CN114436785A - Cannabidiol derivative compounds, preparation method and application thereof - Google Patents
Cannabidiol derivative compounds, preparation method and application thereof Download PDFInfo
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- CN114436785A CN114436785A CN202210145878.9A CN202210145878A CN114436785A CN 114436785 A CN114436785 A CN 114436785A CN 202210145878 A CN202210145878 A CN 202210145878A CN 114436785 A CN114436785 A CN 114436785A
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Abstract
The invention provides a cannabidiol derivative compound, a preparation method and application thereof, including CBD-1-CF3And CBD-2-CF3，
The invention provides a cannabidiol derivative compound, a preparation method and application thereof, CBD-1-CF3And CBD-2-CF3The two compounds are prepared by mixing cannabis sativa seed extract and cannabis sativa seed extractTrifluoromethyl is introduced into the molecular structure of the phenol, so that the lipophilicity of the medicament is greatly improved, the derivative has higher bioavailability compared with cannabidiol, and the clinical treatment effect of the derivative is enhanced.
Description
Technical Field
The invention relates to the field of chemical synthesis, in particular to a cannabidiol derivative compound, a preparation method and application thereof.
Background
Cannabidiol (CBD) is a natural compound from the plant cannabis sativa, and has received increasing attention from researchers for its broad pharmacological effects and efficacy. CBD has important clinical application in the aspect of neuropsychiatric system diseases including epilepsy, depression, Parkinson, anxiety and the like, and simultaneously has great application value in the fields of cardiovascular diseases, tumors, autoimmune diseases and the like.
Although cannabidiol is marketed, including that developed by Giwa pharmaceutical corporation in 2005
The medicine can be used for treating multiple sclerosis and relieving pain related to tumor, and is available under the trade name of
Can be used for treating epilepsy caused by Dravet syndrome and Lennox-Gastaut syndrome in patients of two or more years of age. However, CBD has poor lipophilicity and low bioavailability, which is a problem that researchers have to face, and the bioavailability effect is general during application.
Disclosure of Invention
The invention aims to provide a cannabidiol derivative compound, a preparation method and application thereof, so that the derivative has higher bioavailability compared with cannabidiol.
In order to achieve the above purpose, the invention provides the following technical scheme: cannabidiol derivative compounds including CBD-1-CF3And CBD-2-CF3The structural formula is as follows:
further, in the present invention, the CBD-1-CF3The reaction formula of the synthesis method is as follows:
further, in the present invention, the CBD-1-CF3The synthesis method comprises the following specific steps:
dissolving the initial material compound in toluene solution, adding the initial material compound, reaction heating to 115 deg.c and reflux for 8 hrCooling the reaction liquid to room temperature, adding a 3N hydrochloric acid solution into a reaction bottle, separating an organic phase after stirring, extracting a water phase twice by using toluene, combining the organic phases, drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, removing toluene, adding ethyl acetate, heating until the solid is dissolved, filtering while the solution is hot, standing the filtrate at 0 ℃ for 8 hours, filtering the solution, heating a filter cake to 60 ℃ by using acetone, filtering while the solution is hot, standing the filtrate at 0 ℃ for 8 hours, filtering the solution, drying the obtained filter cake, and obtaining a white solid which is CBD-1-CF3。
Further, in the present invention, the CBD-2-CF3The reaction formula of the synthesis method is as follows:
further, in the present invention, the CBD-2-CF3The synthesis method comprises the following specific steps:
dissolving a raw material compound IV and an initial raw material compound V in a toluene solution, adding the initial raw material compound VI, heating the mixture to 115 ℃, refluxing for 8 hours, cooling the reaction solution to room temperature, adding a 3N hydrochloric acid solution into a reaction bottle, stirring, separating an organic phase, extracting an aqueous phase twice by using toluene, combining the organic phases, drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, removing the toluene, adding ethyl acetate, heating until the solid is dissolved, filtering while hot, standing the filtrate for 8 hours at 0 ℃, filtering the solution, heating a filter cake to 60 ℃ by using 100mL of acetone, standing the filtrate for 8 hours at 0 ℃, filtering the solution, drying the filter cake to obtain a white solid which is CBD-2-CF3。
Application of cannabidiol derivative compound CBD-1-CF3And CBD-2-CF3Making into powder, microcapsule, spray, tablet or capsule.
Application of cannabidiol derivative compounds in powder, microcapsule, spray, tablet or capsule for treating cardiovascular diseases, tumors or autoimmune diseases.
The beneficial effects are that the technical scheme of this application possesses following technological effect:
the invention provides a cannabidiol derivative compound, a preparation method and application thereof, CBD-1-CF3And CBD-2-CF3The two compounds have the lipid-water partition coefficients of 3.76 and 3.98 respectively measured by introducing trifluoromethyl into the molecular structure of the cannabidiol, so that the lipophilicity of the drug is greatly improved, and the lipid-water partition coefficient of the cannabidiol is 6.5, so that the derivatives have higher bioavailability and the clinical treatment effect is enhanced compared with the cannabidiol.
It should be understood that all combinations of the foregoing concepts and additional concepts described in greater detail below can be considered as part of the inventive subject matter of this disclosure unless such concepts are mutually inconsistent.
The foregoing and other aspects, embodiments and features of the present teachings can be more fully understood from the following description taken in conjunction with the accompanying drawings. Additional aspects of the present invention, such as features and/or advantages of exemplary embodiments, will be apparent from the description which follows, or may be learned by practice of specific embodiments in accordance with the teachings of the present invention.
Drawings
The drawings are not intended to be drawn to scale. In the drawings, each identical or nearly identical component that is illustrated in various figures may be represented by a like numeral. For purposes of clarity, not every component may be labeled in every drawing. Embodiments of various aspects of the present invention will now be described, by way of example, with reference to the accompanying drawings, in which:
FIG. 1CBD-1-CF3And CBD-2-CF3Schematic structural diagram of (1).
Detailed Description
In order to better understand the technical content of the present invention, specific embodiments are described below with reference to the accompanying drawings. In this disclosure, aspects of the present invention are described with reference to the accompanying drawings, in which a number of illustrative embodiments are shown. Embodiments of the present disclosure are not necessarily defined to include all aspects of the invention. It should be appreciated that the various concepts and embodiments described above, as well as those described in greater detail below, may be implemented in any of numerous ways, as the disclosed concepts and embodiments are not limited to any one implementation. In addition, some aspects of the present disclosure may be used alone, or in any suitable combination with other aspects of the present disclosure.
The embodiment of the invention provides a structure and a preparation method of a cannabidiol derivative, wherein one trifluoromethyl group and two trifluoromethyl groups are respectively introduced into the structure of cannabidiol so as to improve the lipid solubility of the cannabidiol, including CBD-1-CF3And CBD-2-CF3The molecular structural formula is shown as the following formula:
the preparation line is as follows:
the invention is further illustrated by the following examples.
Example 1 structure and preparation method of a class of cannabidiol derivatives:
CBD-1-CF35g of (1S, 4S) -1-methyl-4- (prop-1-en-2-yl) cyclohex-2-en-1-ol and 12.23 g of 5-pentyl-4- (trifluoromethyl) benzene-1, 3-diol were dissolved in 200mL of a toluene solution, 10mL of p-toluenesulfonic acid was then added, the reaction was heated to 115 ℃ and then refluxed for 8 hours, and the reaction was cooled to room temperature. 500mL of 3N hydrochloric acid solution was added to the reaction flask, and the organic phase was separated after stirring for 30 min. The aqueous phase was extracted twice with 100mL of toluene and the organic phases were combined. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove toluene, added with 200mL of ethyl acetate, heated until the solid is dissolved, filtered while hot, and the filtrate is left to stand at 0 ℃ for 8 hours. The solution is filtered, the filter cake is heated to 60 ℃ with 100mL of acetone, filtered while hot, and the filtrate is left to stand at 0 ℃ for 8 hours. Filtering the solution to obtain a filter cake, drying the filter cakeThe obtained white solid is CBD-1-CF35.13g, yield 28.55% and purity 98.2%.
CBD-2-CF35g of (1S, 4S) -1-methyl-4- (prop-1-en-2-yl) cyclohex-2-en-1-ol and 10.39 g of 5-pentyl-4- (trifluoromethyl) benzene-1, 3-diol were dissolved in 200mL of a toluene solution, 10mL of p-toluenesulfonic acid was then added, the reaction was heated to 115 ℃ and then refluxed for 8 hours, and the reaction was cooled to room temperature. 500mL of 3N hydrochloric acid solution was added to the reaction flask, and the organic phase was separated after stirring for 30 min. The aqueous phase was extracted twice with 100mL of toluene and the organic phases were combined. The organic phase is dried over anhydrous sodium sulfate, concentrated under reduced pressure to remove toluene, added with 200mL of ethyl acetate, heated until the solid is dissolved, filtered while hot, and the filtrate is left to stand at 0 ℃ for 8 hours. The solution is filtered, the filter cake is heated to 60 ℃ with 100mL of acetone, filtered while hot, and the filtrate is left to stand at 0 ℃ for 8 hours. Filtering the solution, drying the obtained filter cake to obtain a white solid which is CBD-2-CF35.28 g, 34.30% yield, 99.1% purity.
The invention provides a cannabidiol derivative compound, a preparation method and application thereof, CBD-1-CF3And CBD-2-CF3The two compounds greatly improve the lipophilicity of the medicament by introducing trifluoromethyl into the molecular structure of the cannabidiol, so that the derivatives have higher bioavailability compared with the cannabidiol, and the clinical treatment effect of the derivatives is enhanced.
Although the present invention has been described with reference to the preferred embodiments, it is not intended to be limited thereto. Those skilled in the art can make various changes and modifications without departing from the spirit and scope of the invention. Therefore, the protection scope of the present invention should be determined by the appended claims.
Claims (7)
1. A cannabidiol derivative compound, which is characterized in that: comprising CBD-1-CF3And CBD-2-CF3The structural formula is as follows:
2. the cannabidiol derivative compounds as claimed in claim 1, wherein: the CBD-1-CF3The reaction formula of the synthesis method is as follows:
3. the cannabidiol derivative compounds as claimed in claim 2, wherein: the CBD-1-CF3The synthesis method comprises the following specific steps:
dissolving a starting raw material compound I and a starting raw material compound II in a toluene solution, adding the starting raw material compound III, heating the mixture to 115 ℃, refluxing for 8 hours, cooling the reaction solution to room temperature, adding a 3N hydrochloric acid solution into a reaction bottle, stirring, separating an organic phase, extracting a water phase twice with toluene, combining the organic phases, drying the organic phase with anhydrous sodium sulfate, concentrating under reduced pressure, removing the toluene, adding ethyl acetate, heating until the solid is dissolved, filtering while hot, standing the filtrate at 0 ℃ for 8 hours, filtering the solution, heating a filter cake to 60 ℃ with acetone, standing the filtrate while hot for 8 hours, filtering the solution, drying the obtained filter cake, and obtaining a white solid which is CBD-1-CF3。
4. The cannabidiol derivative compounds as claimed in claim 1, wherein: the CBD-2-CF3The reaction formula of the synthesis method is as follows:
5. the cannabidiol derivative compounds of claim 4 and method of preparationThe method is characterized in that: the CBD-2-CF3The synthesis method comprises the following specific steps:
dissolving a raw material compound IV and an initial raw material compound V in a toluene solution, adding the initial raw material compound VI, heating the mixture to 115 ℃, refluxing for 8 hours, cooling the reaction solution to room temperature, adding a 3N hydrochloric acid solution into a reaction bottle, stirring, separating an organic phase, extracting an aqueous phase twice by using toluene, combining the organic phases, drying the organic phase by using anhydrous sodium sulfate, concentrating under reduced pressure, removing the toluene, adding ethyl acetate, heating until the solid is dissolved, filtering while hot, standing the filtrate for 8 hours at 0 ℃, filtering the solution, heating a filter cake to 60 ℃ by using 100mL of acetone, standing the filtrate for 8 hours at 0 ℃, filtering the solution, drying the filter cake to obtain a white solid which is CBD-2-CF3。
6. The use of a class of cannabidiol derivative compounds as claimed in claim 1, wherein: CBD-1-CF3And CBD-2-CF3Making into powder, microcapsule, spray, tablet or capsule.
7. Use of a class of cannabidiol derivative compounds as claimed in claim 6, wherein: the powder, microcapsule, spray, tablet or capsule can be used for treating cardiovascular diseases, tumor diseases or autoimmune diseases.
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| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202210145878.9A CN114436785A (en) | 2022-02-17 | 2022-02-17 | Cannabidiol derivative compounds, preparation method and application thereof |
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| CN202210145878.9A CN114436785A (en) | 2022-02-17 | 2022-02-17 | Cannabidiol derivative compounds, preparation method and application thereof |
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| CN114436785A true CN114436785A (en) | 2022-05-06 |
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| CN202210145878.9A Pending CN114436785A (en) | 2022-02-17 | 2022-02-17 | Cannabidiol derivative compounds, preparation method and application thereof |
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- 2022-02-17 CN CN202210145878.9A patent/CN114436785A/en active Pending
Non-Patent Citations (2)
| Title |
|---|
| PAPAHATJIS, DEMETRIS P.等: "Novel 1\',1\'-chain substituted Δ8-tetrahydrocannabinols", BIOORGANIC & MEDICINAL CHEMISTRY LETTERS, vol. 12, no. 24, pages 3583 - 3586, XP055754946, DOI: 10.1016/S0960-894X(02)00785-0 * |
| PETRZILKA, THEODOR等: "Synthesis and chirality of (-)-cannabidiol", HELVETICA CHIMICA ACTA, vol. 50, pages 719 - 723 * |
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