Note: Descriptions are shown in the official language in which they were submitted.
CA 02770448 2012-03-02
CANNABINOID ESTERS
This application is a divisional application of co-pending application Serial
No. 2,504,743, filed on May 3, 2005.
FIELD OF THE INVENTION
The present invention relates to cannabinoid crystalline derivatives and more
particularly to cannabinoid-aryl sulfonates that can be utilized for
purification and/or storage
of cannabinoid compounds.
BACKGROUND OF THE INVENTION
Naturally occurring cannabinoids are the biologically active components of
cannabis.
Pharmaceutical interest in cannabinoids has increased due to FDA approval of g-
tetrahydrocannabinol (THC) for several therapeutic applications. This interest
has lead to the
development of' synthetic cannabinoid compounds.
In general, both natural and synthetic cannabinoids are very difficult
molecules to
work with, as they tend to be hard glasses that are prone to oxidation at room
temperature.
THC is a non-crystalline glass at room temperature, and is susceptible to
rearrangement and
air oxidation. Although THC is typically stored in a dark freezer under an
inert gas,
maintaining purity during storage is very difficult. These characteristics
also complicate the
use of cannabinoids as reactants in other synthesis methods or uses.
Purification of cannabinoids is also complicated by the characteristics listed
above.
Furthermore, many of the impurities commonly found in cannabinoid mixtures are
also
problematic. Conventional methods of purification typically involve the use of
HPLC. =
These methods are inconvenient and expensive, and make scaling up of the
purification
process impractical.
CA 02770448 2013-05-14
It is therefore desirable to provide a method for producing a cannabinoid
derivative
that allows for ease in handling, stable storage, an improved method of
purification, and that
are easily converted back to a cannabinoid.
SUMMARY OF THE INVENTION
An aspect of the present invention is to provide cannabinoid aryl sulfonates
including
those represented by the formula
R1 0
I
S _____________________________________________
0
A
R2 0 1110
R4
R3
Formula A
wherein:
RI, R2, R3, and R4 are independently H or a C1 to C6 alkyl;
A is a saturated alkane, alkene, diene or aromatic ring; and
Y is benzene, C1 to C6 alkyl substituted benzene, halogen substituted benzene,
or C1 to
C6 alkyloxy substituted benzene.
A further aspect of the present invention is to provide a process for the
preparation of
cannabinoid esters comprising reacting cannabinoid with at least one aryl
sulfonyl halide in
the presence of at least one base.
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There is provided herein a process for the preparation of cannabinoid aryl
sulfonates
comprising: reacting at least one cannabinoid with at least one aryl sulfonyl
halide in the presence
of at least one base R5R6R7N, wherein R5, R6 and R7 are lower alkyls of 1 to 6
carbon atoms, and
a solvent, wherein the cannabinoid aryl sulfonates are crystalline and stable
at room temperature
under air.
Further, there is provided herein a process for the purification of a
cannabinoid
comprising: esterifying the cannabinoid with at least one aryl sulfonyl halide
in the presence of at
least one base R5R6R7N, wherein R5, R6 and R7 are lower alkyls of 1 to 6
carbon atoms, to form a
cannabinoid aryl sulfonate; and allowing the cannabinoid aryl sulfonate to
crystallize, wherein the
cannabinoid aryl sulfonate is crystalline and stable at room temperature under
air.
Additionally, there is provided herein a process for the purification of a
cannabinoid
comprising: esterifying the cannabinoid with at least one aryl sulfonyl halide
in the presence of at
least one base R51161Z7N, wherein R5, R6 and R7 are lower alkyls of 1 to 6
carbon atoms, to form a
cannabinoid aryl sulfonate; allowing the cannabinoid aryl sulfonate to
crystallize; and
hydrolyzing the cannabinoid aryl sulfonate to recover the cannabinoid, wherein
the cannabinoid
aryl sulfonate is crystalline and stable at room temperature under air.
Another aspect of the present invention is to provide a process for the
purification of
cannabinoid comprising esterifying the cannabinoid with at least one aryl
sulfonyl halide in the
presence of at least one base to form cannabinoid aryl sulfonate,
crystallizing the
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CA 02770448 2012-03-02
cannabinoid aryl sulfonate, and hydrolyzing the cannabinoid aryl sulfonate to
recover the
cannabinoid. The cannabinoid aryl sulfonate crystals may be recrystallized to
purify the
cannabinoid aryl sulfonate.
These are merely illustrative aspects of the present invention and should not
be
deemed an all-inclusive listing of the innumerable aspects associated with the
present =
invention. These and other aspects will become apparent to those skilled in
the art in light of
the following disclosure.
DETAILED DESCRIPTION
There is provided a process for the esterification of cannabinoids according
to the
reaction as follows:
R1 0
R1 II
"....,...S.s--0
SI OH 0
II
4_ base + X'''''S------Y 4111
R2 0 0
11110 Y
R4
R2 0 5 R4 R3
R3 + s xe
base ¨
Reaction I
wherein Ri, R2, R3, and R.4 are H or an alkyl;
A is a saturated alkane, alkene, diene or aromatic ring; Y is an
aryl and X is a halide.
3
=
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Impure cannabinoids can be treated with at least one aryl sulfonyl halide in
the
presence of at least one base to cause reaction at the phenol hydroxy group
thereby producing
aryl sulfonates.
The base is added to take up the halide acid produced by the esterification.
Therefore,
any suitable base that does not interfere with the esterification reaction may
be used. Lower
alkyl amines, especially tertiary amines such as triethyl amine provide
inexpensive bases that
are suitable for the present invention. Primary and secondary amines may be
used, but will
result in unwanted reactions with the sulfonyl halide. Amines of the formula
R5R6117Isl are
preferred wherein R5, R6 and R7 may typically be lower alkyl radicals having
from about one
to about six carbon atoms.
The aryl group of the sulfonyl halide may be any aromatic system, substituted
or
unsubstituted, that does not interfere with the esterification reaction.
Suitable aromatic
systems include but are not limited to benzene, alkyl substituted benzene,
halogen substituted
. benzene, nitrobenzene, alkyloxy substituted benzene and substituted and
unsubstituted
napthyl compounds. Preferred alkoxy substituents include an alkoxide directly
attached to a
tertiary carbon wherein the alkyloxy substituent may typically be from about
one to about six
carbon atoms.
In a preferred embodiment, the cannabinoid, aryl sulfonyl halide and a
tertiary amine
are mixed in an organic solvent and allowed to react at room temperature until
completion,
typically several hours. The choice of solvent is not critical, and suitable
solvents include, =
but are not limited to toluene, methylene chloride, chloroform and heptane. In
an alternative
embodiment, the reaction may be run at increased temperatures without
affecting the efficacy
of the reaction, although with minimal increase in reaction rate. Temperatures
in the range of
from about room temperature to about 80 C are typical.
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The solvent is then removed by any suitable method so that the cannabinoid
aryl
sulfonate forms an oil that can then be crystallized. The crystallization can
be aided by the
addition of a solvent and seed crystals, as is well known in the art. Suitable
solvents include,
but are not limited to, heptane, hexane, t-butyl methyl ether, n-pentanol, n-
butanol,
isopropanol, isobutanol, ethanol, acetone, acetonitrile and isopropyl acetate.
Alcohols,
including methanol are preferred. In general the purity of this crude
crystalline ester will be
well over 90% pure. About 70 to 80% of the initially assayed cannabinoid can
be obtained in
the first crop of crystals. Purification of up to greater than 99% can
typically be achieved by
one recrystallization, preferable from an alcohol, with minimal losses in
yield. (All
percentages given herein are weight percentages unless otherwise noted.)
The resulting cannabinoid esters are highly crystalline and stable at room
temperature.
They can be stored indefinitely at room temperature under air.
The cannabinoid esters can then be hydrolyzed to recover the pure cannabinoid
by
base hydrolysis, as is shown in the reaction below:
CA 02770448 2012-03-02
Ri 0
R1
111111
OH
+ A
H20
R2 0 R4 R2 0 R4
R3
R3
0
6r 'V
Reaction 2
wherein RI, R2, R3, and R4 are H or an alkyl;
A is a saturated alkane, alkene, diene or aromatic ring,
Y is an aryl, M is a metal and Z is an alkyl, typically 1 C to 10 C.
The hydrolysis can be accomplished by any method known in the art. In a
preferred
embodiment the base comprises at least one metal salt of an alkyl oxide in at
least one alkyl
alcohol. Suitable bases include but are not limited to potassium methoxide,
ethoxide,
propoxide, isopropoxide, t-butoxide and t-pentanoxide, with tertiary alkoxides
preferred.
Suitable alcohols include but are not limited to methanol, ethanol, n-
propanol, isopropanol, t-
butanol and t-pentanol, with tertiary alkoxides preferred. The use of the same
alkyl group for
both the oxide and the alcohol is preferred to prevent exchange of the groups,
for example,
potassium t-butoxide in t-butanol with several equivalents of water added. The
reaction
preferably includes at least 3 equivalents of base and at least 4 equivalents
of water per
equivalent of cannabinoid used. The reaction is preferably run at a
temperature of at least
=
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40 C. The purity of the recovered cannabinoid typically exceeds 99%, with 85%
to 95%
yields. Alkyl oxides and alcohols typically contain alkyl groups of one to
about six carbon
atoms for practical purposes, although larger alkyl groups may be used.
A suitable method of hydrolysis is comprised of placing the tosylate in a
three-necked
flask under an inert atmosphere. The flask is typically equipped for magnetic
stirring and
electronic temperature control, with a condenser, inert gas bubbler and a
heating mantle.
Deionized water and then an alkyl oxide in alcohol are added to the flask. All
solvents
utilized are deoxygenated by bubbling with an inert gas. In one embodiment,
the resulting
slurry is then heated to at least about 40 C to increase the reaction rate
and to force the
reaction to completion. While the reaction will proceed at lower temperatures,
the reaction is
preferably heated to about 40 Cto about 80 C, with about 50 C to about 70 C
being optimum,
the maximum temperature being determined by the boiling point of the solvent
being used.
The reaction mixture is maintained at the desired temperature until the
reaction is
substantially complete, typically about two to twelve hours, and then cooled
to room
temperature.
Deionized water is added, and the reaction stirred. An organic solvent is
added, and
the resulting mixture stirred or agitated and placed in a separatory funnel
and separated. The
organic fraction containing the cannabinoid product is then washed with at
least one aliquot
of deionized deoxygenated water. The organic fraction is then typically dried
with a salt
solution, filtered and evaporated under vacuum to form an oil. Distillation of
the resulting oil
under high vacuum results in a highly purified cannabinoid product.
The following examples are offered to illustrate aspects of the present
invention, and
are not intended to limit or define the present invention in any manner.
Example 1
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Synthesis of e-tetrahydrocannabinol tosylate
64.9g of A9-tetrahydrocannabinol, 292 mL of toluene, 21.7 mL of triethyl
amine, and
41.3 g. of p-toluene sulfonyl chloride were added to a 1000 mL, 3 neck, round
bottom flask
blanketed with nitrogen. The reaction was stirred overnight at room
temperature for about 16
hours. The reaction was checked by LC and was found to be complete. Water (292
mLs)
was added, and the reaction was stirred for 20 minutes. The aqueous layer was
separated,
and the toluene solution was washed two more times with 292 mL aliquots of
water. The
toluene was washed with 292 mL of saturated sodiiim chloride solution to aid
water removal,
and the toluene was then dried with anhydrous magnesium sulfate. The dry
toluene solution
was evaporated on an evaporator down to an oil 99.76 g. The oil was poured
into 500 mL
Erlenmeyer flask and 150 mL of heptane was added. The solution was seeded with
a few
crystals from an earlier run and stored in a refrigerator overnight. The
resulting solids were
filtered. The crystals were washed twice with approximately 10 mL aliquots of
chilled
heptane while on the filter. The crystals were dried under vacuum for 15
minutes on the
Buchner funnel and weighed. The slightly wet crystals weighed 65.4 grams.
After drying
overnight at room temperature in a 23" Hg vacuum the crystals weighed 65.37 g.
A second
crop of crystals, 6.34 g. was obtained by evaporating most of the heptane and
chilling the
mother liquor overnight under refrigeration. '
The crystals were dissolved in 440 mL of hot methanol at reflux. The crystals
dissolved easily at 66 C. The flask was allowed to cool slowly towards room
temperature
and crystallization commenced at 51 C.- The flask was then chilled to near 0 C
in an ice-bath
while fresh methanol was chilled as a wash. The flask was held at 0 C for 1.5
hours and the
slurry was then filtered. The solids were washed with a total of 110 mL of
cold methanol in
two washes. The wet weight of the crystals was 64.09 g. The crystals were
dried in a 23"
vacuum at room temperature over a weekend. The dried crystals weighed 62.64 g.
Unlike
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the free A9-tetrahydrocannabinol, the tosylate derivative has been shown to be
stable at room
temperature in the presence of air and laboratory lighting. The A9 THC-4-
methylbenzene
sulfonate (tosylate) crystals were characterized by IF, proton NMR, CI3 NMR
and MS
methods. The infrared spectrum for the tosylate was consistent with that for
A9 THC, with
additional bands for the organic sulfonate functionality. NMR analysis
strongly supports the
structure of A9 THC-4-methylbenzene sulfonate (tosylate). Mass spectral
results show the
major component to have a molecular weight of 468 Da that is consistent with
the molecular
weight of A9 THC-4-methylbenzene sulfonate (tosylate). Further, the MS/MS
fragmentation
pattern is also consistent with the identification of the major component as
A9 THC-4-
methylbenzene sulfonate (tosylate).
EXAMPLE 2
,e-tetrahydrocannabinol-benzenesulfonate crystals were formed as in Example I
utilizing benzene sulfonyl chloride in place of p-toluene sulfonyl chloride.
The resulting
crystals were stable at room temperature in the presence of air and laboratory
lighting.
EXAMPLE 3
A9-tetrahydrocannabino1-4-methoxybenzene sulfonate crystals were formed as in
Example 1 utilizing 4-methoxybenzene sulfonyl chloride in place of p-toluene
sulfonyl
chloride. The resulting crystals were stable at room temperature in the
presence of air and
laboratory lighting.
EXAMPLE 4
6.9-tetrahydrocannabino1-4-bromobenzenesulfonate crystals were formed as in
Example I utilizing 4-bromobenzene sulfonyl chloride in place of p-toluene
sulfonyl
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chloride. The resulting crystals were stable at room temperature in the
presence of air and
laboratory lighting.
EXAMPLE 5
e-tetrahydrocannabino1-4-chlorobenzenesulfonate crystals were formed as in
Example 1 utilizing 4-chlorobenzene sulfonyl chloride in place of p-toluene
sulfonyl
chloride. The resulting crystals were stable at room temperature in the
presence of air and
laboratory lighting.
EXAMPLE 6
2-tetrahydrocannabino1-2-nitrobenzenesu1fonate crystals were formed as in
Example
1 utilizing 2-nitrobenzene sulfonyl chloride in place of p-toluene sulfonyl
chloride. The
resulting crystals were stable at room temperature in the presence of air and
laboratory
lighting. .
EXAMPLE 7
e-tetrahydrocannabino1-3-nitrobenzenesulfonate crystals were formed as in
Example
1 utilizing 3-nitrobenzene sulfonyl chloride in place of p-toluene sulfonyl
chloride. The
resulting crystals were stable at room temperature in the presence of air and
laboratory
lighting.
EXAMPLE 8
A9-tetrahydrocannabino1-4-nitrobenzenesulfonate was formed as in Example 1
utilizing 4-nitrobenzene sulfonyl chloride in place of p-toluene sulfonyl
chloride, except the
resulting oil did not crystallize.
CA 02770,448 2012-03-02
EXAMPLE 9
e-tetrahydrocannabinol-l-napthylsulfonate was formed as in Example 1 utilizing
1-
napthyl sulfonyl chloride in place of p-toluene sulfonyl chloride, except the
resulting oil did
not crystallize.
EXAMPLE 10
A9-tetrahydrocannabino1-2-napthylsulfonate was formed as in Example 1
utilizing 2-
napthyl sulfonyl chloride in place of p-toluene sulfonyl chloride, except the
resulting oil did
not crystallize.
EXAMPLE 11
A8-tetrahydrocannabino1-4-methylbenzenesulfonate crystals were formed as in
Example 1 utilizing A8-tetrahydrocannabinol in place of A9-
tetrahydrocannabinol. The
resulting crystals were stable at room temperature in the presence of air and
laboratory
lighting.
EXAMPLE 12
Cannabino1-4-methylbenzenesulfonate crystals were formed as in Example 1
utilizing
Cannabinol in place of e-tetrahydrocannabinol. The resulting crystals were
stable at room
temperature in the presence of air and laboratory lighting.
EXAMPLE 13
Hydrolysis of A9-tetrahydrocannabinol tosylate to free A9-
tetrahydrocannabinol
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Twenty-five grams of purified A9-tetrahydrocannabino1-4-methylbenzene
sulfonate
(tosylate) assayed at 99+% pure was placed into a 500 mL, 3 neck, round
bottomed flask
under a nitrogen blanket. The flask was equipped for magnetic stirring,
electronic
temperature control, with a condenser, nitrogen bubbler, and a heating mantle.
All solvents utilized were deoxygenated by bubbling N2 through them for 15
minutes
prior to use. 3.9 mLs of deionized water was added and then 162.5 mLs of 1
molar
potassium butoxide in t-butanol (note 1) was added to the flask. The resulting
slurry was
heated to 65 C. The reaction was slightly exothermic, raising the temperature
to 70.1 C.,
but settled back to 65 C., quickly. The reaction was held at 65 C. for 5
hours, and then
cooled to room temperature.
Water (250 mLs) was added and the reaction was stirred for 1.0 hour. It is
anticipated
that this process destroys a small amount of t-butyl tosylate that is formed
in the reaction.
Heptane (250 mLs) is then added. After stirring for several minutes, the
mixture is transferred
to a separatory funnel (1000 mL) and separated. (A small amount of water may
be added if a
small third phase of t-butanol is noted.) The heptane solution containing the
cannabinoid
product is washed 2 more times with 250 mL aliquots of deionized deoxygenated
water. The
pH of the first wash was 14, the second wash pH 9 and the third was pH 8.
A preliminary drying was done by washing the heptane solution with 250 mL of
saturated sodium chloride solution.
The heptane was then dried with anhydrous MgSO4. The solution was filtered and
evaporated under vacuum to an oil (16.68 g.).
The oil was distilled under high vacuum <2mm Hg at about 200 -220 C. A nearly
colorless glass was obtained and weighed 15.41 g., and 88% yield.
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LC analysis of the product showed that it was > 99.9 area % A9-
tetrahydrocannabinol.
Comparison with a purchased standard material showed a purity of 104%. The
product was
scrupulously protected from light and oxygen and stored in a freezer to
maintain this purity.
Having described the invention in detail, those skilled in the art will
appreciate that
modifications may be made.
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