) in equal yields (40% each) (696). The structure of the latter (Cl or CII) was not confirmed, but on the basis of the results of the corresponding reaction of ethyl acetoacetate (see above), structure (Cl) seems more likely. 

The reaction of biguanide and ethyl luvinate also affords equal proportions of the expected triazine and the pyrimidine (6P9). 

Cyano-esters react with biguanides with results not unlike those of keto-esters. Thus, biguanide and methyl 2-cyano-4-ethyloct-3-enoate (699, 703) [CH3(CH2)3CHEt-CH=CH-CH(CN)C02Me] give a product which may be either a triazine or a pyrimidine, but a choice has so far not been... 

The experimental procedure can be varied by the use of reagents which will give biguanides in situ and thus form the required triazine. Examples include 493, 554) the interaction of arylamines (e.g. p-chloro-aniline hydrochloride) and cyanoguanidine, followed by acetone and hydrochloric acid. Acetone may be replaced by its bisulphite compound, by diethyl acetal or by isopropenyl acetate, but p-chlorophenylbiguanide fails to condense 113) with acetone diethyl acetal at 130°. Under the correct acid conditions, the isomeric p-chloroanilino-triazine (CXXV) is not formed on the other hand, the free p-chlorophenylbiguanide base did not react with acetone in the absence of a catalyst. 

The condensation of 2-naphthylamine hydrochloride, cyanoguanidine and acetone yields, in addition to the expected dihydro-s-triazine, l-(2-naphthyl)biguanide and 3-guanidino-l-methylbenzo[f]quinazoline (554). 

No reaction occurred with 1,4,5-trisubstituted biguanides (e.g. 1-p-chlorophenyl-4,5-dimethylbiguanide) and acetone in basic media. Prolonged action under acid conditions gave small amounts of a picrate which appeared to correspond to the triazine (CXL). 

Studies have recently become available concerning the kinetics and mechanism of the isomerisation, in dilute aqueous solution, of dihydrotriazines of this type (e.g. 4,6-diamino-l-(3,5-dichlorophenyl)-l,2-dihydro-2,2-dimethyl-l,3,5-triazine), and of their degradation to substituted biguanides 683). 

The interaction of biguanide (CL) and isothiocyanate esters in dimethyl-formamide under mild conditions (376) gives excellent 3delds of 1-sub-stituted hexahydro-4,6-di-imino-s-triazine-2-thiones (CLII), together with small quantities of thioammeline (CLIII) and monosubstituted melamines (CLIV). Under more severe conditions, the latter (CLIV) become the main products. The production of these triazines is explained by a mechanism involving the primary formation of addition products (CLI), followed by their cydisation with loss of either ammonia, hydrogen sulphide, or primary amine (376). 

Biguanides [H2NC( = NH)NHC( = NH)NH2] react with lactones, amides, ortho esters, esters, acid anhydrides and acid chlorides to produce a wide range of 6-substituted 2,4-diamino-1,3,5-triazines (515) (59HC(l3)i). Biguanides with carbodiimides, isothiocyanates and ketones give corresponding melamines, thiones and dihydro derivatives, respectively. 

Table 9 Synthesis of 2,4-Diaraino-l,3,5-Triazines from Biguanides N...

There are not many examples of syntheses of fused 1,3,5-triazines from [5 +1] atom cyclizations. The basic synthetic strategy is similar to the syntheses of 1,3,5-triazines from biguanides, but in this case the five-atom component incorporates a heterocyclic substituent. The examples in equations (55)—(57) illustrate the approach (74JHC991,75HCA761,80JHC1121). 

Dicyandiamide (116) reacts with a variety of two-atom components to form 2,4-diamino-1,3,5-triazines. The route, which bears some resemblance to the syntheses from biguanides (see Section 2.20.4.2.1), was discovered by Ostrogovich (11MI22000). He found that 1,3,5-triazines were prepared efficiently on heating alkyl or aryl nitriles with dicyandiamide (equation 59). 

There are too many compounds to discuss efficient routes to all of them. The guidelines below are useful in determining the method of choice (a) 1,3,5-Triazines bearing heteroatomic substituents are often formed from cyanuric chloride, (b) 1,3,5-Triazines bearing 2-amino substituents may be formed efficiently from biguanides (see Section... 

Chloromethyl-4,6-diamino-s-triazine can be prepared in 82% yield by stirring a mixture of biguanide and ethyl chloroacetate in methanol in the same way. 

In the synthesis of 2-amino-4-anilino-6-chloromethyl-i-triazine from phenyl-biguanide hydrochloride (0.3 mole) and ethyl chloroacetate (0.3 mole), the hydrochloride is added to a solution of 0.3 mole of sodium methoxide in methanol, the solution is Altered from sodium chloride, ethyl chloroacetate is added, and the mixture is stirred at room temperature for 14 hrs. The product precipitates and is crystallized from dioxane. 

A number of compounds derived from biguanides, triazines and diami-nopyrimidines have been shown to be potent inhibitors of dihydrofolate reductase (DHFR) and, therefore, occupy an important position in the chemotherapy of human malaria and bacterial infections. 

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