6.1 ~ The Cannabinoids
Cannabis' notorious resin is a complex mixture of cannabinoids,
terpenes, and waxes, etc. There are about 100 known cannabinoids
that occur only in hemp, with the exception of Cannabichromene,
which is found in a few other plants. The entire hemp plant
contains several hundred known chemicals.(1-3)
The cannabinoids are thought to be formed by condensation of
monoterpene derivatives such as geraniol phosphate with a
depside-type olivetolic acid. This leads initially to the
formation of Cannabigerol (CBG) and Cannabichromene (CBC) and
their carboxylic acids, then to Cannabidiolic Acid (CBDA), which
undergoes ring closure to form TetraHydroCannabinol (THC) and
its acid (THCA). The latter decarboxylates to form THC. Other
biogenetic pathways featuring CBC have been proposed by De
Faubert Maunder and by Turner and Hadley. (4, 5) (Fig. 6.1)
Figure 6.1 ~ Cannabinoids
The acids comprise up to 40% of the cannabinoid content of
young plants. THC dehydrogenates to form Cannabidiol (CBD). THC
is a primary psychoactive cannabinoid. The minor constituent
Cannabiverol (CBV) possesses only about 20% of THC’s activity.
CBD and CBN are not psychoactive, but they have valuable medical
properties. (6-10)
Many synthetic analogs of THC are more or less potent than the
parent molecule. The dimethylheptyl derivative is over 50 times
more active, with effects lasting several days. Some nitrogen
and sulfur analogs also are psychoactive.
The total synthesis of THC has been accomplished in many ways,
most of which are difficult. However, the extraction of
cannabinoids, their purification, isomerization and acetylation
are easy experiments for dilettante souffleurs who would
possess this elixir.
6.2 Extraction ~
Cannabis must be dried be it is extracted, because it is not
possible to remove more than 50% of the cannabinoids from fresh
material THC-Acid is difficult to extract If you plant to
convert the THCA to THC, the plant material should be thoroughly
decarboxylated by heating it under nitrogen at 105° C for 1 hour
before performing a solvent extraction.
Chloroform is the most efficient solvent for the extraction of
THC from cannabis. A single extraction will remove 98-99% of the
cannabinoids within 30 minutes. A second extraction removes only
88-99% of the cannabinoids within 30 minutes. A second
extraction removes 100% of the THC. Light petroleum ether
(60-80°) also works well, but a single extraction removes only
88-95% of the cannabinoids; a double extraction removes up to
99%. Ethanol also can be used, but it removes ballast pigments
and sugars which complicate the purification of the resin (11,
12)
Extract the dried cannabis with a suitable solvent for several
hours at room temperature or by refluxing. Filter through
charcoal to clarify the solution, then chill overnight to
precipitate waxes, then filter the solution again. Concentrate
it to one-half volume, and extract it with 2% aqueous sodium
sulfate (to prevent oxidation). Separate the aqueous layer, and
strip the solvent. The residue is crude hemp oil.
The odoriferous terpenes can be removed by steam or vacuum
distillation. Cautious distillation in vacuo yields a fraction
of crude red oil (bp 100-220° C/3 mm). This can be purified by
redistillation or column chromatography. Use ethanol to remove
the residue from the flask while it is still hot. Filter the
solution through charcoal, and strip the solvent. Distill the
residue to yield pure red oil (bp 175-195° C /2 mm).
Distillation must be stopped if smoke appears, indicating
decomposition. (13, 14)
Because THC is heat-sensitive, it is preferable to isolate the
cannabinoids by column chromatography. The simplest method of
column chromatography is performed with ethanol and ether
extracts of hemp on alumina, yielding two major fractions: (1)
chlorophyll, CBD, and CBN, and (2) THC. A second, more difficult
method is performed on Florisil (use 10 times the weight of the
oil) with the solvent system hexane:2% methanol. This yields a
doubly-concentrated, viscous oil which can be repeatedly
chromatographed on alumina to separate the THC and CBD. (15)
6.3 Isomerization ~
The potency of marijuana can be increased by about 50% simply
by simmering a water slurry of the material for 2 hours. Add
water as necessary to maintain the level. Cool and filter the
mixture, and refrigerate the aqueous solution. Dry the leaf
material at low heat. Drink the tea before smoking the
marijuana. The effects are much more intense and last longer
than those from the untreated leaves. The boiling water
treatment isomerizes the inactive CBD, and decarboxylates THCA
to THC.
Although Cannabidiol (CBD) has no psychoactivity, it does
antagonize THC and produces other valuable sedative, antibiotic,
and anti-epileptic effects. CBD can be isomerized to THC. If the
plant is Phenotype III (containing mainly CBD in its resin),
isomerization can double the yield of THC.
The CBD fraction of column chromatography can be distilled (bp
187-190° C/2 mm; pale yellow resin) to purify it. Isomerization
can be accomplished with any of several solvents and acids.
Alcohol and sulfuric acid isomerizes only 50-60% of CBD to THC;
p-TolueneSulfonic Acid (p-TSA) in petroleum ether or other
light, non-polar solvent will convert 90% of CBD to THC upon
refluxing 1 hour at 130° F. (16, 17)
Reflux 3 gr CBD in 100 ml dry benzene for 2 hours with 200 mg
p-TSA monohydrate until the alkaline Beam test (5% KOH in
ethanol) is negative (no color). The Beam test gives a deep
violet color with CBD. Separate the upper layer, wash it with 5%
sodium bicarbonate, wash again with water, and strip the
solvent. The remaining viscous oil should give a negative
reaction to the Beam test. The crude THC can be purified by
distillation (bp 169-172° C/0.03 mm), or by chromatography in 25
ml pentane on 300 gr alumina. Elute with pentane 95:5 ether to
yield fraction of CBD and THC. Combine the THC fractions and
distill (bp 175-178° C/1 mm).
Reflux 2 gr CBD in 35 ml cyclohexane, and slowly add a few
drops of sulfuric acid. Continue to reflux until the Beam test
is negative. Separate the sulfuric acid from the reaction
mixture. Wash the solution twice with aqueous sodium
bicarbonate, the twice again with water. Purify by
chromatography, or distill (bp 165° C/0.01 mm). Any unreacted
CBD can be recycled.
Another method is to reflux a mixture of 6 gr dry pyridine
hydrochloride and 3 gr CBD at 125° C until the Beam test is
negative. Wash the reaction mixture with water to remove the
pyridine, then extract the mixture with ether. Wash the ether
with water, evaporate the ether, and distill the residue i.v. to
yield pure THC.
Similarly, reflux 3 gr CBD in 150 ml ethanol with 50 ml 85%
phosphoric acid until the Beam test is negative. Work up the
reaction mixture, and purify the THC.
Alternatively, reflux 3 gr CBD in 100 ml absolute ethanol
containing 0.05% HCl for 19 hours. Extract the ether, wash the
ether with water, dry, evaporate, and chromatograph on 400 gr
alumina to yield:
(a) 0.5 gr 1-EthoxyHexaHydro-CBN (EHH-CBN: mp 86-87° C); elute
with pentane 98:2 ether. Recrystalize from methanol and water.
(b) 2 gr THC; elute with pentane 95:5 ether. Repeated
chromatography will separate the less polar forms.
(c) 0.5 gr EHH-CBN, eluted with pentane 93:7 ether. It can be
isomerized to THC by refluxing in benzene for 2 hours. Cool the
reaction mixture, wash it with water; separate, dry, and strip
the solvent layer i.v. to yield THC.
CBD also can be isomerized by irradiation of a cyclohexane
solution in a quartz vessel with a mercury lamp (235-265 nm) for
20 minutes. Workup of the reaction mixture yields 7-13% THC. (18-20)
6.4 ~ Acetylation
THC gives an acetate (ATHC) which is as potent as THC. The
mental effects are quite subtle and pleasant. Wohlner, et al.,
prepared ATHC by refluxing the crude distillate of cannabis oil
with approximately 3 volumes of acetic anhydride. It is purified
by distillation i.v. or with steam.
Cahn prepared ATHC thus: add 150 ml acetyl chloride (dropwise
with stirring and cooling) to 185 gr crude resin in 500 ml dry
pyridine. Crystals may separate during the addition, or on
standing a few hours at room temperature. Pour the mixture into
dilute hydrochloric acid/ice. Separate the oil, then dissolve it
in ether. Wash this solution with dilute acid, then with aqueous
sodium carbonate, and again with water. Dry the solution with
calcium chloride. Strip the solvent and distill the residue
(240-270 C°/20 mm). The mixture of acetylated cannabinoids is
separated by dissolving 2 gr in 100 ml benzene and
chromatography over silica (150-200 mesh). Elute with 800 ml
benzene. Combine the washings and the original effluent
solutions, then strip the benzene i.v. to recover about 60%
yield of light yellow oil. The material remaining on the column
contains CBD and other cannabinoid acetates which can be
recovered with ethanol and worked up.(21)
6.5 ~ Identification
Colorimetric tests are the simplest method of identifying
cannabinoids. Hundreds more sophisticated analytical methods
have been developed, as a review of Chemical Abstracts
will reveal.
The Beam test is relatively specific. It gives a purple color
with 5% ethanolic KOH, based on the oxidation of CBD, CBG, etc.,
and their acids to hydroxyquinones. However, THC does not react
to the Beam test. Only two plants (Rosemary and Salvia) out of
129 common species tested give a weakly positive reaction. Among
some 50 pure vegetable substances such as mono- and
sesqui-terpenes, aromatics, etc., only juglone, embelin, and
alkyl dioxyquinone develop a color reaction close to that of
Cannabis. The reaction is not always dependable; it can be
absent if the ethanol is hot. (22, 23)
A modification of the Beam test uses absolute ethanol saturated
with gaseous hydrogen chloride. When added to an extract of
suspect material, it gives a cherry red color which disappears
if water is added. However, the test also gives more or less
similar red color reactions with pinene, tobacco, julep, sage,
rosemary, and lavender, etc..
The colorimetric test of Duquenois and Moustapha is not so
specific as the Beam test, but it is very sensitive. The test
reacts to CBN and CBD, but not to THC:
Vanillin (0.4 gr, acetaldehyde (0.06 gr) and 20 ml 95% ethanol
is stored in a bottle. Extract the plant material with petroleum
ether, then filter it and evaporate the solvent. Add exactly 2
ml of reagent and 2 ml concentrated hydrochloric acid. Stir the
mixture; it turns sea-green, then slate gray, followed by indigo
within 10 minutes. It turns violet within 30 minutes and becomes
more intense.
The Duquenois-Negm hydrogen peroxide/sulfuric acid test is
suitable for following the development of the resin and its
potency. Macerate cannabis in chloroform or light petroleum
ether for several hours. Evaporate 0.2 ml of the extract in a
porcelain dish. Add 2 drops 30% hydrogen peroxide and 0.5 ml
concentrated sulfuric acid. Rotate the dish gently, and observe
the color of the liquid after 5 minutes. A pink color indicates
CBD; blood-red color indicates a high concentration of THC.
Violet or strong brown indicates THC. CBN produces a green color
which quickly turns green-brown. (24)
The identification of cannabinoids has been made irrefutable by
the modern development of gas chromatography, especially when
combined with mass spectrometry.
Laboratories which do not possess these technologies can use
diode-array and programmable variable-wavelength ultraviolet
absorption detectors in conjunction with thin-layer
chromatography (TLC) or high-performance liquid chromatography
(HPLC), or a combination of both, and make comparisons with
published data in conjunction with the specific absorption
spectrum for the cannabinoids (200-300 nm). The combination of
these techniques can overcome the problem of errors due to
interference which often occur when single methods are used. (25)
6.6 ~ Neurology
In 1984, Miles Herkenham and his colleagues at NIMH mapped the
brain receptors for THC, using radioactive analogs of THC
developed by Pfizer Central Research. They found the most
receptors in the hippocampus, where memory consolidation occurs.
There we translate the external world into a cognitive and
spatial "map". Receptors also exist in the cortex, where higher
cognition is performed. Very few receptors are found in the
limbic brainstem, where the automatic life-support systems are
controlled. This may explain why it is so difficult to die from
an overdose of cannabis. The presence of THC receptors in the
nasal ganglia --- an area of the brain involved in the
coordination of movement --- may enable the cannabinoids to
relieve spasticity. Some receptors are located in the spinal
cord, and may be the site of the analgesic activity of cannabis.
A few receptors are found in the testes. These may account for
the effects of THC on spermatogenesis and as an aphrodisiac.
S. Munro, et al., located a peripheral CX5 receptor for
cannabinoids in the marginal zone of the spleen. The
Anandamide/cannabinoid receptor site, a protein on the cell
surface, activates G-proteins inside the cell and leads to a
cascade of other biochemical reactions which generate euphoria.
(26-31)
The brain produces Anandamide (Arachidonylethanolamide), which
is the endogenous ligand of the cannabinoid receptor. It was
first identified by William Devane and Raphael Mechoulam, et
al., in 1992. Anandamide has biological and behavioral
effects similar to THC. Devane named the substance after the
Sanskrit word Ananda (Bliss). The discovery of
Anandamide and its receptor site has unlocked the door to the
world of cannabinoid pharmacology. (32-35)
CBD antagonizes THC and competes with THC to fill the
cannabinoid receptor site. THC also exerts an inhibitory effect
on acetylcholine activity through a GABA-ergic mechanism. It
significantly increases the intersynaptic levels of serotonin by
blocking its reuptake into the presynaptic neuron. THC also
elevates the brain level of 5-hydroxy-tryptamine (5-HT) while
antagonizing the peripheral actions of 5-HT. (36-39)
In 1990, Patricia Reggio, et al., developed a molecular
reactivity template for the design of cannabinoid analgesics
with minimal psychoactivity. The analgesic activity of the
template molecule (9-nor-9b-OH-HHC) is attributed to the
presence and positions of two regions of negative potential on
top of the molecule. The template places all cannabinoid
analgesics on a common map, no matter how dissimilar their
structures. (40)
6.7 ~ References
Top ~ Table of Contents
~ Next ~ Previous
Patents
for
Production of TetraHydroCannabinol, Extraction of Cannabis,
&c...
Conversion of CBD to Delta-8 THC and Delta-9 THC
USPA 2008221339
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 : Barrie Webster, Raphael
Mechoulam, Leonard Sarna
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.
DIRECT SYNTHESIS OF ({31
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