Red oil was prepared by extraction of the plant material with ether, followed by distillation of the concentrated extract at room pressure followed by redistillation under reduced pressure (15-50 mm Hg). The oil was acetylated with acetic anhydride, and the acetylated product was subjected to fractional distillation in vacuo. Six fractions were collected. The head and tail fractions were removed. The remaining four fractions which represented the principal fractions (fractions 2, 3, 4, and 5) were combined and passed over silica gel column in benzene and then passed over activated alumina in carbon tetrachloride solution. The product was hydrolyzed by acid, alkali, or ammonia in alcoholic solution. The authors reported that the deacetylated product has, in each case, a different physiological potency than the acetate. All fractions were not pure compounds.

DeRopp, in 1960 (12), described the isolation of THC from the flowering tops of Cannabis sativa. His method involved adsorption chromatography of the methanolic extract of cannabis followed by partition chromatography on Celite using N,N-dimethyl formamide/cychlohexane mixture and high vacuum distillation. The purity of THC was based on paper chromatographic evidence.

The first isolation of the naturally occurring THC in its pure form was reported by Gaoni and Mechoulam in 1964 (13). THC was isolated from the hexane extract of hashish by repeated column chromatography on florisil and alumina. Further purification was carried out by the preparation of the crystalline 3,5-dinitrophenylurethane of THC followed by mild basic hydrolysis to get the pure THC. The purity of THC was proven by thin layer chromatography (TLC) and spectroscopic analysis (IR and NMR).

Korte, et al., in 1965 (14) reported the isolation of THC from the crude extracts of the female inflorescence of Cannabis sativa indica and Cannabis sativa non indica. The crude extracts were chromatographed over activated alumina in order to remove the coloring impurities like carotinoids, chlorophylls, and xanthophylls. All the cannabinolic fractions were combined and concentrated to give a brownish-red oil. The oil was further purified by a countercurrent distribution method to get THC which was proved to be identical with that described by Gaoni and Mechoulam (13).

<embed flashVars="playerVars=autoPlay=no" src="http://www.metacafe.com/fplayer/506986/how_to_perform_a_vacuum_distillation.swf" width="440" height="248" wmode="transparent" allowFullScreen="true" allowScriptAccess="always" name="Metacafe_506986" pluginspage="http://www.macromedia.com/go/getflashplayer" type="application/x-shockwave-flash"></embed><div style="font-size:12px;"><a href="http://www.metacafe.com/watch/506986/how_to_perform_a_vacuum_distillation/">How To Perform A Vacuum Distillation</a> - <a href="http://www.metacafe.com/">The funniest bloopers are right here</a></div>

Solvent choice

http://blog.restek.com/?p=3018

Medical Marijuana Solvent Extraction Efficiency – Potency Determinations with GC-FID
August 3rd, 2011 by Jack Cochran


Amanda Rigdon and I recently investigated the extraction efficiency of various solvents for medical marijuana potency determinations (although technically we’re not working with medical marijuana; instead we use seized illicit marijuana and did the work under the auspices of the Penn State University Police Department with Randy Hoffman, an Evidence Technician there).

We used an Agilent GC-FID with split injection on a SkyTM 4mm Precision Liner with Wool and a 15m x 0.25mm x 0.25µm Rxi-5Sil MS. A cannabinoids standard containing cannabidiol, delta-9-THC, and cannabinol was used for calibration and quantification. The last eluting compound of interest, cannabinol, had a retention time of about 4.85 min.

One consideration for extraction efficiency in marijuana potency determination is that THCA is the main source for THC determined with GC. (THCA, or delta-9- tetrahydrocannabinolcarboxylic acid, decarboxylates during smoking, or other heating, including in a hot GC inlet, to delta-9-THC.) Solvent polarity index (higher value means more polar solvent) was used to assure a range of tested solvents from non-polar (hexane) to highly polar (acetonitrile and methanol) as we tried to achieve maximum extraction efficiency of THCA from marijuana. Approximately 0.2g ground samples (except in the case of acetonitrile where we ran out of marijuana and only used just over 0.1g) were extracted with 40mL solvent in a precleaned VOA vial.

As seen in the bar graph, methanol was the most efficient extraction solvent for delta-9-THCA (analyzed as THC). Generally, the delta-9-THCA extraction efficiency correlated with solvent polarity, although not dramatically so. We had hoped that the non-polar solvent, hexane, would be equally efficient as the polar solvents for THCA extraction for one very important reason that can be seen in the photograph of the extracted samples, and that is, reduced extraction of chlorophyll by the non-polar solvent. Chlorophyll, a non-volatile substance providing the green color to the extracts quickly degrades GC inlet and column performance and could lead to erroneous potency determinations over time without timely GC inlet maintenance.

More later on the LC analysis of THCA from my colleague Amanda…







Hexane brings across the least chlorophyll because it is non-polar. Boils at 68-69 °C, 341.6-342.2 K, 155-156 °F

Rotary evaporation is most often and conveniently applied to separate "low boiling" solvents such a n-hexane or ethyl acetate from compounds which are solid at room temperature and pressure. However, careful application also allows removal of a solvent from a sample containing a liquid compound if there is minimal co-evaporation (azeotropic behavior), and a sufficient difference in boiling points at the chosen temperature and reduced pressure.

Solvent	Chemical formula	δD Dispersion	δP Polar	δH Hydrogen bonding
Non-polar solvents
Hexane	CH3-CH2-CH2-CH2-CH2-CH3	14.9	0.0	0.0
Benzene	C6H6	18.4	0.0	2.0
Toluene	C6H5-CH3	18.0	1.4	2.0
Diethyl ether	CH3CH2-O-CH2-CH3	14.5	2.9	4.6
Chloroform	CHCl3	17.8	3.1	5.7
1,4-Dioxane	/-CH2-CH2-O-CH2-CH2-O-\	17.5	1.8	9.0

Boiling point

68-69 °C, 341.6-342.2 K, 155-156 °F

http://www.rexresearch.com/links.htm

thanks for that I got one for you I will track down...

Lights

CFL's use few watts and are cheap to buy. I use for veg and clones. They are so very cool you can get the plan an in or two from them. I use warm and cool whites...

Cannabinoid Chemistry

rexresearch.com
Table of Contents ~ Next ~ Previous

Hemp Husbandry

Robert A. NELSON

Copyright 2000


Chapter 6

Cannabinoid Chemistry


1.   The
2.   Extraction
3.   Isomerization
4.   Acetylation
5.   Identification
6.   Neurology
7.   References

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.


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Portland Oregon Dispensories

Portland Oregon Dispensaries

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503-233-4202

The Green Haus 3706 SE Powell Blvd Portland OR 97202
(503) 232-1122

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Oregon Medical Cannabis Club 10055 NE Glisan Portalnd OR 97220
 (503 716-6042

there are many more, craigslist search OMMP,

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