Abstract:Hydrocodone,
a high value active pharmaceutical ingredient (API),
is usually produced in a semisynthetic pathway from morphine, codeine
or thebaine. The latter alkaloid is an attractive precursor as it
is not used as a remedy itself. The key step in this production route
is a selective olefin reduction forming 8,14-dihydrothebaine which
can be subsequently hydrolyzed to yield hydrocodone. Unfortunately,
standard hydrogenation procedures cannot be applied due to severe
selectivity problems. A transfer hydrogena… Show more
“…The flow procedure provided a significant improvement in space–time yield in comparison to the batch synthesis. The reduction of thebaine was also achieved using a multi-injection approach but by using four inlet feeds for hydrazine monohydrate [71]. Scheme 17Continuous flow in situ generation of diimide (HN=NH) by O 2 for the reduction of alkenes applied to a highly reactive alkenes and b a multi-injection strategy for the reduction of artemisinic acid…”
Molecular oxygen (O2) is the ultimate “green” oxidant for organic synthesis. There has been recent intensive research within the synthetic community to develop new selective liquid phase aerobic oxidation methodologies as a response to the necessity to reduce the environmental impact of chemical synthesis and manufacture. Green and sustainable chemical processes rely not only on effective chemistry but also on the implementation of reactor technologies that enhance reaction performance and overall safety. Continuous flow reactors have facilitated safer and more efficient utilization of O2, whilst enabling protocols to be scalable. In this article, we discuss recent advancements in the utilization of continuous processing for aerobic oxidations. The translation of aerobic oxidation from batch protocols to continuous flow processes, including process intensification (high T/p), is examined. The use of “synthetic air”, typically consisting of less than 10% O2 in N2, is compared to pure O2 (100% O2) as an oxidant source in terms of process efficiency and safety. Examples of homogeneous catalysis and heterogeneous (packed bed) catalysis are provided. The application of flow photoreactors for the in situ formation of singlet oxygen (1O2) for use in organic reactions, as well as the implementation of membrane technologies, green solvents and recent reactor solutions for handling O2 are covered.
“…The flow procedure provided a significant improvement in space–time yield in comparison to the batch synthesis. The reduction of thebaine was also achieved using a multi-injection approach but by using four inlet feeds for hydrazine monohydrate [71]. Scheme 17Continuous flow in situ generation of diimide (HN=NH) by O 2 for the reduction of alkenes applied to a highly reactive alkenes and b a multi-injection strategy for the reduction of artemisinic acid…”
Molecular oxygen (O2) is the ultimate “green” oxidant for organic synthesis. There has been recent intensive research within the synthetic community to develop new selective liquid phase aerobic oxidation methodologies as a response to the necessity to reduce the environmental impact of chemical synthesis and manufacture. Green and sustainable chemical processes rely not only on effective chemistry but also on the implementation of reactor technologies that enhance reaction performance and overall safety. Continuous flow reactors have facilitated safer and more efficient utilization of O2, whilst enabling protocols to be scalable. In this article, we discuss recent advancements in the utilization of continuous processing for aerobic oxidations. The translation of aerobic oxidation from batch protocols to continuous flow processes, including process intensification (high T/p), is examined. The use of “synthetic air”, typically consisting of less than 10% O2 in N2, is compared to pure O2 (100% O2) as an oxidant source in terms of process efficiency and safety. Examples of homogeneous catalysis and heterogeneous (packed bed) catalysis are provided. The application of flow photoreactors for the in situ formation of singlet oxygen (1O2) for use in organic reactions, as well as the implementation of membrane technologies, green solvents and recent reactor solutions for handling O2 are covered.
“…The flow procedure provided a significant improvement in space-time yield in comparison to the batch synthesis. The reduction of thebaine was also achieved using a multi-injection approach but by using four inlet feeds for hydrazine monohydrate [71].…”
Molecular oxygen (O 2) is the ultimate "green" oxidant for organic synthesis. There has been recent intensive research within the synthetic community to develop new selective liquid phase aerobic oxidation methodologies as a response to the necessity to reduce the environmental impact of chemical synthesis and manufacture. Green and sustainable chemical processes rely not only on effective chemistry but also on the implementation of reactor technologies that enhance reaction performance and overall safety. Continuous flow reactors have facilitated safer and more efficient utilization of O 2 , whilst enabling protocols to be scalable. In this article, we discuss recent advancements in the utilization of continuous processing for aerobic oxidations. The translation of aerobic oxidation from batch protocols to continuous flow processes, including process intensification (high T/p), is examined. The use of "synthetic air", typically consisting of less than 10% O 2 in N 2 , is compared to pure O 2 (100% O 2) as an oxidant source in terms of process efficiency and safety. Examples of homogeneous catalysis and heterogeneous (packed bed) catalysis are provided. The application of flow photoreactors for the in situ formation of singlet oxygen (1 O 2) for use in organic reactions, as well as the implementation of membrane technologies, green solvents and recent reactor solutions for handling O 2 are covered.
“…Especially, selective olefin reduction is a massive challenge in the total synthesis of natural products. In 2016, the continuous‐flow selective olefin reduction of thebaine ( 1 ) was exploited by Kappe and co‐workers to obtain hydrocodone, a high‐value active pharmaceutical ingredient . The key step in this synthetic route is a selective olefin reduction to 8,14‐dihydrothebaine ( 2 ), which can be subsequently hydrolyzed to yield hydrocodone (Scheme ) .…”
Section: Continuous‐flow Hydrogenation Using Homogeneous Catalystsmentioning
To achieve a safe, efficient, and sustainable (even fully automated) production for the continuous‐flow hydrogenation reactions, which is among the most often used reactions in chemical synthesis, new catalyst types and immobilization methods as well as flow reactors and technologies have been developed over the last years; in addition, these approaches have been combined with new and transformational technologies in other fields such as artificial intelligence. Thus, attention from academic and industry practitioners has increasingly focused on improving the performance of hydrogenation in flow mode by reducing the reaction times, increasing selectivities, and achieve safe operation. This Minireview aims to summarize the most recent research results on this topic with focus on the advantages, current limitations, and future directions of flow chemistry.
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