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Pyridine, known as the “chip” of pesticides, medicines and veterinary drugs, is critical intermediate. It is mostly used (up to 50% of the production) in the manufacture and synthesis of pesticides and, based on which, over 30 kinds of products can be produced.
Pesticides containing pyridine moiety are highly efficient with low toxicity and enhanced longevity. They have good environmental compatibility with human beings and organisms, which meet the development requirements and trends of pesticides. Pyridine-containing pesticides are developing rapidly worldwide and are one of the main directions in pesticide innovation.
The whole industrial chain of pyridine compounds shows a tree-like structure, and the pyridine base is the “root” of the entire pyridine industrial chain. Numerous derivatives and end products can be derived from pyridine intermediates to the back end of the industrial chain.
Early on, it was found that more than 20% of the products in the production of pyridine were methylpyridine compounds, mainly the mixture of 3-methylpyridine, 2-methylpyridine and 4-methylpyridine, and 2-chloro-5-chloromethylpyridine (CCMP). To further promote the development of pyridine industry, people started to research and develop these methylpyridine compounds. After years of development and in-depth exploration, methylpyridine derivatives, especially 3-methylpyridine, are now widely used in the agrochemical industry.
Currently, the pesticide industry has evolved to the fourth generation of pesticides. The first generation is organochlorine pesticides, such as DDT and benzex; the second generation is organophosphorus pesticides, such as methamidophos and parathion; the third generation is pyrethroid pesticides, such as cypermethrin and deltamethrin, and the fourth generation is pyridine pesticides such as haloxyfop-P-methyl, fluazifop-P-butyl, fluazifop-P-butyl, fluazinam, fluopyram and picoxystrobin. Methylpyridine derivatives are mainly used to produce the fourth generation of agrochemical products with high efficacy and low toxicity, and most of the intermediates of the fourth generation of advanced pesticides are fluorine-containing pyridine products.
Commonly used methylpyridine products are CCMP (2-chloro-5-chloromethylpyridine), 2-methylpyridine, 3-methylpyridine, and 4-methylpyridine. These four products belong to the category of pyridine, and are the methylpyridine products with the highest application value in the agrochemical industry.
In terms of the production process, there is not necessarily an upstream or downstream relationship between pyridine and various methylpyridine products. Formerly, pyridine was extracted mainly from coal tar, and now it is primarily obtained through the synthesis method. The aldehyde-ammonia method is the most common chemical synthesis method. Different pyridine compounds can be obtained based on raw material aldehyde and different reaction conditions. For example, acetaldehyde reacts with ammonia to produce pyridine, 2-methylpyridine and 4-methylpyridine; acetaldehyde, formaldehyde react with ammonia to produce pyridine, 3-methylpyridine, etc. CCMP can be obtained from the reaction of 3-methylpyridine downward or from the reaction of dicyclopentadiene (as the starting material) with acrylaldehyde or acrylonitrile.
Derivative products of methylpyridine after chlorination and fluorination
There are many derivatives of methylpyridine products after chlorination and fluorination. The specific derivation modes include adding trichloro or trifluoro in 2-6 positions of pyridine moiety; chloro, fluoro, amino, hydroxyl, bromo or iodo to 2 position; chlorio, fluoro, amino or hydroxyl to 2 and 3 positions. The derived products are 2-trifluoromethyl pyridine, 2-chloro-3-trifluoromethyl pyridine, 2-chloro-4-trichloromethyl pyridine, 2-amino-5-trifluoromethyl pyridine, 2-amino-3-chloro-5-trifluoromethyl pyridine, 2-chloro-6-trifluoromethyl pyridine, etc.
The following three figures show in detail the downstream derivatives and applications of each series of 2-methylpyridine, 3-methylpyridine and 4-methylpyridine.
Downstream derivative of 2-methylpyridine (intermediates in blue and pesticide technicals in green)
2-chloro-6-trichloromethyl pyridine (CTC) is obtained by stepwise deep chlorination of 2-methylpyridine. CTC has a wide range of applications. For example, it can be used to produce chlorfenapyr, a pesticide with certain herbicidal activity and can control cyanobacteria in water.
CTC also has a remarkable effect in the field of nitrogen fertilizer synergists. It can inhibit or regulate the nitrification of ammonia nitrogen in the soil or other plant growth media. The consumption of nitrogen fertilizer can be reduced by 30% by adding 1kg of synergist to 1t of nitrogen fertilizer. At present, nitrogen fertilizer synergists have been widely used in developed areas abroad. The product will have a favorable market development prospect, considering its low use rate in the Chinese market.
CTC is subject to further deep fluorination produces 2-fluoro-6-trifluoromethyl pyridine (FTF). FTF is a key intermediate for the production of pesticides flupyrsulfuron-methyl-sodium, thiazopyr, dithiopyr, bicyclopyrone, sulfoxaflor, etc. 2-amino-6-trifluoromethyl pyridine can be produced by introducing ammonia gas to add amino group.
Another process route is to obtain 2-chloro-6-trifluoromethyl pyridine by fluorination of CTC, and then add the hydroxyl by introducing alkali to produce 2-hydroxy-6-trifluoromethyl pyridine (HTF). HTF can be used to produce picoxystrobin.
Downstream derivatives of 3-methylpyridine
3-methylpyridine is obtained by stepwise chlorination of 2-chloro-3-trichloromethyl pyridine, which is then fluorinated to obtain 2-chloro-3-trifluoromethyl pyridine, an intermediate for the production of flazasulfuron.
3-methylpyridine is chlorinated to 2-chloro-5-methylpyridine and further chlorinated to CCMP, which can be directly used as an intermediate of imidacloprid and acetamiprid. CCMP can also be further fluorinated and chlorinated to produce DCTF, which can be used to produce a variety of pesticides, such as haloxyfop-methyl, haloxyfop-P-methyl, haloxyfop-methyl, chlorfluazuron, and fluazuron. Ammonia gas can be introduced to DCTF to produce 2-amino-3-chloro-5-trifluoromethyl pyridine (ACTF), a key intermediate of fluazinam.
Back to 2-chloro-5-methylpyridine, it is first chlorinated and then fluorinated to obtain 2-chloro-5-trifluoromethyl pyridine (CTF), an intermediate of pyridalyl and fluazifop-butyl series products.
The downstream value of other related derivatives such as 3-trifluoromethyl pyridine and 2-amino-5-trifluoromethyl pyridine is also worth probing.
Among the thirteen pesticide technicals shown in the figure, imidacloprid is currently one of the top three highly effective new insecticides globally. Chinese companies have an annual production capacity of over 10,000 tons for CCMP, an intermediate of imidacloprid. CCMP can be synthesized through two different routes. The first is the route from 3-methylpyridine to 2-chloro-5-methylpyridine and then to CCMP. The second is the route from dicyclopentadiene to CCMP, a more economical and efficient one. Most of the imidacloprid production plants in China use the cyclopentadiene-acrolein process to produce CCMP. The process has a shorter route, costs less and has a better product quality. But it has high pollutant emissions, where every ton of imidacloprid consumes 14~28t of wastewater and generates 1.3~2.9t of waste residues and a large amount of acrolein, acrylonitrile and other toxic gases, which are difficult to treat and cause serious environmental pollution.
Since 2017, China gradually tightened its environmental protection policy, and some small factories with insufficient environmental protection technology and equipment were forced to shut down, decreasing utilization of production capacity of CCMP and imidacloprid, increasing concentration of the industry, and rising product prices.
Downstream derivatives of 4-methylpyridine
The downstream products manufactured with 4-methylpyridine derivatives as an intermediate are mostly high value-added products with excellent development prospects. Besides the well-known 2-chloro-4-trifluoromethyl pyridine obtained by chlorination and fluorination, which is used to produce aminopyralid and flonicamid, 2-amino-4-trifluoromethyl pyridine obtained by chlorination, fluorination and ammonia addition can be used to synthesize the active ingredients of anticancer drugs: MLN2480 and BKM120-AAA, of which the market price can reach several million yuan per ton. As the production of 2-amino-4-trifluoromethyl pyridine involves positioned catalytic chlorination, in-depth chlorination, fluorination and ammonization, and the synthesis is difficult, the product has high technical barriers.
On the whole, pesticide products are still the main direction of downstream development for methylpyridine. The biological activity of pyridine heterocyclic compounds after adding the fluoro is several times that of the original compounds, with less use rate and low residues in the soil, which meet the increasingly stringent environmental requirements. Therefore, the downstream fluorine-containing pyridine pesticides become the mainstay of the latest generation of pesticides. According to incomplete statistics, fluorine-containing compounds account for over 50% of the new pesticides developed in recent ten years.
The market and supply of methylpyridine derivatives
At present, China has a huge production capacity of methylpyridine, distributed mainly in Jiangsu and Shandong. Before 2000, the traditional coal tar separation method was applied to produce pyridine, with a production capacity of less than 200 tons/year, which seriously restricted the development and production of downstream products. Today, the traditional method is replaced by synthetic method, which accounts for over 95% of the total output. The global production capacity of pyridines exceeds 100,000 tons per year. The largest four manufacturers are the USA, Europe, Japan and China, accounting for over 86.75% of the total global output of pyridine compounds.
Pyridine derivatives involve too many products, and the price correlation is not high and varies. To understand the market and price trends of this category of products, four products widely used in the agrochemical market are selected and analyzed as follows.
In 2017, China’s sharp and severe environmental pressure pushed CCMP’s price to its highest level in recent years. During 2018-2019, with more companies satisfying the environmental requirements, the production capacity of CCMP increased and the price gradually fell back. In 2020, the price fell below RMB80,000/t, to the lowest point in recent years. There are two main contributing factors. The first is that the imidacloprid price remained sluggish for a long time in 2020. The second is the vicious competition among CCMP manufacturers in the market, represented by malicious price cuts, with some product prices below the production cost, just for seizing the market share. The second factor is the core reason for the disruption of the CCMP market.
In 2021, the unhealthy market situation gradually returned reasonably due to the rising raw material prices and environmental pressure, and the price rebounded to around RMB94,000/t. With the increase of raw material cost, the CCMP price is still upward. Since the issuance of the national policy on controlling the amount and intensity of carbon emissions in September 2021, some small factories were shut down due to soaring raw material prices. The price of CCMP gradually peaked RMB170,000-190,000/t. By the end of December 2021, the market gradually cooled down, the price of raw materials stabilized, and the price of CCMP was maintained at the level of RMB150,000-160,000/t.
The sudden soaring price did not happen to DCTF when the environmental pressure increased in 2017. But for this reason, the price was maintained at about RMB210,000-220,000/t during 2018-2020. Since the second half of 2020, the DCTF price dropped to below RMB180,000/t after the price collapse of the upstream intermediate CCMP. The cost of DCTF also experienced sharp rise due to the fluctuation of raw material prices since the issuance of the national policy on controlling the amount and intensity of carbon emissions. By the end of December 2021, the market price of DCTF was about RMB240,000/t. Considering the rising cost of the raw materials of CCMP, the upstream intermediate of DCTF, the price of DCTF is expected to rise accordingly.
The price of CTF has been maintained at RMB230,000-240,000/t since the price rise due to the environmental pressure starting from 2017.
The price of CTC is relatively stable and has been maintained at around RMB110,000/t. CTC can also be used as a nitrogen fertilizer booster ，which can prolong the effective time of nitrogen fertilizer, reduce damage to crops, reduce soil compaction, and pollution of water bodies.
Production of methylpyridine series products by Huimeng Bio-Tech
Shandong Huimeng Bio-Tech Co., Ltd.(Huimeng Bio-Tech for short) has strong R&D and production capacity of methylpyridine series products, Huimeng is located in Heze City, Shandong Province, China. The company was established in May 2013 with a total investment of RMB1 billion and covering an area of 320,000㎡. Huimeng Bio-Tech has lined up the industrial chain from primary raw materials, critical intermediates to pesticide technicals and completed the production line of biological fermentation-based chiral compounds for producing intermediates of methylpyridine derivatives as well as the technical production line.
Huimeng Bio-Tech has three production sites and one R&D base, which are shown in the figure below:
Huimeng Bio-Tech’s main intermediate products of methylpyridine are all single products with an annual production capacity of 1,000t level. The annual production capacity will be expanded to 10,000t level for some products. The company’s products are listed as follows.
Most of the leading products listed above have an annual production capacity of 1000 tons or more. All products listed in the table are in production except Anhe’s HPPA and MAQ and Heilong’s intermediate, penoxsulam and glufosinate-P projects, which are still under construction. Over 50% of Huimeng Bio-Tech’s products are for export, and the destination covers twelve countries. In addition, the company has established a good reputation among international customers and maintained a long-term stable partnership with them.
With the improvement of pesticide-related laws and regulations worldwide, the backward pesticides with high toxicity and high residue phased out one by one. The increasingly stringent registration requirements have also shifted the focus to a new generation of pesticide products with increased activity, high selectivity, no toxicity or low toxicity, safe for crops and no residues in crops, agricultural products and soil, atmosphere and water after use, or, even if there is a trace residue, it can be degraded in a short time to become non-toxic natural substances and completely be integrated into nature.
There are three categories of compounds that can meet the requirements for future pesticides:
Huimeng Bio-Tech has been committed to R&D innovation for many years. Up to now, four new substances have been successfully synthesized, namely, 2,3,6-trichloro-5-trifluoromethyl pyridine, 3-chloro-5-trifluoromethyl pyridine, 2,5-dichloro-3-trifluoromethyl pyridine, and 2-methoxy-6 chloro-5-trifluoromethyl pyridine.
There are no specific derivatives and downstream application data of these latest compounds but, after years of research, development, production and practice, there is no doubt that pyridine products have a bright future.
The products developed by Huimeng Bio-Tech are only a small portion of this segment. In agrochemicals, the two links that create value and make it bigger lie in R&D and sales. As the competitiveness of a big power depends on manufacturing, the future development of China’s agrochemical industry needs the collaboration of all participants from R&D to manufacturing. The current direction of Huimeng Bio-Tech’s efforts is highly consistent with the industry’s future direction. It is hoped that more Chinese companies can take part in the front end of the industry chain and create more Chinese value for the global agrochemical industry.
Article source: AgroPages-Chlorinated and Fluorinated Derivatives of Methylpyridine and Their Market and Supply-Agricultural news