EP1773801A1

EP1773801A1 - Method for obtaining pure tetrahydrocannabinol

Info

Publication number: EP1773801A1
Application number: EP04738098A
Authority: EP
Inventors: Enver Arslantas; Ulrich Weigl
Original assignee: Cilag AG
Current assignee: Cilag AG
Priority date: 2004-07-19
Filing date: 2004-07-19
Publication date: 2007-04-18
Also published as: CN1997636A; WO2006007734A1; US20080275237A1; CA2573859A1; CN1997636B; US7923558B2

Abstract

The invention relates to a method for obtaining pure tetrahydrocannabinol from reaction mixtures containing tetrahydrocannabinol compounds or from raw products containing tetrahydrocannabinol compounds. According to said method, the tetrahydrocannabinol compounds in the reaction mixture or in the raw product are converted into crystallisable derivatives, preferably using a suitable solvent, said derivatives are then crystallised and isolated, and the pure tetrahydrocannabinol compounds are then obtained from the crystallised derivatives. The invention also relates to the use of compounds produced in this way for the production of a medicament for human therapy, and to the medicaments thus produced.

Description

Process for recovering pure tetrahydrocannabinol

The present invention relates to a process for the recovery of pure tetrahydrocannabinol, in particular of pure Δ ⁸ -tetrahydrocannabinol (Δ ⁸ -THC) and pure Δ ⁹ -Tertravracannabinol (Δ ⁹ -THC), in particular stereospezi¬ fish (enantiomeric ) pure (-) Δ ⁸ -THC and stereospecific (enantiomerically) pure (-) Δ ⁹ -THC.

Δ ⁸ -tetrahydrocannabinol (Δ ⁸ -THC) and Δ ⁹ -tetrahydrocannabinol (Δ ⁹ -THC) are known compounds and can be obtained, for example, as extract from the plant Cannabis sativa L. Chemical syntheses for these compounds are also known. No. 3,560,528 describes a process for preparing Δ ⁸ -THC by reacting trans-p-mentha-2,8-dien-1-ol with 3-n-pentyl-resorcinol (olivetol) in the presence of a catalytically active compound , US Pat. No. 3,668,224 describes the preparation of Δ ⁹ -THC by attaching, for example, hydrogen chloride to the Δ ⁸ -double bond of Δ ⁸ -THC, where the chlorine atom binds in the 9-position, and then cleaves off hydrogen chloride , where Δ ⁹ -THC forms.

The preparation of Δ ⁸ -THC and Δ ⁹ -THC is generally carried out by isolating Δ ⁸ -THC and Δ ⁹ -THC from the reaction mixture with a suitable organic solvent and, if appropriate, subsequently dissolving the solution ¬ medium away. Thus, Δ ⁸ -THC or Δ ⁹ -THC is obtained as a "crude product" dissolved in a solvent or in an oily form without a solvent.These crude products containing Δ ⁸ -THC or Δ ⁹ -THC contain impurities as impurities. weighing starting materials and reaction by-products (eg, isomers), from which Δ ⁸ -THC or Δ ⁹ -THC have to be separated.

According to the known processes, the THC compounds prepared in this way as crude products are purified by means of chromatographic methods and / or distillation. Die¬ se methods are generally not suitable for the purification of THC compounds on a technical scale. The chromatographic separation requires a large amount of solvent, the subsequent removal of which is complicated. In turn, it is disadvantageous for the distillative separation that the isomeric THC compounds to be separated are very similar both in their boiling points and in their polarities, so that very high demands must be placed on the separation performance of the devices. This requires a reduced material throughput, whereby even at high separation efficiency in larger quantities "Misch¬ fractions" incurred, which significantly reduces the yield. Also, these THC compounds have comparatively high boiling points in the range of 150 ^° C. at 0.02 Torr. Therefore special technical equipment is required for a distillation. Due to the high temperatures, moreover, partial decomposition and / or isomerization of the THC compounds takes place, which is in the range of 18% by weight in the laboratory scale. For longer heating times on a larger scale, a higher decomposition / isomerization rate is thus to be expected.

It has now been found that tetrahydrocannabinol compounds, in particular Δ ⁸ -THC and Δ ⁹ -THC, are present directly in the reaction mixture or already present as "crude product", - ό -

preferably by using a suitable solvent, can be converted into crystallizable derivatives, which crystallize out in very pure form, their crystallization and purification being technically easy to carry out. From the thus crystallized compounds, the pure tetrahydrocannabinol compounds, in particular pure Δ ⁸ -THC or pure Δ ⁹ -THC, can be obtained in very high purity by conventional chemical methods and conventional extractive purification. The recovery of pure tetrahydrocannabinol compounds, such as pure Δ ⁸ -THC or Δ ⁹ -THC, is substantially simplified in this way and complicated chromatographic or distillative separation is not necessary. It is also advantageous that the process according to the invention can be used for all corresponding crude products, independently of the particular synthesis used.

The present invention relates to a process for the extraction of pure tetrahydrocannabinol from tetrahydrocannabinol compound-containing reaction mixtures or from Tetrahydrocannabinol compounds containing crude product, characterized in that the tetrahydro rannan benzin compound in the reaction mixture or in Roh¬ product, preferably below Use of a suitable solvent, converted into a crystallizable derivatives, this crystallized and isolated, and then the pure tetrahydrocannabinol compound from the crystallized derivative wins.

The pure tetrahydrocannabinol compound is obtained as a colorless oil which, when cooled, forms a glass. stares. Further purification steps, eg a distillation or preparative HPLC, are not required.

Preferably, the tetrahydrocannabinol compound Δ ^{8 represents} -THC or Δ ⁹ -THC. In this sense, the vorlie¬ invention preferably relates to a method for obtaining pure Δ ⁸ -THC or Δ ⁹ -THC from Δ ⁸ -THC and / or Δ ⁹ -THC containing reaction mixture or crude product by the Δ ⁸ - contained therein THC or Δ ⁹ -THC converts into a crystallizable derivatives, this crystallized and isolated, and then the pure Δ ⁸ -THC or the pure Δ ⁹ -THC, wins from the crystallized derivative. Preference is given to obtaining stereospecific (enantiomerically) pure Δ ⁸ -THC and stereospecific (enantiomerically) pure Δ ⁹ -THC.

The present invention also relates to the pure tetrahydrocannabinol compounds prepared in this way, in particular the pure compounds Δ ⁸ -THC and Δ ⁹ -THC prepared according to the invention.

The present invention also relates to the crystallizable derivatives of the tetrahydrocannabinol compounds used as intermediate product and to the crystallized derivatives of the tetrahydrocanna-binol compounds used as intermediates, in particular those of Δ ⁸ -THC and Δ ⁹ -THC.

The present invention further relates to the use of the compounds prepared according to the invention for the production of a medicament for human therapy and the medicaments prepared in this way. The term "tetrahydrocannabinol compounds" means compounds of the following formulas (I) and (IA):

Δ ⁸ -THC compounds (I) Δ ⁹ -THC compounds (IA)

wherein R ₁ hydrogen, chlorine, (Ci_i ₀ ) alkyl, preferably nC ₅ Hn.

Preference is given to compounds of the formulas (I ') and (I'A):

Δ ⁸ -THC compounds (I 'Δ -THC compounds (I'A)

wherein Ri has the meanings given above.

The synthesis of crystallizable derivatives of tetrahydrocannabinol compounds is described below using the example of Δ ⁸ -THC and Δ ⁹ -THC. The description, however, analogously includes other known tetrahydrocannabinol compounds.

Crystallizable derivatives of tetrahydrocannabinol compounds which are prepared in virtually quantitative yield. and can be crystallized from solutions are, for example, the 2-naphthoyl ester of Δ ⁸ -THC of the formula (II) and the 2-naphthoyl ester of Δ ⁹ -THC, the formula (IIA):

Δ -THC:

(II)

Δ -THC:

(IIA)

In this case, the naphthoyl radical may be substituted, for example by nitro, bromo or methyl groups, preferably in position 5 or 8. Optionally, the corresponding substituted 1-naphthoyl compounds may also be present. Correspondingly, the amide-bound naphthyl radicals and also polycyclic carboxylic acid derivatives, for example derivatives of 9-anthracenecarboxylic acid or 9-phenanthrenecarboxylic acid, optionally substituted analogously to the naphthoyl derivatives, are crystallizable. Also suitable for carrying out the process according to the invention are esters and amide compounds of Δ ⁸ -THC and Δ ⁹ -THC which contain a salt-capable group in the ester or amide substituent, for example a carboxyl group or an amine moiety.

The crystallizable tetrahydrocannabinol compounds which can be used in the process according to the invention are encompassed by the following formulas (III) and (IIIA):

Δ ⁸ -compound (III) Δ ⁹ -compound (IIIA)

wherein Ri is hydrogen, chloro, (Ci-io) -alkyl, preferably nC ₅ Hii;

X is -O- or -NH-, preferably -O- (oxygen); and R _{2 is} an optionally substituted aliphatic or aromatic radical which optionally carries a substituent capable of forming a salt; or a heterocyclic radical which may itself be capable of salt formation and / or optionally bears a substituent capable of salt formation; or a residue of an aliphatic or aromatic polybasic acid, preferably a dibasic acid, which does not correspond to the

THC derivative-bonded acid group preferably forms a salt-capable radical or is connected to such or the compound is a salt. Preference is given to compounds of the formulas (III ') and (III'A):

Δ-compound (III ') Δ-compound (III'A)

wherein the substituents have the meanings given above.

Ri as (Ci-io) -alkyl, is preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, preferably nC ₅ Hu.

R ₂ as alifatic radical, which preferably carries a salt-capable radical, preferably denotes optionally substituted corresponding methyl, ethyl, propyl, butyl, benzyl, aminobenzyl, cyclopentyl or cyclohexyl.

R ₂ as an aromatic radical which optionally carries a substituent capable of salt formation preferably denotes phenyl optionally substituted by nitro, halogen, methyl or sulfonyl or naphthyl optionally substituted by nitro, halogen, methyl or sulfonyl, preferably unsubstituted naphthyl. R _{2 is} a heterocyclic radical which is optionally itself capable of salt formation and / or optionally carries a substituent capable of salt formation, is, for example, 2-pyridyl, 3-pyridyl, 4-pyridyl, the corresponding picoline, Pyrazine, pyrazole, pyrrole or indole derivatives, preferably substituents derived from pyridinecarboxylic acid or pyridinedicarboxylic acid.

R ₂ as the radical of an aliphatic polybasic acid, preferably a dibasic saturated or unsaturated acid, preferably denotes a radical of an acid of the formula -O (O) C- (CH ₂ ) _n -C (O) OH, or 0 (O) C-CH = CH-C (O) OH, for example the radical of oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, malic acid and analogous acids, where the acid group not attached to the THC derivative is optionally forms with a salt-capable radical or is connected to such. For example, R ₂ may also be asparagine [-O (O) C-CH (NH ₂ ) -CH ₂ CONH ₂ ] or aspartic acid [-O (O) C-CH (NH ₂ ) CH ₂ -C (O) OH] ,

R ₂ as the radical of an aromatic di- or polycarboxylic acid, preferably denotes the radical of phthalic acid or terephthalic acid, wherein the acid group not bonded to the THC derivative is optionally bonded to a salt capable of forming a salt.

For example, the acid group not attached to the THC derivative can be linked to a diamine by means of an amide bond. In this way, salt formation can take place with the salt capable of forming a salt or with the diamine residue and, for example, the corresponding hydro- chloride or hydrobromide, nitrate, oxalate or salts with methylsulfonic acid, toluenesulfonic acid or benzenesulfonic acid.

Thus, for example, the following Δ ⁹ -THC derivative, as base or as salt, can be prepared and crystallized in pure form, the pure Δ ⁹ -THC subsequently being able to be recovered from the derivative with per se known hydrolysis.

In this sense, the following derivatives of tetrahydrocannabinol compounds, preferably of Δ ⁸ -THC and Δ ⁹ -THC, are preferred: esters with 1-naphthoic acid, 2-naphthoic acid, with 1-naphthylacetic acid or with 2-Naphthylessig- acid, wherein the naphthalene radical is optionally substu¬ tuiert. Such substituents are preferably bromine, nitro, methyl, preferably in the 5- or 8-position.

Preference is also given to ester derivatives of tetrahydrocannabinol compounds, preferably of Δ ⁸ -THC and Δ ⁹ -THC, with polycyclic carboxylic acids, such as 9-anthracenecarboxylic acid or 9-phenanthrenecarboxylic acid, whose anthracene radical or phenanthrene radical is optionally substituted. par- Preferred are ester derivatives with 1-naphthoic acid or 2-Naphthoesäureester, especially 2-Naphthoesäureester.

Also preferred are salts of ester derivatives of tetrahydrocannabinol compounds, preferably of Δ ⁸ -THC and Δ ⁹ -THC, with dicarboxylic acids such as phthalic acid, terephthalic acid or oxalic acid with a suitable counterion as cation, this cation preferably an alkali or Alkaline earth ion, preferably Na ⁺ , K ⁺ , Ca ⁺² or Mg ⁺² or ammonium or a primary secondary or tertiary ammonium ion. Suitable ammonium ions are, for example, the cations of the following amines: dibenzylamine, tert-butylamine, choline, trishydroxymethylamine, ethylenediamine.

Salts of ester derivatives of tetrahydrocannabinol compounds, preferably of Δ ⁸ -THC and Δ ⁹ -THC, with dicarboxylic acids, such as phthalic acid, terephthalic acid or oxalic acid, which are attached to the free carboxyl group (not bonded to the THC derivative) are also preferred with a diamine, preferably with piperazine or N-methypiperazine, are linked via an amide bond, and the salt vor¬ preferably as hydrochloride, hydrobromide, nitrate, oxalate, tosylate, mesylate, or besylate present. Preferably, the corresponding N-methylpiperazine derivative of phthalic acid is hydrochloride.

For the preparation of the tetrahydrocannabinol compounds, e.g. so before adding olivetol with menthadienol [(+) - p-mentha-2, 8-dien-l-ol] in the presence of an acidic

Catalyst, preferably p-toluenesulfonic acid or BF ₃ Et ₂ O at elevated temperature, preferably higher than 50 ⁰ C. (> 50 ° C), preferably higher than 80 ⁰ C (> 80 ° C), in a non-reactive organic solvent, for example in toluene, to Δ ⁸ -THC reacted (or Δ ⁹ -THC at BF ₃ -Et ₂ O. ). After washing the reaction mixture with aqueous buffer solution and concentrating the toluene phase, crude Δ ⁸ -THC (or Δ ⁹ -THC in BF ₃ Et ₂ O) with 50-55% purity is obtained. The protection of any reactive groups is not required (Literature: Petrzilka, Helvetica Chimica Acta 1969, 52, 1102; Radzan, J. Am. Chem. Soc., 1974, 96, 5860, cited above).

For the preparation of the derivative, for example the Δ ⁸ -THC naphthoyl ester, the crude Δ ⁸ -THC is dissolved in a water-immiscible aprotic solvent and treated with a desired naphthoic acid chloride using a base, preferably a tertiary amine, at 0-100 ⁰ C, preferably 20-25 ⁰ C reacted to the ester. The reaction mixture is washed with aqueous buffer solution. By adding methanol or another suitable alcohol, the Δ ⁸ -THC naphthoyl ester is precipitated from the solvent. The crude Δ ⁸ -THC naphthoyl ester can be recrystallized from a variety of organic solvents (e.g., acetonitrile).

For the recovery of Δ ⁸ -THC from the Δ ⁸ -THC-naphthoyl ester is the latter at 0-100 ⁰ C, preferably at room temperature, in a mixture of water-miscible solvents (eg, THF and / or alcohols and / or acetone ) and water with a soluble in this solvent mixture strong base (eg sodium hydroxide or diethylamine), preferably hydroxydases, saponified. To neutralizing with acid, the organic solvent is distilled off from the reaction mixture, and the aqueous-oily residue is extracted with a non-water-miscible solvent (eg, a hydrocarbon). After evaporation of the organic phase, the Δ ⁸ -THC is obtained.

For the preparation of crude Δ ⁹ -THC, Δ ⁸ -THC is preferably dissolved in a water-immiscible solvent, for example ethyl acetate. By introducing HCl gas, the reaction mixture is saturated with HCl. For this, a Lewis acid, eg zinc chloride, and stirred the mixture at 0-50 ⁰ C Reaktionsge¬. Then the reaction mixture is washed first with water and then with aqueous buffer solution. The organic phase is evaporated and the residue is dissolved in a water-immiscible solvent, for example in toluene. For this purpose, an excess of a solution of an alkoxide in the appropriate solvent, for example in toluene, is added and the reaction mixture is heated until the elimination of

HCl is complete. The reaction mixture is buffered and worked up with water. After evaporation of the organic phase, the crude Δ ⁹ -THC is obtained (literature: Petrzilka, Helvetica Chimica Acta 1969, 52, 1102).

For the preparation of crude Δ ⁹ -THC-Naphthoylester the crude Δ ⁹ -THC is dissolved in a nonpolar aprotic organic solvent and esterified in the presence of amine bases with the corresponding Naphthoylsäurechlorid derivatives at 0-100 ⁰ C, preferably at room temperature. After complete conversion, the resulting precipitate filtered off and the filtrate washed with buffer solution. The organic phase is evaporated and the residue in a suitable solvent with heating, for example in

Acetonitrile, dissolved. Upon cooling, the Δ ⁹ -THC naphthoyl ester crystallizes and is filtered off.

For the enrichment of Δ ⁹ -THC naphthoyl ester, the crude Δ ⁹ -THC naphthoyl ester (containing <5% Δ ⁸ -THC naphthoyl ester) is dissolved in a suitable organic solvent, for example THF. The enriched Δ ⁹ -THC naphthoyl ester (reduction of the Δ ⁸ -THC naphthoyl ester by 25-90%, as a rule by about 50%) is precipitated by addition of a suitable alcohol.

To recover Δ ⁹ -THC from the Δ ⁹ -THC-naphthoyl ester, the latter is dissolved in a suitable solvent, for example THF, and at least in one equivalent of water, with a strong base soluble in it, for example a diamine and at 0-100 ⁰ C, preferably stirred at room temperature until the ester cleavage is complete. Then, a little water is added and the Δ ⁹ -THC extracted with a unpo¬ laren organic solvent, optionally after vor¬ usual distilling off the einge¬ for the ester cleavage set solvent. The organic phase is evaporated and dried under high vacuum.

The preparation of the THC compounds is known per se from the literature. The ester formation can be carried out by analogous process conditions known per se for the reaction of an alcohol with an acid chloride or, if appropriate, another activated acid derivative (anhydride). chloride, bromide) with base addition. The choice of base is largely arbitrary and known from analogous methods. Suitable solvents are all aprotic solvents. Temperatures in the range of the melting to boiling points of the solvents are prin ciple possible (to at least 100 ⁰ C).

The THC esters can be crystallized / recrystallized in suitable solvents or combinations of solvent / anti-solvent. The solvents are substance-dependent. In principle, aprotic solvents, preferably polar aprotic solvents (for example THF, acetonitrile, acetone) are suitable as solvents.

As anti-solvents are particularly suitable

Alcohols, e.g. polar alcohols, such as methanol or ethanol or higher (nonpolar and polar) alcohols, and optionally (if miscible with the solvent) also water.

To dissolve the compounds, higher temperatures are preferred, for example the boiling point of the solvent. Are preferred for crystallization temperatures below 30 ⁰ C (<30 ° C). Isomers can be enriched by crystallization and recrystallization.

The ester cleavage takes place according to the known method of converting an ester and water with a strong base (pH> 10, preferably at pH> 12). Suitable bases are inorganic bases (if soluble in the solvent chosen) or amines. Due to the required pH, stronger amines such as diamines are preferred. When - Ib -

Solvents are all solvents into consideration, in which ester, base and at least small amounts of water dissolve and which are inert in the chosen system. Preference is given to water-miscible solvents, such as alcohols, THF or acetonitrile, or poorly water-miscible solvents having a certain residual polarity (for example ether, dichloromethane, toluene). Temperatures in the range from the melting point to the boiling point of the Lösungs¬ means are in principle possible (to at least 100 ⁰ C).

The THC compounds are purified by picking them up in a water-immiscible solvent (either directly from the ester cleavage, or, if the solvent used there is water-soluble, by concentration of the mixture, if appropriate after neutralization, and addition a water-immiscible Lösungs¬ means) optionally with the addition of water. Then the impurities (base for ester cleavage, acid for neutralization, naphthoic acid anion) are extracted into the aqueous phase. For the purification, a hydrocarbon is preferred as the solvent, since thereby the separation of the impurities is more effective. The organic phase is then concentrated and dried in vacuo from the extraction solvent.

The above information applies to the synthesis of THC esters of simple acids. In the synthesis of THC esters with diacids or their derivatives, a counterion for the precipitation still has to be added, the conditions being uncritical and known from analogous reactions, and the solvents being optionally adjusted, as mentioned above in the text. It can Alcohols from non-solvents to solvents.

According to the invention, not all of the crude products have to be isolated as described above. Some of the process steps can be carried out as "one-pot" stages (depending on the ester derivative and on the solvent). Thus, for example, the distillation of the solvent after the ester cleavage is omitted if a water-immiscible solvent is used for this. The mother liquors can be recycled, for example by a renewed sequence of addition of HCl and elimination as described above.

The following examples illustrate the invention.

Example 1 [Preparation of (-) - Δ ⁸ -6a, 10a-trans-tetra-hydrocannabinol (2-naphthoyl) ester (Δ ⁸ -2 -naphth.)]

A) Preparation of Δ ⁸ -THC:

To a stirred mixture of 26.5 g (0.140 mol) of olivetol and 4.0 g (0.02 mol) of p-toluenesulfonic monohydrate in 650 g of toluene at 85 ⁰ C internal temperature 24.2 g (0.154 mol) of trans -p-mentha (2, 8) -dien-1-ol added dropwise. After a total of 2.5 hours, the mixture is allowed to cool to room temperature, the reaction mixture is washed with 300 ml of semisaturated NaHCO ₃ solution, then with 150 ml of water and with 150 ml of saturated sodium chloride solution. The organic phase is dried over MgSO ₄ and concentrated under reduced pressure. This gives a brownish oil (49.8 g), which consists of 52% Δ ⁸ -THC by gas chromatography. B) Preparation of crystalline Δ ⁸ -2-naphtha. 22.8 g of the crude product prepared under section A) (0.038 mol of Δ ⁸ -THC) are dissolved in 300 ml of ethyl acetate and stirred with 19.2 g (0.10 mol) of 2-naphthoyl chloride and 16 ml (0.12 mol) of triethylamine. After two hours of stirring at room temperature (RT) are added to 300 ml of water and the separated organic phase is washed with 400 ml of dilute NaHCO ₃ solution and finally with 200 ml of water. The organic phase is concentrated to one third of its volume and mixed with 200 ml of methanol with stirring. It immediately starts a crystallization. After stirring at RT for 16 hours, the precipitate is filtered off with suction and subsequently slurried with methanol. After filtration, (-) - Δ ⁸ -6a, 10a-trans-tetrahydrocannabinol (2-naphthoyl) ester (15.1 g, 32.2 mmol, 43% based on olivetol) is obtained as a colorless crystal powder.

Example 2 [Preparation of (-) - Δ ⁸ -6a, 10a-trans-tetrahydrocannabinol (Δ ⁸ -THC)]

To 15.43 g (33 mmol) of (-) - Δ ⁸ -6a, 10a-tris-J-tetrahydrocannabinol (2-naphthoyl) ester prepared in Example 1 in 150 ml of THF and 25 ml of methanol are added under argon 22 ml of a 2N aqueous NaOH solution added. After a few hours of vigorous stirring, another 25 ml of 1 N NaOH are added. After a total of 24 hours, 2.0 g (33 mmol) of glacial acetic acid are added to work-up and the reaction mixture is concentrated. The aqueous residue is taken up in 140 ml of water and extracted with 100 ml and 50 ml of MTBE (methyl tert-butyl ether), the organic phase is extracted 4-5 times with half-saturated NaHCO ₃ solution (100 ml each) and finally with Washed saturated NaCl solution. Drying over MgSO ₄ and evaporating the solvent gives about 10.7 g of amber oil (GC:> 95% Δ ⁸ -THC).

Example 3 [Preparation of (-) - Δ ⁹ -6a, 10a-trans-tetrahydrocannabinol (Δ ⁹ -THC)]:

A) Preparation of (-) - 9-chloro-6a, 10a-trans-hexahydro-cannabinol (THC-HCl):

10.7 g of the (-) -Δ ⁸ -6a, 10a-fcrane-tetrahydrocannabinol prepared in Example 2 are mixed with 2.90 g of zinc chloride and 95 g of cold 30% HCl in ethyl acetate and warmed to RT with vigorous stirring. After 36 hours, 100 ml of ethyl acetate and 200 ml of ice water are added, and the organic phase is washed with 200 ml of water and 7 ml of saturated sodium bicarbonate solution and 100 ml of water and saturated NaCl solution. Drying (Na ₂ SO ₄ ) and condensing with 3 times 15 mL MTBE (methyl tert-butyl ether) gives THC-HCl (12.42 g) as a dark oil.

B) Preparation of (-) - Δ ⁹ -6a, 10a-trans-tetrahydrocannabinol (Δ ⁸ -THC): 5.74 g of the product prepared in section A) (-) - 9-chloro-6a, 10a Trans-hexahydrocannabinol (THC-HCl) in 50 ml of MTBE (methyl tert-butyl ether) under argon and at RT to 25 ml of a 1.7 N K-tert. Pentylate solution (in toluene) in 30 ml of MTBE. After a total of one hour is heated to reflux for 20-25 minutes, then cooled, treated with 100 ml of MTBE and with 100 ml of saturated sodium bicarbonate solution and 2 ml of glacial acetic acid shaken. The organic phase is washed with 100 ml of saturated NaCl solution, dried over Na ₂ SO ₄ and concentrated. There are obtained 4.85 g of an amber-colored oil having the following composition [gas chromatographic analysis (GC)]: Δ ⁹ -THC: 87.6%, A ⁸ THC: 4.7%, iso-THC: 5.4%

Example 4 Preparation of (-) - Δ ⁹ -6a, 10a-trans-tetra-hydrocannabinol- (2-naphthoyl) ester (Δ ⁹ -2-naphtha)]:

To 5.90 g of the prepared in Example 3 Δ ⁹ -THC (86% / 16.1 mmol) and 3, 0 ml of triethylamine (22 mmol) in 50 ml of ethyl acetate under argon 3.95 g (21 mmol) 2 Added dropwise naphthoyl chloride in 30 ml of ethyl acetate. After stirring for 8 hours at RT, it is washed with 50 ml of water, with 50 ml of semisaturated NaHCO ₃ solution and with 50 ml of water.

The organic phase is concentrated and the residue is crystallized from 20 ml of acetone and 40 ml of methanol. 5.66 g of colorless crystals are formed which are recrystallised from acetone and methanol to give 4.47 g (9.5 mmol, 59%) of (-) - Δ ⁹ -6a, 10a-trans-tetrahydrocannabinol- (2-Naphtho¬ yl) ester is obtained as a white crystalline powder.

Example 5 [Preparation of (-) - Δ ⁹ -6a, 10a-trans-tetrahydrocannabinol (Δ ⁹ -THC)]:

0.50 g (1.07 mmol) of the (-) - Δ ⁹ - 6a, 10a-trans-tetrahydrocannabinol (2-naphthoyl) ester prepared in Example 4 are dissolved in 5 ml of THF and 0.7 ml of MeOH, and 0, 7 ml of 2N NaOH are added under argon. After stirring for 2 hours, another 0.7 ml of 1N NaOH are added. After a total of 9 hours, 20 ml of MTBE and 20 ml of semi-saturated NaHCO ₃ solution and 0.18 ml of glacial acetic acid are added. The organic phase is washed 4-5 times with NaHCO 3 solution and once with saturated NaCl solution, dried over Na ₂ SO _{4 and} dried by evaporation. 0.305 g (0.97 mmol) of (-) - Δ ⁹ - 6a, 10a-trans-tetrahydrocannabinol are obtained as a yellowish oil; GC: Δ ⁹ -THC> 99%, Δ ⁸ -THC <1.0%.

SUBSTITUTE SHEET

Claims

claims

1. Process for obtaining pure tetrahydrocannabinol from reaction mixtures containing tetrahydrocannabinol compounds or crude product comprising tetrahydrocannabinol compounds, which comprises reacting the tetrahydrocannabinol compound in the reaction mixture or in the crude product, preferably using a suitable solvent, converted into a crystallizable derivative, this crystallized and isolated, and then the pure tetrahydrocannabinol compound from the crystallized derivative wins.

2. The method according to claim 1, characterized in that pure Δ ⁸ -THC or Δ ⁹ -THC from Δ ⁸ -THC and / or Δ ⁹ - containing THC reaction mixture or crude product, ge wins, preferably stereospecific (enantiomer) pure Δ ⁸ -THC and stereospecific (enantiomerically) pure Δ ⁹ -THC.

3. The method according to any one of claims 1 or 2, characterized in that one produces compounds of the following formulas (I) and (IA):

Δ ⁸ -THC compounds (I) Δ ⁹ -THC compounds (IA)

wherein Ri is hydrogen, chlorine, (Ci_io) alkyl, preferably nC ₅ Hu.

SUBSTITUTE SHEET

4. The method according to claim 3, characterized in that compounds of the formulas (I ') and (I'A):

Δ ⁸ -THC compounds (I ') Δ ⁹ -THC compounds (I'A)

in which Ri has the meanings according to claim 3.

5. Process according to one of claims 1-4, characterized in that the tetrahydrocannabinol compound in the reaction mixture or in the crude product is converted into a crystallizable derivative of the formula (III) and (IIIA):

Δ ⁸ -compound (III) Δ ⁹ -compound (IIIA)

converts into what

Ri is hydrogen, chloro, (Ci-io) -alkyl, preferably n-CsHn; X is -O- or -NH-, preferably -O- (oxygen); and

R _{2 is} an optionally substituted aliphatic or aromatic radical which optionally carries a substituent capable of salt formation; or a heterocyclic radical which may itself be capable of salt formation and / or optionally bears a substituent capable of salt formation; or a remainder of an ali-

SUBSTITUTE SHEET fatty or aromatic polybasic acid, preferably a dibasic acid, wherein the non-attached to the THC derivative acid group preferably forms a salt-capable radical capable of or is connected to such or the compound is a salt.

6. The method according to claim 5, characterized in that the tetrahydrocannabinol compound in Reaktions¬ or in the crude product in a crystallizable derivative of the formula (III ') and (III'A):

Δ ⁸ -compound (III ') Δ-compound (III'A)

in which the substituents have the meanings given in claim 5.

7. The method according to any one of claims 3-6, characterized ge denotes that Ri is (Ci-io) alkyl, preferably methyl, ethyl, propyl, butyl, pentyl, hexyl, n-CsHn, preferably nC ₅ Hn means.

8. The method according to any one of claims 5-7, characterized ge indicates that R2 has the following meanings: - R _{2 represents} a aliphatic radical which preferably carries a salt capable of capable radical, preferably optionally substituted

SUBSTITUTE SHEET Methyl, ethyl, propyl, butyl, benzyl, aminobenzyl, cyclopentyl or cyclohexyl; or

R _{2 represents} an aromatic radical which optionally bears a substituent capable of salt formation, preferably phenyl optionally substituted by nitro, halogen, methyl or sulfonyl, or naphthyl optionally substituted by nitro, halogen, methyl or sulfonyl, preferably unsubstituted naphthyl.

9. The method according to any one of claims 5-7, characterized ge denotes that R _{2 has} the following meanings:

R _{2 represents} a heterocyclic radical which may itself be capable of salt formation and / or optionally carries a substituent capable of salt formation, preferably 2-pyridyl, 3-pyridyl, 4-pyridyl, the corresponding picoline , Pyrazine, pyrazole, pyrrole or indole derivatives, preferably substituents derived from pyridinecarboxylic acid or pyridinedicarboxylic acid.

10. The method according to any one of claims 5-7, characterized ge denotes that R _{2 has} the following meanings:

R ₂ is an aliphatic polybasic acid, preferably a dibasic saturated or unsaturated acid, preferably a radical of an acid of the formula -O (O) C- (CH ₂ ) _n -C (O) OH, or -O (O) C-CH = CH- C (O) OH, preferably the radical of oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, tartaric acid, malic acid and analogous acids, wherein the acid group not bound to the THC derivative optionally with one for salt formation enabled

SUBSTITUTE SHEET Rest or is associated with such or asparagine or aspartic acid; or R.2 is an aromatic di- or polycarboxylic acid, preferably the radical of phthalic acid or terephthalic acid, wherein the acid group not bonded to the THC derivative is optionally linked to a salt capable of forming a salt.

11. The method according to claim 10, characterized in that the not bound to the THC derivative acid group is linked ver¬ with a diamine by means of an amide bond and the diamine residue forms a salt, preferably a hydrochloride, hydrobromide, nitrate, oxalate or a Salt with methylsulfonic acid, toluenesulfonic acid or benzenesulfonic acid.

12. Crystallisable compounds of the formulas (III) and (IIIA) according to claim 5 and the crystallizable Ver¬ compounds of formulas (III ') and (III'A) according to claim 6, wherein Ri has one of the meanings of claim 5 or 7; and R _{2 have} one of the meanings of any one of claims 5 and 8-11, as well as pharmaceutically acceptable salts of these compounds.

13. Crystallizable compounds of the formulas (III ') and (III'A) according to claim 6, wherein Ri n-CsHn; X is oxygen and R _{2 is} optionally substituted naphthyl, preferably naphthyl.

SUBSTITUTE SHEET

14. Crystallizable compounds according to claim 12, as base and in salt form, of the formula:

15. Crystallizable Δ ⁸ -THC and Δ ⁹ -THC compounds according to claim 12, which are the following compounds: esters with 1-naphthoic acid, 2-naphthoic acid, 1-naphthyl-acetic acid or 2-naphthylacetic acid, wherein the

Naphthalene optionally substituted with bromine, nitro, methyl, preferably in the 5- or 8-position.

16. Crystallizable Δ ⁸ -THC and Δ ⁹ -THC compounds according to claim 12, which represent the following compounds:

Ester derivatives of Δ ⁸ -THC and Δ ⁹ -THC with polycyclic carboxylic acids, preferably with 9-anthracenecarboxylic acid or 9-phenanthrencarboxylic acid whose anthracene radical or phenanthrene radical is optionally substituted, preferably ester derivatives with 1-naphthoic acid or 2-naphthoic acid ester, in particular with 2-naphthoic acid ester.

17. Crystallizable Δ ⁸ -THC and Δ ⁹ -THC compounds according to claim 12, which are the following compounds: salts of ester derivatives of Δ ⁸ -THC and Δ ⁹ -THC compounds, preferably with dicarboxylic acids, preferably with phthalic acid, Terephthalic acid or oxalic acid, with a suitable counterion as cation, this cation

SUBSTITUTE SHEET preferably an alkali or alkaline earth ion, preferably Na ⁺ , K ⁺ , Ca ^{+ 2} or Mg ^{+ 2} or ammonium or a primary secondary or tertiary ammonium ion; preferably a cation of dibenzylamine, tert-butylamine, choline, tris-hydroxymethylamine or ethylenediamine.

18. Crystallizable Δ ⁸ -THC and Δ ⁹ -THC compounds according to claim 12, which are the following compounds: salts of ester derivatives of Δ ⁸ -THC and Δ ⁹ -THC, with dicarboxylic acids, preferably phthalic acid, terephthalic acid or oxalic acid, which are linked to the free, not to the THC derivative, bound carboxyl group with a diamine, preferably with piperazine or N-methypiperazine, via an amide bond, and the salt preferably as hydrochloride, hydrobromide, nitrate, oxalate, tosylate, mesyl lat, or besylate, is present, preferably as the N-methylpiperazine derivative of phthalic acid as the hydrochloride.

19. The pure crystallisable and the crystallized tetrahydrocannabinol compounds, preferably the pure Δ ⁸ -THC and Δ ⁹ -THC compounds, prepared according to any one of claims 1-11.

20. Use of the compounds according to any one of claims 1-4 for the preparation of a medicament for human therapy.

21. The medicaments prepared according to claim 20.

SUBSTITUTE SHEET