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Ultrafast membrane reactor developed for cleaner, more efficient beta-blocker production

Chinese scientists have developed a breakthrough process that significantly improves the efficiency and environmental friendliness of beta-blocker production—with a focus on the widely used compound propranolol, which plays a vital role in managing cardiovascular conditions such as hypertension, arrhythmia, and angina.

Led by Prof. Zhang Xiqi at the Technical Institute of Â鶹ÒùÔºics and Chemistry of the Chinese Academy of Sciences, the research team developed a novel amine-functionalized graphene oxide (NGO) membrane reactor that enables ultrafast, continuous-flow synthesis of propranolol, with nearly 100% conversion and selectivity in under 4.63 seconds at 23 °C.

The study is published in .

Conventional routes for synthesizing propranolol typically involve the ring-opening reaction of naphthyl glycidyl ether with isopropylamine. However, existing catalytic systems often suffer from long reaction times, low conversion rates, formation of undesirable by-products, and challenges in separation and purification—limiting their practical application.

To address these challenges, the researchers constructed membrane reactors using acidic graphene oxide (GO) and alkaline NGO via vacuum-assisted filtration. Both the GO and NGO membranes were employed as nanoreactors to achieve the ring-opening reaction.

Compared to the GO membrane, the NGO membrane exhibited a catalytic flux 4.36 times higher and achieved a turnover frequency (TOF) approximately 8.07 times greater than that of the GO membrane.

Further optimization involved fine-tuning the NGO membrane's interlayer spacing through mild thermal annealing. As interlayer spacing decreased, both conversion and selectivity for propranolol synthesis improved significantly. Density functional theory calculations revealed that the energy barrier for the propranolol formation step decreased along with the reduction in interlayer spacing, thus enhancing conversion.

In addition, the activation energy for by-product formation increased concurrently, significantly hindering by-product formation despite its thermodynamic stability. Consequently, propranolol became the predominant product, indicating that the reaction mechanism shifts toward kinetic control.

Furthermore, to suppress the production of undesired by-products from secondary reactions between residual naphthyl glycidyl ether and propranolol—as well as improve reaction selectivity—the researchers optimized the reactant molar ratio by increasing the isopropylamine equivalence. Experiments demonstrated that the reaction reached nearly 100% conversion and selectivity under a reactant molar ratio of 1:3.

In comparison with previously reported catalytic systems, the NGO membrane reactor demonstrated shorter reaction time, operation under ambient temperature, and higher conversion efficiency—all key metrics of superior performance. Notably, its TOF of 17.48 h^-1 far exceeded that of the NGO powder catalyst, which only achieved 2.27 h^-1 under identical conditions.

The reactor's versatility was further validated by its successful application in the synthesis of other beta-blockers, including metoprolol, bisoprolol, pindolol, and naftopidil—highlighting its broad potential for scalable pharmaceutical production.