One-flow synthesis of tetrahydrocannabinol and cannabidiol using homo- and heterogeneous Lewis acids

Abstract

Continuous flow chemistry holds great potential for the production of biologically relevant molecules. Herein, we present an approach for the continuous synthesis of cannabidiol and tetrahydrocannabinol in a one-flow system. The designed route consists of a reaction cascade involving Friedel-Crafts alkylation, subsequent ring opening and cyclisation in up to 45% yield. The reactions were successfully performed using both hetero- and homogeneous Lewis acids in continuous flow and provide yields that are similar to comparable batch processes. Graphical abstract

Synthesis of Neocannabinoids Using Controlled Friedel–Crafts Reactions

“…We began our investigation by screening numerous Lewis and Brønsted acids to initiate allylic cation chemistry by mimicking the effects of BF 3 ·OEt 2 as reported in the literature. − Previously, Mascal and co-workers obtained normal CBD 3 in 71% yield by para -toluenesulfonic acid ( p -TsOH) acid-catalyzed addition to α-phellandrene 9 (Scheme B). , In an effort to match this efficiency, we considered the well-established Friedel–Crafts alkylation/cationic pathway using olivetol 7 and allylic alcohol 10 to access H 2 CBD isomers 3 and 6 (Scheme C,D). Our catalyst scope included various Lewis acids including Sc­(III)-, La­(III)-, Eu­(III)-, and Yb­(III)-triflates, p -TsOH, and methanesulfonic acid (MsOH), as well as combinations of both Lewis and Brønsted acids.…”

Continuous Flow Synthesis of Anticancer Drugs

“…Pharmaceutical companies thereby opt to target individual steps for flow development, which may be of particular relevance towards the end of the synthesis where the material becomes more valuable, while the reactor containment will mitigate any concerns relating to the cytotoxicity of the final API at the same time. The relevance of natural products towards anticancer drugs has been highlighted in this review, and it is expected that flow technology will continue to facilitate their generation as exemplified in additional studies based on taxol [107], cannabinoids [108], as well as peptide-based systems [109] As this short review has shown, an increase in reported case studies is evident within the last few years demonstrating that flow processing has not only matured as an enabling technology but moreover is accepted and endorsed by both scientists and management within the pharmaceutical industry. A further increase in activity can be expected in this area to realize further autonomy of API production in response to delays and shortages recognized for many drugs during the current pandemic.…”

Ultrasonic or Microwave Modified Continuous Flow Chemistry for the Synthesis of Tetrahydrocannabinol: Observing Effects of Various Solvents and Acids

“…These conditions are usually not environmentally friendly and can produce undesired side products. Flow chemistry has shown to be useful to produce cannabinoids, albeit at small scales. − Flow chemistry is beneficial by closing the gap between small-scale bench chemists and large-scale process engineers by mimicking large-scale production in a laboratory environment through continuous production with a limited need to interact with the system. As shown in Figure , the simple flow design provides the ability to tailor the flow path and add additional sites that lead to the final product (i.e., purification, hydrogenation, sample taking, etc.).…”