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

Article abstract of DOI:10.1002/ejoc.202001633

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).

Full text of DOI:10.1002/ejoc.202001633

Communications
doi.org/10.1002/ejoc.202001633
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A Novel and Practical Continuous Flow Chemical Synthesis
of Cannabidiol (CBD) and its CBDV and CBDB Analogues
Elena Chiurchiù,[a] Susanna Sampaolesi,[a] Pietro Allegrini,[b] Daniele Ciceri,[b] Roberto Ballini,[a]
and Alessandro Palmieri*[a]
This article is dedicated to Prof. Franco Cozzi on the occasion of his 70th birthday.
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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 pharma-
ceutical, nutraceutical, and cosmetic applications. Herein, we
report the first continuous flow chemical synthesis of cannabi-
diol (CBD) and its analogues cannabidivarin (CBDV) and
cannabidibutol (CBDB). This approach permits to synthesize
Figure 1. Molecular structure of cannabidivarin (CBDV), cannabidibutol
(CBDB) and cannabidiol (CBD).
products in very good yields (55–59%), limiting the formation
of psychoactive and illegal cannabinoids such as tetrahydrocan-
nabinol (THC).
Cannabis sativa L. and its derivatives have been used as popular
medicines for 5000 years.[1] Epidiolex, a cannabidiol (CBD) based
medicine developed by GW Pharmaceuticals Inc., has been
recently approved by the European Union for the treatment of
severe forms of epilepsy associated with Lennox Gastaut and
Dravet syndromes.[2] This authorization follows the one granted
by the FDA in 2018. The latter is the first approval among more
than two hundreds clinical trials currently ongoing on CBD,
cannabidivarin (CBDV) and other cannabinoids. Nowadays, the
enormous interest of the pharmaceutical, cosmetic and food
supplements industries, as well as the attention of the
academical research for these derivatives, resulted in a continu-
ous and growing effort to develop new and ever more efficient
syntheses of cannabidiol and its analogues (Figure 1).[3]
CBD, currently the most investigated non-psychoactive
cannabinoid, is mainly synthetically pursued by the acid-
catalysed terpenylation of olivetol 1a or olivetolic acid alkyl
Scheme 1. Synthesis of CBD via terpenylation of olivetol or olivetolic esters.
esters
2 followed by saponification and decarboxylation
(Scheme 1). In this context, important results have been
obtained using isopiperitenol 3a, menthadienol 4a, carene
epoxide 5 or their O-substituted derivatives, as synthetic
equivalents of the carbocation I under Lewis or Brønsted acid
conditions (e.g. ZnCl2, BF3 ·Et2O, p-TsOH).[4]
Alternative synthetic approaches involve (i) the reaction of
diaryl-lithium cuprates with (+)-3,9-dibromocamphor 6 or α-
iodocyclohexenone 7 (Scheme 2, Eq. 1.),[5] and (ii) the derivatiza-
tion of olivetol with appropriate acyclic structures to give, after
a series of synthetic manipulations, the target CBD (Scheme 2,
Eq. 2).[6] The crucial point of all these methodologies is to
minimize the cyclization of CBD into the psychoactive tetrahy-
drocannabinol (Figure 3, THC), which is subject to legal
restrictions in many countries. Due to this problem and in order
to limit its formation, reported methods show important
drawbacks concerning yields and scalability.
[a] Dr. E. Chiurchiù, Dr. S. Sampaolesi, Prof. R. Ballini, Prof. A. Palmieri
Green Chemistry Group, School of Sciences and Technology, Chemistry
Division
University of Camerino
Via S. Agostino n.1, 62032 Camerino (MC), Italy
E-mail: alessandro.palmieri@unicam.it
https://sites.google.com/unicam.it/alessandro-palmieri
[b] Dr. P. Allegrini, Dr. D. Ciceri
Indena S.p.A.
Viale Ortles n.12, 20139 Milano, Italy
Supporting information for this article is available on the WWW under
https://doi.org/10.1002/ejoc.202001633
Part of the “Franco Cozzi’s 70th Birthday” Special Collection.
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doi.org/10.1002/ejoc.202001633
dichloromethane solution of olivetol 1a and acetyl isoper-
itenol 3b (R=Ac), while the reservoir B with a dichloro-
methane solution of BF3 ·Et2O.
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After a series of experiments aimed to profile the process in
terms of stoichiometry, reaction temperature and residence
time, the best result was recorded at room temperature,
starting from a 0.1 M and 0.05 M solutions of 1a and 3b
respectively (Reservoir A), a 0.00125 M solution (2.5 mol% vs 3b)
of BF3 ·Et2O (Reservoir B), and with a residence time of 7 minutes
(Table 1, Entry g). In fact, under these conditions, (À )-CBD was
isolated in 55% of yield. The main by-products were abnormal
cannabidiol and the dialkylated cannabidiol (Figure 3, 8 and 9)
recovered in 19% and 4% of yield respectively. In the end, since
THC was observed in traces (GC<0.4%) its isolation was
unfeasible.
It is important to point out that an extension of the
residence time to over 7 minutes, as well as the use of more
concentrate solution of BF3 ·Et2O led to the formation of
significant amount of THC (>5%). On the other hand, a
diminishing the residence time, the Friedel–Craft reaction
between 1a and 3b was not completed and an 8% of
unreacted isoperitenol was detected in the reaction crude
(Table 1, Entry i).
The process was also investigated starting from isopiper-
itenol 3a, benzoyl isopiperitenol 3c (R=Bz) and menthadienol
4a, however these substrates resulted less efficient than 3b
providing CBD in 48%, 16% and 38% of yield respectively.
It is important to point out that, as depicted in Figure 2, in
order to prevent the conversion of CBD into THC it was crucial
to directly quench the outcoming flow with a saturated solution
of NaHCO3. Furthermore, the use of two equivalents of olivetol
1a (the excess was recovered after purification) permitted to
minimize the formation of the dialkylated cannabidiol.
Successively, with the aim to increase the protocol
productivity, we screened the process trend starting from more
concentrate solutions of starting materials 1a and 3b (Table 2).
Under these conditions, the GC analysis of reaction crudes
highlighted in all cases a significant increase of the THC
formation, nevertheless the isolation of CBD provided more
than satisfactory yields.
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Scheme 2. Alternative synthetic approaches to CBD.
Herein, by means of flow chemistry,[7] and following our
studies concerning the use of this technology for synthesizing
highly functionalized materials,[8] we report an innovative and
high yielding continuous approach for producing (À )-CBD,
strongly reducing its cyclization into THC.
With this aim, we implemented a new flow equipment
(Figure 2) constituted of two different reservoirs (A and B), a
T-mixing piece (T) and a PTFE coil reactor (R, 3 mL, i.d. =
0.8 mm, o.d. =1.58 mm). The reservoir A was filled-up with a
Finally, in order to demonstrate the generality of our
protocol we explored the synthesis of CBDV and CBDB, the two
most studied analogues of CBD.[3b,9] In particular, starting from
the olivetol analogues 1b and 1c and performing the reaction
Figure 3. Molecular structures of tetrahydrocannabinol (THC), abnormal
cannabidiol (8) and the dialkylated form of cannabidiol (9).
Figure 2. General apparatus for the flow synthesis (À )-CBD.
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Table 1. Optimization studies
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Entry
Reservoir A
M of 1a and 3b
Reservoir B
[mol%] of BF3 ·Et2O vs 3b
GC analysis[a]
(À )-CBD/8/THC/9
Residence time [min]
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a
b
c
d
e
f
0.05–0.05
0.075–0.05
0.1–0.05
0.1–0.05
0.1–0.05
0.1–0.05
0.1–0.05
0.1–0.05
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2.5
2.5
2.5
42.6/22.4/9.6/25.4
48.8/22.5/9.5/19.2
61.1/22.7/8.9/7.3
62.5/22.8/7.6/7.1
65.8/22.3/5.2/6.7
66.0/22.4/5.1/6.5
70.8/22.6/0.4/6.2
70.7/22.7/0.2/6.4
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g
i
7[b]
6[c]
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[a] Percentage normalized considering only peaks of (À )-CBD, 8, THC and 9. [b] 55% Of pure (À )-CBD was recovered after flash column chromatography.
[c] A 8% of unreacted isoperitenol 3b was detected in the reaction crude.
Table 2. More concentrated solutions.
analogues CBDV and CBDB in comparable yields (56% and
59%).
M of 1a and 3b[a]
GC analysis[b]
(À )-CBD/8/THC/9
Yield [%][c] of
(À )-CBD
0.2–0.1
0.5–0.25
1.0–0.5
58.3/25.6/8.9/7.2
53.3/24.7/14.2/7.8
46.5/26.1/19.8/7.6
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Experimental Section
General Procedure for the preparation of CBDB, CBV and CBD.
The flow equipment was set up according to Figure 2. Acetyl
isoperitenol 3b (2.5 mmol, 0.486 g) and olivetol 1a [5 mmol,
0.901 g, or its analogues 1b (0.831 g) and 1c (0.761 g)] were taken
up in dichloromethane (50 mL) and filled into reservoir A. BF3 ·Et2O
(0.063 mmol, 7.8 μL) was taken up in dichloromethane (50 mL) and
filled into reservoir B. The two solutions were simultaneously
pumped with a flow rate of 0.214 mL/min for each pump into a T-
connector before passing through a 3 mL coil reactor (residence
time 7 minutes) and then dropped the outflow into a flask
containing 70 mL of a stirring saturated solution of NaHCO3. The
two layers were separated, the aqueous one was extracted with
DCM (3×40 mL) and the combined collected organic phases were
dried over anhydrous Na2SO4. After the filtration and solvent
evaporation under reduced pressure, the residue was purified by
flash column chromatography (hexane:ethyl acetate=95:5) to give
the pure CBD in 55% of yield (1.375 mmol, 0.433 g). CBV and CBDB
were isolated in 56% (1.4 mmol, 0.401 g) and 59% (1.475 mmol,
0.443 g) of yield respectively.
[a] Reaction conducted with a residence time of 7 minutes and using 2.5%
of BF3 ·Et2O. [b] Percentage normalized considering only peaks of (À )-CBD,
8, THC and 9. [c] Yield of the pure isolated product.
under the optimized conditions, CBDV and CBDB were isolated
in 56% and 59% yield respectively (Figure 4). The main by-
products for both reactions were the abnormal derivatives 10
and 11, which were isolated in 30% and 26% of yields.
In conclusion, exploiting the unique features of continuous
flow chemical synthesis, we developed a new efficient and
simple flow protocol for producing CBD in very good yield
(55%), in comparison with similar approaches reported in the
literature,[10] and limiting its cyclization into the psychoactive
tetrahydrocannabinol. Moreover, the process resulted of gen-
eral applicability since was successfully used for preparing the
Acknowledgements
Authors thank Indena S.p.A. and the University of Camerino (FAR
program) for the financial support.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: Cannabidibutol · Cannabidiol · Cannabidivarin ·
Flow chemistry · Friedel–Crafts reaction
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Manuscript received: October 17, 2020
Revised manuscript received: January 14, 2021
Accepted manuscript online: January 15, 2021
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