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    Home > Chemial News > Pharma News > Pharmaceutical intermediates: the future development of adenine

    Pharmaceutical intermediates: the future development of adenine

    Echemi 2021-01-13

    Adenine, also known as 6-aminopurine, has a chemical formula of C5H5N5. It is a fused ring system composed of pyrimidine and imidazole rings. Adenine in organisms is mainly synthesized from amino acids and small molecules as starting materials through a series of enzymatic reactions.

     

     

    However, adenine is not only an important part of DNA and RNA in organisms, but also as a pharmaceutical intermediate for the production of antiviral drugs, plant growth regulators, etc., and its usage has been increasing worldwide in recent years.


    Adenine is mainly produced by microbial fermentation


    At present, the production methods of adenine mainly include chemical synthesis, natural raw material extraction and microbial fermentation.

     

    The chemical synthesis method mainly refers to the acetyl hypoxanthine method. Firstly, acetylhypoxanthine and phosphorus oxychloride undergo chlorination reaction under catalyst conditions to obtain 6-chloropurine; then in the autoclave, 6-chloropurine is blown with ammonia to saturation, the reactor is sealed, and the temperature is increased Until the reaction is complete, adenine is precipitated after cooling. In addition to the acetyl hypoxanthine method, there are other chemical synthesis process routes, but the yields are low, and the reaction time is long and the reaction conditions are harsh. The acetyl hypoxanthine method uses phosphorus oxychloride to produce a large amount of waste liquid, and subsequent environmental protection treatment is difficult.

     

    The natural raw material extraction method mainly extracts adenine enriched in natural substances, but this method has low yield and high cost, and is not suitable for industrial production.


    The microbial fermentation method has mild production conditions, simple process, and reaction conversion rate of over 99%, which is conducive to industrial production. The specific process is as follows: adenosine is hydrolyzed by hydrolase to generate adenine and D-ribose. Mix adenosine and water, adjust the pH of the reaction system to 6.5-7.0, add adenosine hydrolase, heat up to 35-37°C and keep warm and react; after the reaction is completed, solid-liquid separation is performed, and the liquid phase is concentrated to obtain D-ribose. Solid phase washing obtains adenine.

     
     
    China is the world's largest producer and marketer of adenine.


    China is one of the largest API producers in the world. After decades of development, a relatively complete industrial system has been formed. In recent years, with the increasing variety and quantity of patent expired drugs, the variety and quantity of generic drugs have increased rapidly, which has brought huge market opportunities to the API market. The development of the pharmaceutical intermediate industry has also been affected by downstream chemical APIs and chemical drugs. The impact of formulation development is significant.


    China is the world's largest producer and exporter of adenine, and more than half of its annual output is used for export. In recent years, China's adenine production capacity has shown an increasing trend. For example, Henan Julong Biotech's new production capacity is 300 tons/year, but Tuoxin Pharmaceutical and other production capacity exits. In 2019, China's adenine production capacity reached 3,600 tons/year. Affected by the increase in the demand for downstream antiviral drugs, the output increased by 6% annually from 2015 to 2019, reaching 1969 tons in 2019. Most domestic adenine products comply with the USP standards of the United States Pharmacopoeia.


    As a pharmaceutical intermediate, adenine is mainly used to synthesize tenofovir dipivoxil (TDF), adefovir dipivoxil and other raw materials for the treatment of AIDS and hepatitis B. It can also be used to produce plant growth regulator 6-benzylaminopurine (6 -BA) In addition, in the microbial fermentation of biological products such as inosine, guanosine, and inosinic acid, it can be used as a component of the culture medium and play an important role in the growth and metabolism of cells.

     
    In recent years, China's apparent consumption of adenine has shown an increasing trend, with an average annual growth rate of 9% in the past five years. Antiviral drugs, plant growth regulators and biological fermentation additives accounted for 90%, 4%, and 4% of consumption in 2019, respectively. According to the "China Health Statistics Yearbook" released by the National Health Commission, China's adenine consumption is basically positively correlated with the number and incidence of hepatitis B and AIDS.



    The future development of adenine industry


    Taken together, the future adenine industry should focus on the following aspects:


    01Extend the industrial chain


    At present, the industry generally has the problem of over-concentration of upstream adenosine raw material procurement.Enterprises should actively develop new raw material suppliers, and at the same time continue to strengthen cooperation with the original suppliers to ensure a stable supply of raw materials. In addition, it should expand upstream. Henan Julong Biotechnology, Guangdong Zhaoqing Xinghu Biotechnology, and Tongliao Meihua Biotechnology all produce adenosine for adenine production, and the remaining part is exported. The Xinxiang Ruicheng Technology Xinjiang Project will also achieve self-sufficiency in adenosine raw materials, which will not only reduce costs, but also reduce the risk of production shutdown due to shortage of raw materials. In addition to extending upstream, qualified companies can extend down to the production of tenofovir disoproxil prodrug (PMPA) or further extend to the production of tenofovir disoproxil (TDF) to increase the added value of products.
     


     

    02Intensify scientific research

     

     

    At present, all companies in the industry focus on enzymatic hydrolysis processes. In the future, they should optimize the selection of higher-quality enzymes to improve enzymatic hydrolysis efficiency. Reduce product costs or improve product quality and increase the competitiveness of enterprises.

     

        

     

    03Enhance the awareness of safety and environmental protection and realize green and sustainable development

     

     

    With the country's increasing requirements for energy conservation, emission reduction, safety and environmental protection, enterprises are forced to increase industrial transformation and upgrading, improve safety and environmental protection standards, strengthen scientific research investment, and rely on technological innovation to lead enterprise development. The pharmaceutical intermediate industry has transformed from extensive growth in the past to a “green and sustainable” approach such as low pollution and low emissions. Affected by the above factors, some small and medium-sized enterprises are facing the pressure of closure and elimination. The high pressure of environmental protection has caused the cost of the industry to rise and the competition is fierce, but at the same time, compliance companies are also ushering in major opportunities for development. Enterprises should adjust their development thinking in strict accordance with the requirements of environmental protection and safety supervision to enhance their core competitiveness.

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