A Novel and Practical Continuous Flow Chemical Synthesis of Cannabidiol (CBD) and its CBDV and CBDB Analogues

Abstract

This article is dedicated to Prof. Franco Cozzi on the occasion of his 70th birthday. Cannabidiol is one of the main non-psychoactive cannabinoids present in Cannabis sativa and, in the last decade, it is gaining great interest among the scientific community for its pharmaceutical, nutraceutical, and cosmetic applications. Herein, we report the first continuous flow chemical synthesis of cannabidiol (CBD) and its analogues cannabidivarin (CBDV) and cannabidibutol (CBDB). This approach permits to synthesize products in very good yields (55-59 %), limiting the formation of psychoactive and illegal cannabinoids such as tetrahydrocannabinol (THC).

Synthetic Strategies for Rare Cannabinoids Derived from Cannabis sativa

“…1 H and 13 C NMR data agree with those reported in the literature. 54 CBD-C 3 (3b). Prepared according to the general procedure using divarinol (1b) and p-mentha-1,8-dienol (Table 3; entry 3.2).…”

Short and efficient synthesis of alkylresorcinols: a route for the preparation of cannabinoids

“…All reactions of this multistep synthetic sequence (Schemes 3 and 4) were cleaned and characterized by very simple workups; ARs 1a–e (deuterated or not) were isolated in high yields (≥ 87% overall yield from 2 , higher than those reported in the literature using different synthetic strategies 23 ) over only 3 steps without isolation of the intermediate products 4 and 5 , thus allowing a beneficial reduction in the amount of used organic solvents.…”

“…[19][20][21][22] In particular, the development of protocols potentially applicable to automated processes (flow synthesis) represents a future challenge. In this regard, the first automation of the terpenylation step 23 of the synthesis of CBD and CBDV for possible large-scale industrial applications opens up new perspectives and renders the development of simple and efficient methodologies for the production of ARs even more important. In addition, having versatile methodologies that can also be used for the synthesis of deuterated ARs and, consequently, deuterated cannabinoids suitable as internal standards for mass spectrometric analyses, or as starting materials for the production of deuterated metabolites for the study of cannabinoid metabolism and pharmacokinetics in animals and humans, is also important.…”

Stereoselective Synthetic Strategies to (−)‐Cannabidiol

“…A more modern approach to avoid the use of alumina is based on continuous flow chemical synthesis, as reported by Palmieri and co‐workers in 2021 [18] . This automated strategy represents the most modern approach to the stereoselective synthesis of (−)‐CBD.…”

“…[17] A more modern approach to avoid the use of alumina is based on continuous flow chemical synthesis, as reported by Palmieri and co-workers in 2021. [18] This automated strategy represents the most modern approach to the stereoselective synthesis of (À )-CBD. In their work, the authors used flow equipment constituted of two different reservoirs, as reported in Scheme 4.…”