Preparation of 2-chlorin-4-amido-6,7-dimethoxy quinazoline

Abstract

The invention discloses a preparation method of 2-chloro-4-amido-6,7-dimethoxy quinazoline. The preparation method comprises the following steps: 3,4-dimethoxy benzaldehyde is taken as an initial raw material, then the following reactions are sequentially carried out: oxidizing reaction between the 3,4-dimethoxy benzaldehyde and oxydol, nitration reaction between the 3,4-dimethoxy benzaldehyde and nitric acid, reduction reaction of the 3,4-dimethoxy benzaldehyde and hydrogen ion obtained by iron powder and hydrochloric acid, reaction between the 3,4-dimethoxy benzaldehyde and sodium cyanate, chlorination reaction between the 3,4-dimethoxy benzaldehyde and phosphorus oxychloride, ammoniation reaction between the 3,4-dimethoxy benzaldehyde and ammonia liquor, etc., then the 2-chloro-4-amido-6,7-dimethoxy quinazoline is obtained. The synthetic method takes the commercialized 3,4-dimethoxy benzaldehyde as the initial raw material, and potassium permanganate is not used in the oxidizing reaction process, organic solvents (glacial acetic acid, DMF) are not used in the refining process, the noxious solvent N, N-amino dimethylbenzene or the organic solvent N, N-dimethyl formamide with high boiling point is not used in the chlorination process, so the use amounts of the organic solvents and the phosphorus oxychloride are reduced, thus reducing the production cost, simplifying the production process, protecting the health of operators, reducing 'three wastes' pollution, protecting the environment and greatly improving the reaction yield and the production efficiency.

Description

technical field [0001] The invention belongs to the synthesis of oxazin drug intermediates, in particular, it relates to a preparation method for the chemical synthesis of 2-chloro-4-amino-6,7-dimethoxyquinazoline. Background technique [0002] At present, 2-chloro-4-amino-6,7-dimethoxyquinazoline has good biological activity and pharmaceutical activity, and is an important class of pharmaceutical and fine chemical intermediates, which can be used in the synthesis of oxazin drugs . 2-Chloro-4-amino-6,7-dimethoxyquinazoline is synthetic prazosin hydrochloride (treatment of high blood pressure), terazosin hydrochloride (treatment of high blood pressure), doxazosin mesylate ( It is an important intermediate of oxazosin APIs such as treating benign prostatic hyperplasia), brazosin hydrochloride (treating mild to moderate essential hypertension), and alfuzosin (treating benign prostatic hyperplasia). [0003] 1) Using vanillin as the starting material, the target compound (I) w...

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Problems solved by technology

[0003] 1) Using vanillin as the starting material, the target compound (I) was prepared through reactions such as methylation, nitration, oxidation, reduction, cyclization, chlorination, and amination (Qilu Pharmaceutical Affairs 2006 Vol.25, No.9 ), the methylation of this synthetic route uses the highly toxic substance dimethyl sulfate, which affects the health of operators and serious environmental pollution. The oxidation process uses more expensive potassium permanganate waste water and waste residues, and the chlorination process uses highly toxic solvents. N, N-dimethylaniline or high boiling point solvent N, N-dimethylformamide, etc., the total yield of the product is only about 26%, which is not conducive to the industrial production of the product;

[0004] 2) With 3,4-dimethoxybenzene as the starting material, the target compound (I) (patent CN1749250A) is obtained through nitration, reduction, ureaification, compound hydrolysis, and alkalization refining. The use of highly toxic isocyanate has been eliminated, but the reduction process of this process requires the use of expensive heavy metal catalysts and catalytic hydrogenation in autoclaves. The cyclization process uses a large amount of phosphorus pentachloride and phosphorus oxychloride, which increases the pollution of three wastes. The product The total yield is only about 30%, which increases the difficulty of product industrialization;

[0006] 4) In addition, there are many literature reports on the preparation of the target compound (I) through different routes, such as using 4,5-dimethoxy-2-nitrobenzoic acid as raw material, first ammonolysis to 4,5-dimethyl Oxygen-2-nitrobenzamide, then catalytic hydrogenation to obtain 4,5-dimethoxy-2-aminobenzamide, then condensed with hydrocyanic acid to obtain compound (III) (JP59073558); As the starting material, alotic acid is oxidized, then forms acid chloride with phosphorus pentachloride, forms an ester with anhydrous methanol, and undergoes metal-catalyzed hydrogenation to obtain 4,5-dimethoxy-2-aminobenzoic acid methyl ester, and finally with Potassium cyanate was reacted to obtain compound (III) (see patent US3644354 for details); using veratraldehyde as a starting material, compound (III) was obtained through nitration, oxidation, amidation, reduction, and cyclization (J.Chem.Boc. 1948, 1759; J.Med.Chem, 1977; 20:146), the compound (III) was chlorinated and ammonified to obtain the target compound (I). The above methods all have limitations in varying degrees, and the main disadvantage is that the product The total yield is low, the production cost is high, and there are serious three waste pollution and the products are not easy to be industrialized.

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