Recently, Zhang Xiaheng, a researcher of Hangzhou Institute of Advanced Research, Chinese Academy of Sciences University, and the cooperative enterprise published a paper in Nature, describing their latest research results on the transformation of aromatic amines. In the study, they used a new strategy of "direct deamination" to replace stable carbon nitrogen bonds in aromatic amines with various important chemical bonds with different functions through inexpensive reagents, which is expected to avoid the potential explosion risks and heavy metal pollution of traditional processes. This has brought new breakthroughs to the aromatic amine application process that has been in use since 1884, and also brought hope for solving the cost problem of anticancer drugs. The paper was submitted to Nature and officially published in less than 50 days, and received high praise from the reviewers. Scott Bagley, Senior R&D Director at pharmaceutical giant Pfizer, referred to it as a "true masterpiece" in the public review comments. From a microscopic perspective, many compounds can be seen as assembled from countless "small building blocks" to avoid high-risk diazonium salt intermediates. Aromatic amines are equivalent to the "basic building blocks" and have wide applications in fields such as cancer drug synthesis. However, during the assembly process, the original amino groups of aromatic amines need to be removed and transformed into "functional building blocks" that can assemble various functional components. For over a century, the industrial sector has been using a traditional process invented 140 years ago to remove the amino groups of aromatic amines: first, the aromatic amines are converted into diazonium salt intermediates, and then the amino groups are removed through copper salt promotion and other means, introducing new functional groups for subsequent conversion. The key problem with traditional craftsmanship is that diazonium salts are unstable and have explosive hazards. In addition, traditional crafts also face problems such as high copper consumption and high cost of pollutant treatment, which are inconsistent with the current green concept under the "dual carbon" goal. Meanwhile, in the field of anti-cancer drug production, the synthesis routes of many aromatic amine based anti-cancer drug intermediates are complex, and the corresponding equipment costs, raw material costs, pollution treatment costs, etc. will all affect drug prices. Therefore, finding a safe, green, and concise pathway for the conversion of aromatic amines is a direction that scientists around the world are constantly striving for. After three years of dedicated research and development, Zhang Xiaheng's team creatively proposed the "direct deamination" strategy, which does not require converting aromatic amines into diazonium salts, but instead precisely cuts and replaces their carbon nitrogen bonds. Trace by-products are key to synthesis. The team mainly focuses on the development of green drug synthesis methods and processes, precise modification of active molecules, and other cutting-edge fields in biomedicine. In this study, the team and partner companies conducted hundreds or thousands of experiments on the optimization strategy of efficient and safe conversion processes for aromatic amine compounds, but initially there was no breakthrough progress. Until the end of 2022, the team and the company discovered the presence of N-nitroamine in the experimental system, but at that time its content was extremely low and it was considered a byproduct of the experiment. Zhang Xiaheng said that during the analysis and review of various experiments with students, he noticed that the instruments and equipment detected trace amounts of the target product. They further analyzed the experimental by-products in order to obtain more clues about the mechanism of target product generation. Later, the team gradually unraveled the mystery and finally discovered the role of N-nitroamine - it is not simply a byproduct, but a key active intermediate that can efficiently mediate the synthesis of the target product. On this basis, after more than a year of verification and optimization, the team has developed a new method for direct deamination of aromatic amines using N-nitroamine. They used common and inexpensive reagents in the laboratory to form N-nitroamine intermediates in situ under mild conditions using aromatic amines mediated by nitric acid. Subsequently, stable carbon nitrogen bonds in the aromatic amines were broken by removing nitrous oxide, and various functional groups such as hydroxyl, halogen, cyano, alkyl, and aryl were introduced in situ. The entire process does not require the preparation of hazardous intermediates or the involvement of heavy metals, and the reaction conditions are mild and the operation is simple. To further improve operational convenience, the team has also developed a one pot deamination cross coupling strategy. Multiple cross coupling reactions can be completed in the same reaction system by directly adding the corresponding coupling reagents to the intermediate of the deamination reaction. This achievement could have been discovered over 100 years ago. ”Zhang Xiaheng candidly admitted. As early as 1893, N-nitroamine was reported by scientists, but it was not thoroughly studied. The research on adapting new processes to diverse medicinal raw materials is expected to change the current pharmaceutical industry's pharmaceutical path. In this study, the team selected the most commonly used nitrogen-containing intermediates from multiple pharmaceutical companies and conducted synthesis experiments to convert the amino groups. The results showed that this new strategy is almost applicable to all types of medicinal aromatic amines and aniline derivatives with different electrical and structural properties, without being limited by the amino position. Meanwhile, the team has already connected with several pharmaceutical companies and is preparing to apply the new technology to the synthesis of related drug intermediates. The so-called drug intermediate refers to the key intermediate product of drugs from "basic chemical raw materials" to "final finished drugs". According to the "Analysis Report on Market Share and Industry Competition Pattern of Customized Drug Intermediates in China in 2025", many modern innovative drugs, especially small molecule precursors for targeted anticancer drugs, antiviral drugs, and biologics, rely on intermediates containing multiple stereoisomeric centers, which poses extremely high requirements for selective control in the synthesis process. According to estimates from partner companies, the new technology is expected to reduce the production cost of certain pharmaceutical intermediates by 40% to 50% and achieve large-scale green production. By adopting this new strategy, the team has successfully achieved kilogram level continuous synthesis of the target drug intermediate, which means that the relevant technology has completed pilot testing. Zhang Xiaheng said, "A worker from an ordinary pharmaceutical factory can operate our formula." Zhang Xiaheng pointed out that the team has only completed preliminary theoretical research and laboratory scale verification at present. The potential application of this strategy and the safety testing of amplification reactions require further research and promotion by more industry experts, and its long-term accumulation and verification may require a time dimension spanning several years or even decades. (New Society)