SU368752A1 - - Google Patents

Description

METHOD OF OBTAINING OXYD DERIVATIVES 4,6-DIAMINO1, 2-DIGYDRO-1,3,5-TRIAZINE

one

The invention relates to the preparation of new 1,3,5-triazine derivatives, possessing increased pharmacological activity in comparison with the known analogues.

A known method for the preparation of hydroxy derivatives of 4,6-diamino-1,2-dihydro-1,3,5-tr-azine of the general formula

 NH, G 11

yNGSO-them to HjC CH,

where Y is hydrogen, alkyl, halo- or carbalkoxy. Substituted phenyl, naphthyl, anthracyl, phenanthryl, pyrenyl, quinolyl, or its salts by reacting 4,6-diamino-1,2-dihydro-2, 2- / chimethyl-1-hydroxy -1,3,5-triazine with a compound of the general formula YCH2Z, where Y has the above values, Z is chlorine, bromine, iodine, in an inert solvent or diluent medium and the products are isolated in a known manner.

Based on a known reaction, the proposed method for the preparation of hydroxy derivatives of 4,6-diami | HO-1,2-dihydro-1,3,5-triazine of the general formula

NgK N NH

Vy

Ej R (,

phenyl or cyclohexyl, which may be substituted by one or more chlorine atoms; a bivalent group containing 2 to 6 carbon atoms;

hydrogen, methyl, ethyl,

TC in that 4,6-diamino-1,2-digilriaz11n General formula

R., N N NH

Gg

Y-Nx.N R R

where Rs and Ri are as defined above; Y is a hydroxy group or its reactive derivative, for example, the group —OM, where M is a sodium, potassium ion, lithium ion, or a sulfonic acid derivative, is treated with a compound of the general formula RiRgZ, where Ri and R2 have the indicated values, Z is chlorine, bromine, iodine, in diluent or solvent3

bodies, such as dimethyl sulfoxide, dnmethylformamide, ethanol, in the presence of a cadensing agent, followed by isolation of the products in a known manner in free form or in the form of a salt, individual tautomers, isomers, ontic antinodes, or their mixture. These compounds can be represented by the following formulas:

H

,

HoN N NH

™ N NH

Yt

Y y

., R20-N.,.

or

X

Kj.

T {, Rb

Patented compounds are more convenient to obtain not in the form of free bases, which are not stable enough during storage, but in the form of acid salts with various acids, and in the synthesis of pharmaceutical preparations iado choose acids with low toxicity, eg hydrochloric and hydrobromic.

3.0 g of 3- (3,4-dichlorophenyl) propyl bromide is added. The reaction mixture is stirred at room temperature for 1 hour and carefully heated until a clear solution is obtained, which after filtration is evaporated to dryness in vacuo. The residue is suspended in acetone, filtered, the filter cake is washed with a small amount of fresh acetone and dried to constant weight. Obtain 3.2 g of white solid substance, so pl. 190-193 ° C, which is washed with water, recrystallized from methanol and 1.7 g of hydrobromide 4,6-diami "o-1,2-dihydro-2,2-di4 are obtained

In addition, salts of other acids can be used, the choice of which depends on the toxicity, taste of the form (tablets, granules, noroschki), the speed of excretion from the body and the introduction of predrat in the body, for example, they can be prepared in the form of picrates, sahrat, acetates, acid maleates, acid phthalates, succinates, phosphates, genitrobenzoates, stearates, pamoats,

cyclohexyl sulfamates, citrates, tartrates, gluconates, almond salts and N-acetylaminoacetic acid.

Stable salts are usually formed at an equimolar ratio between the triazine.

and monobases by acid. In the case of polybasic acids, an excess of triazine is required. Example 1. A solution of 1.93 g of 4,6-diamino-1,2-dihydro-2, 2-dimethyl-hydroxy-1, 3,5-triazine hydrochloride in 25 ml of methanol is treated

a solution of 0.7 g of potassium hydroxide in 15 ml of methanol, boil for 20 minutes under reflux, the solvent is removed in a vacuum, the residue is suspended in dimethylformamide and

methyl-1 - 3 - (3,4-dichlorophenylpropyloxy) 1, 3, b-triazi, t. pl. 203 ° C.

Example 2. 7- (Cyclohexyl) -hexan-1-ol is treated with a mixture of 48% hydrobromic acid and sulfuric acid (28: 3 by volume), refluxed for 6 hours, cooled to room temperature, diluted with water and extracted with diethyl ether. The extract was successively washed with water, dilute aqueous sodium bicarbonate and water, dried over anhydrous magnesium sulphate, the filtered solution was evaporated to dryness and the small residue was distilled in vacuo (1 mm). Fractions with m. Kip. 112-114 ° C is 6- (q, 1clohexyl) -hexylbromo1 d; 1.48-10. 7.5 g of the obtained bromide is treated with a base isolated from hydrochloride 4,6-dnampno-1,2-dihydro-2,2-dimethyl-1-hydroxy 1, 3,5-triazine (5.8 g) under the action of 2.1 g of potassium hydroxide, as in Example 1. 5.0 g of 4,6-diamino-1,2-dgidro2 hydrobromide, 2-dimethyl-1-6- (cyclohexyl) - hexyloxy 1, 3,5-triazine are obtained, t. nl. 203 ° C. Examples 3-29. Analogously to Example 2, the compounds listed in the table are prepared. Example 30. 1 g of 4,6-diamino-1,2-dihydro2, 2 - dimethyl - 1 - 3- (3,4-dichlorophenylpropyloxy) -1,3,5-triazine is heated for 5 minutes on a steam bath with 10 ml of freshly distilled acetic anhydride, excess acetic anhydride is removed in vacuo, the residue is dissolved in ethyl acetate, petroleum ether (b.p. 40-60 ° C) is added to the solution until cloudy and left in the refrigerator for crystallization. The crystalline precipitate is separated and 0.5 g of the diacetyl derivative is obtained, m.p. 125 ° C. T. pl. does not change after recrystallization from a mixture of ethyl acetate and petroleum ether (m.p. 40-60 ° C). 1 g of 4,5-diamino-1,2-dihydrodimethpl-1- 3 (3,4-dichlorophenylpropyloxy-1,3,5-triazine, 5 ml of triethylamine and 10 ml of freshly distilled acetic anhydride are stirred for 70 hours at room temperature, poured into ice, stirred for 1 hour and extracted with ethyl acetate. The organic layer is washed: watered with water, dried over anhydrous magnesium sulphate, decolorized with activated carbon and filtered. The filtrate is evaporated to dryness in vacuum, the residue is recrystallized from ethyl acetate / petroleum (t Kip. 40-60 ° C). Tetraacetyl product yield 0.4 Mp 84 ° C. After the second recrystallization from ethyl acetate – petroleum ether, 85 ° C. 2 g 4,6-diamino-1,2-dimethyl-1 - 3- (3,4-dichlorf : nilpropyloxy) -1,3,5-triaznna and 10 g of benzoic acid ashpredrda heated 30 on a steam bath, cooled, treated with diethyl ether, the white crystalline precipitate was filtered, washed on the filter with ethyl acetate and cynjaT to constant weight. dibenzampda 128-130 ° C. Object of the invention Method for the preparation of hydroxy derivatives 4, b-diamino-1, 2-dip1Dro-1,3,5-triazine of the general formula N NH2 G 1 | R, where RI is phenyl or cyclohexyl, which can be replaced by one or more chlorine atoms; R2 is a bivalent group, contains 2-b carbon atoms; Ra p R.) is hydrogen, methyl, ethyl, characterized in that 4, b-diam P 0-1,2-d11 gpdro-1, 3,5-triazp ob, formula, YN.N where Ra and R4 have the above values; Y is oxygrunpa or its reactive derivative, for example the group —OM, in which M is a lithium ion, sodium, potassium ion, or a sulfonic acid derivative, is treated with a compound of the general formula RiRoZ, where Z is chlorine, bromine, iodine; RI and RO are as defined above, followed by the isolation of products in a known manner in free form or in the form of a salt, a mixture of isomers or racemates or in the form of their individual representatives, or in the form of K-cell ions and 1X1.