Process for the production of cannabidiol and delta-9-tetrahydrocannabinol

Abstract

The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof. The cannabidiol compound or derivatives thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be converted under reducing conditions to a cannabidiol compound or derivatives thereof.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This application claims the benefit of and priority to U.S. Provisional Patent Application No. 62 / 191,097, filed on Jul. 10, 2016, the entire content of which is incorporated herein by reference.FIELD OF THE INVENTION[0002]The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof. The cannabidiol compound or derivative thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be converted under reducing conditions to a cannabidiol compound or derivatives thereof.BACKGROUND OF THE INVENTION[0003]More than 100 phytocannabinoids have been isolated to date. See Pertwee, et al. “Hand b...

AI Technical Summary

Benefits of technology

[0011]The present disclosure relates to the preparation of a cannabidiol compound or a derivative thereof. The cannabidiol compound or derivative thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene (e.g, a cyclic alkene containing a 1-methyl-1-ethenyl substituent) to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be converted under reducing conditions to a cannabidiol compound or derivative thereof.

[0012]The present disclosure also relates to the preparation of a Δ-9-tetrahydrocannabinol compound or derivative thereof. The Δ-9-tetrahydrocannabinol compound or derivative thereof can be prepared by an acid-catalyzed reaction of a suitably selected and substituted di-halo-olivetol or derivative thereof with a suitably selected and substituted cyclic alkene to produce a dihalo-cannabidiol compound or derivative thereof. The dihalo-cannabidiol compound or derivative thereof can be produced in high yield, high stereospecificity, or both. It can then be reacted with a Lewis acid catalyst to produce a dihalo-Δ-9-tetrahydrocannabinol compound or derivative thereof. The dihalo-Δ-9-tetrahydrocannabinol compound or derivative thereof can then be converted under reducing conditions to a Δ-9-tetrahydrocannabinol compound or derivative thereof. Alternatively, the reduction and cyclization steps can be performed in reverse order.

[0060]The processes of the present disclosure provide a number of advantages over current methods. As described in the prior art, the Lewis acid catalyzed condensation of olivetol or olivetolate esters with menthadienol to prepare cannabidiol or cannibidiolate esters suffers from poor selectivity resulting low yields and mixtures of isomers requiring tedious purification procedures. For example, the use of boron trifluoride etherate results in uncontrolled conversion of cannabidiol and the cyclization of Δ-9-tetrahydrocannabinol to Δ-8-tetrahydrocannabinol. In the present disclosure, one or both of the 4 and 6 positions of olivetol or derivatives thereof can be blocked with a halogen selected from the group consisting of Br, F, I and Cl. In particular, both positions can be blocked with a halogen selected from the group consisting of Br, F, I and Cl. In one embodiment, both positions can be blocked with a Br. In another embodiment, both positions can be blocked with a F. In yet another embodiment, both positions can be blocked with a Cl. The position can be blocked to control the conversion and prevent the formation of unwanted cannabidiol isomers, such as the abn cannabidiol. In addition, the process can be designed, such as by using excess equivalents of an alkene relative to a halogen substituted olivetol or derivatives thereof to form the corresponding halogen substituted cannabidiol or derivative thereof in a high yield, high selectivity or both. In some embodiments, deficient amount can be used for economical purposes. The halogen substituted cannabidiol can also remain stable and not undergo uncontrolled conversion to one or more cyclized products. The halogen substituted cannabidiol or derivative thereof can also be easily converted to a cannabidiol or derivative thereof by reacting with a suitably selected reducing agent, under mild conditions, to yield the desired product in high yield, high purity or both.

[0061]The processes of the present disclosure can achieve high yield, high purity or both without the need to use organo-aluminum Lewis acid catalysts. The processes of the present disclosure can use a wide selection of catalysts including boron trifluoride etherate and aluminum trichloride. The processes of the present disclosure can achieve high yield, high purity cannabinoid or derivative, or both without the need for purification by formation of a polar ester group, crystallization of the resulting ester, and / or hydrolysis to purified cannabidiol or related derivative, or related purification. The processes of the present disclosure do not require additional derivatization of the isolated cannabidiol or related derivative, e.g., Δ-9-tetrahydrocannabinol, prior to pharmaceutical use.

Problems solved by technology

U.S. Pat. No. 7,674,922 describes a similar reaction using a Lewis acid catalyst instead of p-toluenesulfonic acid which results in the formation of significant amounts of the unwanted cannabidiol isomer along with cannabidiol.

The prior art demonstrates the difficulties of manufacturing cannabidiol compounds or derivatives thereof, e.g., Δ-9-tetrahydrocannabinol, in high yield, high stereospecificity, or both.

The causes of these difficulties can include the non-crystalline nature of the materials which renders them difficult or impossible to separate and purify without chromatography.

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