PROCEDE DE PREPARATION DE DRONABINOL

PROCESS FOR THE PRODUCTION OF DRONABINOL

Abrégé français

Procédé de préparation de dronabinol qui consiste (a) à isoler du cannabidiol sous forme d'acide de cannabidiol à partir de chanvre indien, (b) éventuellement à cycliser le cannabidiol obtenu par décarboxylation en présence d'acides de Lewis dans un solvant non polaire pour obtenir du dronabinol, (c) à isoler ce dernier par un procédé chromatographique et (d) à purifier par distillation sous vide le résidu obtenu à partir de l'éluat, après élimination du solvant par distillation. Le dronabinol peut par ex. être utilisé, pour des préparations pharmaceutiques, dans une seringue remplie de ladite matière, et en tant que solution d'inhalation, par nébulisation thermique à l'aide d'air chaud.

Abrégé anglais

A method for the production of dronabinol is disclosed, whereby: a)
cannabidiol is isolated from fibrous hemp as cannabidiol acid, b) the
cannabidiol, optionally obtained by decarboxylation, is cyclised in the
presence of Lewis acids in a non-polar solvent to give dronabinol, c) the
above is isolated by a chromatographic method and d) the residue obtained from
the eluant after distilling off the solvent is purified by vacuum
distillation. The dronabinol can be used for dispensing purposes in a syringe
filled therewith and as inhalation solution for thermal nebulisation with hot
air.

Revendications

7
CLAIMS:
1. A process for synthesizing dronabinol from a starting material comprising
active
ingredients in a solvent, characterized in that
A) the starting material used for the synthesis of dronabinol is cannabidiolic
acid,
cannabidiol or a mixture thereof, and
B) the cannabidiol, which is optionally obtained by decarboxylation of
cannabidiolic acid, is cyclized with the aid of a Lewis catalyst into the
dronabinol.
2. The process of claim 1, characterized in that the starting material is
fibrous hemp.
3. The process of claim 1 or 2, further characterized in that the dronabinol
is purified by
a chromatographic process.
4. The process of any one of claims 1 to 3, further characterized in that a
residue
obtained from an eluate after distilling off the solvent is purified by vacuum
distillation
5. A process for preparing dronabinol, characterized in that
a) cannabidiol or cannabidiolic acid is isolated from fibrous hemp,
b) the cannabidiol, which is optionally obtained by decarboxylation of
cannabidiolic acid, is cyclized in the presence of a Lewis catalyst in a non-
polar solvent to give dronabinol, and either
c) the dronabinol is isolated by a chromatographic process, or
d) a residue obtained from an eluate from step b) after the solvent has been
distilled off is purified by vacuum distillation.
6. The process of any one of claims 1 to 5, characterized in that the active
ingredients
are extracted from the flowers or leaves of fibrous hemp.
7. The process of any one of claims 1 to 6, characterized in that the active
ingredients
are isolated from constituents obtained by extraction of the starting material
using a non-
polar solvent.

8
8. The process of any one of claims 1 to 7, characterized in that the active
ingredients
of the starting material are accumulated in the solvent by extracting fresh
plant material with
a solvent which already comprises active ingredients without distilling off
the solvent.
9. The process of any one of claims 5 to 8, characterized in that the active
ingredients
obtained by extraction are purified by
a) treating the extract with aqueous alkali, from which the free carboxylic
acids
are precipitated after the acidification; and/or
b) distilling off the solvent and dissolving the residue in a polar organic
solvent
to precipitate out undesired lipophilic constituents which are filtered off
and
obtaining the active ingredient present in the filtrate by evaporative
concentration;
c) decarboxylating the residue obtained in a) and/or b) by heating;
d) distilling the product of step c) under reduced pressure; and
e) crystallizing the cannabidiol formed.
10. The process of any one of claims 1 to 9 characterized in that the Lewis
catalyst used
is an anhydrous salt of silver, tin, zinc or magnesium in an organic solvent.
11. The process of claim 10 characterized in that the Lewis catalyst is
selected from the
group consisting of zinc chloride, zinc bromide, zinc iodide, zinc
trifluoromethanesulphonate,
tin chloride, tin bromide, tin iodide, tin trifluoromethanesulphonate,
magnesium chloride,
magnesium bromide, magnesium iodide, magnesium trifluoromethanesulphonate,
silver
chloride, silverbromide, silveriodide, and silvertrifluoromethanesulphonate.
12. The process of any one of claims 1 to 9, characterized in that the
cannabidiol is
cyclized to dronabinol by adding BF3 etherate, optionally in the presence of
an alkaline
desiccant in an organic solvent.
13. The process of claim 12, characterized in that the alkaline desiccant used
is
potassium carbonate.
14. The process of any one of claims 1 to 9, characterized in that the
cannabidiol is
cyclized to dronabinol by adding a weak Lewis acid in an organic solvent.

9
15. The process of claims 13 and 14, characterized in that the solution
comprising
dronabinol is chromatographed on a silica gel column.
16. The process of any one of claims 9 to 15, characterized in that the
residue of
dronabinol obtained from the eluate is purified by a vacuum distillation.
17. The process of claim 16 wherein the vacuum distillation is a high-vacuum
distillation.
18. An inhalation solution for thermal nebulization with hot air,
characterized in that it
comprises dronabinol prepared according to one of claims 1 to 16.
19. The inhalation solution of claim 18, characterized in that it additionally
comprises
cannabidiol, a local anaesthetic and/or etherical oils.
20. A process for producing a medicament comprising dronabinol which is
obtained by
the process of any one of claims 1-17, characterized in that, in a first step,
the dronabinol
is introduced into a calibrated gas-tight glass syringe and, in a second step,
the liquefied
contents are delivered in a controlled dosage, the ingredients being delivered
without the
remaining amount of dronabinol introduced coming into contact with air.

Description

CA 02472561 2008-12-05
PROCESS FOR THE PRODUCTION OF DRONABINOL
The object of the invention is a process for the production of dronabinol from
fibrous
hemp.
Dronabinol is a cannabinoid with the chemical description (6aR-trans)-
6a,7,8,10a-
tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-ol. Dronabinol A9-
tetrahydrocannabinol) is a natural constituent of various cannabis plants,
from which it
can be obtained by extraction. Dronabinol can also be chemically synthesised
and is a
pale-yellow, resinous oil, which is sticky at room temperature and hardens in
cool
storage. It is insoluble in water, but can be dissolved in oils such as sesame
oil.
US patent 4 025 516 already discloses a process for the production of A9-
tetrahydrocannabinol by condensation of the (+)-p-mentha-2,8-dien-1-ol with
olivetol in
the presence of BF3 etherate. US Patent 5 342 971 also describes synthesis of
dronabinol from cannabidiol acid esters in the presence of Lewis acids and
subsequent
hydrolysis. In addition, synthesis of dronabinol from hydroxy-cannabidiol with
Lewis
acids is also already known in US Patent 5 227 537. The production of
dronabinol from
tetrahydrocarbinol-rich cannabis with subsequent distillation and/or
chromatography is
described in international patent application WO 00/25127.
The abovementioned synthetic processes were developed because isolation of A9-
tetra hydroca nnabi nol from cannabis indica is legally prohibited, e.g. by
the conditions
of German narcotics legislation. Since synthetic processes are very expensive,
dronabinol on the other hand is gaining increasing medicinal importance, due
to its
immunosuppressive and cytostatic properties, but especially for alleviating
the side
effects occurring in cancer therapy, and the problem arose of creating a
simple process
for producing dronabinol from plant materials, which would comply with legal
requirements. Obtaining O9-tetrahydrocannabinol from fibrous hemp (cannabis
sativa)
is considered permissible.
The object of the invention is therefore a process for the production of
dronabinol,
wherein
a) cannabidiol or cannabidiol acid is isolated from fibrous hemp,

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2
b) the cannabidiol optionally obtained by decarboxylation is cyclised in the
presence of
Lewis acids in a non-polar solvent to give dronabinol,
c) this is isolated by a chromatographic process and
d) the residue obtained from the eluant after distilling off the solvent is
purified by
vacuum distillation.
In order to produce dronabinol according to the present invention the blossoms
or also
the leaves of fibrous hemp derived from certified seed are advantageously
separated
out from other plant material and sifted after drying. But it is also possible
to use the
plant material freed and cut from the stalks without preliminary sifting for
extraction of
active ingredients. Because cannabidiol acid and cannabidiol are concentrated
especially in the resinous glands found on the leaf or blossom surface, and
these
glands can be separated mechanically by sifting from the remaining plant
material, this
method is successful in obtaining a material containing cannabidiol acid and
cannabidiol which are required as starting materials for dronabinol synthesis
in
sufficiently high concentrations.
The active ingredients are isolated by extraction with a non-polar solvent,
e.g. benzine,
from the blossom constituents or the cut plant material obtained by sifting as
per the
present invention. The extraction of active ingredients is effectively carried
out in such
a way that fresh blossoms or fresh plant material are treated with a solvent,
which has
been concentrated with already active ingredients via an earlier extraction
procedure.
In this way the active ingredient concentration increases continuously in the
solvent,
without distillation of the solvent being necessary. Since the solvent
treatment of the
plant material can be undertaken at room temperature, thermal decarboxylation
of the
cannabidiol acid isolated from the blossom constituents is largely avoided.
In the resulting solvent extract cannabidiol and cannabidiol acid are
frequently present
according to age and preliminary treatment of the plant material. Whereas
cannabidiol
acid is obtained predominantly from fresh plant material, cannabidiol
predominates in
older plant material.
The further steps for obtaining the cannabidiol now depend on whether it is
predominantly cannabidiol acid or cannabidiol present in the blossom extract.

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3
To obtain cannabidiol acid from the solvent extract the latter is treated with
an aqueous
lye, preferably in counter-current extraction in the presence of a reducing
agent,
whereby the cannabidiol acid is dissolved with salification in the aqueous
phase. The
acid is precipitated from this ensuing acidification.
But if the active ingredient is predominantly present as free cannabidiol, the
solvent is
distilled off and the residue is dissolved in a polar organic solvent, whereby
unwanted
lipophilic constituents precipitate and are filtered off. The active
ingredient is then
obtained by evaporating the filtrate.
If the solvent extract contains a mixture of cannabidiol acid and cannabidiol,
it is
recommended to first treat the solvent extract with an aqueous alkali solution
and
subsequent extraction of the cannabidiol remaining in the organic solvent by
means of
a polar organic solvent.
The cannabidiol acid contained in the resulting extracts is then
decarboxylated by
heating, and the resulting cannabidiol is distilled off in a vacuum and
crystallised.
Decarboxylation is carried out with the exclusion of oxygen, thus either in a
vacuum or
with an inert gas such as nitrogen. Crystallisation of the cannabidiol is
facilitated by
trituration of the distillate e.g. with petrol ether.
The resulting cannabidiol is cyclised according to the inventive process
advantageously
by means of Lewis catalysts, optionally with the addition of basic drying
agents to give
dronabinol. Anhydrous salts of silver, tin, zinc or magnesium, e.g. zinc
chloride, zinc
bromide, zinc iodide, zinc trifluormethansulfonate, tin chloride, tin bromide,
tin iodide,
tin trifluormethansulfonate, magnesium chloride, magnesium bromide, magnesium
iodide, magnesium trifluormethansulfonate, silver chloride, silver bromide,
silver iodide,
silver trifluormethansulfonate are used in an organic solvent as suitable
Lewis acids.
The resulting raw dronabinol is then purified chromatographically. To this is
added a
solution of the raw dronabinol in an organic solvent e.g. via a silica gel
column. After
the solvent is removed from the eluant the residue then undergoes high-vacuum
distillation, whereby flash distillation or distillation in a bulb tube,
preferably with the
addition of bases, have proven particularly effective.

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The resulting end product is very pure dronabinol, which at room temperature
is a
viscous fluid, but liquefies at higher temperatures and e.g. at a temperature
of 60 to
80 C can be easily filled into a calibrated, gas-tight glass syringe. This
dronabinol-filled
glass syringe is delivered to pharmacies, where the liquefied contents are
precisely
metered after the glass syringe has been gently heated, from which various
pharmaceuticals can be produced, such as e.g. liquid drugs by adding precisely
measured quantities of dronabinol e.g. to sesame oil or other edible oils, and
gelatine
capsules filled with dronabinol, in which the dronabinol is taken up by oleum
cacao and
fixed in the capsules, and also inhalation solutions, in which the dronabinol
is dissolved
in alcohol.
The resulting dronabinol can also be applied from an alcohol solution by means
of a
special inhaler (e.g. Inhalator Vulcano marketed by Vapormed), such that the
active
ingredient is evaporated by means of a hot air current in a closed pouch, from
which it
can then be inhaled as aerosol. This form of application ensures particularly
high
bioavailability. Bioavailability can be further improved by adding other
substances such
as cannabidiol and/or essential oils and/or local anaesthetic, as irritation
of airways is
decreased during inhalation and a longer dwell time of the aerosol in the
lungs is thus
possible.
The process according to the present invention is distinguished by a series of
considerable advantages. First it should be emphasised that the fibrous hemp
used as
starting material can be added in without problem, as it is not subject to any
legal
restrictions.
In procedural terms it is a particular advantage that the use of an organic
solvent
containing already active ingredients for extracting the plant materials leads
to an
overall desired increase in the active ingredient concentration, without the
consequence of loading via thermal concentration when obtaining the extract.
This
extensively prevents decarboxylation of cannabidiol acid. At the same time
extraction
of cannabidiol acid from the solvent extract by means of aqueous alkali, which
effectively leads to selective concentration of the active ingredients via
counter-current
extraction, also considerably reduces the content of any possible pesticides.

CA 02472561 2008-12-05
An added advantage is that thermal decarboxylation of the extract residue
obtained
from plant material prevents problems which might arise during distillative
treatment of
the raw product through ensuing generation of gas.
A further procedural advantage can be achieved by the dronabinol obtained via
cyclising of cannabidiol first being cleaned via distillation and
crystallisation, thus
facilitating subsequent chromatographic treatment.
With all synthesis of O9-tetrahydrocannabinol it must be taken into
consideration that
the thermodynamically more stable A8-tetrahydrocannabinol, although not of
interest for
medical applications, does not occur. There is also the danger of developing
A8-
tetrahydrocannabinol basically during cyclising according to the present
invention with
BF3 etherate, though this unwanted reaction can be prevented if a basic drying
agent is
employed during cyclising.
Even more beneficial is the use of weak Lewis acids, since the formation of A8-
tetrahydrocannabinol is then clearly reduced.
A particularly significant embodiment of the present invention is in filling
highly purified
dronabinol into syringes, from which smaller quantities of dronabinol can
easily be
taken for dispensing purposes, without the remaining quantities of the oxygen-
sensitive
substance coming into contact with air.
The process according to the present invention thus opens up novel and simple
access
to dronabinol which is becoming more and more important for medical purposes.
Example I
Production of dronabinol
5 ml of boron trifluoride etherate is added to a solution of 5 g of
cannabidiol in 1600 ml
of methylene chloride with stirring and the solution is left to stand at room
temperature.
On completion of reaction the procedure is stopped with the addition of 500 ml
water.
The residue obtained after distillation of the solvent contains
A8-tetrahydrocannabinol 5.59%

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dronabinol 74.60%
The mixture is separated into its constituents by means of preparative HPLC
and the
purified dronabinol undergoes vacuum distillation.
Example 2
ml of boron trifluoride etherate is added to a solution of 5 g of cannabidiol
in 1600 ml
of methylene chloride and 5 g of potassium carbonate with stirring and the
solution is
left to stand at room temperature. On completion of reaction the procedure is
stopped
with the addition of 500 ml water. The residue obtained after distillation of
the solvent
contains
A8-tetrahydrocannabinol 1.59%
dronabinol 82.40%
The treatment is the same as for Example 1
Example 3
A solution of 5 g cannabidiol in 1600 ml dichloro ethane with 10 g zinc
chloride is
cooked for 24 hours on reflux. On completion of reaction the procedure is
stopped with
the addition of 500 ml water. The residue obtained after distillation of the
solvent
contains
A8-tetrahydrocannabinol 5.01%
dronabinol 86.37%
The treatment is the same as for Example 1