SU439091A3 - METHOD OF OBTAINING 4-AMINO-6,7,8-TRIALCOXYCHINAZOLINES - Google Patents

Description

one

This invention relates to a process for the preparation of 4-amino-6,7,8-trialkoxy-quinazoliums, which can be used in the pharmaceutical industry.

A known method for producing benzalkoxy-4-aminoquinazolines by reacting ammonia with quinazolines containing in the 4 position substituted groups (halo, alkoxyl, thioalkyl).

Based on a well-known reaction, we propose a method for the treatment of 4-amio-6,7,8-trialkoxy-iiiiazolines of the general formula

CH2 (CH2) (CH2) zON02 2, in which R2 is hydrogen or a residue of the general formula (CH2) tCH3 or (CH2) yONO2; “- 1-6, mostly 3-5; t - O-4; y-1-4; Z-1-4, moreover, R and RI together contain the miiimu .m one and maxim.mum two nitro groups; one of these means hydrogen or alkyl, if the other is a coarse common

ten

Formulas CH2 (CH) j, ON02. j.jgg meanings

NRRi

non other than hydrogen; the sum of lht does not exceed shchista, but - seven, or R and Ri together with the nitrogen atom form a residue of the general formula

where Y, Y and Yj are the same or different Ci-C3-alkoxy groups; R and Ri are hydrogen, C -C4-alkyl or a group of the general form

N-demolished2)

-N

where Y, YI and Ya have the above value of HPie; Q is chlorine, bromine or a residue of the general formula VZ, where W is oxygen or sulfur; Z is alkyl, phenyl or benzyl, is treated with an amine of the general formula HNRiR, in which R and RI are as indicated above, and the desired product is isolated with known iriemems.

The reaction is usually carried out in an organic solvent (benzene, ether, dioxane, isopropanol) at 10-SO C in the presence of a basic agent, for example sodium carbonate.

Example 1. 4- 3-Bis- (2-hydroxyethyl) -amiopropyl-amino-5,7,8-trimethoxyquinazolindinitrate.

To 10.5 g of phosphorus bromide at 70 ° C are added in portions of 1 g o, 7,8-trimethoxyquinazolin-4-ZN-oia, heated for 0.5 hour, poured into a flask with ice and 25 ml of ammonia, extracted three times the aqueous layer is methylene chloride, the extracts are dried with magnesium sulfate, the solvent is evaporated and recrystallized 4-bromo-6,7,8 - trimethoxyquinazoline from chloroform, so pl. 107-108 ° C.

A solution of 11.3 g of 3-bis- (2-hydroxyethyl) aminopropylamine in 8 ml of tetrahydrofuran is added over 15 minutes at 0-5 ° C to a mixture of 49 ml of acetic anhydride and 16.3 ml of 90% nitric acid, incubated for 45 min at {-5) - (-10) 0, 500 ml of dry diethyl ether was added with stirring, stirred for 10 min, the ether layer was decanted, 500 ml of very cold water was added to the oil, the resulting solution was neutralized with solid sodium carbonate, saturated with sodium chloride and extracted with 2 x 50 ml of ethyl acetate. The magnesium sulfate-dried extracts are evaporated, the obtained oil is chromatographed on silica gel, and 3-bis (2-hydroxyethyl) amino aminopropylamine single nitrate is obtained in the form of an oil.

0.96 g of 4-bromo-6,7,8-trimethoxyquinazoline was added to a solution of 2.7 g of 3-bis- (2-hydroxyethyl) -amiopropylaminodinitrate in 5 ml of dioxane, stirred for 24 hours, 100 ml of chloroform was added, and filtered solid and condense the residue to obtain an oil, which is dissolved in chloroform to remove residual dioxane, and evaporated. The resulting oil is chromatographed on silica gel, eluting with chlorofor.m-methanol (99: 1 and 98: 2). The eluates are evaporated, the residue is dissolved in 2 ml of methanol, 0.385 g of maleic acid in 15 ml of metaiol is added, filtered, the filtrate is evaporated, and 500 ml of diethyl ether are added to the residue while cooling with ice

, the crystals are washed with a mixture of methanol-diethyl ether (1: 1) and dried under high vacuum to give 4-3-bis- (2oxyethyl) -amino-yl-amino-6,7,8-trimethoxyhydroxynazolindinitrate dimelate, m.p. 107 ° C (decomp.).

Example 2. Analogously to example 1 receive:

maleate 4- (6-hydroxyhexyl) -amino - 6,7,8 - trimethoxy-nasolynnitrate, so pl. 106-107 ° C (ethanol-diethyl ether);

dihydrochloride (2-hydroxyethyl) - 1-piperazino-6, 7,8-triethoxyquinazoline nitrate, t. pl. 170 ° C (decomp.);

4- 3-bis- (2-hydroxyethyl) -aminopropyl-amino-6,7,8 - triethoxyquinazolindinitrate dihydrochloride, t. pl. 130 ° C (decomp.);

4- (4-hydroxymethyl-5-hydroxypentyl) amino-6, 7,8 hydronitrate - trimethoxyquinazolindinitrate, t. pl. 114.5-115 ° C;

fumarate 4- {N-methyl-M- 3-bis- (2-hydroxyethyl) aminopropyl - amino} -6,7,8 - trimethoxyquinazolindinitrate, t. pl. 79-81 ° C;

4-di- (2-hydroxyethyl) -amino-6,7,8trimethoxyquinazolindinitrate hydronitrate, m.p. 121 - 122 ° С (decomp.);

maleate 4- (5-hydroxypentyl) -amino - 6,7,8 - trimethoxyxynazoline nitrate, so pl. 110 ° C (decomp.), Which crystallizes upon addition of diethyl ether to the oily product;

maleate 4- (4-hydroxybutyl) -amino-6,7,8-trime1oxyquinazolinnitrate, t. pl. 114-115 ° C (methanol-diethyl ether and ethanol);

4- (5-hydroxypentyl) -amino-6,7, triethoxyquinazolinnitrate hydronitrate, m.p. 78-79 ° C;

4- 3-bis- (3-hydroxypropyl) - aminopropyl amino - 6,7,8 - trimethoxyquinazolindinitrate, t.nl. 120-12GS;

4- 4-bis- (2-hydroxyethyl) -aminobutyl-amino-6,7,8-trimethoxyquinazolindia nitrate dihydrochloride (hygroscopic product);

maleate 4- (2,3-dioxypropyl) -amino - 6,7,8 trimethoxyquinazolindinitrate, so pl. 139-140 ° C;

4- 2-bis- (2-hydroxyethyl) -aminoethyl-amino-6,7,8,8-trimethoxyquinazolindinitrate dihydrochloride, m.p. 136 ° C (decomp.).

Subject invention

The method of obtaining 4-a.mino-6,7,8-trialkoksikhinazolinov general formula

NRRi

where Y, YI and Y2 are the same or different Ci, C3-alkoxy groups; R and Ri are hydrogen. GI-S.ralkil or a group of common form