Recently, Asymchem (stock code: 002821.SZ) co-published a paper with Amgen Inc.-“Development and Execution of a Production-Scale Continuous [2+2] Photocycloaddition” in the academic journal of American Chemical Society (ACS) called “Org. Process Res. Dev.”. This was a major breakthrough in the field of photochemical scaled-up applications and was jointly achieved by Amgen’s Process Development Group and Asymchem’s Center for Process Sciences (CEPS).

The conventional chemical synthesis of cyclobutane dicarboxylic acid lactones is a six-step reaction with a total yield of 10.6% and it requires the use of bromine, dichlorosulfoxide and even editpotassium cyanide, a highly toxic compound. Also, a high-pressure and high-temperature decarboxylation reaction is involved. Therefore, the overall process of this synthetic route is in need of optimization based on the current weaknesses like long reaction sequence, harsh conditions, low safety assurance and low total yield.

Past literatures have suggested that a direct [2+2] cycloaddition using ethylene and maleic anhydride with a proper light source can be obtained by only one step and result in the cis-1, 2-cyclobutane dicarboxylic anhydride product. However, due to limitations in light source technology and equipment, the existing reports of this [2+2] cycloaddition reaction were mainly under the gram/day laboratory scale. As a result, the commercial production of this product remained unreachable. In order to solve this issue, researchers from both sides proposed a two-stage approach to scale up this [2+2] cycloaddition reaction. First, they tested the practicability of producing 500g in lab per day and after validating that concept, they developed corresponding equipment for the target capacity of >5Kg/day. Subsequent trials and the formal production were completed afterwards.

In the first stage, the researchers investigated extensively and optimized the type of light source, light intensity, reaction solvent, catalyst’s type and amount, substrate concentration and type of reactor. They eventually came up with the best reaction condition as followed: using the 365nm wavelength LED as the light source, setting the light intensity to 60 mW/cm2, choosing 10mol% benzophenone as photosensitizer and acetone as solvent, adjusting the reaction concentration to 0.25M. Under room temperature, such upgraded reaction route done in the FEP coil reactor could reach a conversion rate higher than 99%. At the same time, after a large number of solvent screening and condition optimization, the purification process of crude products were developed, and finally a stable version of post processing purification process was obtained. The final content ratio of the product was over 97% and the GC purity was higher than 98%, which successfully fulfilled Amgen’s downstream production demands.

Under the optimal reaction condition, the [2+2] cycloaddition reaction was initially scaled up using laboratory equipment to achieve a production capacity of 646 g/day, which confirmed the high stability and scalability of the reaction condition and corresponding equipment. This progress broke through the scale limitation of such reaction and provided strong supports for the next stage.

After achieving the target with a 500g/day capacity in the first stage, researchers further improved the laboratory equipment aiming for a 5kg/day production capacity ultimately and completed a thorough risk assessment and installation check. Then, three 24h batch testing were carried out in Asymchem’s flow chemistry specialized module. As the equipment’s performance was stable as expected, these optimized equipment were put into the formal production soon after and offered a satisfying average separation yield which was over 65%. The final content ratio was over 97% and the purity was high than 98%, meeting the 300kg production demand from Amgen.

Asymchem has overcame the long-standing scale limitation of the traditional [2+2] cycloaddition reaction by establishing a multi-kilogram scale production system and has become a global pioneer in industry manufacturing using [2+2] photocycloaddition reaction. The perfect combination of photochemistry and continuous reaction leads to the industry-wide technological innovation, and brings photochemistry into real industrial applications, which is of great importance and value. Asymchem has always taken “Maximizing customers’ benefits” as the guideline, and continuously strived for excellence in project quality and efficiency.