CN112898190B - Cannabidiol derivative and preparation method thereof - Google Patents
Cannabidiol derivative and preparation method thereof Download PDFInfo
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- CN112898190B CN112898190B CN202110177223.5A CN202110177223A CN112898190B CN 112898190 B CN112898190 B CN 112898190B CN 202110177223 A CN202110177223 A CN 202110177223A CN 112898190 B CN112898190 B CN 112898190B
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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 10
- 125000001797 benzyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C([H])([H])* 0.000 claims abstract description 19
- 150000001875 compounds Chemical class 0.000 claims description 141
- 238000006243 chemical reaction Methods 0.000 claims description 78
- KDLHZDBZIXYQEI-UHFFFAOYSA-N Palladium Chemical compound [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 claims description 23
- 230000035484 reaction time Effects 0.000 claims description 16
- 239000003054 catalyst Substances 0.000 claims description 15
- 238000000034 method Methods 0.000 claims description 12
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- IJGRMHOSHXDMSA-UHFFFAOYSA-N nitrogen Substances N#N IJGRMHOSHXDMSA-UHFFFAOYSA-N 0.000 claims description 12
- -1 nitrogen heterocyclic compound Chemical class 0.000 claims description 12
- AGEZXYOZHKGVCM-UHFFFAOYSA-N benzyl bromide Chemical compound BrCC1=CC=CC=C1 AGEZXYOZHKGVCM-UHFFFAOYSA-N 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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- 239000003153 chemical reaction reagent Substances 0.000 claims description 2
- 230000002152 alkylating effect Effects 0.000 claims 1
- QHMBSVQNZZTUGM-UHFFFAOYSA-N Trans-Cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CCC(C)=C1 QHMBSVQNZZTUGM-UHFFFAOYSA-N 0.000 abstract description 25
- 229950011318 cannabidiol Drugs 0.000 abstract description 25
- ZTGXAWYVTLUPDT-UHFFFAOYSA-N cannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1C1C(C(C)=C)CC=C(C)C1 ZTGXAWYVTLUPDT-UHFFFAOYSA-N 0.000 abstract description 25
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- PCXRACLQFPRCBB-ZWKOTPCHSA-N dihydrocannabidiol Natural products OC1=CC(CCCCC)=CC(O)=C1[C@H]1[C@H](C(C)C)CCC(C)=C1 PCXRACLQFPRCBB-ZWKOTPCHSA-N 0.000 description 24
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- HBENZIXOGRCSQN-VQWWACLZSA-N (1S,2S,6R,14R,15R,16R)-5-(cyclopropylmethyl)-16-[(2S)-2-hydroxy-3,3-dimethylpentan-2-yl]-15-methoxy-13-oxa-5-azahexacyclo[13.2.2.12,8.01,6.02,14.012,20]icosa-8(20),9,11-trien-11-ol Chemical compound N1([C@@H]2CC=3C4=C(C(=CC=3)O)O[C@H]3[C@@]5(OC)CC[C@@]2([C@@]43CC1)C[C@@H]5[C@](C)(O)C(C)(C)CC)CC1CC1 HBENZIXOGRCSQN-VQWWACLZSA-N 0.000 description 3
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Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
- C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
- C07D207/30—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members
- C07D207/32—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
- C07D207/325—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms with substituted hydrocarbon radicals directly attached to the ring nitrogen atom
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
- C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
- C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
- C07D233/60—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms with hydrocarbon radicals, substituted by oxygen or sulfur atoms, attached to ring nitrogen atoms
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
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- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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 on the basis of CBD through improvement of a benzyl substituent and side chain improvement, and can improve the anti-inflammatory effect and reduce the toxicity.
Description
Technical Field
The invention relates to the field of medicines, in particular to a cannabidiol derivative and a preparation method thereof.
Background
Of the 60 more phytocannabinoids identified in cannabis extracts, the most abundant two major active ingredients are the psychoactive ingredient Δ9-Tetrahydrocannabinol (THC) and the non-psychoactive ingredient Cannabidiol (CBD). Cannabinoids have shown a broad therapeutic spectrum, and many cannabinoids, especially CBD, have been shown to have potent anti-inflammatory and immunomodulatory activity. There are also studies in the prior art to design molecules for CBD to improve the effect of CBD.
For example, juknat, A. Introduction of two methyl groups at the benzyl position of the CBD carbon chain significantly increases the anti-inflammatory activity of the CBD derivative and decreases IL6 and TNFα mRNA expression (Juknat, A.J Basic Clin Physiol Pharmacol2016,27 (3), 289-96.). Again, as CBD was more cytotoxic, LPS-treated BV-2 cells showed significant death after 6h at a CBD concentration of 10. Mu.M (Kozela, E.journal of Biological Chemistry 2010,285 (3), 1616-1626.). And Kinney, W.A. obtains KLS-13019 by introducing a polar group into the side chain carbon number 4 (Kinney, W.A. ACS Med Chem Lett 2016,7 (4), 424-8), the therapeutic index and neuroprotective activity are markedly improved.
However, the existing CBD and its derivatives have poor anti-inflammatory effect and high toxicity, and limit the application of the CBD and its derivatives.
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 the CBD.
The invention provides a cannabidiol derivative, which has a structure shown as a formula I:
wherein:
R 1 selected from the following structures:
R 2 selected from: h or C1-C4 alkyl;
R 3 selected from: a hydrogen atom, halogen, carboxyl or amino group;
n is 0 to 12.
Preferably, R 2 Selected 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, one or more selected from the structures shown in the formulas I-1 to I-9:
the invention also provides a preparation method of the cannabidiol derivative in the technical scheme, which comprises the following steps:
a) Reacting the compound X with benzyl bromide to form a 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 the compound c with an azacyclic compound to form a compound d;
e) Removing benzyl from the compound d, and reacting the compound d with trans-menthyl-2, 8-dien-1-ol to form a compound of formula I;
or (b)
Removing benzyl group from compound d, reacting with trans-menthyl-2, 8-dien-1-ol, and reacting with R 3 I, reacting to form a compound shown as a formula I;
wherein:
R 3 selected from: a hydrogen atom, halogen, carboxyl or amino group;
R 4 selected from: COCH (chip on board) 3 or-CHO;
R 1 selected 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 C1-C12 alkane.
Preferably, in the step a), the reaction temperature is 20-60 ℃ and the reaction time is 12-48 h;
the mol ratio of the compound X to the benzyl bromide is 1:2-6.
Preferably, in the 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 mol ratio of the compound a to the compound Y is 1:1-3.
Preferably, in the step c):
the reaction temperature is 20-120 ℃ and the reaction time is 4-12 h;
the mol ratio of the compound b to the phosphorus tribromide is 1:1-3.
Preferably, in said step d);
the reaction is carried out under the action of NaH;
the introduction temperature of NaH is-40 to-20 ℃;
the reaction temperature is 20-100 ℃ and the reaction time is 12-48 h;
the mol 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 the step e):
the reaction temperature is 20-35 ℃ and the reaction time is 2-6 h.
Preferably, in the step e):
R 2 for H, after removal of the benzyl group, compound d is reacted with trans-menthyl-2, 8-dien-1-ol to form a compound of formula I;
or (b)
R 2 Removing benzyl from compound d, reacting with trans-menthyl-2, 8-dien-1-ol, and reacting with R 2 I, reacting to form a compound shown as a formula I;
the benzyl removal is carried out under the action of Pd/C catalyst;
the mol 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 on the basis of CBD through improvement of a benzyl substituent and side chain improvement, 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 drug concentration IC50 of NO generated by BV-2 cells treated by lipopolysaccharide, reduce the expression of inflammatory factor mRNA and reduce the Viability value in cytotoxicity test, and has 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 that are required to be used in the embodiments or the description of the prior art will be briefly described below, and it is obvious that the drawings in the following description are only embodiments of the present invention, and that other drawings can be obtained according to the provided drawings without inventive effort for a person skilled in the art.
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of a product 1f obtained in example 1;
FIG. 2 is a nuclear magnetic resonance 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 showing the effect of CBD derivatives in inhibiting the production of NO and cytotoxicity of lipopolysaccharide-treated BV-2 cells;
FIG. 5 is a graph showing the effect of CBD and CIAC003, which is a compound obtained in example 3, on inhibiting the production of inflammatory factor mRNA;
FIG. 6 is a graph showing the effect of the compound CIAC003 obtained in example 3 on the inhibition of inflammatory factors.
Detailed Description
The invention provides a cannabidiol derivative, which has a structure shown as a formula I:
wherein:
R 1 selected from the following structures:
R 2 selected from: h or C1-C4 alkyl; preferably, it is: methyl, ethyl, propyl, isopropyl, n-butyl or tert-butyl.
R 3 Selected from: a hydrogen atom, halogen, carboxyl or amino group; among them, 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 represented by formula I is selected from one or more of structures represented by formulas I-1 to I-9:
the cannabidiol derivative provided by the invention forms a structure shown in a formula I on the basis of CBD through improvement of a benzyl substituent and side chain improvement, 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 the compound X with benzyl bromide to form a 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 the compound c with an azacyclic compound to form a compound d;
e) Removing benzyl from the compound d, and reacting the compound d with trans-menthyl-2, 8-dien-1-ol to form a compound of formula I;
or (b)
Removing benzyl group from compound d, reacting with trans-menthyl-2, 8-dien-1-ol, and reacting with R 3 I, reacting to form a compound shown as a formula I;
wherein:
R 3 selected from: a hydrogen atom, halogen, carboxyl or amino group;
R 4 selected from: COCH (chip on board) 3 or-CHO;
R 1 selected 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 C1-C12 alkane.
Regarding step a): compound X reacts with benzyl bromide to form compound a.
The structures of the compound X and benzyl bromide are respectively as follows:
wherein R is 3 In accordance with the above technical solutions, no further description is given here. R is R 4 Selected from: COCH (chip on board) 3 or-CHO.
The molar ratio of the compound X to the benzyl bromide is preferably 1:2-6.
The reaction is preferably carried out under weakly basic conditions, which provide weakly basic conditions capable of ionizing the phenolic hydroxyl groups on compound X, promoting the reaction 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 to 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 temperature of the reaction is preferably 20-60 ℃; the reaction time is preferably 12 to 48 hours. After the above reaction, the compound a is produced in the system.
In the present invention, it is preferable to further carry out a post-treatment after the above reaction. The post-processing includes: the reaction system was diluted with water, extracted with ethyl acetate, washed with saturated NaCl, and dried Na 2 SO 4 Drying, and then, gradient elution and separation are carried out by using methylene dichloride and methanol as mobile phases and a silica gel column, so that a product a is obtained.
Wherein R is 3 、R 4 In accordance with the above technical solutions, no further description is given here. Bn represents benzyl, also known as benzyl.
Regarding step b): compound a reacts with compound Y to form compound b.
The compound Y is sodium borohydride or C1-C12 alkane. 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, compound a is dissolved in an organic solvent, then compound Y is added at a certain temperature, and after stirring and mixing, the mixture is transferred to room temperature for reaction. The room temperature may be specifically 20-35 ℃, and the reaction time is preferably 2-8 hours. Through the above reaction, the compound b is produced.
In the present invention, it is preferable to further carry out a post-treatment after the above reaction. The post-treatment preferably comprises: adding water to quench the system, separating organic phase, extracting with ethyl acetateThe aqueous phase was taken, the organic phases were combined, washed with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying the solvent to obtain compound b.
Regarding step c): compound b reacts with phosphorus tribromide to form compound c.
The molar 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 temperature of the reaction is preferably 20-120 ℃; the reaction time is preferably 4 to 12 hours. After the reaction, the compound c is produced.
In the present invention, it is preferable to further carry out a post-treatment after the above reaction. The post-treatment preferably comprises: adding saturated sodium bicarbonate to quench, separating the organic phase, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with saturated NaCl, anhydrous Na 2 SO 4 Drying and spin-drying the solvent to obtain compound c.
Regarding step d): compound c reacts with the 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: (1.5-3).
The reaction is carried out under the action of NaH, the H atom on the N of the nitrogen heterocycle can be pulled out by introducing NaH, N is negatively charged, and bromine-connected C is relatively positively charged, so that the reaction of the two is promoted. The molar ratio of the compound c to NaH is preferably 1:2-4. The introduction temperature of 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, the nitrogen heterocyclic compound is dissolved in a solvent, naH is added to be mixed uniformly, then the solution of the compound c is added dropwise, and the reaction temperature is controlled to carry out the 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 dosage ratio of the compound c to the solution is preferably 1mmol to (5-10) mL. Wherein the solvent in which the nitrogen heterocyclic compound is dissolved is preferably the same as the solvent in which the compound c is dissolved; the kind of the solvent is the same as the solvent medium. The reaction temperature is preferably 20-100 ℃, and the reaction time is preferably 12-48 h. After reaction, compound d is produced:
wherein R is 3 In accordance with the above technical solutions, no further description is given here. R is R 1 Selected from the following structures:
in the present invention, it is preferable to further carry out a post-treatment after the above reaction. The post-treatment preferably comprises: diluting with water, extracting with diethyl ether, mixing organic phases, washing with saturated NaCl, and anhydrous Na 2 SO 4 Drying, and then, using petroleum ether and ethyl acetate as mobile phases, and performing gradient elution and separation by using a silica gel column to obtain the compound d.
Regarding step e): removing benzyl from the compound d, and reacting the compound d with trans-menthyl-2, 8-dien-1-ol to form a compound of formula I; or removing benzyl group from compound d, reacting with trans-menthyl-2, 8-dien-1-ol, and reacting the obtained reactant with R 2 I, to form the compound of formula I.
The reaction of removing benzyl groups of the compound d preferably comprises: the compound d is dissolved in a solvent, a Pd/C catalyst is added, and hydrogen is introduced for reaction, so that a debenzylated compound e is formed.
Wherein the solvent is preferably one or more of methanol, ethyl acetate and ethanol. The dosage ratio of the compound d to the solvent is preferably 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 common 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 to 1.5. The amount of the hydrogen gas to be introduced is preferably such that the system pressure is 0.1013 to 0.2026MPa. The reaction temperature is preferably 20-35 ℃, and the reaction time is preferably 2-8 h. After reaction, debenzylation product e:
wherein R is 1 、R 3 In accordance with the above technical solutions, no further description is given here.
In the present invention, it is preferable to further carry out a post-treatment after the above-mentioned benzyl group removal reaction. The post-treatment preferably comprises: the obtained reactant is filtered to remove Pd/C catalyst, then the solvent is dried by spin, and then dichloromethane and methanol are taken as mobile phases, and gradient elution and separation are carried out by a silica gel column to obtain the compound e.
According to the invention, after obtaining compound e, it is reacted with trans-menthyl-2, 8-dien-1-ol to form a compound of formula I (corresponding R 2 H).
The structure of the trans-menthyl-2, 8-dien-1-ol is as follows:
the molar ratio of the compound e to the trans-menthyl-2, 8-dien-1-ol is preferably 1:1.5-3.
The reaction is preferably carried out under the action of HCOOH, which is added to promote the reaction of trans-menthyl-2, 8-dien-1-ol to form a carbonium ion with the benzene ring. The molar ratio of HCOOH to 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 temperature of the reaction is preferably room temperature, and can be specifically 20-35 ℃; the reaction time is preferably 2 to 8 hours. After reaction, a compound of formula I (corresponding R 2 H).
In the present invention, it is preferable to further carry out a post-treatment after the above reaction. The post-treatment preferably comprises: adding saturated sodium bicarbonate to quench, separating the organic phase, extracting the aqueous phase with ethyl acetate, combining the organic phases, washing with saturated NaCl, anhydrous Na 2 SO 4 Drying, and gradient eluting with petroleum ether and ethyl acetate as mobile phase to obtain compound of formula I (corresponding R) 2 H).
According to the invention, R is obtained 2 After the compound of formula I (denoted as compound f) being H, it is reacted with R 2 I, R can be obtained 2 Other compounds of formula I than H.
The R is 2 In I, R 2 Is C1-C4 alkyl. The compounds f and R 2 The molar ratio of I is preferably 1:1.2-2.
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 to 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, a compound of formula I (R 2 Not H).
In the present invention, it is preferable to further carry out a post-treatment after the above reaction. The post-treatment preferably comprises: into the systemDiluting with water, extracting with ethyl acetate, mixing the organic phases, washing with saturated NaCl, anhydrous Na 2 SO 4 Drying, and gradient eluting with petroleum ether and ethyl acetate as mobile phase to obtain compound of formula I (corresponding R) 2 Not H).
The preparation method provided by the invention is simple and easy to implement, has mild conditions, and can be used for efficiently obtaining the compound shown in the formula I.
For a further understanding of the present invention, preferred embodiments of the invention are described below in conjunction with the examples, but it should be understood that these descriptions are merely intended to illustrate further features and advantages of the invention, and are not limiting of the claims of the invention.
EXAMPLE 1 Synthesis of CIAC001
The synthetic route is as follows:
the synthesis process is as follows:
s1, synthesizing a compound 1a:
3, 5-dihydroxyacetophenone (16 mmol) and benzyl bromide (40 mmol) were dissolved in acetone (50 mL), potassium carbonate (32 mmol) was added and the reaction was refluxed at 65℃overnight. After the reaction was completed, water was added to dilute, ethyl acetate was used for extraction, and the organic phases were combined, washed with saturated NaCl and dried Na 2 SO 4 Drying, and gradient elution with silica gel column using dichloromethane and methanol as mobile phase afforded product 1a (95.4% yield).
S2, synthesizing a compound 1b:
compound 1a (5 mmol) was dissolved in 110mL of a mixed solvent of dichloromethane and methanol (dichloromethane: methanol volume ratio=10:1), sodium borohydride (6 mmol) was added at-20 ℃, stirred for 10 minutes, and then transferred to room temperature (25 ℃) for 2 hours. After the reaction is completed, adding water for quenching, separating an organic phase, extracting an aqueous phase by ethyl acetate, combining the organic phases, washing by saturated NaCl and anhydrous Na 2 SO 4 Drying and spin-drying the solvent gave compound 1b (97.9% yield).
S3, synthesizing a compound 1c:
compound 1b (4 mmol) was dissolved in 50mL of diethyl ether, phosphorus tribromide (4.8 mmol) was added and the reaction was refluxed at 50℃for 6h. After the reaction is completed, saturated sodium bicarbonate is added for quenching, the organic phase is separated, the aqueous phase is extracted by ethyl acetate, the organic phase is combined, saturated NaCl is used for washing, and anhydrous Na is used for 2 SO 4 Drying and spin-drying the solvent gave compound 1c (94.4% yield).
S4, synthesizing a compound 1d:
1,2, 3-triazole (5 mmol) was dissolved in anhydrous DMF (50 mL), naH was added at-20℃and stirred for 10min to give a reaction solution; compound 1c (2.5 mmol) was dissolved in anhydrous DMF (5 mL), the resulting solution was added dropwise to the reaction solution, and the mixture was transferred to 120℃for reaction for 24h. After the reaction was completed, water was added to dilute, ether was used for extraction, and the organic phases were combined, washed with saturated NaCl and with anhydrous Na 2 SO 4 Drying, and gradient eluting with silica gel column using petroleum ether and ethyl acetate as mobile phase to obtain product 1d (yield 25.2%).
S5, synthesizing a compound 1e:
compound 1d (2 mmol) was dissolved in 22mL of mixed solvent (methanol: ethyl acetate volume ratio=10:1), pd/C catalyst (10% w/vPd/C,200 mg) was added, and hydrogen was introduced for reaction for 4h. After the reaction was completed, pd/C was removed by filtration, the solvent was dried by spin-drying, and the product 1e (yield 80.4%) was obtained by gradient elution with a silica gel column using methylene chloride and methanol as mobile phases.
S6, synthesizing a compound 1f:
compound 1e (1 mmol) was dissolved in dichloromethane (5 mL), trans-menthyl-2, 8-dien-1-ol (2 mmol) and HCOOH (2 mmol) were added and reacted at room temperature (25 ℃ C.) for 12h. After the reaction is completed, saturated sodium bicarbonate is added to quench the reaction, the organic phase is separated, the aqueous phase is extracted by ethyl acetate, the organic phases are combined, saturated NaCl is used for washing, and anhydrous Na is used for 2 SO 4 Drying, and gradient eluting with silica gel column using petroleum ether and ethyl acetate as mobile phase to obtain product 1f (purity 97.5%).
The 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, synthesizing a compound 2a:
3, 5-dihydroxybenzaldehyde (26 mmol) and benzyl bromide (65 mmol) were dissolved in acetone (100 mL), potassium carbonate (52 mmol) was added, and the mixture was reacted at 60℃under reflux overnight. After the reaction was completed, water was added to dilute, ethyl acetate was used for extraction, and the organic phases were combined, washed with saturated NaCl and dried Na 2 SO 4 Drying, and gradient elution with silica gel column using dichloromethane and methanol as mobile phase afforded product 2a (90.2% yield).
S2, synthesizing a compound 2b:
compound 2a (10 mmol) was dissolved in 100mL of anhydrous dichloromethane, n-butylating reagent (15 mmol) was added at-20℃and reacted at room temperature (25 ℃) for 2h. After the reaction is completed, adding water for quenching, separating an organic phase, extracting an aqueous phase by ethyl acetate, combining the organic phases, washing by saturated NaCl and anhydrous Na 2 SO 4 Drying and spin-drying the solvent gave compound 2b (92.9% yield).
S3, synthesizing a compound 2c:
compound 2b (8 mmol) was dissolved in 50mL of diethyl ether, phosphorus tribromide (9.6 mmol) was added and the reaction was refluxed at 50℃for 6h. After the reaction is completed, saturated sodium bicarbonate is added for quenching, the organic phase is separated, the aqueous phase is extracted by ethyl acetate, the organic phase is combined, saturated NaCl is used for washing, and anhydrous Na is used for 2 SO 4 Drying and spin-drying the solvent gave compound 2c (96.2% yield).
S4, synthesizing a compound 2d:
imidazole (10 mmol) is dissolved in anhydrous DMF (100 mL), naH is added at-20 ℃ and stirred for 10min to obtain a reaction solution; compound 2c (5 mmol) was dissolved in anhydrous DMF (8 mL), the resulting solution was added dropwise to the reaction solution, and the mixture was transferred to 120℃for reaction24h. After the reaction was completed, water was added to dilute, ether was used for extraction, and the organic phases were combined, washed with saturated NaCl and with anhydrous Na 2 SO 4 Drying, and gradient eluting with silica gel column using petroleum ether and ethyl acetate as mobile phase to obtain product 2d (yield 30.4%).
S5, synthesizing a compound 2e:
compound 2d (4 mmol) was dissolved in 50mL of mixed solvent (methanol: ethyl acetate volume ratio=10:1), pd/C catalyst (10% w/vPd/C,400 mg) was added, and hydrogen was introduced for reaction for 4h. After the reaction was completed, pd/C was removed by filtration, the solvent was dried by spin-drying, and the product 2e (yield 76.4%) was obtained by gradient elution with a silica gel column using methylene chloride and methanol as mobile phases.
S6, synthesizing a compound 2f:
compound 2e (2 mmol) was dissolved in dichloromethane (10 mL) and trans-menthyl-2, 8-dien-1-ol (4 mmol), HCOOH (4 mmol) was added and reacted at room temperature (25 ℃ C.) for 12h (product yield 27.8%). After the reaction is completed, saturated sodium bicarbonate is added to quench the reaction, the organic phase is separated, the aqueous phase is extracted by ethyl acetate, the organic phases are combined, saturated NaCl is used for washing, and anhydrous Na is used for 2 SO 4 Drying, and gradient eluting with silica gel column and petroleum ether and ethyl acetate as mobile phase 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: as in example 2.
S7, synthesizing 2g of a compound:
compound 2f (1 mmol) was dissolved in acetone (8 mL) and CH was added 3 I (2.5 mmol), potassium carbonate (2 mmol) and reflux overnight (94.1% product yield). After the reaction was completed, water was added to dilute, ethyl acetate was used for extraction, and the organic phases were combined, washed with saturated NaCl and dried Na 2 SO 4 Drying, and purifying with silica gel column and petroleumThe ether and ethyl acetate were mobile phases and the product was isolated 2g (80.3% yield, 98.1% purity) by gradient elution.
Example 4
Anti-inflammatory and cytotoxic assays
S1, cell count, 5×10 with DMEM medium (10% serum, 1% diabody) 4 Cell density/mL, 200. Mu.L per well of 96-well plate was added and incubated for 24h.
S2, removing the culture medium, adding 200 mu L of DMEM culture medium without serum and double antibodies, adding different doses of medicaments, and incubating for 24 hours.
S3, testing the concentration of NO: mu.L of the medium was taken, 10. Mu.L of 2, 3-diaminonaphthalene solution (concentration: 0.5 mg/mL) was added, incubated for 15min, and then 5. Mu.L of NaOH solution (concentration: 3M) was added to terminate the reaction. Excitation was performed at 360nm and absorbance at 430nm was measured. The test results are shown in FIG. 1.
S4, cytotoxicity test: removing the residual culture medium, adding 100 mu L of paraformaldehyde solution (with the concentration of 5% w/v), incubating for 5min, removing paraformaldehyde, adding 100 mu L of crystal violet (with the concentration of 0.5% w/v), incubating for 15min, removing crystal violet, washing 3 times with distilled water, adding 150 mu L of absolute ethyl alcohol, incubating for 20min, and testing the absorbance value at 540 nm. The test results are shown in fig. 4.
The above test was carried out using CBD (cannabidiol) and the compound CIAC001 synthesized in example 1 as drugs, respectively, 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 and cytotoxicity of BV-2 cells treated with lipopolysaccharide, wherein A is a graph showing the anti-inflammatory test effect of CBD, C is a graph showing the anti-inflammatory test effect of the compound CIAC001 of example 1, B is a graph showing the cytotoxicity test effect of CBD, and D is a graph showing the cytotoxicity test effect of the compound CIAC001 of example 1.
In FIG. 4, the graph A, C shows the amount of Nitric Oxide (NO), and when Lipopolysaccharide (LPS) is treated on cells, inflammation is induced to increase the amount of NO released, in this experiment, the change of NO after adding different doses of drugs is measured with the amount of NO in the non-drug LPS group as 100%, and the IC50, which is the concentration of drug required for calculating the amount of NO by fitting to 50% of the non-drug LPS group, is calculated, so that the lower the IC50 value, the better the anti-inflammatory effect of the drug is.
In fig. 4, B, D graph shows cytotoxicity of the drug, and in this experiment, the number of living cells was measured by crystal violet staining, the number of living cells was changed after the addition of different concentrations of the drug was measured by taking the group treated with LPS without drug as 100%, and the drug concentration, i.e., the Viability, at which the living cells became 50% of the group treated with LPS without drug was calculated by fitting, so that the toxicity was smaller as the Viability value was larger.
As can be seen from the test results of fig. 4, the compound CIAC001 obtained in example 1 has improved IC50 and Viability values compared to CBD, which proves that it has improved anti-inflammatory effect and reduced toxicity.
Example 5
Anti-inflammatory test
S1, cell count, 5×10 with DMEM medium (10% serum, 1% diabody) 4 Cell density/mL, 2mL per well of 6-well plate was added and incubated for 24h.
S2, removing the culture medium, adding 2mL of DMEM culture medium without serum and double antibodies, adding different doses of medicines, and incubating for 6h.
S3, removing the culture medium, washing with 1mL of PBS buffer solution for 2 times, adding 1mL of Trizol cell lysate, and incubating for 5min. The lysate was transferred to a 1mL RNA-free centrifuge tube, 200. Mu.L chloroform was added, and the mixture was centrifuged at 12000g for 10min at 4℃with vortexing. 400. Mu.L of isopropyl alcohol was added to 400. Mu.L of the supernatant, and the mixture was left on ice for 10 minutes after mixing, and then centrifuged at 12000g at 4℃for 7 minutes. The supernatant was removed, 1mL of the mixed solution (ethanol: DEPC aqueous solution volume ratio=3:1) was added, 12000g was centrifuged at 4℃for 5min. Removing the supernatant, standing on ice for 3min, adding 25 mu L DEPC water solution, mixing uniformly, measuring RNA concentration, and performing reverse transcription to obtain cDNA.
S4, measuring cDNA concentration, preparing 600ng/mL template, adding DNA synthetase and different primers for qPCR amplification, and measuring the content of different genes.
Test results referring to fig. 5-6, the test experiments of fig. 5 and 6 were performed in accordance with the above procedure except that primers were used. The effect of CBD derivatives in inhibiting the production 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 in inhibiting the production of inflammatory factor mRNA. FIG. 5 shows the mRNA content of inflammatory factors, and the selected 3 genes are all inflammatory factors positively correlated with the intensity of inflammation; when LPS is added, the inflammatory factors of the Control group are obviously improved, which shows that the LPS treatment induces inflammation, when CBD is given, the CBD only has an inhibiting effect on IL-1 beta at the concentration of 10 mu M, while CIAC003 has obvious downregulation on 3 inflammatory factors at the concentration of 1 mu M and has dose-dependent benefit at the concentration of 10 mu M, so that the CIAC003 can better reduce the mRNA expression of the inflammatory factors and has better anti-inflammatory effect compared with the CBD.
The mechanism of the CBD derivative for inhibiting inflammatory factors is explored in FIG. 6, and FIG. 6 is a diagram showing the effect of the mechanism of the compound CIAC003 obtained in example 3 for inhibiting inflammatory factors. As can be seen from fig. 6, after the microglial LPS treatment, the resting state M0 is changed to the activated state M1, the M1 cells release a large amount of pro-inflammatory factors, which results in deepening the inflammation, the body converts the M1 cells to the M2 state, and the M2 state releases anti-inflammatory factors, which has an effect of inhibiting the inflammation, thereby protecting itself. In the figure, IL-1 beta, IL-6 and iNOS are M1 state specific inflammatory factors, and the three are obviously down-regulated after CIAC003 is added, thus indicating that M1 state cells are reduced. On the other hand, the M2-state specific inflammatory factor IL-10 is obviously up-regulated after CIAC003 is added, which indicates that M2-state cells are increased. CIAC003 achieves an anti-inflammatory effect by promoting conversion of microglial cells from M1 to M2.
The above description of the embodiments is only for aiding in the understanding of the method of the present invention and its core ideas. 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 (9)
1. A cannabidiol derivative having a structure represented by formula i:
wherein:
R 1 selected from the following structures:
R 2 selected from: h is formed;
R 3 selected from: a hydrogen atom;
n is 0 to 3.
2. The cannabidiol derivative according to claim 1, wherein the cannabidiol derivative is selected from one or more of structures represented by formulas i-1 to i-4:
3. a process for the preparation of a cannabidiol derivative as claimed in any one of claims 1-2, comprising the steps of:
a) Reacting the compound X with benzyl bromide to form a 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 the compound c with an azacyclic compound to form a compound d;
e) Removing benzyl from the compound d, and reacting the compound d with trans-menthyl-2, 8-dien-1-ol to form a compound of formula I;
wherein:
R 3 selected from: a hydrogen atom;
R 4 selected from: COCH (chip on board) 3 or-CHO;
R 2 selected from: h is formed;
R 1 selected 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 a C1-C4 alkylating reagent.
4. The method according to claim 3, wherein in the step a), the reaction is carried out at a temperature of 20 to 60 ℃ for a time of 12 to 48 hours;
the mol ratio of the compound X to the benzyl bromide is 1:2-6.
5. A method according to claim 3, 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 mol ratio of the compound a to the compound Y is 1:1-3.
6. A method according to claim 3, wherein in step c):
the reaction temperature is 20-120 ℃ and the reaction time is 4-12 h;
the mol ratio of the compound b to the phosphorus tribromide is 1:1-3.
7. A method of preparation according to claim 3, wherein in step d);
the reaction is carried out under the action of NaH;
the introduction temperature of NaH is-40 to-20 ℃;
the reaction temperature is 20-100 ℃ and the reaction time is 12-48 h;
the mol 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.
8. A method according to claim 3, wherein in step e):
the reaction temperature is 20-35 ℃ and the reaction time is 2-6 h.
9. A method according to claim 3, wherein in step e):
the benzyl removal is carried out under the action of Pd/C catalyst;
the mol ratio of the compound d to the Pd/C catalyst is 1:0.5-1.5.
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| CN106456573A (en) * | 2014-01-13 | 2017-02-22 | 康纳生物技术有限公司 | Novel functionalized 1,3-benzene diols for the treatment of hepatic encephalopathy and their method of use |
| CN108024973A (en) * | 2015-07-16 | 2018-05-11 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | CBD compounds, its composition and the purposes of fluorination |
| WO2021000053A1 (en) * | 2019-07-04 | 2021-01-07 | Canopy Growth Corporation | Cannabinoid derivatives |
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| US9517989B2 (en) * | 2012-10-17 | 2016-12-13 | Northeastern University | 2-cycloalkyl resorcinol cannabinergic ligands |
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| CN106456573A (en) * | 2014-01-13 | 2017-02-22 | 康纳生物技术有限公司 | Novel functionalized 1,3-benzene diols for the treatment of hepatic encephalopathy and their method of use |
| CN108024973A (en) * | 2015-07-16 | 2018-05-11 | 耶路撒冷希伯来大学伊森姆研究发展有限公司 | CBD compounds, its composition and the purposes of fluorination |
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