AU2008200935B2

AU2008200935B2 - Method for the Production of Dronabinol

Info

Publication number: AU2008200935B2
Application number: AU2008200935A
Authority: AU
Inventors: Christian Steup
Original assignee: THC PHARM HEALTH CONCEPT GmbH
Current assignee: THC PHARM HEALTH CONCEPT GmbH
Priority date: 2001-02-05
Filing date: 2008-02-28
Publication date: 2010-02-04
Anticipated expiration: 2022-02-05
Also published as: AU2008200935A1

Description

P/00/011 28/5/91 Regulation 3.2 AUSTRALIA Patents Act 1990 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Name of Applicant: Steup, Christian Actual Inventor Steup, Christian Address for service is: WRAY & ASSOCIATES Level 4, The Quadrant 1 William Street Perth, WA 6000 Attorney code: WR Invention Title: Method for the Production of Dronabinol The following statement is a full description of this invention, including the best method of performing it known to me: 1 PROCESS FOR THE PRODUCTION OF DRONABINOL The object of the invention is a process for the production of dronabinol from fibrous 5 hemp. Dronabinol is a cannabinoid with the chemical description (6aR-trans)- 6a,7,8,10a tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1 -ol. Dronabinol (= A 9 tetrahydrocannabinol) is a natural constituent of various cannabis plants, from which 10 it can be obtained by extraction. Dronabinol can also be chemically synthesised and is a pale-yellow, resinous oil, which is sticky at room temperature and hardens in cool storage. It is insoluble in water, but can be dissolved in oils such as sesame oil. US patent 4 025 516 already discloses a process for the production of Ag 15 tetrahydrocannabinol by condensation of the (+)-p-mentha-2,8-dien-1-ol with olivetol in the presence of BF 3 etherate. US Patent 5 342 971 also describes synthesis of dronabinol from cannabidiol acid esters in the presence of Lewis acids and subsequent hydrolysis. In addition, synthesis of dronabinol from hydroxy-cannabidiol with Lewis acids is also already known in US Patent 5 227 537. The production of 20 dronabinol from tetrahydrocarbinol-rich cannabis with subsequent distillation and/or chromatography is described in international patent application WO 00/25127. The abovementioned synthetic processes were developed because isolation of A 9 tetrahydrocannabinol from cannabis indica is legally prohibited, e.g. by the conditions 25 of German narcotics legislation. Since synthetic processes are very expensive, dronabinol on the other hand is gaining increasing medicinal importance, due to its immunosuppressive and cytostatic properties, but especially for alleviating the side effects occurring in cancer therapy, and the problem arose of creating a simple process for producing dronabinol from plant materials, which would comply with legal 30 requirements. Obtaining A 9 -tetrahydrocannabinol from fibrous hemp (cannabis sativa) is considered permissible. The object of the invention is therefore a process for the production of dronabinol, wherein 35 2 a) cannabidiol or cannabidiol acid is isolated from fibrous hemp, b) the cannabidiol optionally obtained by decarboxylation is cyclised in the presence of Lewis acids in a non-polar solvent to give dronabinol, C) this is isolated by a chromatographic process and d) the residue obtained from the eluant after distilling off the solvent is purified by vacuum distillation. In one embodiment of the invention, there is provide a process for the synthesis of dronabinol, wherein (a) cannabidiol and/or cannabidiol acid is used as the starting materials for the synthesis of dronabinol; (b) the cannabidiol acid is converted to cannabidiol by decarboxylation; (c) the cannabidiol is cyclised by means of Lewis catalysts to generate raw dronabinol. Preferably, fibrous hemp is provided as the source of the starting material. Preferably, the raw dronabinol is purified by a chromatographic process. Preferably, the raw dronabinol is dissolved in a solvent and then subjected to a chromatographic process and wherein the solvent in an eluant generated by the chromatographic process is distilled off to produce a residue which is then cleaned by vacuum distillation. In another embodiment of the invention, there is provided a process for the production of dronabinol, wherein: (a) cannabidiol or cannabidiol acid is isolated from fibrous hemp; (b) the cannabidiol acid is converted to cannabidiol by decarboxylation; (c) cannabidiol is cyclised in the presence of Lewis catalysts in a non-polar solvent to generate dronabinol; (d) the raw dronabinol is dissolved in a solvent and then isolated by a chromatographic process; and 3A (e) wherein the solvent in an eluant generated by the chromatographic process is distilled off to produce a residue which is then cleaned by vacuum distillation. Preferably, the anhydrous salts of silver, tin, zinc or magnesium, e.g. zinc chloride, zinc bromide, zinc iodide, zinc trifluormethansulfonate, tin chloride, tin bromide, tin iodide, tin trifluormethansulfonate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluormethansulfonate, silver chloride, silver bromide, silver iodide, silver trifluormethansulfonate, are used as the Lewis catalysts. Preferably, the cannabidiol or cannabidiol acid are extracted from the flowers or leaves of the fibrous hemp. Preferably, the starting materials are extracted with a non-polar solvent from the sifted constituents of the fibrous hemp. Preferably, the starting materials are concentrated in a solvent by extraction of the starting materials from fresh plant material with a solvent which already contains starting material, without distilling off the solvent. Preferably, the starting materials are purified by: (a) treating an extract comprising the starting materials with aqueous lye, from which the free carbonic acids are precipitated following acidification; and/or (b) distilling off the solvent used to extract the starting materials to leave a residue and dissolving the residue in a polar, organic solvent, whereby unwanted iipophilic constituents are precipitated and filtered out, and the starting materials contained in the filtrate are isolated by evaporation; and (c) decarboxylating the starting materials purified by (a) or (b) by heating the materials then distilling them in a vacuum to generate crystallised cannabinoid. Preferably, the cannabidiol is cyclised to give dronabinol by addition of BF 3 etherate, optionally in the presence of an alkaline drying agent in an organic 3B solvent. Preferably, the alkaline drying agent is potassium carbonate. Preferably, the cannabidiol is cyclised by addition of weak Lewis acids in an organic solvent to give dronabinol. Preferably, the solution containing dronabinol is dissolved in a solvent and then chromatographed on a silicagel column. Preferably, the solvent in an eluant generated by the chromatographic process is distilled off to produce a residue which is then cleaned by vacuum distillation. Preferably, the vacuum distillation is high-vacuum distillation. In another embodiment of the present invention, there is provide an inhalation solution for thermal atomisation with hot air, wherein the inhalation solution contains dronabinol obtained by a process according to the process substantially as mentioned above. In yet another embodiment of the present invention, there is provided a pharmaceutical containing dronabinol, wherein the dronabinol is produced as claims in a process substantially as mentioned above. In order to produce dronabinol according to the present invention the blossoms or also the leaves of fibrous hemp derived from certified seed are advantageously separated out from other plant material and sifted after drying. But it is also possible to use the plant material freed and cut from the stalks without preliminary sifting for extraction of active ingredients. Because cannabidiol acid and cannabidiol are concentrated especially in the resinous glands found on the leaf or blossom surface, and these glands can be separated mechanically by sifting from the remaining plant material, this method is successful in obtaining a material containing cannabidiol acid and cannabidiol which are required as starting materials for dronabinol synthesis in sufficiently high concentrations. The active ingredients are isolated by extraction with a non-polar solvent, e.g. benzine, 3C from the blossom constituents or the cut plant material obtained by sifting as per the present invention. The extraction of active ingredients is effectively carried out in such a way that fresh blossoms or fresh plant material are treated with a solvent, which has been concentrated with already active ingredients via an earlier extraction procedure. In this way the active ingredient concentration increases continuously in the solvent, without distillation of the solvent being necessary. Since the solvent treatment of the plant material can be undertaken at room temperature, thermal decarboxylation of the cannabidiol acid isolated from the blossom constituents is largely avoided. In the resulting solvent extract cannabidiol and cannabidiol acid are frequently present according to age and preliminary treatment of the plant material. Whereas cannabidiol acid is obtained predominantly from fresh plant material, cannabidiol predominates in older plant material. The further steps for obtaining the cannabidiol now depend on whether it is predominantly cannabidiol acid or cannabidiol present in the blossom extract. 3D To obtain cannabidiol acid from the solvent extract the latter is treated with an aqueous lye, preferably in counter-current extraction in the presence of a reducing agent, whereby the cannabidiol acid is dissolved with salification in the aqueous phase. The acid is precipitated from this ensuing acidification. But if the active ingredient is predominantly present as free cannabidiol, the solvent is distilled off and the residue is dissolved in a polar organic solvent, whereby unwanted lipophilic constituents precipitate and are filtered off. The active ingredient is then obtained by evaporating the filtrate. If the solvent extract contains a mixture of cannabidiol acid and cannabidiol, it is recommended to first treat the solvent extract with an aqueous alkali solution and subsequent extraction of the cannabidiol remaining in the organic solvent by means of a polar organic solvent. The cannabidiol acid contained in the resulting extracts is then decarboxylated by heating, and the resulting cannabidiol is distilled off in a vacuum and crystallised. Decarboxylation is carried out with the exclusion of oxygen, thus either in a vacuum or with an inert gas such as nitrogen. Crystallisation of the cannabidiol is facilitated by trituration of the distillate e.g. with petrol ether. The resulting cannabidiol is cyclised according to the inventive process advantageously by means of Lewis catalysts, optionally with the addition of basic drying agents to give dronabinol. Anhydrous salts of silver, tin, zinc or magnesium, e.g. zinc chloride, zinc bromide, zinc iodide, zinc trifluormethansulfonate, tin chloride, tin bromide, tin iodide, tin trifluormethansulfonate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluormethansulfonate, silver chloride, silver bromide, silver iodide, silver trifluormethansulfonate are used in an organic solvent as suitable Lewis acids. The resulting raw dronabinol is then purified chromatographically. To this is added a solution of the raw dronabinol in an organic solvent e.g. via a silica gel column. After the solvent is removed from the eluant the residue then undergoes high-vacuum distillation, whereby flash distillation or distillation in a bulb tube, preferably with the addition of bases, have proven particularly effective. 4 The resulting end product is very pure dronabinol, which at room temperature is a viscous fluid, but liquefies at higher temperatures and e.g. at a temperature of 60 to 800C can be easily filled into a calibrated, gas-tight glass syringe. This dronabinol filled glass syringe is delivered to pharmacies, where the liquefied contents are precisely metered after the glass syringe has been gently heated, from which various pharmaceuticals can be produced, such as e.g. liquid drugs by adding precisely measured quantities of dronabinol e.g. to sesame oil or other edible oils, and gelatine capsules filled with dronabinol, in which the dronabinol is taken up by oleum cacao and fixed in the capsules, and also inhalation solutions, in which the dronabinol is dissolved in alcohol. The resulting dronabinol can also be applied from an alcohol solution by means of a special inhaler (e.g. Inhalator Vulcano marketed by Vapormed), such that the active ingredient is evaporated by means of a hot air current in a closed pouch, from which it can then be inhaled as aerosol. This form of application ensures particularly high bioavailability. Bioavailability can be further improved by adding other substances such as cannabidiol and/or essential oils and/or local anaesthetic, as irritation of airways is decreased during inhalation and a longer dwell time of the aerosol in the lungs is thus possible. The process according to the present invention is distinguished by a series of considerable advantages. First it should be emphasised that the fibrous hemp used as starting material can be added in without problem, as it is not subject to any legal restrictions. In procedural terms it is a particular advantage that the use of an organic solvent containing already active ingredients for extracting the plant materials leads to an overall desired increase in the active ingredient concentration, without the consequence of loading via thermal concentration when obtaining the extract. This extensively prevents decarboxylation of cannabidiol acid. At the same time extraction of cannabidiol acid from the solvent extract by means of aqueous alkali, which effectively leads to selective concentration of the active ingredients via counter current extraction, also considerably reduces the content of any possible pesticides. 5 An added advantage is that thermal decarboxylation of the extract residue obtained from plant material prevents problems which might arise during distillative treatment of the raw product through ensuing generation of gas. A further procedural advantage can be achieved by the dronabinol obtained via cyclising of cannabidiol first being cleaned via distillation and crystallisation, thus facilitating subsequent chromatographic treatment. With all synthesis of A 9 -tetrahydrocannabinol it must be taken into consideration that the thermodynamically more stable A 8 -tetrahydrocannabinol, although not of interest for medical applications, does not occur. There is also the danger of developing A 8 _ tetrahydrocannabinol basically during cyclising according to the present invention with BF 3 etherate, though this unwanted reaction can be prevented if a basic drying agent is employed during cyclising. Even more beneficial is the use of weak Lewis acids, since the formation of A 8 tetrahydrocannabinol is then clearly reduced. A particularly significant embodiment of the present invention is in filling highly purified dronabinol into syringes, from which smaller quantities of dronabinol can easily be taken for dispensing purposes, without the remaining quantities of the oxygen-sensitive substance coming into contact with air. The process according to the present invention thus opens up novel and simple access to dronabinol which is becoming more and more important for medical purposes. Example 1 Production of dronabinol 5 ml of boron trifluoride etherate is added to a solution of 5 g of cannabidiol in 1600 ml of methylene chloride with stirring and the solution is left to stand at room temperature. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains

A

8 -tetrahydrocannabinol 5.59% dronabinol 74.60% 6 The mixture is separated into its constituents by means of preparative HPLC and the purified dronabinol undergoes vacuum distillation. Example 2 5 ml of boron trifluoride etherate is added to a solution of 5 g of cannabidiol in 1600 ml of methylene chloride and 5 g of potassium carbonate with stirring and the solution is left to stand at room temperature. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains

A

8 -tetrahydrocannabinol 1.59% dronabinol 82.40% The treatment is the same as for Example 1 Example 3 A solution of 5 g cannabidiol in 1600 ml dichloro ethane with 10 g zinc chloride is cooked for 24 hours on reflux. On completion of reaction the procedure is stopped with the addition of 500 ml water. The residue obtained after distillation of the solvent contains

A

8 -tetrahydrocannabinol 5.01% dronabinol 86.37% The treatment is the same as for Example 1 Throughout this specification, unless the context requires otherwise, the word "comprise", or variations such as "comprises" or "comprising", will be understood to imply the inclusion of a stated integer or group of integers but not the exclusion of any other integer or group of integers. The preceding discussion of the background art is intended to facilitate an understanding of the present invention only. It should be appreciated that the discussion is not an acknowledgement or admission that any of the material referred to was part of the common general knowledge in Australia as at the priority date of the application. 7

Claims

1. A process for the synthesis of dronabinol, wherein (a) cannabidiol and/or cannabidiol acid is used as the starting materials for the synthesis of dronabinol; (b) the cannabidiol acid is converted to cannabidiol by decarboxylation; (c) the cannabidiol is cyclised by means of Lewis catalysts to generate raw dronabinol.

2. The process as claimed in Claim 1, wherein fibrous hemp is provided as the source of the starting material.

3. The process as claimed in Claims 1 or 2, wherein the raw dronabinol is purified by a chromatographic process.

4. The process as claimed in Claims 1 to 3, wherein the raw dronabinol is dissolved in a solvent and then subjected to a chromatographic process and wherein the solvent in an eluant generated by the chromatographic process is distilled off to produce a residue which is then cleaned by vacuum distillation.

5. A process for the production of dronabinol, wherein: (a) cannabidiol or cannabidiol acid is isolated from fibrous hemp; (b) the cannabidiol acid is converted to cannabidiol by decarboxylation; (c) cannabidiol is cyclised in the presence of Lewis catalysts in a non-polar solvent to generate dronabinol; (d) the raw dronabinol is dissolved in a solvent and then isolated by a chromatographic process; and (e) wherein the solvent in an eluant generated by the chromatographic process is distilled off to produce a residue which is then cleaned by vacuum distillation.

6. The process as claimed in any one of claims 1 to 5 wherein the anhydrous salts of silver, tin, zinc or magnesium, e.g. zinc chloride, zinc bromide, zinc iodide, zinc trfluormethansulfonate, tin chloride, tin bromide, tin iodide, tin trifluormethansulfonate, magnesium chloride, magnesium bromide, magnesium iodide, magnesium trifluormethansulfonate, silver chloride, silver bromide, silver iodide, silver trifluormethansulfonate, are used as the Lewis catalysts. 8

7. The process as claimed in any one of Claims 1 to 6, wherein the cannabidiol or cannabidiol acid are extracted from the flowers or leaves of the fibrous hemp.

8. The process as claimed in Claim 2, 5 or 7, wherein the starting materials are extracted with a non-polar solvent from the sifted constituents of the fibrous hemp.

9. The process as claimed in any one of Claims 1 to 8, wherein the starting materials are concentrated in a solvent by extraction of the starting materials from fresh plant material with a solvent which already contains starting material, without distilling off the solvent.

10. The process as claimed in any one of Claims 8 or 9, wherein the starting materials are purified by: (a) treating an extract comprising the starting materials with aqueous lye, from which the free carbonic acids are precipitated following acidification; and/or (b) distilling off the solvent used to extract the starting materials to leave a residue and dissolving the residue in a polar, organic solvent, whereby unwanted iipophilic constituents are precipitated and filtered out, and the starting materials contained in the filtrate are isolated by evaporation; and (c) decarboxylating the starting materials purified by (a) or (b) by heating the materials then distilling them in a vacuum to generate crystallised cannabinoid.

11. The process as claimed in any one of Claims 1 to 10, wherein the cannabidiol is cyclised to give dronabinol by addition of BF 3 etherate, optionally in the presence of an alkaline drying agent in an organic solvent.

12. The process as claimed in claim 11, wherein the alkaline drying agent is potassium carbonate.

13. The process as claimed in any one of Claims 1 to 12, wherein the cannabidiol is cyclised by addition of weak Lewis acids in an organic solvent to give dronabinol.

14. The process as claimed in Claims 12 or 13, wherein the solution containing dronabinol is dissolved in a solvent and then chromatographed on a silicagel column. 9

15. The process as claimed in claim 14, wherein wherein the solvent in an eluant generated by the chromatographic process is distilled off to produce a residue which is then cleaned by vacuum distillation.

16. The process as claimed in Claim 15 wherein the vacuum distillation is high-vacuum distillation.

17. An inhalation solution for thermal atomisation with hot air, wherein the inhalation solution contains dronabinol obtained by a process according to any one of claims 1 to 16.

18. A pharmaceutical containing dronabinol, wherein the dronabinol is produced as claims in a process according to any one of claims 1 to 16.

19. A process for the synthesis of dronabinol substantially as described hereinbefore with reference to the examples. 10