Note: Descriptions are shown in the official language in which they were submitted.
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PROCESS FOR THE PREPARATION OF
(-) - DELTA 9 -TETRAHYDROCANNABINOL
BACKGROUND OF THE DISCLOSURE
[0001] The present disclosure is generally directed to a process for the
chemical synthesis of
(-)-L9-tetrahydrocannabinol (A9-THC) and/or structurally related compounds. In
particular, the process
comprises a one-pot condensation and sulfonylation reaction sequence that
produces crude &9-THC
aryl sulfonate ester or related compounds. Sulfonylation of t9-THC, or
structurally related compounds,
immediately upon their formation imparts stability to the cannabinoids, and
prevents formation of the
thermodynamically more stable corresponding AB-isomer. W-THC aryl sulfonate
ester or structurally
related compounds may also be readily separated from the corresponding 08-THC
isomer using reverse
phase chromatography. Hydrolysis of the A9-THC aryl sulfonate ester or related
compounds after
separation produces A9-THC or related compounds containing relatively low
amounts of the
corresponding b-isomer.
[0002] Cannabis preparations in the form of marijuana, hashish, etc, have been
known and
used for many years for their psychoactive and therapeutic properties. The
major active constituent of
the resin which is extruded from the female plants of Cannabis sativa L. is (-
)-A9-tetrahydrocannabinol
(L9-THC). The FDA has approved Y-THC for several therapeutic applications. In
particular, the anti-
emetic and appetite stimulating properties of A9-THC have proven
therapeutically beneficial.
Consequently, research has been directed towards the preparation of 09-THC via
a synthetic method, in
order to eliminate the need to obtain the material by extraction from natural
sources.
[0003] Also known by the generic name dronabinol, A9-THC presents several
unique
challenges for its synthetic production on a commercial scale, the primary
challenge being the instability
of the double bond in the cyclohexane ring. In particular, A9-THC readily
undergoes double-bond
isomerization to its more thermodynamically stable regioisomer, A8-THC. Such
an inherent propensity
to isomerize means that precautions are to be taken when manipulating A9-THC
in both its crude and
pure forms to minimize formation of L8-THC. Minimizing A8-THC formation is
particularly desirable
when the A9-THC is to be used therapeutically, as USP guidelines limit A8-THC
levels in Y-THC
preparations to 2 weight% or less for the dronabinol API. Additionally,
separation of 08-THC from A9-
THC is challenging and typically requires multiple chromatographic
purifications or the use of expensive
silver-impregnated substrates for its removal. Such extensive handling and
purification requirements
tend to make commercial-scale production of L19-THC economically unattractive.
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[0004] It would therefore be desirable to provide a scalable process for
synthesizing A9-THC,
or structurally related compounds, that minimizes the formation of the
corresponding A8-regioisomer,
and furthermore allows for easy separation of A9-THC (or related product
compound) from the
corresponding A8-regioisomer.
SUMMARY OF THE DISCLOSURE
[0005] The present disclosure is generally directed to a process for the
chemical synthesis of
(-)-A9-tetrahydrocannabinol (A9-THC), or alternatively a structurally related
compound. In general, the
process comprises a "one-pot" condensation and sulfonylation reaction sequence
that produces crude
A9-THC aryl sulfonate ester, or alternatively a structurally related compound.
More particularly, the
process comprises the preparation of a crude reaction mixture comprising, for
example, A9-THC,
followed by the direct sulfonylation (e.g., tosylation) of that reaction
mixture (i.e., sulfonylation without an
intervening separation or purification step to isolate the A9-THC reaction
product, or other structurally
related compound reaction product), in order to obtain the corresponding aryl
sulfonate ester.
[0006] The present disclosure is further directed to a process for the
synthesis of a
cannabinoid having general Formula l::
R
OH
R2
d
R
T\O R1
Re
R3 (I)
wherein:
R1 to R3 are independently selected from the group consisting of H, alkyl,
substituted alkyl, OH,
aryl, acyl, halide, nitrate, sulphonate, phosphate, and OR', wherein R' is
alkyl, aryl, substituted alkyl,
substituted aryl, silyl, acyl, or phosphonate; and
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R , Rd, and Re are independently selected from the group consisting of H,
alkyl, or substituted
alkyl. The process comprises reacting a substituted resorcinol having general
Formula 11:
OH
RZ
HO R1
R3 (II)
wherein R1, R2, and R3 are as defined above, with a compound having general
Formula III:
R ORa
RdORb
Re (III}
wherein: Ra is H, alkyl, aryl, acyl, or silyl; Rb is H, alkyl aryl, or acyl;
and Re, Rd, and Re are as defined
above, in the presence of an acid catalyst and a non-alkaline dehydrating
agent to form a first reaction
mixture comprising a cannabinoid having general Formula I. The first reaction
mixture, which contains
the cannabinoid having general Formula I, is then contacted with an aryl
sulfonyl halide and a base to
produce a second reaction mixture comprising an aryl sulfonate having general
Formula IV:
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R 0
I
S\ O
0/
Y
R2
R 0 R1
Re
R3 (IV)
wherein R1, R2, R3, Rc, Rd, and Re are as defined above, and Y is selected
from the group consisting of
a substituted aryl group, an unsubstituted aryl group, a substituted alkyl
group, and an unsubstituted
alkyl group. The aryl sulfonate is isolated from the second reaction mixture,
and is then hydrolyzed to
produce the cannabinoid having general Formula I.
[0007] The present disclosure is still further directed to a process for the
synthesis of an aryl
sulfonate having general Formula IV:
R O
I
O
O
R2
I Y
R 0 R1
Re
R3 (IV)
wherein:
R1 to R3 are independently selected from the group consisting of H, alkyl,
substituted alkyl, OH,
aryl, acyl, halide, nitrate, sulphonate, phosphate, and OR, wherein R is
alkyl, aryl, substituted alkyl,
substituted aryl, silyl, acyl, or phosphonate;
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Rc, Rd, and Re are independently selected from the group consisting of H,
alkyl, or substituted
alkyl;
and Y is selected from the group consisting of a substituted aryl group, an
unsubstituted aryl
group, a substituted alkyl group, and an unsubstituted alkyl group. The
process comprises reacting a
substituted resorcinol having general Formula II:
OH
R2
HO R1
R3 (II)
wherein R1, R2, and R3 are as defined above, with a compound having general
Formula III:
R c ORa
Rd ORb
Re (ill)
wherein Ra is H, alkyl, aryl, acyl, or silyl; Rb is H, alkyl aryl, or acyl;
and Rc, Rd, and Re are as defined
above, in the presence of an acid catalyst and a non-alkaline dehydrating
agent to form a first reaction
mixture comprising a cannabinoid having general Formula I:
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Rc
OH
LLLR2
d
R
~\O R1
Re
R3 (II)
wherein R1, R2, R3, Rc, Rd, and Re are as defined above. The first reaction
mixture containing the
cannabinoid having general Formula I is then contacted with an aryl sulfonyl
halide and a base to
produce a second reaction mixture comprising the aryl sulfonate.
[0008] The present disclosure is still further directed to a process for the
synthesis of an aryl
sulfonate having general Formula IV:
R O
li
S O
O
Y
R2
R d O R1
Re
R3 (IV)
wherein
R1 to R3 are independently selected from the group consisting of H, alkyl,
substituted alkyl, OH,
aryl, acyl, halide, nitrate, sulphonate, phosphate, and OR', wherein R' is
alkyl, aryl, substituted alkyl,
substituted aryl, silyl, acyl, or phosphonate;
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Rc, Rd, and Re are independently selected from the group consisting of H,
alkyl, or substituted
alkyl; and
Y is selected from the group consisting of a substituted aryl group, an
unsubstituted aryl group,
a substituted alkyl group, and an unsubstituted alkyl group. The process
comprises reacting a
substituted resorcinol having general Formula II:
OH
R2
HO R1
R3 (II)
wherein R1, R2, and R3 are as defined above; with a compound having general
Formula VI:
R c ORa
R
(VI)
wherein Ra is H, alkyl, aryl, acyl, or silyl; Rb is H, alkyl, aryl, or acyl;
and Rc is as defined above, in the
presence of an acid catalyst and an excess of a non-alkaline dehydrating agent
to form a first reaction
mixture comprising a cannabinoid having general Formula I:
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R
OH
R2
Rd 7`O R1
Re
R3 (I)
wherein R1, R2, R3, and Re are as defined above, and Rd and Re are as defined
above. The first
reaction mixture, and in particular the cannabinoid having general Formula I
present therein, is then
reacted with an aryl sulfonyl halide in the presence of a base to produce a
second reaction mixture
comprising the aryl sulfonate.
[0009] The present disclosure is still further directed to a process for the
preparation of (-)-A9-
tetrahydrocannabinol aryl sulfonate. The process comprises reacting olivetol
with a compound selected
from the group consisting of p-mentha-2-en-1,8-diol and p-mentha-2,8-dien-1-ol
in the presence of an
acid catalyst and an excess of a non-alkaline dehydrating agent to form a
first reaction mixture
comprising (-)- 9-tetrahydrocannabinol. The first reaction mixture, and in
particular the (-)-Li9-
tetrahydrocannabinol therein, is then reacted with an aryl sulfonyl halide in
the presence of a base to
produce a second reaction mixture comprising an aryl sulfonate having general
Formula IV:
R O
II
S O
O
Y
R2
R O R1
Re
R3 (IV)
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wherein R' is C5H11; R2 and R3 are H; Rc, Rd, and Re are -CH3; and Y is a
substituted or unsubstituted
aryl group.
[0010] Other features will be in part apparent and in part pointed out
hereinafter.
DETAILED DESCRIPTION OF THE DISCLOSURE
[0011] As generally illustrated in Reaction Scheme I, below, the present
disclosure is
generally directed to a process for the chemical synthesis of (-)-L 9-
tetrahydrocannabinol (L9-THC), or
alternatively a structurally similar or related compound. In particular, the
process comprises a one-pot
condensation and sulfonylation reaction sequence that produces crude
sulfonated reaction product
(e.g,, a A9-THC aryl sulfonate, or alternatively a structurally similar or
related sulfonate compound),
which may then be converted (e.g., hydrolyzed) to the desired product.
Synthesis of deltas-THC-Tosylate in one pot
OH OH
8F3=OEt2 OH Et9N, TSCI OT,
OH MgSOA
12 C
T T
ouvetol -_OH { _O / 051'Iti t O / 05HIt
p- enttha-2-en-1444 l deltas-THC deHas-THC-Tosylate+lmpurilies
1. Chmmatographlc Purification
2. Rocrysteltiratlon of Tosytata
3. Hydrolysis of Tosyrate
OH
-O C.H..
detlao-THC
REACTION SCHEME I
[0012] By monitoring the progression of the reaction (by means generally known
in the art),
and in particular the ratio of the desired isomer (e.g., A9-THC, or a
structurally similar or related
compound) to the undesired isomer (e.g., A8-THC, or a structurally similar or
related compound) to
ensure it does not exceed a desired threshold (e.g., the ratio of the desired
isomer, such as W-THC, to
the undesired isomer, such as L8-THC, being about 49:1 or more), and/or by
sulfonating the desired
isomer (e.g., A9-THC, or some other structurally similar or related compound)
soon after it has been
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formed in order to impart stability thereto, formation of the undesired isomer
may be limited. A9-THC
aryl sulfonate, or a structurally similar or related compound, may also be
readily separated from O8-THC
aryl sulfonate isomer, using for example reverse phase chromatography.
Subsequent conversion (e.g.,
hydrolysis) of the A9-THC aryl sulfonate, or other structurally related
compound, produces the desired
product (e.g., A9-THC, or other structurally related compound) containing
relatively low amounts of the
corresponding A8-isomer.
[0013] In this regard it Is to be noted that the phrase "structurally similar
or related"
compound generally refers to a compound that has the same 3-ring core
structure of THC, but that
differs in terms of the substituent(s) and/or location of the substituent(s)
on the 3-ring core structure. It
is therefore to be understood that reference to the preparation of O9-THC is
also generally intended to
refer to the preparation of other structurally similar or related compounds.
[0014] It is to be further noted that a "one-pot" reaction process generally
refers to a process
wherein (i) the condensation reaction to initially prepare a reaction product
mixture that includes Q9-
THC, or alternatively a structurally similar or related compound, and (ii) the
subsequent sulfonylation
(e.g., tosylation) reaction, are performed without an intervening step
involving isolation or purification of
the reaction product from the condensation reaction mixture (e.g., a
filtration or washing step, a
recrystallization step, chromatography step, etc.). Accordingly, the
sulfonylation reaction may be
performed in the same container or reaction vessel in which the condensation
reaction was performed.
Alternatively, however, the contents of that reaction container or vessel may
be transferred to a new
container or vessel without departing from the scope of the invention, provide
this transfer does not
involve some act of purification, as noted above (e.g., filtration,
recrystallization, chromatography, etc.).
Accordingly, the present process involves the "direct" sulfonylation of the
first (or condensation) reaction
mixture formed.
1. Overview
[0015] As noted above, the synthesis and isolation of A9-THC and related
compounds has
proven difficult. In particular, A9-THC is prone to acid-catalyzed
isomerization to the thermodynamically
more stable A8-THC regioisomer. Isomerization of A9-THC to A8-THC is
represented by the following
formula:
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OH OH
Isomerization
O CSH1i
/ T 'O C5H11
O9-THC p8-TH C
[0016] This inherent propensity to isomerize means precautions are to be taken
when
manipulating ^9-THC in both its crude and pure forms to minimize A8-THC
formation. As noted above,
minimizing t8-THC levels in synthetic 9-THC reaction mixtures is
particularly desirable when the A9-
THC is to be used in pharmaceutical products. Specifically, USP guidelines
limit A8-THC levels in a ^9-
THC preparation to about 2 weight% or less, as compared to the sum of the
weight of L9-THC and Ae-
THC; stated another way, USP guidelines call for the weight ratio of the A9-
THC to A8-THC to be less
than or equal to about 98:2 (or49:1) or less. If the A8-THC level exceeded
this amount, further
separation of the ^9-THC from A8-THC contaminant will typically be needed.
Separation of A9-THC
from its A8 regioisomer has, however, proven to be challenging, and typically
requires multiple
chromatographic purifications or the use of expensive equipment.
[0017j In accordance with the present disclosure, it has now been discovered
that
cannabinoids, such as A9-THC and structurally similar related compounds,
having general Formula I:
R
OH
L)~LR2
d -
R
7\O R1
Re
R3 Formula I
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wherein:
R1 to R3 are independently selected from the group consisting of H, alkyl,
substituted alkyl
(e.g., substituted or unsubstituted C1-Go, including for example methyl,
ethyl, propyl, butyl, pentyl, etc.,),
-OH, aryl, acyl, halide, nitrate, sulphonate, phosphate, and -OR', wherein IT
is alkyl, aryl, substituted
alkyl or aryl, silyl, acyl, or phosphonate; and
Rc, Rd, and Re are independently selected from the group consisting of H,
alkyl, or substituted
alkyl;
can be synthesized by condensing a substituted resorcinol compound having
general Formula
Il:
OH
R2
HO / R1
R3 Formula II
wherein:
R1 to R3 are as defined above, with a compound having general formula III (or
a stereoisomer
thereof, such as wherein the confirmation of the Cl chiral carbon is "S"
rather than "R", as shown here,
the combination of chiral carbons thus being S,R rather than R,R):
ORa
4
Rd 1'~ORb
Re Formula III
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wherein:
Ra is H, alkyl, aryl, acyl, or silyl; Rb is H, alkyl, aryl, or acyl; and,
Rc, Rd, and Re are as defined above,
in the presence of an acid catalyst and a non-alkaline dehydrating agent. As
further discussed in
greater detail herein below, in one particular embodiment, the reaction is
optimized, and/or the progress
of the reaction is monitored (e.g., by performing repeated analyses on the
reaction over a period of time,
using means generally known in the art, such as HPLC) such that the ratio of
the A9-THC isomer,
relative to the L18-THC isomer, is about 49:1 or greater (e.g., about 50:1,
about 55:1, about 60:1, about
75:1, about 85:1, about 95:1, about 99:1, etc.). Such ratios may be achieved,
for example, by
monitoring the concentration of the L 8-THC isomer, relative to the A9-THC, or
both, during the reaction,
and/or by monitoring first the appearance and then disappearance of a reaction
intermediate (as further
detailed herein below). The reaction may then be quenched once the presence of
the intermediate is
sufficiently low, or no longer detectable, and/or before the concentration of
the t -THC isomer is too
high (by, for example, introduction of a base, such as triethylamine, to the
reaction mixture). In this way,
the formation of the desired product (e.g., L9-THC) is maximized, while the
formation of the undesired
product (e.g., L8-THC) is minimized.
[0018] In this regard it is to be noted, however, that the ratio of the A9-THC
isomer, relative to
the L8-THC isomer, may in an alternative embodiment be less than about 49:1
without departing from
the intended scope of the invention (the ratio, for example, being about 45:1,
about 40:1, about 35:1 or
less).
[0019] The reaction produces a first reaction mixture comprising a cannabinoid
having
general Formula I, which includes A9-THC, as well as various impurities,
including for example L 8-THC,
Upon completion of the condensation reaction, the cannabinoids of Formula I
present in the first
reaction mixture are then sulfonated, and in one particular embodiment are
immediately sulfonated (i.e.,
as soon as the desired ratio of isomers is achieved, sulfonylation is
initiated by addition of the aryl
sulfonyl halide reagent to the first reaction mixture), by treating the first
reaction mixture with an aryl
sulfonyl halide in the presence of a base (such as, for example, the base
noted above added to quench
the initial condensation reaction), to produce a second reaction mixture
comprising an aryl sulfonate
having general Formula IV:
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R 0
11
O
Y
R2
d
R O R1
Re
R3 Formula IV
wherein R1, R2, R3, Rc, Rd, and Re are as defined above, and Y is selected
from the group consisting of
a substituted or unsubstituted aryl group (e.g., an alkylaryl group, such as a
methylphenyl group), and a
substituted or unsubstituted alkyl group.
[0020] Sulfonylation of the compound of Formula 1, present in the first
reaction mixture,
imparts stability to these compounds by preventing formation of the
corresponding ^8-isomer. Addition
of the aryl sulfonyl halide reagent to the first reaction mixture also acts to
sulfonate any A8-isomer of the
Formula I compound that formed during the initial condensation reaction.
Advantageously, the Formula
IV aryl sulfonate may be readily separated from the corresponding A8-isomer
using chromatographic
purification, for example, reverse phase chromatography. The isolated Formula
IV aryl sulfonates may
then be subjected to hydrolysis to reform the cannabinoid of Formula I. The
resulting Formula 1
cannabinoid therefore has high purity and a low level of A8-isomer impurity.
[0021] Advantageously, the process of the present disclosure is a one-pot
reaction, and
therefore does not involve any isolation or purification of the O9-THC (or
structurally similar or related
compound) between the condensation reaction and the subsequent sulfonylation
(e.g., tosylation)
reaction. Rather, the aryl suifonyl halide and base are added to the first
reaction mixture after
completion of the condensation reaction, and in one particular embodiment
immediately after the
reaction (the base being added to quench the condensation reaction, for
example, when the desired
isomeric ratio is reached), to sulfonate the compound of Formula I present
therein. In this way, further
isomerization of the Formula I compound may be limited, and desirably is
substantially prevented.
[0022] Sulfonylation of the Formula t compound present in the first reaction
mixture also
improves the ease with which the 08-isomer impurity can be removed. As noted
above, separation of,
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for example, the A9-THC (or structurally related compounds) from the
corresponding A8-isomer is
typically inefficient, requiring multiple chromatographic separations or use
of expensive equipment. In
accordance with the present disclosure, the Formula IV aryl sulfonate
synthesized during the process of
the present disclosure can be readily separated from the corresponding
sulfonated A8-isomer using
reverse phase chromatography.
[0023] Following separation of the Formula IV aryl sulfonate from the
corresponding A8-
isomer, the Formula IV aryl sulfonates may be hydrolyzed to re-form the
compound having general
Formula I, such as A9-THC. Optionally, the Formula IV aryl sulfonates may be
recrystallized, using
means generally known in the art, following chromatographic purification to
further purify the
compounds prior to hydrolysis.
[0024] The process of the present disclosure advantageously produces compounds
of
Formula I, such as A9-THC, that are at least 90% pure, at least about 92%
pure, at [east about 94%
pure, at least about 95% pure, at least about 96% pure, at least about 98%
pure or more (e.g., about
99%, or even about 100%). In particular embodiments, however, the compounds of
Formula I produced
using the process of the present disclosure are at least about 95% pure, or
even at least about 98%
pure. Additionally, or alternatively, as previously noted above, the
concentration of the corresponding
A8-isomer is, in one particular embodiment, not more than about 2%, and may be
not more than about
1 %, or even about 0.5%, relative to the amount of the desired isomer of
Formula I.
II. Condensation Reaction
[0025] As noted above, formation of the first reaction mixture occurs by way
of a
condensation reaction between a substituted resorcinol having general Formula
li:
OH
R2
HO R1
R3 Formula II
wherein R1 to R3 are as previously defined above; and a compound of general
Formula III:
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R% ORa
Rd OR
Re
Formula III
wherein Ra, Rb, RG, Rd and Re are as defined above, in the presence of an acid
catalyst and a non-
alkaline dehydrating agent (and in a particular embodiment in the presence of
a molar excess of the
agent relative to the Formula III compound).
[0026] In this regard it is to be noted that, as used herein, a "substituted"
alkyl group may
contain substituents such as halide, hydroxyl, amine, and thiol. It is to be
further noted that "alkyl," as
used in various embodiments herein, may desirably refer to C1 to Cio alkyl.
Additionally, the alkyl group
may optionally be saturated or unsaturated, acyclic or cyclic.
[0027] As noted above, the compound of Formula II is a substituted resorcinol.
In one
embodiment, R2 and R3 are H. R1 may suitably be an alkyl group or substituted
alkyl group. In a
particular embodiment, R1 is an alkyl having from about 1 to about 10 carbon
atoms, or an alkyl having
from 1 to 5 carbon atoms, and still more preferably is C5H11. Optionally or
additionally, R1 may contain
groups (e.g., as a substituent or within the chain itself) that promote water
solubility (e.g., ketone, ester,
hydroxyl, or amine groups). In one particular embodiment, however, the
substituted resorcinol of
Formula II is olivetol, wherein R2 and R3 are H, and R1 Is C5H11. Olivetol has
the following structure:
OH
HO
[0028] Other structures of interest include those wherein the side chain CsH11
is replaced by
a C4H9, a C3H7, a C2H5, or even a CH3 side chain or group.
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[0029] Referring again to Formula 111, in one embodiment, Rb is acyl and ORb
is an ester
group. Suitable ester groups include acetate, propionate, butyrate,
trimethylacetate, phenylacetate,
phenoxyacetate, diphenylacetate, benzoate, p-nitrobenzoate, phthalate, and
succinate.
[0030] In another embodiment, both Ra and Rb are acyl groups so that the
compound of
Formula III is a diester. The two ester groups are suitably chosen
independently from acetate,
propionate, butyrate, trimethylacetate, phenylacetate, phenoxyacetate,
diphenylacetate, benzoate, p-
nitrobenzoate, phthalate, and succinate. In one particular aspect, both Ra and
Rb are diphenylacetate.
[0031] In yet another embodiment, both Ra and Rb are H.
[0032] Rc, Rd, and Re can be varied independently of Ra and Rb. In one
particular
embodiment, Rc is selected from the group consisting of -CHs or H. In this or
another embodiment, Rd
and Re are independently selected from the group consisting of -CH3 or -CH2OH.
In one particular
embodiment, one or more of Re, Rd, and Re is -CH3.
[0033] In this or another particular embodiment, the compound of Formula III
is p-mentha-2-
en-1,8-diol, wherein Rc, Rd, and Re are -CH3, and Ra and Rb are both H. p-
mentha-2-en-1,8-diol has
the following structure (with the stereochemical conformation noted
parenthetically):
OH
(R
(R)
---~OH
[0034] In one alternate embodiment, the first reaction mixture may be prepared
by reacting a
substituted resorcinol of Formula 11 with a compound of general Formula VI:
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Rr- ORa
Rb"
Formula VI
wherein Ra, Rb, and Rc are as defined above, in the presence of an acid
catalyst and an excess of a
non-alkaline dehydrating agent (and in a particular embodiment in the presence
of a molar excess of the
agent relative to the Formula VI compound).
[0035] In this or another particularly embodiment, the compound of Formula VI
is p-mentha-
2,8-dien-1-ol, wherein Rb and Re are -CH3, and Ra is -H. p-Mentha-2,8-dien-1-
ol has the following
structure (with the stereochemical conformation noted parenthetically):
OH
(R)
(R)
[0036] The condensation reaction is typically carried out by combining about
equal molar
amounts of a compound of Formula II with a compound of Formula III or Formula
Vl, in order to obtain a
reaction mixture that includes the compound of Formula I, plus impurities
(including, for example, the
A8-isomer of the compound of Formula I). However, more generally speaking, the
compound of
Formula I may be prepared by combining a compound of Formula II with a
compound of Formula III or
Vl in a molar ratio of from about 2:1 to about 0.75:1, or from about 1.5:1 to
about 0.85:1. In one
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embodiment, olivetol is reacted with about an equal molar amount of p-mentha-2-
en-1,8-diol or p-
mentha-2,8-dien-1-ol.
[0037] Although the condensation reaction does not exclusively yield the
compound of
Formula I, under optimal conditions (e.g., proper selection of reagents,
concentration of reagents,
reaction conditions, etc.), it is possible to obtain the compound of Formula I
where the amount thereof,
as compared to other products (such as the A8-isomer), is maximized. For
example, in various
embodiments the yield of Formula I compound may be from about 15 wt.% to about
40 wt.%, or about
20 wt.% to about 35 wt.%, of the reaction product mixture.
[0038] In carrying out the condensation reaction, any conventional inert
organic solvent, such
as petroleum ether, diethyl benzene, toluene, tetrahydrofuran, dioxane,
heptane, and halogenated
aliphatic or aromatic hydrocarbons such as methylene chloride, chloroform,
carbon tetrachloride,
bromobenzene, and 2-methyl-THF can be used. When ethers such as diethyl ether,
dioxane, and
tetrahydrofuran are used, a higher concentration of acid catalyst may be
needed. Use of chlorinated
hydrocarbons, and in particular methylene chloride, may be particularly
advantageous in one or more
embodiments herein.
[0039] Generally speaking, a quantity of solvent will be used which acts to
optimize the
overall yield of the reaction, Typically, however, a quantity of solvent is
used that is sufficient to dissolve
(e.g., the compounds of Formula II, ill and/or IV) and/or thorough suspend
(e.g., the dehydrating agent)
all the condensation reaction reagents therein. For example, a quantity of
solvent will typically be used
which ensure the concentration of the compound of Formula II, 1I1 and/or IV is
within the range of about
15 g/L and about 200 g/L, or about 17 g/L to about 180 g/L, or about 18 g/L to
about 170 g/L.
[0040] As noted above, the reaction between the substituted resorcinol of
Formula II and the
compound of Formula III or VI is carried out in the presence of an acid
catalyst. The use of boron
trifluoride may be advantageous, in one or more embodiments, although other
Lewis acids such as
aluminum chloride, zinc chloride, stannic chloride, iron chloride, and
antimony pentafluoride can also be
used. A convenient form for use of boron trifluoride is boron trifluoride
complexed with diethyl ether,
also known as boron trifluoride etherate. Boron trifluoride can also be
dissolved in inert anhydrous
solvents, and the use of such solutions would also be suitable. Protonic acids
such as p-
toluenesulfonic, methanesulfonic, and trifluoracetic acid can also be used,
but the yields are generally
lower. Other suitable catalysts include metal triflates, such as indium (Ill)
triflate, scandium (III) triflate,
ytterbium (III) triflate, bismuth (Ill) triflate, and the like.
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[0041] A quantity of acid catalyst will be used which acts to optimize the
overall yield of the
reaction. Typically, the quantity of catalyst used is within the range of
about 1 gIL to about 5 g/L, or
about 1.2 g/L to about 4.8 g/L, or about 1.5 g/L to about 4.5 gIL, or about
1.75 gIL to about 4 g/L,
relative to the volume of solvent used. Alternatively, the quantity of acid
catalyst may be expressed in
terms molar equivalents relative to the moles of the compound of Formula Ito
be formed. For example,
in various embodiments the molar ratio of the acid catalyst to the moles of
compound Formula I may be
in the range of from about 0.1:1 to about 0.4:1, or from about 0.2:1 to about
0.3:1.
[0042] As noted above, a non-alkaline dehydrating agent is used in the
preparation of the
compound of Formula I. Any conventional material which has the ability to
readily combine with a
molecule of water, and is non-alkaline and otherwise chemically inert can be
used. Agents useful in the
practice of this disclosure include calcium sulfate, magnesium sulfate, sodium
sulfate, calcium chloride,
aluminum oxide, silica, and molecular sieves such as those formed from
potassium aluminum silicate.
The reaction is advantageously carried out by thoroughly mixing an excess of
the non-alkaline
dehydrating agent with the reactants so as to efficiently remove water as it
is formed during the reaction.
[0043] In this regard it is to be noted that by "excess" is meant a quantity
which is sufficient to
react with the water formed during the condensation and any water which is
present in the solvent.
Typically, however, a quantity may be used within the range of the range of
about 30 g/L to about 360
g/L, or about 60 g/L to about 330 g/L, or about 90 gIL to about 300 gIL,
relative to the volume of solvent
used.
[0044] In accordance with the present process, a compound of Formula 11(e.g.,
olivetol) and
of Formula III (e.g., p-mentha-2-en-1,8-diol) or Formula VI (e.g., p-mentha-
2,8-dien-1-ol) are dissolved
or suspended in a solvent (e.g., dicholoromethane) in the presence of a
dehydrating agent (e.g.,
magnesium sulfate). The resulting solution or suspension is then optionally
chilled or cooled (e.g., to a
temperature of less than about 15 C, about 10 C or even 5 C), and then a
catalyst (e.g., boron
trifluoride etherate) is added, optionally in a solution of the same solvent
(such as for example
dichloromethane), and also optionally over a period of time (e.g., 5 minutes,
10 minutes, 20 minutes or
more, depending on the quantity to be added, the quantity of the reaction
mixture, and/or the ability to
control the temperature adequately if an exothermic reaction occurs).
[0045] Once the addition of the catalyst is completed, the temperature of the
resulting
solution or suspension may then be heated, as necessary, in order to ensure
the reaction proceeds
within an acceptable period of time and to an acceptable endpoint (i.e., yield
of the compound of
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Formula I). Typically, the condensation reaction is carried out within a
temperature range of from about
C to about 20 C, and more typically from about 8 C to about 15 C, for a period
of time sufficient to
optimize the yield of the compound of Formula I, and furthermore to minimize
the formation of the AL
isomer thereof. Typically, however, the reaction is carried out for about 1 to
about 10 hours, or more
typically about 3 to about 8 hours, with lower reaction temperatures requiring
longer reaction times and
vice versa.
[0046] In this regard it is to be noted that experience to-date indicates the
acid catalyst
concentration (or amount used in the reaction) impacts the rate of reaction
and/or yield of the desired
product, this impact varying with the temperature at which the reaction is
carried out. Additionally, the
type of acid used may also impact the process conditions used. For example,
Lewis acids, such as BF3,
allow the reaction to be carried out at a lower temperature than that needed
for protic acids. When
protic acids are used, the reaction is typically carried out under refluxing
conditions, or extended
reaction times (and may be more prone to yielding the AG isomer).
Ill. Sulfonylation
[0047] As noted above, once the desired condensation reaction endpoint is
reached, the
reaction is optionally quenched and the product compound I is sulfonated to
prevent further conversion
of this product compound to the A8-isomer. Accordingly, following the
condensation reaction between
the Formula II substituted resorcinol with the Formula Ill or VI compound, at
least one aryl sulfonyl
halide in the presence of at least one base is added to the first reaction
mixture to sulfonate the
compound of Formula I, and A8-isomer thereof, that is present in the first
reaction mixture. Specifically,
the aryl sulfonyl halide reacts with the compound of Formula I (and the A8-
isomer thereof) at the phenyl
hydroxyl group, thereby producing aryl sulfonates.
[0048] Sulfonylation desirably occurs immediately upon completion of the
condensation
reaction to prevent further formation of A8-isomers, and facilitates the
separation of A9- and A8-isomers
(using techniques generally known in the art, including for example reverse
phase chromatography). As
used herein, "immediate" sulfonylation generally means the sulfonylation
reagents (i.e., aryl sulfonyl
halide and base) are added to the first reaction (i.e., condensation reaction)
mixture as soon as
conversion of the Formula II and Formula Ill or VI compounds to the product
compound of Formula I is
deemed to be sufficiently complete. Completion of the condensation reaction
may be monitored
through use of techniques known in the art, including forexample high
performance liquid
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chromatography (HPLC). Specifically, the condensation reaction produces an
intermediate product
having the following general Formula V:
R
OH
R2
Rd
HO R1
Re OH
R3 Formula V
wherein R1, R2, R3, R , Rd, and Re are as defined above. Disappearance of
intermediate Formula V
compounds from the reaction mixture correlates directly to formation of the
Formula I compound. As
such, HPLC may be used to monitor the presence of the intermediate compounds
in the reaction
mixture, and thus the progress of the condensation reaction. The condensation
reaction may be
deemed complete upon sufficient disappearance of the intermediate Formula V
compounds from the
first reaction mixture. This typically occurs when the concentration of
intermediate compound in the first
reaction mixture is about 10 wt.% or less (e.g., about 8 wt.%, about 6 wt.%,
about 4 wt.%, about 2 wt.%,
or less).
[0049] Accordingly, the sulfonylation reagents (i.e., aryl sulfonyl halide and
base) are added
to the first reaction mixture immediately following completion of the
condensation reaction. The aryl
sulfonyl halide forms a sulfonate of both the compound of Formula I present in
the first reaction mixture,
as well as any A,8_isomers that may have formed during the condensation
reaction. By adding the
sulfonylation reagents immediately upon completion of the condensation
reaction, formation of the
product compound of Formula I is maximized, while also minimizing the presence
of the corresponding
O$-isomers in the reaction mixture.
[0050] The base used in the sulfonylation reaction is added, at least in part,
to neutralize the
halide acid produced as a by-product during the reaction. Therefore, any
suitable base that does not
interfere with the sulfonylation reaction may be used. Exemplary bases include
lower alkyl amines,
especially tertiary amines such as triethyl amine, which provide inexpensive
bases that are suitable for
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the present invention. Primary and secondary amines may also be used, but may
result in unwanted
reactions with the sulfonyl halide. In particular, amines of the formula
R5R6R7N may be used, wherein
R5, R6, and R7 may typically be lower alkyl substituents having from about one
to about six carbon
atoms.
[0051] The aryl group of the sulfonyl halide maybe any aromatic system,
substituted
(including multiply substituted) or unsubstituted, that does not interfere
with the sulfonylation 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. Particularly suitable alkyl substituents include an alkyl
group directly attached to
an aromatic ring carbon where the alkyl substituent may typically be from
about one to about six carbon
atoms. In one embodiment, the aryl sulfonyl halide is p-toluenesulfonyl
chloride.
[0052] Ina particular embodiment, the aryl sulfonyl halide and base are added
to the first
reaction mixture, and allowed to react at about room temperature (e.g., about
20 C to about 25 C) until
sulfonylation is complete, forming a second reaction mixture. Typically, the
suifonylation reaction will be
complete after from about 2 hours to about 16 hours, more typically after from
about 4 hours to about 12
hours, and still more typically after about 6 or about 8 hours. In an
alternative embodiment, the reaction
may be run at increased temperatures, although doing so may result in minimal
increase in reaction
rate. Reaction temperatures in the range of from about room temperature to
about 75 C, or about 35 C
to about 55 C, may therefore alternatively be used.
IV. Product Isolation
[0053] Following sulfonylation, the reaction product maybe separated or
isolated from the
second reaction mixture using essentially any means generally known in the
art. For example, in one
embodiment, the drying agent is removed from the second reaction mixture, such
as by means of
filtration, and then the filtrate is subject to a solvent extraction step
(using for example sodium
bicarbonate and brine solutions). The solvent is then removed from the second
reaction mixture by any
suitable method, such as evaporation (e.g., rotary evaporation), supercritical
fluid chromatography,
normal phase liquid chromatography, and the like, yielding an oily residue
that contains the aryl
sulfonates present in the second reaction mixture (including compounds of
Formula IV). The crude aryl
sulfonates may then be subjected to additional separation and purification
steps generally known in the
art, including for example reverse-phase chromatography, to remove sulfonated
A6-THC or related
compounds, as well as additional reaction by-products. In one particular
embodiment, the crude aryl
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sulfonates are purified using reverse-phase chromatography using a Prodigy ODS-
Prep 250 x 21,2 mm
ID column; and an eluant comprising 77 volume percent methanol, 10 volume
percent tetrahydrofuran,
and 13 volume percent water, at a flow rate of 20 mLlminute, and UV detection
at 255 nm.
[0054] The isolated fractions containing the aryl sulfates of Formula IV
obtained from
chromatographic purification may optionally comprise not more than about 2
wt.%, or not more than
about 1 wt.%, or even not more than about 0.5 wt.%, of the sulfonated A8-
isomers. If desired, however,
isolated fractions of the Formula IV aryl sulfonates containing these amounts
of sulfonated Q$-isomers
may be further purified, alone or in combination, using recrystallization
techniques generally known in
the art to remove other impurities from the isolated fractions. Suitable
solvents for recrystallization
include, but are not limited to, heptane, hexane, t-butyl methyl ether, n-
pentanol, n-butanol, isopropanol,
isobutanol, ethanol, acetone, acetonitrile, and isopropyl acetate, In
particular, alcohols, including
methanol, may be used.
[0055] In general, the purity of the aryl sulfonates obtained, after
separation and optional
recrystallization, is typically greater than about 90 weight%, and more
typically is great than about 95
weight%, and still more typically is greater than about 99 weight%. The
resulting aryl sulfonates having
Formula IV are highly crystalline and stable at room temperature.
[0056] In this regard it is to be noted that all percentages given herein are
weight
percentages unless otherwise noted.
[0057] The crystalline Formula IV aryl sulfonates can then be hydrolyzed to
recover the
purified compound of Formula I by, for example, base hydrolysis, as
illustrated in the reaction below:
R`
Re O
II o OH
O / \
R2
Y F12 OO ZOH
+ M OZ HBO + e%-=O
R T O Y
R a / O R1 M
Re O Ri Re
R3
R3
Formula IV Formula I
wherein R1, R2, R3, Rc, Rd, Re, and Y are as defined above; M is a metal; and
Z is an alkyl group,
typically having 1 to about 10 carbon atoms, or about 2 to about 8 carbon
atoms,
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[0058] The hydrolysis can be accomplished by any method known in the art. In a
particular
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 being used in one or more
embodiments. Suitable
alcohols include, but are not limited to, methanol, ethanol, n-propanol,
isopropanol, t-butanol, and t-
pentanol, with tertiary alcohols being used in one or more embodiments. The
use of the same alkyl
group for both the oxide and the alcohol, such as for example potassium t-
butoxide in t-butanol,
optionally with several equivalents of water, may be desirably to, for
example, prevent exchange of the
alkyl groups present therein. The reaction may include about 2, about 3 or
more equivalents of base,
and about 3, about 4 or more equivalents of water, per equivalent of the
sulfonated compound (i.e., the
compound of Formula IV). The reaction is typically carried out at a
temperature in excess of room
temperature (e.g., a temperature in excess of about 20 C or about 25 C), and
may optionally be carried
out at a temperature of about 50 C, about 65 C or more.
[0059] A suitable method of hydrolysis comprises placing the crystalline
Formula IV aryl
sulfonates in a flask, or some other type of vessel, under an inert
atmosphere. The flask is typically
equipped for or with (i) magnetic stirring, or some other type of agitation,
(ii) electronic temperature
control, (iii) a condenser, (iv) an inert gas bubbler, and/or (v) a heating
mantle. Deionized water and an
alkyl oxide in alcohol are added to the flask. All solvents utilized are
optionally deoxygenated by
bubbling with an inert gas. In one embodiment, the resulting slurry is then
heated (to for example about
65 C or more), to increase the reaction rate and to force the reaction to
completion. While the reaction
will proceed at lower temperatures, the reaction may optionally be heated to a
temperature between
about 40 C to about 80 C, with about 50 C to about 70 C being used in one or
more embodiments, 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, which is
typically between about 2 to about 12 hours, more typically between about 2.5
to about 8 hours, and
more typically about 3 hours. The reaction mixture is then cooled to room
temperature.
[0060] After cooling, deionized water is added, and the reaction mixture is
stirred or agitated.
An organic solvent is added, and then resulting mixture is again stirred or
agitated. The resulting
mixture is then placed in a separatory funnel and then the phases are
separated. The organic fraction
containing the product compound of Formula I 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
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evaporated under vacuum to form an oil. Distillation of the resulting oil
under vacuum, using means
generally known in the art, results in a highly purified cannabinoid product.
[0061] The purity of the recovered cannabinoid product typically is about 90
weight%, about
95 weight%, about 98 weight% or more. Additionally, the overall yield of the
reaction sequence used to
obtain this highly pure cannabinoid product is at least about 15 wt.%, about
20 wt.%, about 25 wt.%,
about 30 wt.% or more.
[0062] The synthetic cannabinoid produced using the process of the present
disclosure will,
in at least one embodiment, advantageously comprise not more than about 2
wt.%, more typically not
more than about 1 wt.%, and more typically not more than about 0.5 wt.% of the
corresponding A8-
isomer, which is within the 2% USP limit for O8-isomer levels for A9-THC
preparations.
[0063] The process of the present disclosure is applicable to both small scale
and large,
commercial scale production of synthetic A9-THC or related compounds. For
example, the process of
the present disclosure is effective for the production of A9-THC, or
structurally similar or related
compounds, using as little as about 1 g up to about 50 g, about 100 g, about
250 g, about 500 g, or
more, of a Formula II compound as the starting material.
[0064] Having described the disclosure in detail, it will be apparent that
modifications and
variations are possible without departing from the scope of the disclosure
defined in the appended
claims.
EXAMPLES
[0065] The following non-limiting examples are provided to further illustrate
the present
disclosure.
EXAMPLE I
[0066] In this example, A9-THC tosylate was synthesized.
[0067] To begin, 0.53 g olivetol and 0.50 g of p-mentha-2-en-1,8-dial were
dissolved in 35
mL dichloromethane in a flask. 2.12 g magnesium sulfate was added to the
flask. The resulting
suspension was chilled to less than 50C. A solution of 37 L boron trifluoride
etherate in 5 mL
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dichloromethane was added dropwise to the suspension over a period of five
minutes. The temperature
of the reaction mixture was increased to 12 C, and maintained at that
temperature for 6 hours to allow
the reaction to occur.
[0068] 0.82 mL triethylamine and 1.12 g p-toluenesulfonyl chloride were added
to the
reaction mixture. The temperature of the reaction mixture was raised to room
temperature, and the
reaction was stirred overnight.
[0069] The resulting reaction mixture was filtered using vacuum filtration
through Whatman
541 filter paper to remove the magnesium sulfate. Evaporation of the solvent
produced an oily residue
containing crude A9-THC tosylate. The crude tosylate was purified using a
single pass through of a
reverse-phase preparative chromatography column under the following
conditions: Column: 250 x 10
mm, packed with Develosil RP-Aqueous Phase; Eluant: 3/312/2
acetonitrilelmethanol[THF/water
isocratic; Flow Rate 4.7 mL/min.
[0070] The fractions of A9-THC tosylate isolated using chromatography that
contained less
than 2% A8-THC tosylate were identified using reverse-phase liquid
chromatography with UV detection
(255 nm), and were combined and recrystallized. Specifically, 0.48 grams of
the isolated fractions of
A9-THC tosylate was dissolved in 7 mL of refiuxing methanol. Upon cooling to
room temperature, the
A9-THC tosylate began to precipitate. The crystals were collected by vacuum
filtration and dried under
high vacuum overnight. The purity of the resulting crystalline A9-THC tosylate
was determined using
reverse-phase liquid chromatography with UV detection (255 nm). The
crystalline A9-THC tosylate was
found to be 99.6% pure, and contained only 0.34% A8-THC tosylate.
EXAMPLE 2
[0071] In this example, the A9-THC tosylate prepared in Example 1 was
hydrolyzed to obtain
A9-THC.
[0072] 0.28 g of the A9-THC tosylate prepared in Example 1 was placed in a
flask along with
1.64 mL t-butanol and 0.043 mL water. 0.02 g of potassium butoxide was then
added, and the resulting
slurry was stirred and heated at 65 C for 5 hours. 5 mL of water was then
charged into the reactor, and
the resulting solution was cooled to 25 C. 5 mL of hexane was then added, and
the resulting biphasic
solution was stirred for 10 minutes. The organic phase was then separated and
washed twice with 5
mL of water and once with 5 mL of brine. The organic phase was then dried over
magnesium sulfate
and filtered through Whatman 541 filter paper. The solvent was evaporated to
give 56 mg of pure A9-
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THC as a light yellow oil. The resulting A9-THC was 95% pure A9-THC, and
contained only 0.44% A9-
THC.
EXAMPLE 3
[0073] In this example, A9-tetrahydrocannabivarn (3-propyl-THC) is
synthesized.
[0074] To begin, a 1 L jacketed reaction vessel was charged with 14.31 g of 1
R,4R-p-mentha-
2-en-1,8-diol, 14.08 g of 5-propylresorcinol, and 990 mL of dichloromethane.
The resulting mixture was
stirred vigorously at room temperature until all solids were dissolved,
approximately 10 minutes. The
reaction vessel was then charged with 60.74 g of magnesium sulfate. The
resulting suspension was
stirred at room temperature for 10 minutes, then cooled to 3 C with a
circulating chiller. A solution of
1.1 mL of boron trifluoride etherate in 10 mL of dichloromethane was then
added drop-wise to the
reaction mixture over a period of 5 minutes. Upon completion of the addition,
the temperature was
increased to 12 C, and the progress of the reaction was monitored by high
performance liquid
chromatography (HPLC). After 5 hours, 23.4 mL of triethylamine was added to
the reaction mixture.
This was followed immediately by the addition of 32.1 g of p-toluenesulfonyl
chloride.
[0075] The resulting mixture was then allowed to warm to room temperature, and
stirred
overnight. The reaction mixture was then filtered through Whatman 541 filter
paper, and extracted twice
with 500 mL saturated sodium bicarbonate, and once with 500 mL brine. The
resulting organic phase
was evaporated to give a reddish-yellow oil.
[0076] The oil was purified using reversed phase preparative chromatography,
as described
in Example 1. Column fractions were combined and concentrated to give an oily
residue. The 3-propyl-
THC tosylate was obtained by dissolving the oil in a heated solution of 10:1
methanol:acetone, allowing
the solution to cool to room temperature, and recovering the 3-propyl-THC
tosylate crystals by vacuum
filtration.
[0077] A 250 mL 3-necked round bottom flask, equipped with a stir bar,
thermocouple, and
nitrogen purge, was charged with 9.4 grams of the tetrahydrocannabivarin
tosylate. The reaction flask
was then charged with 55 mL t-butanol and 0.95 mL of degassed water. 6.90 g of
potassium t-butoxide
was then added, and the reaction mixture was heated at 65 C for 4.5 hours.
After 4.5 hours, the heat
was removed, and the reaction was allowed to cool to 50 C. The reaction
mixture was then charged
with 95 mL of degassed water, and the resulting mixture was allowed to cool to
room temperature with
stirring for 1 hour.
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[0078] The resulting mixture was charged with 95 mL of degassed n-heptane, and
stirred for
20 minutes. The mixture was transferred to a 500 mL separatory funnel, and the
phases were allowed
to separate under a nitrogen blanket. The aqueous (bottom) phase was then
removed, and the
extraction was repeated once more with 95 mL of degassed water. The organic
phase was extracted
with 95 mL of degassed brine solution. The organic phase was dried over
magnesium sulfate, filtered
as previously described, and concentrated. The resulting product was an amber-
colored oil. The oil
was dried under high vacuum overnight to give 6.24 grams of L9-
tetrahydrocannabivarin. The purity of
the L 9-tetrahydrocannabivadn was determined using HPLC to be 97% pure.
[0079] When introducing elements of the present disclosure or the
embodiments(s) thereof,
the articles "a", "an", "the" and "said" are intended to mean that there are
one or more of the elements.
The terms "comprising", "including" and "having" are intended to be inclusive
and mean that there may
be additional elements other than the listed elements.
[0080] In view of the above, it will be seen that the several objects of the
disclosure are
achieved and other advantageous results attained.
[0081] As various changes could be made in the above compositions, products,
and methods
without departing from the scope of the disclosure, it is intended that all
matter contained in the above
description shall be interpreted as illustrative and not in a limiting sense.
29
