CN112898190A - Cannabidiol derivative and preparation method thereof - Google Patents
Cannabidiol derivative and preparation method thereof Download PDFInfo
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- CN112898190A CN112898190A CN202110177223.5A CN202110177223A CN112898190A CN 112898190 A CN112898190 A CN 112898190A CN 202110177223 A CN202110177223 A CN 202110177223A CN 112898190 A CN112898190 A CN 112898190A
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- QHMBSVQNZZTUGM-ZWKOTPCHSA-N cannabidiol Chemical class OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-ZWKOTPCHSA-N 0.000 title claims abstract description 48
- 238000002360 preparation method Methods 0.000 title claims abstract description 9
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 17
- 150000001875 compounds Chemical class 0.000 claims description 146
- 238000006243 chemical reaction Methods 0.000 claims description 79
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 31
- 230000035484 reaction time Effects 0.000 claims description 17
- 239000003054 catalyst Substances 0.000 claims description 15
- 229910052757 nitrogen Inorganic materials 0.000 claims description 15
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 15
- -1 nitrogen heterocyclic compound Chemical class 0.000 claims description 15
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 0.000 claims description 10
- 238000000034 method Methods 0.000 claims description 10
- PHSPJQZRQAJPPF-UHFFFAOYSA-N N-alpha-Methylhistamine Chemical compound CNCCC1=CN=CN1 PHSPJQZRQAJPPF-UHFFFAOYSA-N 0.000 claims description 9
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- 230000009471 action Effects 0.000 claims description 6
- 125000003277 amino group Chemical group 0.000 claims description 6
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- 239000012279 sodium borohydride Substances 0.000 claims description 5
- 125000004178 (C1-C4) alkyl group Chemical group 0.000 claims description 4
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- 125000002496 methyl group Chemical group [H]C([H])([H])* 0.000 claims description 4
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- 125000001309 chloro group Chemical group Cl* 0.000 claims description 3
- 125000001495 ethyl group Chemical group [H]C([H])([H])C([H])([H])* 0.000 claims description 3
- 229910052731 fluorine Inorganic materials 0.000 claims description 3
- 125000001153 fluoro group Chemical group F* 0.000 claims description 3
- 229910052740 iodine Inorganic materials 0.000 claims description 3
- 125000001449 isopropyl group Chemical group [H]C([H])([H])C([H])(*)C([H])([H])[H] 0.000 claims description 3
- 125000001436 propyl group Chemical group [H]C([*])([H])C([H])([H])C([H])([H])[H] 0.000 claims description 3
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- 230000002441 reversible effect Effects 0.000 description 1
- 230000001225 therapeutic effect Effects 0.000 description 1
- 231100001274 therapeutic index Toxicity 0.000 description 1
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Abstract
The invention provides a cannabidiol derivative and a preparation method thereof. The cannabidiol derivative provided by the invention forms a specific structure shown in a formula I by improving a benzyl substituent and a side chain on the basis of CBD, and can improve the anti-inflammatory effect and reduce the toxicity.
Description
Technical Field
The invention relates to the field of medicines, and particularly relates to a cannabidiol derivative and a preparation method thereof.
Background
Of the 60 phytocannabinoids identified in cannabis extracts, the two most abundant major active ingredients are the psychoactive ingredient Δ 9-Tetrahydrocannabinol (THC) and the non-psychoactive ingredient Cannabidiol (CBD). Cannabinoids have shown a wide range of therapeutic effects, and many cannabinoids, especially CBD, have been shown to have potent anti-inflammatory and immunomodulatory activity. There are also studies in the prior art on the molecular design of CBD to improve the effect of CBD.
For example, the introduction of two methyl groups at the benzyl positions of the CBD carbon chains can obviously improve the anti-inflammatory activity of the CBD derivatives and reduce the expression of IL6 and TNF alpha mRNA (Jukant, A.J Basic clean physiological Pharmacol 2016,27(3), 289-96.). Again as CBD is more cytotoxic, LPS treated BV-2 cells showed significant death after 6h at 10. mu.M CBD concentration (Kozela, E.journal of biological chemistry2010,285(3), 1616-1626.). And Kinney, W.A. obtains KLS-13019(Kinney, W.A. ACS Med Chem Lett2016,7(4),424-8) by introducing a polar group into the carbon number 4 of the side chain, and the therapeutic index and the neuroprotective activity of the KLS-13019 are obviously improved.
However, the existing CBD and the derivatives thereof have poor anti-inflammatory effect and high toxicity, and the application of the CBD and the derivatives thereof is limited.
Disclosure of Invention
In view of the above, the present invention aims to provide a cannabidiol derivative and a preparation method thereof. The cannabidiol derivative provided by the invention can effectively improve the anti-inflammatory activity of CBD and reduce the cytotoxicity of CBD.
The invention provides a cannabidiol derivative which has a structure shown in a formula I:
wherein:
R1selected from the following structures:
R2selected from: h or C1-C4 alkyl;
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
n is 0 to 12.
Preferably, R2Selected from: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl;
the halogen is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
Preferably, the structure is selected from one or more of the structures shown in formula I-1 to formula I-9:
the invention also provides a preparation method of the cannabidiol derivative in the technical scheme, which comprises the following steps:
a) reacting compound X with benzyl bromide to form compound a;
b) reacting compound a with compound Y to form compound b;
c) reacting compound b with phosphorus tribromide to form compound c;
d) reacting compound c with a nitrogen heterocyclic compound to form compound d;
e) after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I;
or
Removing benzyl from compound d, reacting with trans-menthyl-2, 8-diene-1-ol, reacting with R3I reacting to form a compound of formula I;
wherein:
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
R4selected from: -COCH3or-CHO;
R1selected from the following structures:
the nitrogen heterocyclic compound is selected from one or more of the following compounds:
the compound Y is sodium borohydride or alkane of C1-C12.
Preferably, in the step a), the reaction temperature is 20-60 ℃ and the reaction time is 12-48 h;
the molar ratio of the compound X to the benzyl bromide is 1: 2-6.
Preferably, in step b):
the introduction temperature of the compound Y is-78 to-20 ℃,
the reaction temperature is 20-35 ℃, and the reaction time is 2-8 h;
the molar ratio of the compound a to the compound Y is 1: 1-3.
Preferably, in step c):
the reaction temperature is 20-120 ℃, and the reaction time is 4-12 h;
the molar ratio of the compound b to the phosphorus tribromide is 1: 1-3.
Preferably, in step d);
the reaction is carried out under the action of NaH;
the introduction temperature of the NaH is-40 to-20 ℃;
the reaction temperature is 20-100 ℃, and the reaction time is 12-48 h;
the molar ratio of the compound c to the nitrogen heterocyclic compound is 1: 1.5-3;
the molar ratio of the compound c to NaH is 1: 2-4.
Preferably, in step e):
the reaction temperature is 20-35 ℃, and the reaction time is 2-6 h.
Preferably, in step e):
R2is H, compound d is debenzylated and then reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in formula I;
or
R2Instead of H, compound d is debenzylated, reacted with trans-menthyl-2, 8-dien-1-ol and the resulting reaction mass is reacted with R2I reacting to form a compound of formula I;
the benzyl removal is carried out under the action of a Pd/C catalyst;
the molar ratio of the compound d to the Pd/C catalyst is 1: 0.5-1.5.
The cannabidiol derivative provided by the invention forms a specific structure shown in a formula I by improving a benzyl substituent and a side chain on the basis of CBD, and can improve the anti-inflammatory effect and reduce the toxicity. Experimental results show that the cannabidiol derivative provided by the invention can effectively reduce the concentration IC50 of NO generated by BV-2 cells treated by lipopolysaccharide, reduce the mRNA expression of inflammatory factors and reduce the Viability value in a cytotoxicity test, and shows better anti-inflammatory effect and lower cytotoxicity.
Drawings
In order to more clearly illustrate the embodiments of the present invention or the technical solutions in the prior art, the drawings used in the description of the embodiments or the prior art will be briefly described below, it is obvious that the drawings in the following description are only embodiments of the present invention, and for those skilled in the art, other drawings can be obtained according to the provided drawings without creative efforts.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product 1f obtained in example 1;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of the product 1f obtained in example 1;
FIG. 3 is a mass spectrum of the product 1f obtained in example 1;
FIG. 4 is a graph of the effect of CBD derivatives in inhibiting NO production and cytotoxicity in lipopolysaccharide treated BV-2 cells;
FIG. 5 is a graph showing the effect of CIAC003 on the inhibition of the production of mRNA by the inflammatory factor in CBD and the compound obtained in example 3;
FIG. 6 is a graph showing the effect of the compound CIAC003 obtained in example 3 on the mechanism of inhibition of inflammatory factors.
Detailed Description
The invention provides a cannabidiol derivative which has a structure shown in a formula I:
wherein:
R1selected from the following structures:
R2selected from: h or C1-C4 alkyl; preferably: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
R3Selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group; among them, the halogen is preferably a fluorine atom, a chlorine atom, a bromine atom or an iodine atom.
n is an integer of 0 to 12.
More preferably, the cannabidiol derivative shown in the formula I is selected from one or more of the structures shown in the formulae I-1 to I-9:
the cannabidiol derivative provided by the invention forms a structure shown in a formula I by improving a benzyl substituent and a side chain on the basis of CBD, and can improve the anti-inflammatory effect and reduce the toxicity.
The invention also provides a preparation method of the cannabidiol derivative in the technical scheme, which comprises the following steps:
a) reacting compound X with benzyl bromide to form compound a;
b) reacting compound a with compound Y to form compound b;
c) reacting compound b with phosphorus tribromide to form compound c;
d) reacting compound c with a nitrogen heterocyclic compound to form compound d;
e) after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I;
or
Removing benzyl from compound d, reacting with trans-menthyl-2, 8-diene-1-ol, reacting with R3I reacting to form a compound of formula I;
wherein:
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
R4selected from: -COCH3or-CHO;
R1selected from the following structures:
the nitrogen heterocyclic compound is selected from one or more of the following compounds:
the compound Y is sodium borohydride or alkane of C1-C12.
With respect to step a): compound X is reacted with benzyl bromide to form compound a.
The structures of the compound X and benzyl bromide are respectively as follows:
wherein R is3The above technical solutions are the same, and are not described herein again. R4Selected from: -COCH3or-CHO.
The molar ratio of the compound X to the benzyl bromide is preferably 1 to (2-6).
The reaction is preferably carried out under weakly basic conditions, which provide weakly basic conditions that enable the phenolic hydroxyl groups on compound X to ionize, forcing the reaction to proceed in the forward direction. The alkaline substance providing the weakly alkaline condition is preferably one or more of potassium carbonate, sodium hydroxide and sodium carbonate. The molar ratio of the weakly basic substance to the compound X is preferably (0.1-1) to 1.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of acetone, tetrahydrofuran, acetonitrile and N, N-dimethylformamide. The dosage ratio of the compound X to the solvent is preferably 1mmol to (5-20) mL.
The reaction temperature is preferably 20-60 ℃; the reaction time is preferably 12-48 h. After the above reaction, the compound a is produced in the system.
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-processing comprises: diluting the reaction system with water, extracting with ethyl acetate, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, and then, using dichloromethane and methanol as mobile phases, and performing gradient elution separation by using a silica gel column to obtain a product a.
Wherein R is3、R4The above technical solutions are the same, and are not described herein again. Bn represents benzyl, also known as benzyl.
With respect to step b): compound a is reacted with compound Y to form compound b.
The compound Y is sodium borohydride or alkane of C1-C12. The molar ratio of the compound a to the compound Y is preferably 1: 1-3. The introduction temperature of the compound Y is preferably-78 to-20 ℃.
The reaction is preferably carried out in an organic solvent medium. The organic solvent is preferably one or more of dichloromethane, methanol, tetrahydrofuran and N, N-dimethylformamide. The dosage ratio of the compound a to the organic solvent is preferably 1mmol to (10-20) mL.
Specifically, the compound a is dissolved in an organic solvent, the compound Y is added at a certain temperature, and after being uniformly stirred, the mixture is transferred to room temperature for reaction. The room temperature can be 20-35 ℃, and the reaction time is preferably 2-8 h. The compound b is produced through the reaction.
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: adding water to the system for quenching, separating organic phase, extracting water phase with ethyl acetate, combining organic phases, washing with saturated NaCl, anhydrous Na2SO4Drying and spin-drying the solvent to obtain the compound b.
With respect to step c): compound b is reacted with phosphorus tribromide to form compound c.
The mol ratio of the compound b to the phosphorus tribromide is preferably 1: 1-3.
The reaction is preferably carried out in a solvent. The solvent is preferably one or more of diethyl ether, toluene and N, N-dimethylformamide. The dosage ratio of the compound b to the solvent is preferably 1mmol to (1.5-3) mL.
The reaction temperature is preferably 20-120 ℃; the reaction time is preferably 4-12 h. After the reaction, compound c is produced.
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: adding saturated sodium bicarbonate to quench, separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated NaCl, and adding anhydrous Na2SO4Drying and spin-drying the solvent to obtain the compound c.
With respect to step d): compound c is reacted with a nitrogen heterocyclic compound to form compound d.
The nitrogen heterocyclic compound is selected from one or more of the following compounds:
the molar ratio of the compound c to the nitrogen heterocyclic compound is preferably 1 to (1.5-3).
The reaction is carried out under the action of NaH, the introduction of NaH can pull out H atoms on nitrogen heterocyclic rings, N is negatively charged, and C connected with bromine is relatively positively charged, so that the reaction of the N atoms and the N atoms is promoted. The mol ratio of the compound c to NaH is preferably 1 to (2-4). The introduction temperature of the NaH is preferably-40 to-20 ℃.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of anhydrous DMF, anhydrous THF and anhydrous N, N-dimethylacetamide.
Specifically, dissolving the nitrogen heterocyclic compound in a solvent, adding NaH, uniformly mixing, then dropwise adding a solution of a compound c, and controlling the reaction temperature to carry out reaction. Wherein the dosage ratio of the nitrogen heterocyclic compound to the solvent is preferably 1mmol to (1.5-3) mL. The solution of the compound c is a solution of the compound c dissolved in a solvent, and the using amount ratio of the compound c to the solvent is preferably 1mmol to (5-10) mL. Wherein, the solvent for dissolving the nitrogen heterocyclic compound is preferably the same as the solvent for dissolving the compound c; the solvent is of the same kind as the solvent medium described above. The reaction temperature is preferably 20-100 ℃, and the reaction time is preferably 12-48 h. After the reaction, compound d:
wherein R is3The above technical solutions are the same, and are not described herein again. R1Selected from the following structures:
in the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: diluting with water, extracting with diethyl ether, mixing organic phases, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, and gradient eluting with petroleum ether and ethyl acetate as mobile phase and silica gel column to obtain compound d.
With respect to step e): after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I; or compound d is debenzylated, then is reacted with trans-menthyl-2, 8-diene-1-alcohol, and the obtained reactant is reacted with R2I reacting to form the compound of formula I.
The reaction of compound d to remove benzyl groups preferably comprises: and dissolving the compound d in a solvent, adding a Pd/C catalyst, and introducing hydrogen to react to form a debenzylation compound e.
Wherein, the solvent is preferably one or more of methanol, ethyl acetate and ethanol. The preferable dosage ratio of the compound d to the solvent is 1mmol to (4-10) mL. The Pd/C catalyst is a palladium-carbon catalyst, the source of the Pd/C catalyst is not particularly limited, and the Pd/C catalyst is a general commercial product; in the present invention, the Pd/C catalyst is preferably a 10% Pd/C catalyst. In the present invention, the molar ratio of the compound d to the Pd/C catalyst is preferably 1: (0.5-1.5). The amount of the hydrogen gas is preferably such that the system gas pressure is 0.1013 to 0.2026 MPa. The reaction temperature is preferably 20-35 ℃, and the reaction time is preferably 2-8 h. After the reaction, debenzylation product e is generated:
wherein R is1、R3The above technical solutions are the same, and are not described herein again.
In the present invention, after the above-mentioned reaction for removing a benzyl group, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: and filtering the obtained reactant to remove the Pd/C catalyst, spin-drying the solvent, and then performing gradient elution separation by using dichloromethane and methanol as mobile phases through a silica gel column to obtain a compound e.
According to the invention, after compound e has been obtained, it is reacted with trans-menthyl-2, 8-dien-1-ol to form the compound of formula I (corresponding R)2Is H).
The trans-menthyl-2, 8-dien-1-ol has the following structure:
the molar ratio of the compound e to the trans-menthyl-2, 8-diene-1-ol is preferably 1 to (1.5-3).
The reaction is preferably carried out under the action of HCOOH, which is added to promote the formation of carbenium ions of trans-menthyl-2, 8-dien-1-ol which react with the benzene ring. The molar ratio of HCOOH to the compound e is preferably (1.5-3) to 1.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of dichloromethane and THF. The dosage ratio of the compound e to the solvent is preferably 1mmol to (5-20) mL.
The reaction temperature is preferably room temperature, and can be 20-35 ℃; the reaction time is preferably 2-8 h. After reaction, the compound of formula I (corresponding R) is produced2Is H).
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: adding saturated sodium bicarbonate to quench, separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, eluting with petroleum ether and ethyl acetate as mobile phase by silica gel column gradient to obtain compound of formula I (corresponding R)2Is H).
According to the invention, R is obtained2After the compound of the formula I which is H (denoted as compound f), it is reacted with R2I reaction to obtain R2Other compounds of formula I than H.
The R is2In I, R2Is C1-C4 alkyl. The compounds f and R2The molar ratio of I is preferably 1 to (1.2-2).
The reaction is preferably carried out under weakly basic conditions. The alkaline substance providing the weakly alkaline condition is preferably one or more of potassium carbonate, sodium carbonate and sodium hydroxide. The molar ratio of the weakly basic substance to the compound f is preferably (0.1-1) to 1.
The reaction is preferably carried out in a solvent medium. The solvent is preferably one or more of acetone, THF and acetonitrile. The dosage ratio of the compound f to the solvent is preferably 1mmol to (10-15) mL.
The reaction temperature is preferably 20-60 ℃, and the reaction time is preferably 8-16 h. After reaction, the compound (R) of formula I is produced2Not H).
In the present invention, after the above reaction, it is preferable to further perform a post-treatment. The post-treatment preferably comprises: diluting with water, extracting with ethyl acetate, mixing organic phases, washing with saturated NaCl, and extracting with anhydrous Na2SO4Drying, eluting with petroleum ether and ethyl acetate as mobile phase by silica gel column gradient to obtain compound of formula I (corresponding R)2Not H).
The preparation method provided by the invention is simple and feasible, has mild conditions, and can efficiently obtain the compound shown in the formula I.
For a further understanding of the invention, reference will now be made to the preferred embodiments of the invention by way of example, and it is to be understood that the description is intended to further illustrate features and advantages of the invention, and not to limit the scope of the claims.
EXAMPLE 1 Synthesis of CIAC001
The synthetic route is as follows:
the synthesis process is as follows:
s1, synthesis of compound 1 a:
3, 5-dihydroxy acetophenone (16mmol) and benzyl bromide (40mmol) were dissolved in acetone (50mL), potassium carbonate (32mmol) was added, and the reaction was refluxed at 65 ℃ overnight. After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, silica gel column chromatography with dichloromethane and methanol as mobile phase and gradient elution separated to obtain product 1a (95.4% yield).
S2, synthesis of compound 1 b:
compound 1a (5mmol) was dissolved in 110mL of a mixed solvent of dichloromethane and methanol (dichloromethane: methanol volume ratio: 10: 1), and sodium borohydride (6mmol) was added at-20 ℃ and stirred for 10 minutes, and then transferred to room temperature (25 ℃) to react for 2 hours. After the reaction is finished, adding water for quenching, separating an organic phase, extracting an aqueous phase by ethyl acetate, combining the organic phase, washing by saturated NaCl, and washing by anhydrous Na2SO4Drying and spin-drying the solvent gave compound 1b (97.9% yield).
S3, synthesis of compound 1 c:
compound 1b (4mmol) was dissolved in 50mL of diethyl ether, phosphorus tribromide (4.8mmol) was added, and the reaction was refluxed at 50 ℃ for 6 hours. Adding saturated sodium bicarbonate to quench after the reaction is finished, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phase, washing with saturated NaCl, and adding anhydrous Na2SO4Drying and spin-drying the solvent gave compound 1c (94.4% yield).
S4, synthesis of compound 1 d:
dissolving 1,2, 3-triazole (5mmol) in anhydrous DMF (50mL), adding NaH at-20 ℃, and stirring for 10min to obtain a reaction solution; compound 1c (2.5mmol) was dissolved in anhydrous DMF (5mL), and the resulting solution was added dropwise to the above reaction mixture, and the mixture was transferred to 120 ℃ for reaction for 24 hours. After the reaction is finished, adding water for dilution, extracting by diethyl ether, combining organic phases, washing by saturated NaCl, and anhydrous Na2SO4Drying, silica gel column chromatography, petroleum ether and ethyl acetate as mobile phase, gradient elution to obtain product 1d (25.2% yield).
S5, synthesis of compound 1 e:
compound 1d (2mmol) was dissolved in 22mL of a mixed solvent (methanol: ethyl acetate volume ratio: 10: 1), Pd/C catalyst (10% w/vPd/C, 200mg) was added, and reaction was carried out for 4h with hydrogen gas. After the reaction, Pd/C was removed by filtration, the solvent was dried by evaporation, and the product 1e was isolated by gradient elution on a silica gel column using dichloromethane and methanol as mobile phases (yield 80.4%).
S6, synthesis of compound 1 f:
dissolving the compound 1e (1mmol) in dichloromethane (5mL), adding trans-menthyl-2, 8-diene-1-ol (2mmol),HCOOH (2mmol), room temperature (25 ℃) for 12 h. After the reaction is finished, adding saturated sodium bicarbonate to quench the reaction, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phase, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, separating with silica gel column and gradient elution with petroleum ether and ethyl acetate as mobile phase to obtain product 1f (purity 97.5%).
Structural characterization of the obtained product 1f is shown in fig. 1-3, fig. 1 is a nuclear magnetic resonance hydrogen spectrum of the product 1f obtained in example 1, fig. 2 is a nuclear magnetic resonance carbon spectrum of the product 1f obtained in example 1, and fig. 3 is a mass spectrum of the product 1f obtained in example 1.
Example 2 Synthesis of CIAC002
The synthetic route is as follows:
the synthesis process is as follows:
s1, synthesis of compound 2 a:
3, 5-dihydroxybenzaldehyde (26mmol) and benzyl bromide (65mmol) were dissolved in acetone (100mL), potassium carbonate (52mmol) was added, and the reaction was refluxed at 60 ℃ overnight. After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, silica gel column chromatography with dichloromethane and methanol as mobile phase and gradient elution to obtain product 2a (yield 90.2%).
S2, synthesis of compound 2 b:
compound 2a (10mmol) was dissolved in 100mL of anhydrous dichloromethane, n-butyl (15mmol) was added at-20 ℃ and reacted at room temperature (25 ℃) for 2 h. After the reaction is finished, adding water for quenching, separating an organic phase, extracting an aqueous phase by ethyl acetate, combining the organic phase, washing by saturated NaCl, and washing by anhydrous Na2SO4Drying and spin-drying the solvent gave compound 2b (92.9% yield).
S3, synthesis of compound 2 c:
compound 2b (8mmol) was dissolved in 50mL of diethyl ether, phosphorus tribromide (9.6mmol) was added, and the reaction was refluxed at 50 ℃ for 6 hours. After the reaction is finished, saturated sodium bicarbonate is addedQuenching, separating organic phase, extracting water phase with ethyl acetate, mixing organic phases, washing with saturated NaCl, and removing anhydrous Na2SO4Drying and spin-drying the solvent gave compound 2c (96.2% yield).
S4, synthesis of compound 2 d:
dissolving imidazole (10mmol) in anhydrous DMF (100mL), adding NaH at-20 ℃, and stirring for 10min to obtain a reaction solution; compound 2c (5mmol) was dissolved in anhydrous DMF (8mL), and the resulting solution was added dropwise to the above reaction mixture, and the mixture was transferred to 120 ℃ for reaction for 24 hours. After the reaction is finished, adding water for dilution, extracting by diethyl ether, combining organic phases, washing by saturated NaCl, and anhydrous Na2SO4Drying, silica gel column chromatography, petroleum ether and ethyl acetate as mobile phase, gradient elution to obtain product 2d (30.4% yield).
S5, synthesis of compound 2 e:
compound 2d (4mmol) was dissolved in 50mL of a mixed solvent (methanol: ethyl acetate volume ratio: 10: 1), Pd/C catalyst (10% w/vPd/C, 400mg) was added, and reaction was carried out for 4h with hydrogen gas. After the reaction, the Pd/C was removed by filtration, the solvent was dried by evaporation, and the product 2e was isolated by gradient elution on a silica gel column using dichloromethane and methanol as mobile phases (yield 76.4%).
S6, synthesis of compound 2 f:
compound 2e (2mmol) was dissolved in dichloromethane (10mL), and trans-menthyl-2, 8-dien-1-ol (4mmol), HCOOH (4mmol) were added and reacted at room temperature (25 ℃ C.) for 12h (product yield 27.8%). After the reaction is finished, adding saturated sodium bicarbonate to quench the reaction, separating an organic phase, extracting an aqueous phase with ethyl acetate, combining the organic phase, washing with saturated NaCl, and adding anhydrous Na2SO4Drying, silica gel column chromatography, petroleum ether and ethyl acetate as mobile phase, gradient elution separation to obtain product 2f (purity 95.2%).
EXAMPLE 3 Synthesis of Compound CIAC002
The synthetic route is as follows:
the synthesis process is as follows:
S1-S6: the same as in example 2.
S7, synthesis of compound 2 g:
compound 2f (1mmol) was dissolved in acetone (8mL) and CH was added3I (2.5mmol), potassium carbonate (2mmol) and reflux overnight (94.1% yield of product). After the reaction is finished, water is added for dilution, ethyl acetate is used for extraction, organic phases are combined, saturated NaCl is used for washing, and anhydrous Na2SO4Drying, silica gel column, petroleum ether and ethyl acetate as mobile phase, gradient elution separation to obtain 2g of product (yield 80.3%, purity 98.1%).
Example 4
Anti-inflammatory and cytotoxic assays
S1, cell count, 5X 10 in DMEM medium (10% serum, 1% double antibody)4Cell density per mL, 200 μ L per well of 96-well plate, and incubation for 24 h.
S2, removing the culture medium, adding 200 mu L of DMEM culture medium without serum and double antibodies, simultaneously adding different doses of the drugs, and incubating for 24 h.
S3, NO concentration test: mu.L of the medium was added with 10. mu.L of 2, 3-diaminonaphthalene solution (concentration: 0.5mg/mL), incubated for 15min, and then 5. mu.L of NaOH solution (concentration: 3M) was added to terminate the reaction. And exciting at 360nm, and detecting the light absorption value at 430 nm. The test results are shown in FIG. 1.
S4, cytotoxicity test: removing residual culture medium, adding 100 μ L paraformaldehyde solution (concentration of 5% w/v), incubating for 5min, removing paraformaldehyde, adding 100 μ L crystal violet (concentration of 0.5% w/v), incubating for 15min, removing crystal violet, washing with distilled water for 3 times, adding 150 μ L anhydrous ethanol, incubating for 20min, and testing absorbance value at 540 nm. The test results are shown in FIG. 4.
The above test was carried out with CBD (cannabidiol) and the compound CIAC001 synthesized in example 1, respectively, as the drugs, and the results are shown in fig. 4. FIG. 4 is a graph showing the effects of CBD derivatives in inhibiting the production of NO by BV-2 cells treated with lipopolysaccharide, wherein A is the anti-inflammatory effect of CBD, C is the anti-inflammatory effect of CIAC001 of the compound in example 1, B is the cytotoxicity effect of CBD, and D is the cytotoxicity effect of CIAC001 of the compound in example 1.
In fig. 4, the A, C graph shows the content of Nitric Oxide (NO), which induces inflammation and thus increases the amount of NO released when Lipopolysaccharide (LPS) is treated on the cells, and in this experiment, the change in NO after the addition of different doses of the drug is measured using the NO content of the non-dosed LPS group as 100%, and the concentration of the drug required when the NO content becomes 50% of the non-dosed LPS group, i.e., IC50, is calculated by fitting, so that a lower value of IC50 indicates a better anti-inflammatory effect of the drug.
In FIG. 4, the B, D graph shows the cytotoxicity of the drug, and this experiment shows that the number of living cells was measured by crystal violet staining, the LPS treatment group without the drug was regarded as 100%, the change in the number of living cells after the addition of the drug at different concentrations was measured, and the concentration of the drug at which the living cells became 50% of the LPS treatment group without the drug, i.e., the Viability, was calculated by fitting, so that the greater the value of Viability, the less the toxicity.
As can be seen from the test results in fig. 4, the IC50 and viatility values of the compound CIAC001 obtained in example 1 are both improved compared with CBD, which demonstrates that it has improved anti-inflammatory effect and reduced toxicity.
Example 5
Anti-inflammatory test
S1, cell count, 5X 10 in DMEM medium (10% serum, 1% double antibody)4Cell density/mL, 2mL per well of 6-well plate, incubate for 24 h.
S2, removing the culture medium, adding 2mL of DMEM culture medium without serum and double antibodies, adding different doses of drugs, and incubating for 6 h.
S3, removing the culture medium, washing with 1mL of PBS buffer solution for 2 times, adding 1mL of Trizol cell lysate, and incubating for 5 min. The lysate was transferred to a 1mL RNA-free centrifuge tube, 200. mu.L chloroform was added, vortexed for 1min, 12000g, and centrifuged at 4 ℃ for 10 min. Adding 400 μ L isopropanol into 400 μ L supernatant, mixing, standing on ice for 10min, then 12000g, centrifuging at 4 deg.C for 7 min. The supernatant was removed, and 1mL of the mixed solution (ethanol: DEPC aqueous solution volume ratio: 3:1) was added thereto, 12000g was added, and the mixture was centrifuged at 4 ℃ for 5 min. Removing supernatant, standing on ice for 3min, adding 25 μ L DEPC water solution, mixing, measuring RNA concentration, and reverse transcribing to cDNA.
And S4, determining the cDNA concentration, configuring the template amount to 600ng/mL, adding DNA synthetase and different primers to carry out qPCR amplification, and determining the content of different genes.
Test effects referring to fig. 5-6, the test experiments of fig. 5 and 6 were performed in the same manner except that the primers were used. Wherein, the effect of CBD derivatives on the inhibition of the generation of inflammatory factor mRNA is shown in FIG. 5, and FIG. 5 is a graph showing the effect of CBD and the compound CIAC003 obtained in example 3 on the inhibition of the generation of inflammatory factor mRNA. FIG. 5 shows the measurement of the mRNA level of inflammatory factors, and 3 selected genes are inflammatory factors positively correlated with the intensity of inflammation; when LPS is added, the inflammatory factors in the Control group are obviously improved, which indicates that inflammation is caused after LPS treatment, when CBD is given, IL-1 beta is inhibited only under the concentration of 10 mu M, and CIAC003 has obvious down-regulation on 3 inflammatory factors under the concentration of 1 mu M, and has dose-dependent benefit under the concentration of 10 mu M, therefore, CIAC003 can better reduce the mRNA expression of the inflammatory factors compared with CBD, and has better anti-inflammatory effect.
The research on the mechanism of inhibiting inflammatory factors by CBD derivatives is shown in figure 6, and figure 6 is a diagram of the research effect of the compound CIAC003 obtained in example 3 on the mechanism of inhibiting inflammatory factors. As can be seen from FIG. 6, after LPS treatment, microglia cells change from resting state M0 to activated state M1, M1 cells release a large amount of proinflammatory factors, which leads to deepening of inflammation, while the body can convert M1 cells to M2 cells, and M2 cells release anti-inflammatory factors, which has an inflammation inhibiting effect, thereby protecting the microglia cells. In the figure, IL-1 beta, IL-6 and iNOS are specific inflammatory factors of M1 state, and are all obviously reduced after CIAC003 is added, which indicates that M1 state cells are reduced. On the other hand, the specific inflammatory factor IL-10 in M2 state is obviously up-regulated after CIAC003 is added, which indicates that the cells in M2 state are increased. Thus, CIAC003 achieves anti-inflammatory effects by promoting the conversion of microglia from the M1 state to the M2 state.
The above description of the embodiments is only intended to facilitate the understanding of the method of the invention and its core idea. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles defined herein may be applied to other embodiments without departing from the spirit or scope of the invention. Thus, the present invention is not intended to be limited to the embodiments shown herein but is to be accorded the widest scope consistent with the principles and novel features disclosed herein.
Claims (10)
2. The cannabidiol derivative of claim 1, wherein R is2Selected from: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl;
the halogen is selected from fluorine atom, chlorine atom, bromine atom or iodine atom.
4. a method of preparing a cannabidiol derivative as claimed in any one of claims 1 to 3, comprising the steps of:
a) reacting compound X with benzyl bromide to form compound a;
b) reacting compound a with compound Y to form compound b;
c) reacting compound b with phosphorus tribromide to form compound c;
d) reacting compound c with a nitrogen heterocyclic compound to form compound d;
e) after the compound d is subjected to benzyl removal, the compound d reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in the formula I;
or
Removing benzyl from compound d, reacting with trans-menthyl-2, 8-diene-1-ol, reacting with R3I reacting to form a compound of formula I;
wherein:
R3selected from: a hydrogen atom, a halogen, a carboxyl group or an amino group;
R4selected from: -COCH3or-CHO;
R1selected from the following structures:
the nitrogen heterocyclic compound is selected from one or more of the following compounds:
the compound Y is sodium borohydride or alkane of C1-C12.
5. The preparation method according to claim 4, wherein in the step a), the reaction temperature is 20-60 ℃ and the reaction time is 12-48 h;
the molar ratio of the compound X to the benzyl bromide is 1: 2-6.
6. The method of claim 4, wherein in step b):
the introduction temperature of the compound Y is-78 to-20 ℃,
the reaction temperature is 20-35 ℃, and the reaction time is 2-8 h;
the molar ratio of the compound a to the compound Y is 1: 1-3.
7. The method of claim 4, wherein in step c):
the reaction temperature is 20-120 ℃, and the reaction time is 4-12 h;
the molar ratio of the compound b to the phosphorus tribromide is 1: 1-3.
8. The method according to claim 4, wherein in the step d);
the reaction is carried out under the action of NaH;
the introduction temperature of the NaH is-40 to-20 ℃;
the reaction temperature is 20-100 ℃, and the reaction time is 12-48 h;
the molar ratio of the compound c to the nitrogen heterocyclic compound is 1: 1.5-3;
the molar ratio of the compound c to NaH is 1: 2-4.
9. The method of claim 4, wherein in step e):
the reaction temperature is 20-35 ℃, and the reaction time is 2-6 h.
10. The method of claim 4, wherein in step e):
R2is H, compound d is debenzylated and then reacts with trans-menthyl-2, 8-diene-1-ol to form a compound shown in formula I;
or
R2Instead of H, compound d is debenzylated, reacted with trans-menthyl-2, 8-dien-1-ol and the resulting reaction mass is reacted with R2I reacting to form a compound of formula I;
the benzyl removal is carried out under the action of a Pd/C catalyst;
the molar ratio of the compound d to the Pd/C catalyst is 1: 0.5-1.5.
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