Production method of coenzyme Q10
June 05, 2024
Development process
In the early 1980s, Japan achieved the synthesis and production of coenzyme Q10 from solanesol extracted from tobacco leaves, which significantly reduced the cost of coenzyme Q10. This played an important role in promoting the application, popularization, and promotion of coenzyme Q10. The semi chemical synthesis method is relatively mature in technology and has achieved industrialization. The product cost is low and the price is moderate. However, although products produced using semi chemical synthesis have price advantages, there is a significant gap in usage compared to products produced using biological extraction methods. The reason is that the biological extraction method produces natural and organic products that are easily absorbed and transformed by the human body, while the chemical synthesis method produces artificially synthesized organic products with extremely poor biological activity, which are not easily absorbed by the human body and difficult to fully exert the pharmacological effects of coenzyme Q10. The chemical synthesis method of coenzyme Q10 has always been a hot topic of research both domestically and internationally. In the past half century, developed countries achieved the production of coenzyme Q10 through microbial fermentation in 1977. In recent years, microbial fermentation extraction has made significant progress. This new bioengineering method combines the advantages of biological extraction process and chemical synthesis process, and overcomes their disadvantages. Therefore, it is the most promising method for industrialization. There are two main requirements for achieving industrial production using microbial fermentation extraction method: (1) Require high-quality genetically modified strains of coenzyme Q10 with stable large-scale production processes; (2) Require technology with high-precision separation instruments. Japan is the world's earliest and most important producer of coenzyme Q10. According to statistics, 90% of coenzyme Q10 worldwide comes from Japan. The two Japanese companies with the highest production of coenzyme Q10 are Nissin Flour and Concord Fermentation Co., Ltd. Numerous experts have conducted research and exploration mainly from two aspects: one is to introduce decaprenol groups on the parent compound, and the other is to first introduce shorter side chains on the parent compound, and then introduce the desired long chain. In 1959, R Ruegg et al. reported the synthesis of coenzyme Q10 using the route shown in equation (1). Although the product was obtained, the yield was only 20%, and the application of this method was limited due to the fact that the allylation reagent obtained from solanesol is a mixture of cis and trans isomers that need to be separated. In 1972, Sato K. et al. reported the synthesis of coenzyme Q10 using the route shown in the formula. In the fourth step of the reaction, Ni was used as a catalyst and the two phenolic hydroxyl groups were protected, which to some extent increased the coupling yield (28%). The main problem with this synthesis route is the instability of the allyl moiety under acidic conditions, making it difficult to maintain the double bond configuration. In 1979, Naruta Y. et al. reported the partial conversion of isoprene into stantane, which was reacted with quinone using the strong nucleophilicity of stantane. The reaction was carried out using BF3OEt2 catalyst under low temperature conditions (-78 to -60 ℃). Finally, a product with satisfactory geometric configuration was obtained (E/Z=85/15), but the yield calculated as isoprene stantane was only 51%. The synthesis route is shown in Figure 3. Subsequently, Naruta Y. extended his method to the synthesis of VK1 and VK2. From the above synthesis routes, it can be seen that this type of method reacts with the parent compound and polyisoprene based compound, and the yield of this key step is not very high. Therefore, this synthesis strategy cannot be said to be ideal. As early as 1978, Terao S. used coenzyme Q7 to synthesize coenzyme Q10. However, due to the high cost of raw material coenzyme Q7, this route has little practical value. In 1979, the group carried out a highly effective synthesis using the route shown in the formula. The raw materials used in this route were inexpensive and easy to obtain, the reaction conditions were mild, and the side chains combined with the parent compound with a high yield (90.9% disappeared). The drug concentration in the lung, heart, liver, and kidney tissues of rats increased 4 hours after administration, and the drug concentration in the adrenal gland, liver, and stomach tissues increased 10 hours later. After 7 days of administration, the total yield decreased due to the complex chain synthesis steps. In 1982, Sato K et al. made varying degrees of improvements to the above route and the reagents used, as shown in equation (5). The yield of the final step reached 83%, and the geometric configuration of the double bond was also satisfactory (E/Z=100/0). Since the 1970s, China has been conducting technological research on coenzyme Q10 and quickly built several production lines using biological extraction methods, mainly extracting from pig myocardium. Domestic companies that use biological extraction processes to produce coenzyme Q10 mainly include Beijing Pharmaceutical Factory, Taizhou Biochemical Pharmaceutical Factory, Qingdao Biochemical Pharmaceutical Factory, Hangzhou Pharmaceutical Factory, Changsha Biochemical Pharmaceutical Factory, Zhejiang Tiantai County Pharmaceutical Factory, Guiyang Biochemical Pharmaceutical Factory, Gejiu Biochemical Pharmaceutical Factory, Taiyuan Biochemical Pharmaceutical Factory, Datong Biochemical Pharmaceutical Factory, and more than ten other enterprises. The total production capacity is around 600kg. China is a major tobacco producing country in the world, with a large amount of waste tobacco leaves that cannot be used for cigarettes, which are not utilized and cause environmental pollution and resource waste. As early as the late 1970s, China began to research and develop the extraction of solanesol from waste tobacco leaves. In the early 1990s, China invested a lot of energy in the research of new coenzyme Q10 processes and achieved gratifying results. The Institute of Tobacco Chemical Technology Development and Research at Henan University collaborated with Shangqiu Tobacco Fine Chemical Factory to jointly research and develop the use of tobacco to extract solanesol. Based on years of research, industrialization was officially achieved in January 1996. It can produce 100 tons of crude solanesol with a content of ≥ 15% and 20 tons of refined solanesol with a content of ≥ 75% per year, laying a good foundation for the industrial production of coenzyme Q10 in China.
Fermentation method
In 1977, the production of coenzyme Q10 by recombinant microbial fermentation method was achieved. This production process is considered the most promising synthetic process, and in recent years, microbial fermentation has become a hot topic for development both domestically and internationally. Red polar hairy bacteria, denitrifying polar hairy bacteria, methane microcyclic bacteria, etc. are the main strains producing coenzyme Q10. Semi synthetic method The developed semi synthetic process uses p-methylphenol as raw material to obtain methyldimethoxybenzene through bromination, etherification, and oxidation, and then condenses with solanesol extracted from tobacco or potato leaves to obtain coenzyme Q10. The key to this method is how to connect the side chains to the mother ring. Total synthesis method
The total synthesis process for producing coenzyme Q10 developed by Eem and Kanan in 1988 is the only successful total synthesis technology, but there are certain difficulties in synthesizing linear unsaturated side chains. And the synthesis conditions are harsh, and there is still a certain distance from industrialization. Biological extraction method
The yield of coenzyme Q10 in the alcohol alkali saponification manufacturing process is 61.2mg/kg fresh pig heart, which is a commonly used process in China. In the presence of ethanol, prolonged saponification may result in the exchange of methoxy groups in coenzyme Q10 and ethoxy groups in ethanol, generating single or double ethoxy derivatives to avoid the generation of these impurities. KOH can be used instead of NaOH and methanol for saponification, but it is also necessary to add pyrogallic acid, otherwise coenzyme Q10 will be completely destroyed during the saponification process, accounting for 5% -7% of the starting material. Nitrogen can be introduced during the saponification process. The alcohol ether mixed extraction method is similar to the alcohol alkali saponification manufacturing process, except that the saponification reaction is omitted. The biological extraction method is the oldest and most basic production process in the world, and has been the only production method for coenzyme Q10 for a period of time. However, due to the low content of coenzyme Q10 in animals and plants, complex chemical components, and limited raw material sources (mainly extracted from fresh animal liver), product costs are high, prices are expensive, and large-scale production is limited to a certain extent. Cell culture method
Plant cell culture technology is a technique that involves aseptic treatment of a certain part of a plant body, placing it on an artificial culture medium to promote cell proliferation, and then cultivating it as needed. Various parts of plants, such as roots, stems, leaves, flowers, fruits, anthers, and pollen, can serve as explants to initiate cell culture. The resulting dedifferentiated cell clusters are called callus tissue, and transferring the callus tissue to liquid culture medium for cultivation is called suspension culture.
Shaanxi Huike Botanical Development Co., Ltd. a integrated enterprise which is focus on natural products, Plant extract related products and services.We mainly focus on pharmaceutical, functional food, Freeze-dried powder,Natural Pigment,Homology of medicine and food,beverages and other business services.
For more information about inulin, please contact us!
Email:marketing@huikes.com
2024-06-05
Shaanxi Huike Botanical Development Co., Ltd.
