Alkylating triazine derivatives

Tanaka etal, US Patent 6,130,332 (October 10, 2000) Assignee Nissan Chemical Industries, Ltd. 

Cyanuric chloride (1.0 mol) was dissolved in 800 ml acetonitrile, the solution cooled to 0°C, and 28% NH4OH solution (5.0 mol) added over 2 hours while keeping the temperature less than 10 °C. Thereafter, the mixture was stirred at ambient temperature one hour then warmed to 45 °C for 4 hours. The mixture was filtered, washed with water, dried, and the product isolated in 79% yield. 

A mixture of the product from Step 1 (0.1 mol), 100 ml water, and butylamine (0.4 mol) were refluxed 6 hours, filtered, washed with water, toluene, and the product isolated in 96% yield, mp = 167 °C. 

Cyanuric chloride (0.1 mol) was dissolved in 150 ml of acetonitrile at 0°C and butylamine (0.1 mol) dissolved in 200 ml water added over 1 hour. Thereafter, a solution of KHCO3 (0.1 mol) in 100 ml water was added dropwise, the mixture stirred 1 hour, and 28% NH4OH solution (0.4 mol) added. The mixture was heated to 50 °C 5 hours, filtered, and washed with water. The crude product was suspended in 100 ml water containing dissolved butylamine (0.4 mol), refluxed 6 hours, and extracted with 200 ml toluene. Toluene was removed by distillation and the product isolated in 93% yield, mp = 73°C. 

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The preparation of W-alkyl derivatives of 6-benzyl-3,5-dioxo-l,2,4-triazine by hydrolysis of the corresponding alkylmercapto derivatives was systematically studied by Cattelain. The conversion to known alkyl derivatives of dioxotriazines was used to determine the structure of alkylated methylmercapto derivatives. As will be shown later (e.g., Section H,B,4,b) this procedure has a general preparative significance for 1-alkyl derivatives of 6-azauracil. ... 

Alkylation of chlorotheophylline with chloroacetonitrile gave 608 and cyclization with hydrazine gave [88CI(L)785] triazine derivative 609. Condensation of the latter with different aldehydes gave the corresponding hydrazones. 

Hydrolytic cleavage of condensed 1,2,3-triazine derivatives is normally a straightforward, high-jneld process which results in production of one or other of several distinct types of product. 3-Alkyl- and 3-aryl-3,4-dihydro-l,2,3-benzotriazines, for example, undergo facile hydrolysis in concentrated hydrochloric acid to give, via the diazonium compound, A(-alkyl- and W-aryl-substituted o-chlorobenzylamines (100, R = Cl). If the reaction is carried out in water or in dilute mineral acid, the corresponding -alkyl and iV-aryl-substituted o-hydroxybenzylamines (100, R = OH) are obtained. 

The UV spectra of other types of 1,2,3-triazine derivatives are generally more complicated than those of the 3-alkyl- and 3-aryl-1,2,3-benzotriazin-4(3if)-ones, and in most cases data are available for only a small number of compounds of each type. Consequently, the utility of this information in diagnostic and structural elucidation work is not very... 

The 2-alkyl and 2-aryl derivatives are best prepared by the reaction between 1,3,5-triazine and an imidate or amidine (see Section 2.20.3.1.2). 2-Amino-l,3,5-triazines may be prepared efficiently by (a) treatment of 1,3,5-triazine with 1-amidinopyrazole (see Section 2.20.3.1) (b) condensation of triformidomethane and a formylguanidine (see Section 2.20.4.3.3). 2-Aryloxy derivatives are produced by hydrogenation of the corresponding dichloro-l,3,5-triazine derivative (see Section 2.20.3.12). 

Alkylated triazines of the current have also been prepared by heating melamine or melamine derivative and an alcohol in the presence of a hydrogenation-dehydrogenation mixed catalyst such as 5% palladium on carbon (50% hydrated) with 25 mg of Cu0/Cr203/Ni0/Ba0 and is reviewed (4). 

Morioka, M., Kato, M., Yoshida, H., Ogata, T. Anomalous Bamford-Stevens reaction of cis-N-alkyl-3-phenyl-2-aziridinyl phenyl ketones. Preparation of 1,6-dihydro-1,2,3-triazine derivatives. Heterocycles 1996, 43, 1759-1765. 

Cyanuric chloride on monosubstitution with nucleophiles such as methanol or 4-amino-azobenzene followed by displacement of a second chlorine with alanine amide gave compounds which are used for precolumn derivatization of amino acids. The diastereoisomers formed are resolved by reverse-phase HPLC <92MI 6l2-0i>. Enantiomeric amino acids are separated by HPLC on bis[carbamoyl(alkyl)methylamino]-6-chloro-l,3,5-triazine derived stationary phases <93JC277>. 

However, the reaction proceeds preferentially via route (a), as evidenced by the isolation of 72 % of the tetrameric cyanogen chloride XXXVIII. The triazine derivative XXXVIII can also be obtained by chlorination of the corresponding isothiocyanate C% A somewhat lower yield of the triazinyl-bis-carbonimidoyl chloride was obtained in the chlorination of 2,6-bis(di-methylamino)-4-chloro-l,3,5-triazine ( ). If cyclic carbamoyl chlorides, or carbamoyl chlorides having alkyl substituents other than methyl are chlorinated, the expected imidoyl chlorides are obtained For... 

A systematic investigation of various 4,6-diamino-l, 2-dihydro-l-aryl-2-alkyl-s-triazine derivatives was undertaken with the knowledge that cycloguanil is rapidly excreted from the body and that dihydrotriazines are therefore unlikely to induce systemic toxicity by accumulating in other tissues following release from a depot site. Synthetic approaches involved the preparation of macromolecules, amide and urea derivatives, and insoluble salts. Macromolecules, such as the bis[4,6-diamino-l,2-dihydro-2,2-dimethyl-s-triazines] (XVa and b) [70, 71], and amide and urea derivatives including XVI and XVII [51] were devoid of repository activity. 

Pyridone 136 reacts with excess alkyl isocyanates in the presence of tetramethylguani-dine to give the 1 2 adducts 137. A two-step addition of two different isocyanates produces 1,3-dialkyl-1,3,5-triazine derivatives having different alkyl substituents... 

There have been many reports of syntheses of deoxy nucleosides by standard sugar-base condensation reactions. These include 5 -deoxy-ribo nucleosides and 5 -mono- or 5",5-di-deuterated analogues, as well as derivatives of 5-deoxy-D-xylose and 5-deoxy-D-glucose, 5-alkylated thymidine derivatives, 2 -deoxy-6-methyl-5-azacytidine and its a-anomer, the thymidine analogue 4-(2-deoxy-B-D-erythro-pento-furanosyl)-6-methyl-l,2,4-triazine 3(HH)-one-1-oxide, 6-aza-3-deaza analogues of 2 -deoxy-cytidine and 2 -deoxyuridine,3 -deoxycytidine from a 3-deoxy-ribofuranose obtained from a fermentation broth producing the 3 -deoxy nucleoside antibiotic, cordycepin, 4-deoxy-DL-threo-pentopyranosyl pyrimidine nucleosides, and 5 -C-methyluridines derived from 6-deoxy-D-allose and 6-deoxy-D-talose. A range... 

Organic Derivatives. Although numerous mono-, di-, and trisubstituted organic derivatives of cyanuric and isocyanuric acids appear in the hterature, many are not accessible via cyanuric acid. Cyanuric chloride 2,4,6-trichloro-j -triazine [108-77-0], is generally employed as the intermediate to most cyanurates. Trisubstituted isocyanurates can also be produced by trimerization of either aUphatic or aromatic isocyanates with appropriate catalysts (46) (see Isocyanates, organic). Alkylation of CA generally produces trisubstituted isocyanurates even when a deUberate attempt is made to produce mono- or disubstituted derivatives. There are exceptions, as in the production of mono-2-aminoethyl isocyanurate [18503-66-7] in nearly quantitative yield by reaction of CA and azitidine in DMF (47). 

The pyrimidine compounds are known to undergo a rearrangement of the 0-alkyl derivatives to the iV-alkyl ones. The methoxy derivatives of 1,3,5-triazine display a similar behavior. On applying methyl iodide to 2,4-dimethoxy-l,3,5-triazine one of the methyl groups is shifted giving rise to l-methyl-4-methoxy-derivative (22). This compound was also obtained by methylation of 4-methoxy-2-oxo-1,2-dihydro-1,3,5-triazine (18) with diazomethane. At higher temperature (100°C) in presence of methyl iodide a shift of both methyl groups takes place and methiodide is formed simultaneously (23). Similarly,... 

The 6-alkyl derivatives of 2,4-dioxohexahydro-l,3,5-triazine have been known for some time and have been reviewed earlier. ... 

Hydrogenation with Adams catalyst took place only with the 6-alkyl derivatives. Dioxohexahydrotriazine itself acted as a catalyst poison (in common with 1,3,5-triazine and cyanuric acid ). Dioxo-tetrahydrotriazine as well as its A-alkyl and 6-alkyl derivatives can be readily hydrogenated by using Raney nickel. ... 

It was observed already by BougaulU that the reaction of 6-benzyl-3,5-dioxo-2,3,4,5-tetrahydro-l,2,4-triazines with alkyl halides in an alkaline solution yields a mixture of the 4-mono- and 2,4-dialkyl derivatives. This mixture of alkylation products can be readily sepa-... 

Alkylation reactions were recently performed with all the thio derivatives of 6-azauraciI and 6-azathymine. In agreement with previous findings, the methylmercapto derivatives were obtained by alkylation of all these substances in alkaline solution. Thus, e.g., 3-ihethylmercapto-5-oxo-2,5-dihydro-1,2,4-triazine (96), 5-methylmer-capto-3-oxo-2,3-dihydro-l,2,4-triazine (90), and 3,5-dimethylmer-capto-1,2,4-triazine (91) were obtained. The last-named of these was... 

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