Total chemical synthesis method of adenine

Abstract

The invention relates to a total chemical synthesis method of adenine. The method comprises the following steps of: 1) dissolving primary amine in strong-acid solution, dripping sodium nitrite solution to prepare diazonium salt, adding malononitrile for dissolving, and dripping alkaline solution to regulate a pH value of reaction solution and generate coupling reaction, thereby obtaining an azo compound; 2) adding the azo compound into formamide, and introducing liquid ammonia, heating to carry out high-temperature condensation and cyclization reaction, thereby obtaining a pyrimidine-azo compound; 3) dissolving the pyrimidine-azo compound into water, adding a catalyst, and introducing hydrogen for hydrogenation, thereby obtaining 4,5,6-triamidopyrimidine; and 4) dissolving the 4, 5, 6-triamidopyrimidine into the formamide to carry out high-temperature cyclization with the formamide, thereby obtaining an adenine crude product, and after recrystallization, obtaining white crystalline powder, i.e., a high-purity refined adenine product. The total chemical synthesis method has the advantages that water is used as a solvent in the step 1), and solvents used in the steps 2), 3) and 4) can be repeatedly used, so that the 'three wastes' are fewer, and the environment-friendly effect is achieved; and the total yield is 64.75% (calculated according to the amount of malononitrile), and the cost is low, so that the industrialization is easy and the economic benefit is obvious.

Description

technical field [0001] The invention belongs to the technical field of medicine synthesis, and in particular relates to a chemical synthesis method of adenine. Background technique [0002] The chemical name of adenine is 6-aminopurine. Adenine is a needle-like white crystalline powder with a strong salty taste. Hardly soluble in cold water, soluble in boiling water, acid and alkali, slightly soluble in ethanol, insoluble in ether and chloroform. It can form many different tautomers, and its structural formula is shown in formula (1): [0003] [0004] Adenine occurs naturally in foods such as tea and beet juice. It is an important pharmaceutical raw material and intermediate, used in the production of adenosine, ATP, ADP, new anti-AIDS drugs, vitamin B4 and plant growth hormone 6-benzyl adenine, etc., and is now mainly used in the production of anti-hepatitis B drug Ade Fuvir dipivoxil and the anti-AIDS drug tenofovir dipivoxil, etc. [0005] At present, there are ma...

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Problems solved by technology

[0019] Chinese patent CN 103709164A reports that malononitrile and thiourea are used as raw materials to carry out ring closure reaction under the action of sodium alkoxide to prepare 4,6-diamino-2-mercaptopyrimidine, which is then oxidized, desulfurized, Nitrosation, reduction, and cyclization to obtain adenine. This route is improved on the basis of the process route reported in the above-mentioned document Organic & Biomolecular Chemistry, 2011, 9(7), 2227-2232. There is still a long synthetic route, Raw material prices are high, pollution is serious, total yield is not high, etc.

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