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CN116983266B - Embedding system of dihydrocannabidiol difurancarboxylate and preparation method and application thereof - Google Patents

Embedding system of dihydrocannabidiol difurancarboxylate and preparation method and application thereof Download PDF

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CN116983266B
CN116983266B CN202311266129.2A CN202311266129A CN116983266B CN 116983266 B CN116983266 B CN 116983266B CN 202311266129 A CN202311266129 A CN 202311266129A CN 116983266 B CN116983266 B CN 116983266B
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dihydrocannabidiol
difurancarboxylate
organic solvent
preparation
embedding system
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CN116983266A (en
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王凤忠
范蓓
王博
孙玉凤
佟立涛
唐璐
魏静
张亮
孙晶
卢聪
刘佳萌
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Heilongjiang Fengyou Hemp Planting Co ltd
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Institute of Food Science and Technology of CAAS
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    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • A61K31/341—Heterocyclic compounds having oxygen as the only ring hetero atom, e.g. fungichromin having five-membered rings with one oxygen as the only ring hetero atom, e.g. isosorbide not condensed with another ring, e.g. ranitidine, furosemide, bufetolol, muscarine
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    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics

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Abstract

The invention discloses an embedding system of dihydrocannabidiol difurancarboxylate and a preparation method and application thereof, wherein the preparation method comprises the following steps: mixing cannabidiol, an organic solvent A and a catalytic system to obtain dihydro cannabidiol; mixing the dihydrocannabidiol, an organic solvent B, 2-furoyl chloride and an alkaline reagent to obtain dihydrocannabidiol difurancarboxylate; and (3) dissolving the dihydrocannabidiol difurancarboxylate in an organic solvent C to obtain an oil solution, mixing the oil solution with a cellulose nanocrystalline suspension, and shearing to obtain an embedding system of the dihydrocannabidiol difurancarboxylate. The dihydrocannabidiol difurancarboxylate and the embedding system thereof have good stability, have a protective effect on nerve cell injury and a relieving effect on insulin resistance, can be used for preparing nerve cell protective medicaments and hypoglycemic medicaments, and have practical application values in medical production.

Description

Embedding system of dihydrocannabidiol difurancarboxylate and preparation method and application thereof
Technical Field
The invention belongs to the technical field of chemical industry, and particularly relates to an embedding system of dihydrocannabidiol difurancarboxylate, and a preparation method and application thereof.
Background
Industrial cannabis is a Sang Keda cannabis plant, has important medicinal value, and the terpenoid secondary metabolite, namely cannabinoid, has various biological activities. Tetrahydrocannabinol (THC) and Cannabidiol (CBD) are the higher content components of cannabinoids. While tetrahydrocannabinol is useful in the treatment of emesis caused by cancer, it is prohibited in many countries because of its addictive nature. Unlike tetrahydrocannabinol, cannabidiol has no mental addiction, and has anticonvulsant, sedative-hypnotic, anxiolytic, antipsychotic, antiinflammatory and neuroprotective effects, and is a natural active ingredient with great application prospect in the fields of medicine, cosmetics and food.
Current studies have shown that cannabidiol can produce tetrahydrocannabinol in artificial gastric juice containing ethanol (Zhang Xuran, fan Dekai, sun Wuxing, etc., CBD and water-soluble CBD are stable in artificial gastric juice, intestinal juice for green technology, 2020, 8:5). Additional studies have shown that cannabidiol can be converted to tetrahydrocannabinol under acidic conditions (Michal P. Dybowski, andrzej L. Dawidowicz, rafal Typek, michal Rombel Conversion of Cannabidiol (CBD) to Δ9-tetrahydrocanabinol (Δ9-THC) during protein precipitations prior to plasma samples analysis by chromatography-Troubles with reliable CBD quantitation when acidic precipitation agents are applied Talanta, 2020, 220: 121390). Therefore, the possibility of formation of tetrahydrocannabinol is eliminated, the key for guaranteeing the use safety of tetrahydrocannabinol is provided, and the application scene of tetrahydrocannabinol can be greatly expanded. The dihydrocannabidiol is used as a derivative of cannabidiol, is not present in cannabidiol extract, and cannot be converted into tetrahydrocannabidiol in vivo or by other synthetic means, and has better safety than cannabidiol.
Therefore, the designed and synthesized dihydrocannabidiol derivative based on the cannabidiol structure can be used as an important way for obtaining the compound with good stability and activity, and has important significance for preparing novel medicines.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides an embedding system of dihydrocannabidiol difurancarboxylate, and a preparation method and application thereof. The research shows that the dihydrocannabidiol difurancarboxylate and the embedding system thereof have better nerve cell protection effect and blood sugar reducing effect.
In a first aspect of the present invention, there is provided a method for preparing an embedding system of dihydrocannabidiol difurancarboxylate, the method comprising the steps of:
(1) Preparation of dihydrocannabidiol difurancarboxylate:
a: mixing cannabidiol, an organic solvent A and a catalytic system to obtain dihydro cannabidiol;
b: mixing the dihydrocannabidiol, an organic solvent B, 2-furoyl chloride and an alkaline reagent to obtain dihydrocannabidiol difurancarboxylate;
(2) Preparing an embedding system:
and (3) dissolving the dihydrocannabidiol difurancarboxylate in an organic solvent C to obtain an oil solution, mixing the oil solution with a cellulose nanocrystalline suspension, and shearing to obtain an embedding system of the dihydrocannabidiol difurancarboxylate.
Further, the structure of the dihydrocannabidiol difurancarboxylate is shown as a formula I:
。
further, the organic solvent A is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene, in particular dichloromethane.
Further, the catalytic system is a catalyst and/or hydrogen.
Further, the catalyst is a metal catalyst and/or a carbon carrier.
Further, the pressure of the hydrogen gas is 1-5 MPa, specifically 1, 2, 3, 4, 5 MPa, especially 2 MPa.
Further, the metal catalyst is selected from one or more of platinum (Pt), palladium (Pd), rhodium (Rh), molybdenum (Mo), tin (Sn) and uranium (Ur), in particular palladium.
Further, the carbon support is selected from one or more of activated carbon (C), carbon nanotubes, activated carbon fibers, graphene, and carbon black, in particular activated carbon.
In some embodiments of the invention, the catalytic system is a 10% palladium on carbon catalyst.
Further, the mass ratio of cannabidiol to the catalytic system is 10-30:1, specifically 10:1, 11:1, 12:1, 13:1, 14:1, 15:1, 16:1, 17:1, 18:1, 19:1, 20:1, 21:1, 22:1, 23:1, 24:1, 25:1, 26:1, 27:1, 28:1, 29:1, 30:1.
In some embodiments of the invention, the mass ratio of cannabidiol to catalytic system is 20:1.
Further, in the step A, the reaction time is 4-12 h, especially 6 h.
Further, the organic solvent B is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene, in particular dichloromethane.
Further, the molar ratio of the dihydrocannabidiol to the 2-furoyl chloride is 1:2-4, such as 1:2, 1:3 and 1:4.
In some embodiments of the invention, the molar ratio of dihydrocannabidiol to 2-furoyl chloride is 1:3.
Further, the alkaline reagent is selected from one or more of triethylamine, dimethylamine, diethylamine, di-N-propylamine, diisopropylamine, N-ethylmethylamine, di-N-butylamine, diisobutylamine, di-sec-butylamine, di-tert-butylamine, dipentamine, di-N-octylamine, diallylamine, dicyclohexylamine and diphenylamine, in particular triethylamine.
Further, the molar ratio of the dihydrocannabidiol to the alkaline agent is 1:2-4, such as 1:2, 1:3, 1:4.
In some embodiments of the invention, the molar ratio of the dihydrocannabidiol to the alkaline agent is 1:3.
Further, in step B, the reaction time is 6-24 h, especially 12-h.
Further, in the step B, the reaction is performed at room temperature.
Further, the organic solvent C is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene, especially propylene glycol.
Further, the oil solution has a mass concentration of 0.1-5%, such as 0.1, 0.5, 1, 1.5, 2, 2.5, 3, 3.5, 4, 4.5, 5%, especially 2%.
Further, the mass concentration of the cellulose nanocrystal suspension is 0.01-2%, such as 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9, 2%, especially 0.2%.
Further, the volume ratio of the oil solution to the cellulose nanocrystal suspension is 1:0.1-5, such as 1:0.1, 1:0.5, 1:1, 1:1.5, 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, especially 1:1.
Further, the shearing method is selected from one or more of ultrasonic shearing, mechanical shearing, laser shearing, thermal shearing and water jet shearing, and particularly ultrasonic shearing.
Further, the parameters of the ultrasonic shearing are as follows: the ultrasonic power is 100-1000W (such as 100, 200, 300, 400, 500, 600, 700, 800, 900, 1000W), and the ultrasonic time is 1-10 min (such as 1, 2, 3, 4, 5, 6, 7, 8, 9, 10 min).
In some embodiments of the invention, the parameters of the ultrasonic shearing are: the ultrasonic power is 400W and the ultrasonic time is 5min.
In some embodiments of the present invention, the step (1) specifically includes: mixing cannabidiol, dichloromethane and 10% Pd/C, replacing nitrogen for 3 times, replacing hydrogen for 3 times, reacting for 6 hours under 2Mpa hydrogen, filtering, concentrating by rotary evaporation, and separating and purifying by column chromatography to obtain the dihydrocannabidiol; mixing the dihydrocannabidiol, 2-furoyl chloride, triethylamine and dichloromethane, reacting for 12 hours at room temperature, concentrating by rotary evaporation, dissolving with dichloromethane, washing by water, drying by anhydrous magnesium sulfate, rotary evaporation, separating and purifying by column chromatography to obtain the dihydrocannabidiol difurancarboxylate.
In some embodiments of the present invention, the step (2) specifically includes: dissolving dihydrocannabidiol difuranate in propylene glycol to obtain an oil solution of the dihydrocannabidiol difuranate; and (3) carrying out ultrasonic shearing on the oil solution of the dihydrocannabidiol difurancarboxylate and the cellulose nanocrystalline suspension to obtain an embedding system of the dihydrocannabidiol difurancarboxylate.
In a second aspect of the present invention, there is provided an embedding system of dihydrocannabidiol difurancarboxylate prepared by the method of preparation as described in the first aspect.
In a third aspect of the present invention, there is provided a process for the preparation of dihydrocannabidiol difurancarboxylate as described in the first aspect.
In a fourth aspect of the present invention there is provided a dihydrocannabidiol difurancarboxylate prepared by the method of preparation as described in the third aspect.
In a fifth aspect, the invention provides an embedding system of dihydrocannabidiol difurancarboxylate as described in the second aspect for use in the preparation of a hypoglycemic agent.
In a sixth aspect, the present invention provides the use of an embedding system of dihydrocannabidiol difurancarboxylate as described in the second aspect for the preparation of a neuroprotective medicament.
In a seventh aspect, the present invention provides the use of the dihydrocannabidiol difurancarboxylate as described in the fourth aspect in the preparation of a hypoglycemic agent.
In an eighth aspect of the invention, there is provided the use of a dihydrocannabidiol difurancarboxylate as described in the fourth aspect in the manufacture of a medicament for neuroprotection.
In a ninth aspect of the present invention, there is provided a pharmaceutical composition comprising a dihydrocannabidiol difurancarboxylate as described in the fourth aspect, or a pharmaceutically acceptable salt thereof, or a solvate thereof, or an entrapment system of a dihydrocannabidiol difurancarboxylate as described in the second aspect.
Further, the pharmaceutical composition also comprises pharmaceutically acceptable auxiliary materials.
Further, the pharmaceutically acceptable auxiliary materials comprise excipient, diluent, filler and the like.
Further, the dosage form of the pharmaceutical composition is powder or granule.
The invention has the following beneficial effects:
(1) The dihydrocannabidiol difurancarboxylate and the embedding system thereof have good stability, have a protective effect on nerve cell injury and a relieving effect on insulin resistance, can be used for preparing nerve cell protective medicaments and hypoglycemic medicaments, and have practical application values in medical production.
(2) The preparation method of the dihydrocannabidiol difurancarboxylate and the embedding system thereof has the advantages of simple operation, low raw material cost, mild reaction, low energy consumption and high yield.
Detailed Description
Unless defined otherwise, all scientific and technical terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention relates.
In the present invention, the structural formula and chinese name of the compound used are as follows:
in the invention, the term Pickering emulsion, also called Pickering emulsion, is a novel emulsion which uses solid particles to replace the traditional organic surfactant to stabilize an emulsion system.
In the present invention, the term "room temperature" means that the temperature of an item is close to or the same as the temperature of a space, such as the location of a fume hood in which the item is located. Typically, room temperature is about 20 ℃ to about 30 ℃, or about 22 ℃ to 27 ℃, or about 25 ℃.
Embodiments of the present invention will be described in detail below with reference to examples, but it will be understood by those skilled in the art that the following examples are only for illustrating the present invention and should not be construed as limiting the scope of the present invention. The specific conditions are not noted in the examples and are carried out according to conventional conditions or conditions recommended by the manufacturer. The reagents or apparatus used were conventional products commercially available without the manufacturer's attention.
EXAMPLE 1 preparation of Dihydrocannabidiol derivatives and embedding System therefor
1.1 preparation of the Dihydrocannabidiol derivatives
1.1.1 Synthesis routes to the dihydrocannabidiol difurancarboxylate
31.4 g (0.1 mol) cannabidiol, 1.57g 10% Pd/C and 200ml anhydrous dichloromethane were added to a 500 mL reactor, nitrogen was replaced 3 times, hydrogen was replaced 3 times, and the reaction was stirred under 2MPa hydrogen for 6 hours. The reaction solution was filtered, concentrated by rotary evaporation, and purified by column chromatography to give a colorless liquid 25.8. 25.8 g in 82% yield.
1.96 g (15 mmol) of 2-furoyl chloride and 20 mL of anhydrous dichloromethane are added into a 50 mL single-mouth bottle, stirred, 1.58 g (5 mmol) of dihydrocannabidiol is added, 1.51g (15 mmol) of triethylamine is added, stirring is carried out at room temperature for 12 hours, after the reaction is completed, rotary evaporation concentration is carried out, dichloromethane dissolution, water washing, drying with anhydrous magnesium sulfate, rotary evaporation and column chromatography separation and purification are carried out, and 2.30g of colorless liquid is obtained, and the yield is 91%.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 7.66 (d,J= 1.7 Hz, 2H), 7.31 (d,J= 3.4 Hz, 2H), 6.88 (s, 2H), 6.58 (dd,J= 3.5, 1.7 Hz, 2H), 5.18 (s, 1H), 3.55 (dt,J= 10.7, 2.7 Hz, 1H), 2.61 (dd,J= 8.9, 6.9 Hz, 2H), 1.95 (m,J= 12.8, 10.6, 2.3 Hz, 1H), 1.75 (t,J= 8.4 Hz, 2H), 1.71 – 1.60 (m, 3H), 1.59 – 1.50 (m, 2H), 1.33 (m,J= 3.7 Hz, 3H), 1.30 (d,J= 1.8 Hz, 4H), 0.92 – 0.87 (m, 3H), 0.86 (d,J= 6.9 Hz, 3H), 0.71 (d,J= 6.9 Hz, 3H).； 13 C NMR (126 MHz, Chloroform-d) δ 156.7, 149.3, 146.9, 144.1, 142.3, 133.9, 127.3, 124.1, 119.1, 112.0, 53.4, 42.9, 37.5, 35.2, 31.5, 30.4, 30.3, 27.9, 22.8, 22.4, 22.2, 21.7, 16.0, 14.0。
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical value 505.2584 and measured value 505.2578.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol difurancarboxylate.
1.1.2 synthetic routes to the Dihydrocannabidiol dioctanoate
2.43 g (15 mmol) octanoyl chloride and 20 mL anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) dihydrocannabidiol, 1.18g (15 mmol) pyridine are added, stirred at room temperature, reacted for 9 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, rotary evaporated, separated and purified by column chromatography, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.70 (s, 2H), 5.14 (d,J= 2.4 Hz, 1H), 3.46 – 3.36 (m, 1H), 2.55 (m,J= 9.2, 6.6 Hz, 4H), 2.44 (t,J= 7.5 Hz, 4H), 2.31 (m,J= 29.1, 7.6 Hz, 1H), 1.79 – 1.65 (m, 8H), 1.68 – 1.55 (m, 9H), 1.00 – 0.92 (m, 2H), 0.91 – 0.86 (m, 21H), 0.82 (d,J= 7.0 Hz, 4H), 0.75 (d,J= 6.8 Hz, 3H).
13 C NMR (126 MHz, Chloroform-d)) δ 171.9, 150.0, 141.9, 132.8, 126.4, 125.1, 42.7, 37.5, 35.3, 34.3, 31.7, 30.5, 29.2, 29.0, 27.9, 26.9, 24.7, 24.2, 23.4, 22.6, 22.5, 21.6, 16.1, 14.1.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 568.4570 and measured 568.4573.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol dioctanoate.
1.1.3 synthetic routes to the dihydrocannabidiol diisononanoate
2.64 g (15 mmol) isononyl chloride and 20 mL anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol, 1.18g (15 mmol) of pyridine are added, stirred at room temperature, reacted for 9 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, rotary evaporated, separated and purified by column chromatography, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.62 (s, 2H), 5.07 (s, 1H), 3.38 – 3.31 (m, 1H), 2.52 – 2.43 (m, 3H), 1.31 – 1.20 (m, 10H), 1.12 (m,J= 14.0, 6.5, 2.4 Hz, 3H), 1.01 (dd,J= 6.6, 2.5 Hz, 8H), 0.90 – 0.84 (m, 26H), 0.83 – 0.80 (m, 4H), 0.75 (d,J= 6.9 Hz, 3H), 0.69 (m,J= 6.9, 2.2 Hz, 3H).
13 C NMR (126 MHz, Chloroform-d)) δ 171.1, 150.0, 141.9, 132.7, 126.3, 125.0, 50.7, 43.8, 42.7, 37.6, 35.2, 31.5, 31.1, 30.9, 30.4, 30.0, 30.0, 27.9, 26.9, 23.4, 22.7, 22.5, 21.5, 14.0.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 597.4883 and measured 597.4884.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol diisononanoate.
1.1.4 synthetic routes to the dihydrocannabidiol dipelargonate
2.65 g (15 mmol) of nonanoyl chloride and 20 mL of anhydrous dichloromethane are added into a 50 mL round bottom flask and stirred, 1.57g (5 mmol) of dihydrocannabidiol and 1.18g (15 mmol) of pyridine are added, stirring is carried out at room temperature, the reaction is carried out for 12 hours, rotary evaporation concentration, dichloromethane dissolution, water washing, anhydrous magnesium sulfate drying, rotary evaporation and column chromatography separation and purification are carried out, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.60 (t,J= 1.0 Hz, 2H), 6.19 (d,J= 9.1, 1.3 Hz, 1H), 3.42 (m,J= 10.1, 9.2, 2.3, 1.0 Hz, 1H), 2.61 – 2.47 (m, 6H), 2.16 – 2.03 (m, 2H), 1.82 – 1.45 (m, 13H), 1.43 – 1.18 (m, 24H), 0.89 (s, 15H).
13 C NMR (125 MHz, Chloroform-d)) δ 171.8, 151.2, 143.2, 138.7, 124.1, 120.2, 115.2, 44.8, 35.8, 35.7, 34.4, 31.3, 31.0, 30.8, 30.7, 29.6, 29.3, 29.2, 24.7, 24.1, 23.4, 22.6, 22.5, 20.0, 14.0 .
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 597.4883 and measured 597.4889.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol dipelargonate.
1.1.5 synthetic route to dihydrocannabidiol diacetate
1.53 g (15 mmol) of acetic anhydride and 20 mL of anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol and 1.18g (15 mmol) of pyridine are added, stirred at room temperature, reacted for 9 hours, concentrated by rotary evaporation, dissolved by dichloromethane, washed by water, dried by anhydrous magnesium sulfate, purified by rotary evaporation, and separated by column chromatography, thus obtaining colorless liquid.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d) δ 6.58 (t,J= 1.0 Hz, 2H), 6.19 (d,J= 9.1, 1.3 Hz, 1H), 3.42 (m,J= 10.1, 9.2, 2.8, 0.9 Hz, 1H), 2.57 (tt,J= 7.7, 1.1 Hz, 2H), 2.50 (s, 5H), 2.17 – 2.02 (m, 2H), 1.83 – 1.46 (m, 10H), 1.43 – 1.27 (m, 4H), 0.92 – 0.86 (m, 9H).
13 C NMR (125 MHz, Chloroform-d)) δ 168.1, 151.8, 143.1, 138.7, 124.1, 121.2, 115.6, 44.8, 35.8, 35.7, 31.3, 31.0, 30.8, 29.2, 24.1, 23.4, 22.5, 20.7, 20.0, 14.0.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 401.2692 and measured 401.2689.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol diacetate.
1.1.6 synthetic route to Dihydrocannabidiol Di-p-methylbenzoate
2.31 g (15 mmol) of p-methylbenzoyl chloride and 20 mL of anhydrous dichloromethane are added into a 50 mL three-necked flask, stirred, 1.57g (5 mmol) of dihydrocannabidiol and 1.51g of triethylamine (15 mmol) are added, stirred at room temperature for reaction for 6 hours, washed with water, dried over anhydrous magnesium sulfate, distilled, separated and purified by column chromatography, and colorless liquid is obtained.
The nuclear magnetic hydrogen spectrum of the product is characterized as follows:
1 H NMR (500 MHz, Chloroform-d δ 8.21 – 8.16 (m, 4H), 7.52 – 7.49 (m, 4H), 6.89 (d,J= 3.4 Hz, 2H), 5.24 (t,J= 1.9 Hz, 1H), 2.68 – 2.54 (m, 2H), 2.33(s, 6H) 2.03-1.88(m, 2H), 1.73 – 1.49 (m, 10H), 1.39 – 1.26 (m, 4H), 0.95 – 0.76 (m, 9H)
13 C NMR (126 MHz, Chloroform-d) δ 165.0, 150.3, 142.3, 135.3, 133.6, 131.5, 130.1, 128.9, 128.5, 127.1, 124.7, 43.2, 37.7, 35.3, 31.6, 30.5, 27.9, 26.9, 23.0, 22.5, 21.8, 16.3, 14.0.
the high resolution mass spectrum of the product was characterized as follows:
HRMS [M+H] + : theoretical 553.3318 and measured 553.3320.
The nuclear magnetic hydrogen spectrum and the high-resolution mass spectrum detection result show that the preparation method provided by the invention can be used for effectively preparing the dihydrocannabidiol di-p-methyl benzoate.
1.2 preparation of embedding System for Dihydrocannabidiol derivatives
The dihydrocannabidiol difuranate was dissolved in propylene glycol to prepare an oil solution of dihydrocannabidiol difuranate at a concentration of 2% (w/v). And (3) carrying out ultrasonic shearing on the oil solution of the dihydrocannabidiol difurancarboxylate and 0.2% (w/v) cellulose nanocrystalline suspension in a ratio of 1:1 to obtain Pickering emulsion embedded with the dihydrocannabidiol difurancarboxylate. The configuration parameters are as follows: ultrasonic power 400W, ultrasonic time 5min.
The embedding system of other dihydrocannabidiol derivatives (such as dihydrocannabidiol di-p-methyl benzoate, dihydrocannabidiol diisononanoate, dihydrocannabidiol dioctanoate, dihydrocannabidiol diacetate and dihydrocannabidiol dipelargonoate) is prepared by the same method as above.
EXAMPLE 2 determination of neuronal injury protection effect of Dihydrocannabidiol derivatives
The dihydrocannabidiol difurancarboxylate (prepared in example 1) and its analogues (e.g., cannabidiol-2-imidazole-1-carboxylate, cannabidiol-2-propionate, cannabidiol-2-butyrate, cannabidiol-2-nicotinate, cannabidiol-2- (N-acetyl) piperidine acid ester, cannabidiol-2-pyrrolidone acid ester, cannabidiol-2-piperazine acid ester, cannabidiol-2-dioxopiperazine acid ester) were dissolved in DMSO under aseptic conditions to prepare a 10 mM mother liquor. Human neuroblastoma cells SH-SY5Y are inoculated into 96-well plates, the compounds are respectively added into culture media, diluted to 5.0, 2.5, 1.0, 0.5, 0.25 and 0.1 mu M, 5 compound holes are set in each group, after 24 hours of culture, a cell damage model is constructed by stimulation of hydrogen peroxide, after 24 hours of continuous culture, 10 mu L of CCK-8 reagent is added into each hole, and the culture is continued for 2 hours. The experiment was carried out in a normal control group and in a SH-SY5Y cell damage group caused by hydrogen peroxide. The cell viability was calculated by measuring OD values in 96-well plates on an enzyme-labeled instrument at a wavelength of 450 nm.
Cell viability (%) = (treatment OD-blank OD)/(control OD-blank OD) ×100%.
The test results are shown in Table 1.
TABLE 1 protection of nerve cell injury by Hydrogen peroxide by different Compounds
Note that: in the SH-SY5Y cell damage caused by hydrogen peroxide as a model, the cell survival rate (%) of a normal control group is 100, and the cell survival rate (%) of the SH-SY5Y cell damage group is 68.67 +/-2.82.
From the results shown in Table 1, it can be seen that the dihydrocannabidiol difurancarboxylate has the effect of antagonizing the oxidative stress of hydrogen peroxide on SH-SY5Y cells, and can improve the cell survival rate. And the activity of the dihydrocannabidiol difurancarboxylate is higher than that of the analogue thereof under the same concentration. The research results show that the dihydrocannabidiol difurancarboxylate has a protective effect on nerve cell injury.
EXAMPLE 3 determination of neuronal injury protection effect of Dihydrocannabidiol derivatives and their embedding System
Under aseptic conditions, the dihydrocannabidiol difuranformate and its embedding system (prepared in example 1), other dihydrocannabidiol derivatives and its embedding system (such as dihydrocannabidiol dimethyl benzoate, dihydrocannabidiol diisononanoate, dihydrocannabidiol dicaprylate, dihydrocannabidiol diacetate, dihydrocannabidiol dipelargonate) and CBD were dissolved in DMSO to prepare a 10 mM mother solution. Human neuroblastoma cells SH-SY5Y are inoculated into a 96-well plate, the above compounds and Pickering emulsion thereof are respectively added into a culture medium, diluted into 10.0, 2.5, 0.5 and 0.1 mu M of each group of 6 compound wells, after 24 hours of culture, a cell injury model is constructed by stimulation of hydrogen peroxide, after the culture is continued for 24 hours, 10 mu L of CCK-8 reagent is added into each well, and the culture is continued for 2 hours. The experiment was carried out in a normal control group and in a SH-SY5Y cell damage group caused by hydrogen peroxide. The cell viability was calculated by measuring OD values in 96-well plates on an enzyme-labeled instrument at a wavelength of 450 nm.
Cell viability (%) = (treatment OD-blank OD)/(control OD-blank OD) ×100%.
The test results are shown in Table 2.
TABLE 2 protection of different compounds and their embedding systems against SH-SY5Y cell damage by hydrogen peroxide
Note that: in the SH-SY5Y cell damage caused by hydrogen peroxide as a model, the cell survival rate (%) of a normal control group is 100+/-0, and the cell survival rate (%) of the SH-SY5Y cell damage group is 65 67+/-2.82 a 。
As can be seen from the results in Table 2, the CBD and the dihydrocannabidiol derivative and the embedding system thereof have the protection effect on SH-SY5Y cell damage caused by hydrogen peroxide, and the cytoprotection effect of the dihydrocannabidiol derivative and the embedding system thereof is best at 0.5 mu M. After embedding, the cytoprotective activity of the dihydrocannabidiol difurancarboxylate is obviously improved. The activity of the dihydrocannabidiol di-p-methyl benzoate after embedding is obviously improved, and the activity of the dihydrocannabidiol diisopelargonate, the dihydrocannabidiol dioctanoate, the dihydrocannabidiol diacetate and the dihydrocannabidiol dinonoate after embedding also has certain cytoprotective effect, but has no obvious difference with the activity before embedding, and even certain derivatives are reduced relative to the activity before embedding. The research results show that the dihydrocannabidiol derivative and the embedding system thereof have a certain effect of relieving SH-SY5Y cell damage caused by hydrogen peroxide, and the protective effect of the dihydrocannabidiol difurancarboxylate after embedding on SH-SY5Y cell damage caused by hydrogen peroxide is obviously improved.
EXAMPLE 4 determination of insulin resistance of Dihydrocannabidiol derivatives and embedding System thereof
Under aseptic conditions, the dihydrocannabidiol difuranformate and its embedding system (prepared in example 1), other dihydrocannabidiol derivatives and its embedding system (such as dihydrocannabidiol dimethyl benzoate, dihydrocannabidiol diisononanoate, dihydrocannabidiol dicaprylate, dihydrocannabidiol diacetate, dihydrocannabidiol dipelargonate) and CBD were dissolved in DMSO to prepare a 10 mM mother solution. Human hepatoma cells HepG2 are inoculated into a 96-well plate, an insulin resistance model is built by high-concentration insulin induction, after the culture is carried out for 24 hours, the compounds and Pickering emulsion thereof are added into a culture medium and diluted to 10.0, 2.5, 0.5 and 0.1 mu M respectively, after each group of 6 compound wells is continuously cultured for 24 hours, 5 mu L of supernatant is sucked from each well, 195 mu L of glucose content detection working solution is added, and the culture is incubated for 20 minutes at 37 ℃. Experimental setup of insulin resistance model group, metformin (10 -3 M) positive control group and compound experimental group. The OD value was measured by placing the 96-well plate on an enzyme-labeled instrument at 550 nm wavelength, and the glucose consumption was calculated.
Glucose consumption (μm) =5550- (OD-0.0554 per group)/0.0002.
The test results are shown in Table 3.
TABLE 3 hypoglycemic effects of different Compounds and their embedding systems on insulin-resistant liver cancer cell model
Note that: in the modified insulin resistance model, the glucose consumption of the insulin resistance model group is: 3122.18 + -183.29 a The method comprises the steps of carrying out a first treatment on the surface of the The metformin positive group was: 3845.57 + -103.96 g 。
As can be seen from the results in Table 3, the above-mentioned dihydrocannabidiol derivatives and the embedding system thereof all have the effect of reducing glucose in insulin resistant HepG2 cells, and the compound has the best effect of reducing glucose at 0.5. Mu.M. Among the above compounds, 0.5. Mu.M of the embedded dihydrocannabidiol difurancarboxylate had the highest hypoglycemic activity, which was closest to the positive control group and significantly improved compared to the hypoglycemic activity before embedding. The dihydrocannabidiol di-p-methyl benzoate, dihydrocannabidiol diisopelargonate, dihydrocannabidiol dioctanoate, dihydrocannabidiol diacetate and dihydrocannabidiol dinonoate also have a certain hypoglycemic effect after embedding, but have no significant difference from before embedding, even certain derivatives have reduced activity relative to the activity before embedding. The research results show that the dihydrocannabidiol derivative and the embedding system thereof have a certain relieving effect on the insulin resistance of HepG2 cells, and the relieving effect on the insulin resistance of the HepG2 cells is obviously improved after the dihydrocannabidiol difurancarboxylate is embedded.
Finally, it should be noted that: the above embodiments are only for illustrating the technical solution of the present invention, and not for limiting the same; although the invention has been described in detail with reference to the foregoing embodiments, it will be understood by those of ordinary skill in the art that: the technical scheme described in the foregoing embodiments can be modified or some or all of the technical features thereof can be replaced by equivalents; such modifications and substitutions do not depart from the spirit of the invention.

Claims (15)

1. The preparation method of the embedding system of the dihydrocannabidiol difurancarboxylate is characterized by comprising the following steps of:
(1) Preparation of dihydrocannabidiol difurancarboxylate:
a: mixing cannabidiol, an organic solvent A and a catalytic system to obtain dihydro cannabidiol;
b: mixing the dihydrocannabidiol, an organic solvent B, 2-furoyl chloride and an alkaline reagent to obtain dihydrocannabidiol difurancarboxylate;
(2) Preparing an embedding system:
dissolving the dihydrocannabidiol difurancarboxylate in an organic solvent C to obtain an oil solution, mixing the oil solution with a cellulose nanocrystalline suspension, and shearing to obtain an embedding system of the dihydrocannabidiol difurancarboxylate;
the structure of the dihydrocannabidiol difurancarboxylate is shown in formula I:
；
the organic solvent A is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene;
the catalyst system is 10% palladium/carbon catalyst and hydrogen;
the organic solvent B is selected from one or more of dichloromethane, cyclohexane, methanol, ethanol, isopropanol, diethyl ether, chloroform, propylene glycol, n-butanol, acetone, tetrahydrofuran and xylene;
the alkaline reagent is selected from one or more of triethylamine, dimethylamine, diethylamine, di-N-propylamine, diisopropylamine, N-ethylmethylamine, di-N-butylamine, diisobutylamine, di-sec-butylamine, di-tert-butylamine, dipentamine, di-N-octylamine, diallylamine, dicyclohexylamine and diphenylamine;
the organic solvent C is propylene glycol;
the shearing method is ultrasonic shearing.
2. The process of claim 1, wherein the organic solvent a is methylene chloride.
3. The preparation method according to claim 1, wherein the mass ratio of cannabidiol to the catalytic system is 10-30:1.
4. The method according to claim 1, wherein the hydrogen gas has a pressure of 1 to 5 MPa.
5. The process according to claim 1, wherein the organic solvent B is methylene chloride.
6. The process according to claim 1, wherein the molar ratio of dihydrocannabidiol to 2-furoyl chloride is 1:2-4.
7. The method according to claim 1, wherein the basic reagent is triethylamine.
8. The method according to claim 1, wherein the molar ratio of the dihydrocannabidiol to the alkaline agent is 1:2-4.
9. The preparation method according to claim 1, wherein the mass concentration of the oil solution is 0.1-5%.
10. The method of claim 1, wherein the volume ratio of the oil solution to the suspension of cellulose nanocrystals is 1:0.1-5.
11. The method according to claim 1, wherein the ultrasonic shearing parameters are: the ultrasonic power is 100-1000W, and the ultrasonic time is 1-10 min.
12. An embedding system of dihydrocannabidiol difurancarboxylate prepared by the method of any one of claims 1-11.
13. Use of the embedding system of dihydrocannabidiol difurancarboxylate as claimed in claim 12 for the preparation of a hypoglycemic agent.
14. The application of the dihydrocannabidiol difurancarboxylate in the preparation of hypoglycemic drugs is characterized in that the structure of the dihydrocannabidiol difurancarboxylate is shown as a formula I:
。
15. a pharmaceutical composition comprising dihydrocannabidiol difuranate, or a pharmaceutically acceptable salt thereof, or an embedding system of dihydrocannabidiol difuranate as claimed in claim 12;
the structure of the dihydrocannabidiol difurancarboxylate is shown in formula I:
。
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WO2012011112A1 (en) * 2010-07-22 2012-01-26 Yissum Research Development Company Of The Hebrew University Of Jerusalem, Ltd. Non psychoactive cannabinoids and uses thereof
WO2019232740A1 (en) * 2018-06-07 2019-12-12 汉义生物科技（北京）有限公司 Pharmaceutical composition for preventing diabetes and use thereof
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