U.S. patent application number 12/052354 was filed with the patent office on 2008-09-11 for conversion of cbd to delta8-thc and delta9-thc.
Invention is credited to Raphael Mechoulam, Leonard P. Sarna, G. R. Barrie Webster.
Application Number | 20080221339 12/052354 |
Document ID | / |
Family ID | 23044747 |
Filed Date | 2008-09-11 |
United States Patent
Application |
20080221339 |
Kind Code |
A1 |
Webster; G. R. Barrie ; et
al. |
September 11, 2008 |
CONVERSION OF CBD TO DELTA8-THC AND DELTA9-THC
Abstract
Methods of converting cannabidiol to
.DELTA..sup.8-tetrahydrocannabinol or
.DELTA..sup.9-tetrahydrocannabinol are described. The described
methods produce higher yields and higher purity compared to prior
art methods.
Inventors: |
Webster; G. R. Barrie;
(Manitoba, CA) ; Sarna; Leonard P.; (Manitoba,
CA) ; Mechoulam; Raphael; (Jerusalem, IL) |
Correspondence
Address: |
ADE & COMPANY INC.
2157 Henderson Highway
WINNIPEG
MB
R2G1P9
CA
|
Family ID: |
23044747 |
Appl. No.: |
12/052354 |
Filed: |
March 20, 2008 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
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10469928 |
Feb 25, 2004 |
7399872 |
|
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PCT/CA02/00451 |
Mar 7, 2002 |
|
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12052354 |
|
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60273628 |
Mar 7, 2001 |
|
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Current U.S.
Class: |
549/390 |
Current CPC
Class: |
C07D 311/80
20130101 |
Class at
Publication: |
549/390 |
International
Class: |
C07D 311/80 20060101
C07D311/80 |
Claims
1. A method of converting CBD to .DELTA..sup.8-THC comprising:
providing a reaction mixture comprising a Lewis acid in an organic
solvent; adding CBD to the reaction mixture; refluxing said
reaction mixture; diluting the mixture with an organic solvent;
pouring the mixture into cold water; mixing the mixture; allowing
the mixture to separate into an aqueous phase and an organic phase;
removing the organic phase; and eluting .DELTA..sup.8-THC from the
organic phase.
2. The method according to claim 1 wherein the reaction mixture is
mixed under a nitrogen atmosphere.
3. The method according to claim 1 wherein the Lewis acid is
p-toluenesulfonic acid in toluene.
4. The method according to claim 1 wherein the Lewis acid is boron
trifluoride.
5. The method according to claim 1 wherein the .DELTA..sup.8-THC is
eluted by HPLC.
6. The method according to claim 1 wherein the .DELTA..sup.8-THC is
eluted by RP-HPLC.
7. The method according to claim 1 including washing the organic
phase with aqueous NaHCO.sub.3 prior to eluting.
8. The method according to claim 7 including drying the organic
phase over MgSO.sub.4 and evaporating the organic phase following
washing.
9. The method according to claim 5 wherein the .DELTA..sup.8-THC is
eluted with ether in petroleum ether.
10. The method according to claim 9 wherein the ether in petroleum
ether is 5-10% ether in petroleum ether.
11. The method according to claim 6 wherein the .DELTA..sup.8-THC
is eluted with water-methanol or water-acetonitrile.
Description
PRIOR APPLICATION INFORMATION
[0001] This application is a divisional application of U.S. Ser.
No. 10/469,928, filed Feb. 25, 2004 which is the National Stage of
International Application No. PCT/CA02/00451, filed Mar. 7, 2002
which claims the benefit under 35 U.S.C. 119(e) of U.S. provisional
application Ser. No. 60/273,628, now abandoned, filed Mar. 7,
2001.
FIELD OF THE INVENTION
[0002] The present invention relates generally to the field of
chemical synthesis. More specifically, the present invention
relates methods of converting CBD to .DELTA..sup.8-THC or
.DELTA..sup.9-THC.
BACKGROUND OF THE INVENTION
[0003] Recently, public interest in Cannabis as medicine has been
growing, based in no small part on the fact that Cannabis has long
been considered to have medicinal properties, ranging from
treatment of cramps, migraines, convulsions, appetite stimulation
and attenuation of nausea and vomiting. In fact, a report issued by
the National Academy of Sciences' Institute of Medicine indicated
that the active components of Cannabis appear to be useful in
treating pain, nausea, AIDS-related weight loss or "wasting",
muscle spasms in multiple sclerosis as well as other problems.
Advocates of medical marijuana argue that it is also useful for
glaucoma, Parkinson's disease, Huntington's disease, migraines,
epilepsy and Alzheimer's disease.
[0004] Marijuana refers to varieties of Cannabis having a high
content of .DELTA..sup.9-tetrahydrocannabinol (.DELTA..sup.9-THC),
which is the psychoactive ingredient of marijuana whereas
industrial hemp refers to varieties of the Cannabis plant that have
a low content of .DELTA..sup.9-THC.
[0005] Furthermore, .DELTA..sup.9-THC is only one of a family of
about 60 bi- and tri-cyclic compounds named cannabinoids. For
example, .DELTA..sup.8-THC is a double bond isomer of
.DELTA..sup.9-THC and is a minor constituent of most varieties of
Cannabis (Hollister and Gillespie, 1972, Clin Pharmacol Ther 14:
353). The major chemical difference between the two compounds is
that .DELTA..sup.9-THC is easily oxidized to cannabinol whereas
.DELTA..sup.8-THC does not and is in fact very stable.
.DELTA..sup.8-THC, for the most part, produces similar psychometric
effects as does .DELTA..sup.9-THC, but is generally considered to
be 50% less potent than .DELTA..sup.9-THC and has been shown in
some cases to be 3-10 times less potent. .DELTA..sup.8-THC has also
been shown to be more (200%) effective an anti-emetic than
.DELTA..sup.9-THC and has been used as an anti-emetic in children,
based on the belief that the side effects of .DELTA..sup.9-THC and
.DELTA..sup.8-THC, such as anxiety and dysphoria, are more
prevalent in adults than children (Abrahamov et al, 1995, Life
Sciences 56: 2097-2102). On the other hand, CBD has no activity on
its own when administered to humans. It is of note that CBD is
typically about 2% (0.5-4%) dry weight of hemp chaff,
.DELTA..sup.8-THC is approximately 0.2% (0.05-0.5%) dry weight and
.DELTA..sup.9-THC is approximately 0.1% (0.05-0.3%).
[0006] Gaoni and Mechoulam (1966, Tetrahedron 22: 1481-1488) teach
methods of converting CBD to, among other compounds,
.DELTA..sup.8-THC and .DELTA..sup.9-THC comprising boiling a
solution of CBD (3.0 g) in absolute ethanol (100 ml) containing
0.05% HCl for 18 hours. The solution was then poured into water and
extracted with ether. The ether solution was washed with water,
dried (Na.sub.2SO.sub.4) and evaporated. .DELTA..sup.8-THC and
.DELTA..sup.9-THC were eluted from the resulting oil and separated
by chromatography. In another experiment, CBD (3.14 g) was
dissolved in benzene (100 ml) containing 2 mg/ml p-toluenesulphonic
acid and boiled for two hours. The reaction mixture was poured into
water and the upper layer was separated, washed with 5%
NaHCO.sub.3, then with water, dried and evaporated. Elution with
pentane-ether (95:5) gave an oily material which was subsequently
distilled. Percentage yield of .DELTA..sup.8-THC
(.DELTA..sup.1(6)-THC) was given as 64% of the crude material in
this paper. The crude oil product, which showed only one spot by
thin layer chromatography, was purified by vacuum distillation.
[0007] Gaoni and Mechoulam (1964, J Amer Chem Soc 86: 1646) also
described a method for converting CBD to .DELTA..sup.9-THC
comprising boiling a mixture of CBD in ethanol containing 0.05%
hydrogen chloride for 2 hours. Percentage yield of
.DELTA..sup.9-THC (.DELTA..sup.1-THC) was 2% (Mechoulam et al,
1972, J Amer Chem Soc 94: 6159-6165; Mechoulam and Gaoni, 1965, J
Amer Chem Soc 87: 3273). Using boron trifluoride, the yield was 70%
(Gaoni and Mechoulam, 1971, J Amer Chem Soc 93: 217-224) although
purity was not given.
[0008] Clearly, as the cannabinoids are of potential medicinal
value, improved methods of converting CBD to .DELTA..sup.9-THC or
.DELTA..sup.8-THC are needed.
SUMMARY OF THE INVENTION
[0009] According to a first aspect of the invention, there is
provided a method of converting CBD to a tetrahydrocannabinol
comprising:
[0010] providing a reaction mixture comprising a catalyst in an
organic solvent;
[0011] adding CBD to the reaction mixture;
[0012] mixing said reaction mixture;
[0013] allowing the mixture to separate into an aqueous phase and
an organic phase;
[0014] removing the organic phase; and
[0015] eluting the tetrahydrocannabinol from the organic phase.
[0016] According to a second aspect of the invention, there is
provided a method of converting CBD to .DELTA..sup.8-THC
comprising:
[0017] providing a reaction mixture comprising a Lewis acid in an
organic solvent;
[0018] adding CBD to the reaction mixture;
[0019] refluxing said reaction mixture under a nitrogen
atmosphere;
[0020] diluting the mixture with an organic solvent;
[0021] pouring the mixture into cold water;
[0022] mixing the mixture;
[0023] allowing the mixture to separate into an aqueous phase and
an organic phase;
[0024] removing the organic phase; and
[0025] eluting .DELTA..sup.8-THC from the organic phase.
[0026] According to a third aspect of the invention, there is
provided a method of converting CBD to .DELTA..sup.9-THC
comprising:
[0027] providing a reaction mixture comprising CBD in an organic
solvent;
[0028] adding a catalyst to the reaction mixture under a nitrogen
atmosphere;
[0029] stirring the reaction mixture;
[0030] adding NaHCO.sub.3 to the reaction mixture;
[0031] allowing the mixture to separate into an aqueous phase and
an organic phase;
[0032] removing the organic phase; and
[0033] eluting .DELTA..sup.9-THC from the organic phase.
[0034] According to a fourth aspect of the invention, there is
provided a method of preparing a pharmaceutical composition
comprising:
[0035] converting CBD to a tetrahydrocannabinol by: [0036]
providing a reaction mixture comprising a catalyst in an organic
solvent; [0037] adding CBD to the reaction mixture; [0038] mixing
said reaction mixture; [0039] allowing the mixture to separate into
an aqueous phase and an organic phase; [0040] removing the organic
phase; and [0041] eluting the tetrahydrocannabinol from the organic
phase; and
[0042] mixing the eluted tetrahydrocannabinol with a suitable
excipient.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
[0043] Unless defined otherwise, all technical and scientific terms
used herein have the same meaning as commonly understood by one of
ordinary skill in the art to which the invention belongs. Although
any methods and materials similar or equivalent to those described
herein can be used in the practice or testing of the present
invention, the preferred methods and materials are now described.
All publications mentioned hereunder are incorporated herein by
reference.
DEFINITIONS
[0044] As used herein, CBD refers to cannabidiol.
[0045] As used herein, .DELTA..sup.9-THC refers to
.DELTA..sup.9-tetrahydrocannabinol.
[0046] As used herein, .DELTA..sup.8-THC refers to
.DELTA..sup.8-tetrahydrocannabinol.
[0047] As used herein, "Lewis acid" refers to a powerful electron
pair acceptor. Examples include but are by no means limited to
BF.sub.3Et.sub.2O, p-toluenesulfonic acid and boron
trifluoride.
[0048] Described herein are methods and protocols for converting
cannabidiol (CBD) to .DELTA..sup.8-tetrahydrocannabinol
(.DELTA..sup.8-THC) or .DELTA..sup.9-tetrahydrocannabinol
(.DELTA..sup.9-THC). As will be appreciated by one knowledgeable in
the art and as discussed below, the reaction times may be varied
somewhat, producing product at different yields and purities.
Furthermore, functional equivalents may be substituted where
appropriate.
[0049] Specifically, described herein is a method of converting CBD
to a tetrahydrocannabinol comprising: providing a reaction mixture
comprising a catalyst in an organic solvent, adding CBD to the
reaction mixture, mixing said reaction mixture, allowing the
mixture to separate into an aqueous phase and an organic phase;
removing the organic phase, and eluting the tetrahydrocannabinol
from the organic phase. The tetrahydrocannabinol may then be
combined with suitable excipients known in the art, thereby forming
a pharmaceutical composition.
[0050] In some embodiments, the tetrahydrocannabinol at
therapeutically effective concentrations or dosages be combined
with a pharmaceutically or pharmacologically acceptable carrier,
excipient or diluent, either biodegradable or non-biodegradable.
Exemplary examples of carriers include, but are by no means limited
to, for example, poly(ethylene-vinyl acetate), copolymers of lactic
acid and glycolic acid, poly(lactic acid), gelatin, collagen
matrices, polysaccharides, poly(D,L lactide), poly(malic acid),
poly(caprolactone), celluloses, albumin, starch, casein, dextran,
polyesters, ethanol, mathacrylate, polyurethane, polyethylene,
vinyl polymers, glycols, mixtures thereof and the like. Standard
excipients include gelatin, casein, lecithin, gum acacia,
cholesterol, tragacanth, stearic acid, benzalkonium chloride,
calcium stearate, glyceryl monostearate, cetostearyl alcohol,
cetomacrogol emulsifying wax, sorbitan esters, polyoxyethylene
alkyl ethers, polyoxyethylene castor oil derivatives,
polyoxyethylene sorbitan fatty acid esters, polyethylene glycols,
polyoxyethylene stearates, colloidol silicon dioxide, phosphates,
sodium dodecylsulfate, carboxymethylcellulose calcium,
carboxymethylcellulose sodium, methylcellulose,
hydroxyethylcellulose, hydroxypropylcellulose,
hydroxypropylmethylcellulose phthalate, noncrystalline cellulose,
magnesium aluminum silicate, triethanolamine, polyvinyl alcohol,
polyvinylpyrrolidone, sugars and starches. See, for example,
Remington: The Science and Practice of Pharmacy, 1995, Gennaro
ed.
[0051] In some embodiments, the catalyst is a Lewis acid, for
example, p-toluenesulfonic acid, boron trifluoride or
BF.sub.3Et.sub.2O. In some embodiments, the BF.sub.3Et.sub.2O is in
dry methylene chloride, ethyl acetate, ethanol, hexane or other
organic solvent. In yet other examples, the catalyst may be
hydrochloric acid in ethanol or sulfuric acid in cyclohexane.
[0052] In some embodiments, a weak base is added to the reaction
mixture prior to allowing the reaction mixture to separate into
organic and aqueous phases. The base may be an alkali metal
hydrogen carbonate or a carbonate of an alkali metal.
[0053] In some embodiments, the organic layer is dried prior to
eluting. In these embodiments, a suitable drying or dehydration
compound, for example, MgSO.sub.4 or Na.sub.2SO.sub.4 is used.
[0054] In yet other embodiments, the process may be carried out
under a nitrogen atmosphere.
[0055] As discussed below, yield is determined by looking at the
peak area for the isolated compound in the gas chromatography--mass
spectra analysis of the crude reaction product mixture. It is
important to note that in the prior art, yield is often calculated
on the basis of the basis of first isolated crude product before
final purification. In some embodiments of the process, as
discussed below, yield is at least 50%. In other embodiments, the
yield is at least 60%. In other embodiments, yield is at least 70%.
In yet other embodiments, yield is 70-85%.
[0056] Purity is also determined by GC-MS and also by analytical
HPLC. The total ion chromatogram from the GC-MS gives information
similar to that provided by an FID-GC in that the peak area is
proportional to the mass of the analytes detected. Total peak area
and the peak areas of the individual analytes can be compared in
the GC-MS case as long as the masses are in generally the same
range. As discussed below, in some embodiments, purity of the
tetrahydrocannabinols isolated by the process is greater than 90%.
In yet other embodiments, purity is greater than 95%. In yet other
embodiments, purity is greater than 97%. In yet other embodiments,
purity is 98-99%.
[0057] The invention will now be described by means of examples,
although the invention is not limited to these examples.
EXAMPLE I
Conversion of CBD TO .DELTA..sup.8-THC
[0058] CBD (300 mg) was added to dried p-toluenesulfonic acid (30
mg) in toluene (15 ml), under N.sub.2 atmosphere. In this example,
the mixture was refluxed (under N.sub.2) for 1 hour, although other
time periods may also be used, as discussed below. It was then
diluted with ether (20 ml) and poured into cold water, The upper
layer was separated, washed with aqueous 5% NaHCO.sub.3, then with
water, dried over MgSO.sub.4 and evaporated. The viscous oil showed
mainly one spot on TLC (using 20% ether in petroleum ether as
eluent). HPLC, on the crude oil, showed the presence of 86%
.DELTA..sup.8-THC. The oil was chromatographed on a silica gel
column (6 g). Elution with 5 to 10% ether in petroleum ether gave a
fraction (244 mg, 81%) of .DELTA..sup.8-THC 98.6% pure. When the
reaction was carried out using various reflux times showed the
presence of 79.33% .DELTA..sup.8-THC (15 minutes), 81.7%
.DELTA..sup.8-THC (30 minutes) and 84.6% .DELTA..sup.8-THC (2
hours).
[0059] In the example described above, normal phase HPLC separation
is used wherein the column is for example a silica gel and the
mobile phase is organic, for example, hexane or ethyl ether-hexane.
In other embodiments, reverse phase HPLC separation is used,
wherein the column is for example C18 bonded silica gel and the
mobile phase is water-methanol or water-acetonitrile. In each case,
solvent programming is used.
[0060] The p-toluenesulfonic acid is used as a catalyst in the
above example. It is of note that boron trifluoride could also be
used as a catalyst, as could a number of other Lewis acids known in
the art. It is of note that the exact proportion is not essential
to the reaction proceeding. It is of further note that the nitrogen
atmosphere does not appear as necessary as during the conversion of
CBD to .DELTA..sup.9-THC. It is also of note that other solvents
may also be used, for example, benzene, but toluene has produced
the best results so far.
[0061] In other embodiments, anhydrous Na.sub.2SO.sub.4 or another
suitable drying or dehydration agent known in the art is used in
place of the MgSO.sub.4.
[0062] In other embodiments, an alkali metal hydrogen carbonate or
carbonate of an alkali metal is used instead of NaHCO.sub.3.
[0063] The nitrogen atmosphere may prevent oxidation of the
reaction intermediate, thereby enhancing the yield. Diluting into
ether first and then adding the water again prevents undue exposure
to oxidizing conditions. The water still quenches the reaction
catalyst, but the reaction product is dissolved in the toluene and
ether and is to some extent protected. That is, it is not in as
intimate contact with the water and not as susceptible to oxidation
as it would be if the water were to be added first.
EXAMPLE II
Conversion of CBD to .DELTA..sup.9-THC
[0064] BF.sub.3Et.sub.2O (50 .mu.l) was added, under nitrogen
atmosphere, to ice cold solution of CBD (300 mg) in dry methylene
chloride (15 ml). The solution was stirred at 0.degree. C. for 1
hour. Saturated aqueous solution of NaHCO.sub.3 (2 ml) was added
until the red color faded. The organic layer was removed, washed
with water, dried over MgSO.sub.4 and evaporated. The composition
of the oil obtained (determined by HPLC):
trans-.DELTA..sup.8-isoTHC 27%, .DELTA..sup.9-THC 66.7%. The oil
was chromatographed on silica gel column (20 g) and eluted with
petroleum ether followed by graded mixtures, up to 2:98 of ether in
petroleum ether. The first fraction eluted was the
.DELTA..sup.8-iso THC (30 mg, 9.5%) followed by a mixture of
.DELTA..sup.8-iso THC and .DELTA..sup.9-THC (100 mg). The last
compound to be eluted was the .DELTA..sup.9-THC (172 mg, 57%). The
purity of .DELTA..sup.9-THC (as determined by HPLC) was 98.7%.
[0065] It is of note that when the reaction was carried in the
presence of MgSO.sub.4 (120 mg), the composition of the oil
obtained (determined by FIPLC) was: trans-.DELTA..sup.8-isoTHC
20.15%, .DELTA..sup.9-THC 56.7%.
[0066] In the example described above, normal phase HPLC separation
is used wherein the column is for example a silica gel and the
mobile phase is organic, for example, hexane or ethyl ether-hexane.
In other embodiments, reverse phase HPLC separation is used,
wherein the column is for example C18 bonded silica gel and the
mobile phase is water-methanol or water-acetonitrile. In each case,
solvent programming is used.
[0067] In other embodiments, anhydrous Na.sub.2SO.sub.4 or another
suitable drying or dehydration agent known in the art is used in
place of the MgSO.sub.4.
[0068] In other embodiments, another alkali metal hydrogen
carbonate or carbonate of an alkali metal is used instead of
NaHCO.sub.3.
[0069] In other embodiments, BF.sub.3Et.sub.2O is dissolved in
ethyl acetate, ethanol, hexane or other suitable organic
solvent.
[0070] In other embodiments, the catalyst is hydrochloric acid in
ethanol or sulfuric acid in cyclohexane (reaction mixture refluxed
rather than stirred).
[0071] While the preferred embodiments of the invention have been
described above, it will be recognized and understood that various
modifications may be made therein, and the appended claims are
intended to cover all such modifications which may fall within the
spirit and scope of the invention.
* * * * *