CN118084627A - Preparation method of cannabigerol and analogues thereof - Google Patents

Preparation method of cannabigerol and analogues thereof Download PDF

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CN118084627A
CN118084627A CN202410051176.3A CN202410051176A CN118084627A CN 118084627 A CN118084627 A CN 118084627A CN 202410051176 A CN202410051176 A CN 202410051176A CN 118084627 A CN118084627 A CN 118084627A
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biphenyl
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cycloalkyl
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CN118084627B (en
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柯庆勇
陈云
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Xiamen Walker Ward Medical Technology Co ltd
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    • C07C39/00—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring
    • C07C39/18—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring
    • C07C39/19—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring monocyclic with unsaturation outside the aromatic ring containing carbon-to-carbon double bonds but no carbon-to-carbon triple bonds
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    • C07C37/00—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring
    • C07C37/50—Preparation of compounds having hydroxy or O-metal groups bound to a carbon atom of a six-membered aromatic ring by reactions decreasing the number of carbon atoms
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    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
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    • C07C39/205—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings
    • C07C39/21—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing only six-membered aromatic rings as cyclic parts with unsaturation outside the rings with at least one hydroxy group on a non-condensed ring
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    • C07C39/23—Compounds having at least one hydroxy or O-metal group bound to a carbon atom of a six-membered aromatic ring polycyclic, containing six-membered aromatic rings and other rings, with unsaturation outside the aromatic rings
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    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/307—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by introduction of halogen; by substitution of halogen atoms by other halogen atoms
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    • C07C67/00—Preparation of carboxylic acid esters
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    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
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Abstract

The invention belongs to the field of medicine synthesis, and provides a method for synthesizing cannabigerol and analogues thereof. The synthetic method comprises the steps that 4, 6-dihydroxyl-2-alkyl isophthalate (compound 1) is taken as an initial raw material, a halogenation reaction is carried out under the action of a halogenating reagent to obtain a compound 2, and the compound 2-1 are subjected to Suzuki Cross-Coupling under an alkaline condition to obtain a compound 3; compound 3 is subjected to basic hydrolysis and acidic decarboxylation to afford the target compound 4. The preparation process of cannabigerol and analogues thereof developed by the invention has the remarkable advantages of short steps, good reaction selectivity, single product and the like.

Description

Preparation method of cannabigerol and analogues thereof
Technical Field
The invention relates to the technical field of medicine synthesis, in particular to a preparation method of cannabigerol and analogues thereof.
Background
Cannabigerol (Cannabigerol, CBG) is a non-psychoactive and non-addictive cannabinoid, and has great potential in lowering glaucoma tension, treating inflammatory bowel disease, inhibiting colon cancer, treating huntington's disease, resisting bacteria, diminishing inflammation, treating psoriasis, and the like, and also has the functions of resisting depression, regulating appetite, helping sleep and emotion regulation, improving immunity, and the like. At present, cannabigerol is mainly extracted from industrial cannabis, but the content of cannabis plant seeds is less than 1% and the cannabigerol does not have extraction value. Therefore, how to realize a large amount of synthesis of cannabigerol and its analogues is attracting attention in the field of research.
Tetrahedron Letters,1968,60,5349-5352;W02014013428IAl;W020160030828A1;WO2021237371;J.Nat.Prod.2020,83,2587-2591 And the like provides a scheme for preparing cannabigerol (2) by Friedel-Crafts alkylation reaction of olive alcohol and geraniol or linalool under the catalysis of acid or Lewis acid, and the scheme is accompanied with the generation of major byproducts such as a position isomer (1), a polyalkyl substituent (3) and the like. The main problem of the route is that the reaction yield is low and the separation and purification difficulty is high.
WO2020249184 provides a scheme for increasing the selectivity of the alkylation reaction by blocking one site on the benzene ring with an ester. The olive alcohol methyl ester is used as a starting material and is subjected to Friedel-Crafts alkylation reaction with geraniol under the action of boron trifluoride diethyl ether to obtain cannabigerol methyl esterification product (5), positional isomer (4) and the like. The physical and chemical properties of the cannabigerol methyl esterification product (5) are obviously different from those of the over-alkylated byproducts (high boiling point) and the unreacted geraniol (low boiling point), and the pure product of the cannabigerol methyl esterification product (5) can be obtained through distillation, chromatographic purification and recrystallization, but the yield is only 6 percent. The methyl ester is hydrolyzed and decarboxylated under alkaline condition to obtain cannabigerol (2) with the yield of 50 percent.
In addition, WO2017011210 and WO2020249184, etc., provide a scheme for the highly selective alkylation of position 4 using halogen to block both side reaction sites in position 2 and 6 of the phenyl ring of olive alcohol. The liquid bromine reacts with olive alcohol at the temperature of minus 30 ℃ to obtain dibromo olive alcohol (6, yield is 73%), friedel-Crafts alkylation is carried out to obtain (7), and sodium sulfite dehalogenation is carried out to obtain the target product cannabigerol (2).
Bromine only slightly deactivates the aromatic ring, has little effect on alkylation, and reversibility of the bromination process enables it to be used as a protecting group. According to the scheme provided by CN116217352, the bromine can also selectively replace the No. 4 (9) of the olive alcohol, the yield is up to 90%, which indicates that under the action of liquid bromine, the possibility of coexistence of single substitution and multiple substitution (10) exists, and the difficulty of obtaining the No. 2 and No. 6 dibromo products (6) with high selectivity is high. In addition, WO2020243588A1 shows that 5 different substitution results, such as mono-, di-and tri-substitution, can be obtained by reacting aqueous hydrogen bromide with olive alcohol.
In conclusion, the electronic cloud density of the oleuropein is higher, the control of the halogenation reaction site and the regioselectivity are difficult to realize by simply adjusting the bromination reagent and the reaction condition, more proper substituent groups need to be developed to seal the No. 2 position and the No. 6 position of the oleuropein benzene ring, the side reaction is controlled, and the efficient and directional synthesis of cannabigerol (2) and analogues thereof by utilizing Friedel-Crafts alkylation reaction is ensured.
Disclosure of Invention
In order to solve the technical problems, the invention provides a chemical synthesis method of cannabigerol and analogues thereof, which comprises the steps of taking 4, 6-dihydroxyl-2-alkyl isophthalate (compound 1) as a starting material, carrying out bromination reaction under the action of a brominating reagent to obtain a compound 2, and carrying out Suzuki Cross-Coupling on the compound 2-1 under alkaline conditions to obtain a compound 3; compound 3 is subjected to basic hydrolysis and acidic decarboxylation to afford the target compound 4. The preparation process of cannabigerol and analogues thereof developed by the invention has the remarkable advantages of short steps, good reaction selectivity, single product and the like. The synthesis route is classical chemical reaction, the condition is mild, the byproducts are few, the product is easy to purify, the process cost is low, and the industrial mass production is easy to realize.
Specifically, the invention provides a method for synthesizing cannabigerol and analogues thereof, which comprises the following steps:
S1: compound 1 is reacted with a halogenating agent to form compound 2;
s2: the compound 2 and the compound 2-1 are subjected to a coupling reaction to generate a compound 3;
S3: decarboxylation reaction of the compound 3 to obtain a compound 4;
wherein, the cannabigerol and analogues thereof have the structure shown in the compound 4;
R 1 and R 2 are each independently C 1-10 alkyl or C 3-6 cycloalkyl;
r 3 is C 1-12 alkyl, C 2-10 alkynyl, C 2-10 alkenyl, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, 5-to 10-membered heteroaryl or C 6-10 aryl; optionally, C 1-12 alkyl, C 2-10 alkynyl, C 2-10 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 6-10 aryl are each independently substituted with 1, 2, 3, or 4 substituents selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl;
n is 1, 2 or 3.
In some embodiments of the present invention, in some embodiments,
R 1 and R 2 are each independently C 1-6 alkyl or C 3-6 cycloalkyl;
R 3 is C 1-10 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, 5-to 10-membered heteroaryl or C 6-10 aryl; optionally, C 1-10 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 6-10 aryl are each independently substituted with 1,2, 3, or 4 substituents selected from C 1-10 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, or C 6-10 aryl.
In some embodiments, R 1 and R 2 are each independently methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl, or cyclopentyl;
R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, propenyl, butenyl, propynyl or butynyl; optionally, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, propenyl, butenyl, propynyl and butynyl are each independently substituted with 1, 2, 3 or 4 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, propenyl, butenyl, propynyl and butynyl.
In some embodiments, the cannabigerol and its analogues are selected from the following structures:
in some embodiments, the molar ratio of compound 1 to the halogenating agent is 1: (0.4-1.5).
In some embodiments, the molar ratio of compound 1 to the halogenating agent is 1: (0.5-1.2).
In some embodiments, the halogenating agent is selected from a chlorinating agent, a brominating agent, or an iodinating agent; preferably, the halogenating reagent is selected from chlorine, N-chlorosuccinimide (NCS), thionyl chloride, phosphorus pentachloride, carbon tetrachloride, dichlorohydantoin (DCDMH), hydrobromic acid, bromine, N-bromosuccinimide (NBS), N-bromophthalimide (NBSac), dibromohydantoin (DBH), pyridinium tribromide (PyHBr 3), carbon tetrabromide, dibromocyanoacetamide (DBNPA), 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-trione (DBI), N-bromophthalimide (NBP), elemental iodine, N-iodosuccinimide (NIS), iodine chloride (ICl), potassium iodide or cuprous iodide.
In some embodiments, the molar ratio of compound 2 to compound 2-1 is 1: (1.0-2.0).
In some embodiments, the molar ratio of compound 2 to compound 2-1 is 1: (1.1-1.5).
In some embodiments, the coupling reaction is performed in an organic solvent under the influence of a palladium catalyst and a first base;
Wherein the palladium catalyst is selected from the group consisting of chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) ] palladium (II) (XPhos-Pd-G2), methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (tBuXPhos-Pd-G3), chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos-Pd-G2), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (SPhos-Pd-G2), methanesulfonic acid (2-dicyclohexylphosphino-3, 6' -dimethoxy-2 ',4' -biphenyl-2 ',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (BrettPhos-Pd-G3) and chloro [ (tricyclohexylphosphine) -2- (2-aminobiphenyl) ] palladium (II) (PCy 3-Pd-G2);
The first base is selected from potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate or sodium hydride;
The organic solvent is selected from 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, acetonitrile, toluene, tertiary butanol, ethanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane or cyclopentyl methyl ether.
In some embodiments, compound 3 is hydrolyzed in a second aqueous base solution prior to decarboxylation by an acid.
In some embodiments, the second aqueous base solution is an aqueous solution of one or a mixture of any ratio of potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate; the molar ratio of compound 3 to the second base is 1: (8-15).
In some embodiments, the second aqueous base concentration is 20 wt% to 30wt%.
In some embodiments, the acid is one of hydrochloric acid, sulfuric acid, phosphoric acid, or a mixture of any ratio; the molar ratio of compound 3 to the acid is 1: (10-20).
In some embodiments, the acid is concentrated sulfuric acid.
Description of the terms
Reference will now be made in detail to certain embodiments of the application, examples of which are illustrated in the accompanying structural and chemical formulas. The application is intended to cover all alternatives, modifications and equivalents, which may be included within the scope of the application as defined by the appended claims. Those skilled in the art will recognize that many methods and materials similar or equivalent to those described herein can be used in the practice of the present application. The present application is in no way limited to the methods and materials described herein. In the event of one or more of the incorporated references, patents and similar materials differing from or contradictory to the present application (including but not limited to defined terms, term application, described techniques, etc.), the present application controls.
It should further be appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.
Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. All patents and publications referred to herein are incorporated by reference in their entirety.
In the description of the present specification, a description referring to terms "one embodiment," "some embodiments," "examples," "specific examples," or "some examples," etc., means that a particular feature, structure, material, or characteristic described in connection with the embodiment or example is included in at least one embodiment or example of the present invention. In this specification, schematic representations of the above terms are not necessarily directed to the same embodiment or example. Furthermore, the particular features, structures, materials, or characteristics described may be combined in any suitable manner in any one or more embodiments or examples. Furthermore, the different embodiments or examples described in this specification and the features of the different embodiments or examples may be combined and combined by those skilled in the art without contradiction.
In the following, all numbers disclosed herein are approximate, whether or not the word "about" or "about" is used. The numerical value of each number may vary by 1%, 2%, 5%, 7%, 8%, 10%, 15% or 20%. Whenever a number is disclosed having a value of N, any number having a value of N+/-1%, N+/-2%, N+/-3%, N+/-5%, N+/-7%, N+/-8%, N+/-10%, N+/-15% or N+/-20% is explicitly disclosed, where "+/-" means plus or minus.
Detailed Description
The present invention will be described in further detail with reference to the following examples in order to make the objects, technical solutions and advantages of the present invention more apparent. The specific embodiments described herein are for purposes of illustration only and are not to be construed as limiting the invention in any way. In addition, in the following description, descriptions of well-known structures and techniques are omitted so as not to unnecessarily obscure the concepts of the present disclosure. Such structures and techniques are also described in a number of publications.
The reagents used in the present invention are all commercially available or can be prepared by the methods described herein.
Synthesis of intermediates
The synthesis of compounds 1a-1d can be found in the patent: a preparation method of cannabidiol intermediate (application number or patent number: 202310458229.9) is disclosed. The preparation method takes acetoacetic acid alkyl ester and different aldehydes as starting materials, and can be prepared with high yield through Knoevenagel condensation, michael addition, intramolecular Aldol condensation, aromatization, decarboxylation and other reactions.
When (when)
Compound 1a: r 1＝Me,R2＝R3＝t-Bu,R4＝R5 =h, n=3; MS (ESI) m/z 381.49.
Compound 1b: r 1＝R4＝R5＝Me,R2＝R3 =t-Bu, n=5; MS (ESI) m/z 437.60.
Compound 1c: r 1＝Ph,R2＝R3＝t-Bu,R4＝R5 =h, n=1; MS (ESI) m/z 415.51.
Compound 1d: r 1＝R2＝R3＝Me,R4＝R5 =h, n=3; MS (ESI) m/z 279.33.
The synthesis of the compound 1e can be referred to Journal ofOrganic Chemistry (1988), 53 (23), 5568-9, NC 1709858, JP2003277331 and the like, and dinitrated intermediates are prepared by using simple and easily available bulk material olive alcohol as a starting material through the steps of sulfonation, nitration, desulfonation and the like; pd/H 2 catalytic hydrogenation reduction of nitro groups gives compound 1e, cf. CN1569813, EP1048644 and CN112500545.
Compound 1e: MS (ESI) m/z 211.29.
Example 1
Synthesis of Compound 2a
Dibromocyanoacetamide (DBNPA, 51 mmol) was added to a tetrahydrofuran mixture of compound 1a (100 mmol) at-10℃and stirred for 1.5 hours after the addition, at-5 ℃. The reaction mixture was quenched with a saturated aqueous solution of sodium thiosulfate, then extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give compound 2a,90mmol, as a pale yellow solid, 97% pure, 90% yield, MS (ESI) m/z 460.39[ M+H ] +.
Synthesis of Compound 3a
Compound 2a (90 mmol), compound 2a-1 (99 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (XPhos-Pd-G2, 0.9 mmol) and tripotassium phosphate aqueous solution (1M) were sequentially added to a reaction flask containing THF (3V) and reacted at 80 ℃ for 6 hours. The reaction was cooled to room temperature, extracted with water, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the resulting crude product was crystallized with a mixed solvent of toluene and n-heptane to give compound 3a,83mmol, an off-white solid, purity 98%, yield 92.2%, MS (ESI) m/z 517.73[ M+H ] +.
Synthesis of Compound 4a
An aqueous potassium hydroxide solution (830 mmol,20% w/w) and compound 3a (83 mmol) were added sequentially to the reaction flask and incubated at 70℃for 8 hours until the reaction was completed. The temperature was lowered to room temperature and concentrated sulfuric acid (996 mmol) was added thereto to adjust the pH of the reaction solution to 1-2, and the mixture was stirred at a temperature of 5℃for 2 hours, during which time a large amount of solids were precipitated. The filter cake obtained by filtration was recrystallized from toluene and air-dried to give compound 4a as a white solid, 80mmol, purity 99%, yield 96.3%, MS (ESI) m/z 317.49[ M+H ] +.
Nuclear magnetic data ：1H NMR(400MHz,Chloroform-d)δ6.27(s,2H),5.34-5.26(m,1H),5.15(s,2H),5.11-5.05(m,1H),3.42(d,J＝7.1Hz,2H),2.55-2.43(m,2H),2.10(dq,J＝12.2,6.2Hz,4H),1.84(d,J＝1.4Hz,3H),1.72-1.68(s,3H),1.65-1.54(m,5H),1.33(tq,J＝6.6,4.1,3.2Hz,4H),0.91(t,J＝6.8Hz,3H).
Example 2
Synthesis of Compound 2b
Dibromocyanoacetamide (DBNPA, 43.4 mmol) was added to a tetrahydrofuran mixture of compound 1b (85 mmol) at-10deg.C, and the mixture was stirred for 2 hours at-5deg.C. The reaction solution was quenched with saturated aqueous solution of sodium thiosulfate, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give compound 2b,74.8mmol, as a pale yellow solid with a purity of 95% and a yield of 88%, MS (ESI) m/z 516.49[ M+H ] +.
Synthesis of Compound 3b
Compound 2b (74.8 mmol), compound 2b-1 (82.3 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (SPhos-Pd-G2, 0.75 mmol) and aqueous tripotassium phosphate (1M) were sequentially added to a reaction flask containing THF (3V) and reacted at 90℃for 5 hours. The reaction was cooled to room temperature, extracted with water, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the crude product obtained was crystallized from a mixed solvent of toluene and n-heptane to give compound 3b,71.4mmol, an off-white solid, 97% purity, 91% yield, MS (ESI) m/z 573.84[ M+H ] +.
Synthesis of Compound 4b
An aqueous potassium hydroxide solution (785 mmol,20% w/w) and compound 3b (71.4 mmol) were added sequentially to the reaction flask and incubated at 75℃for 10 hours. The temperature was lowered to room temperature and concentrated sulfuric acid (857 mmol) was added thereto to adjust the pH of the reaction solution to 1-2, and the mixture was stirred at a temperature of 10℃for 2 hours, during which time a large amount of solids were precipitated. The filter cake obtained by filtration was recrystallized from toluene and air-dried to obtain compound 4b as a white solid, 67.8mmol, purity 99%, yield 95%, MS (ESI) m/z 373.60[ M+H ] +. Nuclear magnetic data ：1H NMR(400MHz,Chloroform-d)δ6.53(s,2H),5.46-5.30(m,3H),5.18-5.03(m,1H),3.50-3.44(m,2H),2.20-2.01(m,5H),1.90(s,3H),1.75(s,3H),1.62(s,3H),1.55-1.51(m,2H),1.29-1.18(m,12H),1.18-1.14(m,2H),0.95-0.81(m,3H).
Example 3
Synthesis of Compound 2c
1, 3-Dibromo-1, 3, 5-triazine-2, 4, 6-trione (DBI, 26 mmol) was added to a tetrahydrofuran mixture of compound 1c (50 mmol) at-10℃and the mixture was stirred for 1 hour after the addition was completed, and the temperature was raised to 0 ℃. The reaction mixture was quenched with saturated aqueous sodium thiosulfate, extracted with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated to give compound 2c,43.5mmol, as a pale yellow solid, 96% pure, 87% yield, and MS (ESI) m/z 494.40[ M+H ] +.
Synthesis of Compound 3c
Compound 2c (43.5 mmol), compound 2c-1 (50 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (SPhos-Pd-G2, 0.75 mmol) and aqueous potassium acetate (1M) were sequentially added to a reaction flask containing 1, 4-dioxane (3V), and the mixture was reacted at 95℃for 3 hours. The reaction was cooled to room temperature, extracted with water, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the crude product obtained was crystallized from a mixed solvent of toluene and n-heptane to give compound 3c,42.2mmol, an off-white solid, 96% pure, 95% yield, MS (ESI) m/z 551.74[ M+H ] +.
Synthesis of Compound 4c
An aqueous potassium hydroxide solution (460 mmol,20% w/w) and compound 3c (42.2 mmol) were added sequentially to the reaction flask, and the mixture was incubated at 95℃for 6 hours. Cooling to room temperature, adding concentrated hydrochloric acid (506 mmol) to adjust the pH of the reaction solution to 1-2, controlling the temperature to 15 ℃ and stirring for 2 hours, wherein a large amount of solid is precipitated. The filter cake obtained by filtration was recrystallized from a mixed solvent of toluene and cyclohexane, and after air-drying, compound 4c, a white solid, 38.4mmol, purity 98%, yield 91%, MS (ESI) m/z 351.51[ M+H ] + was obtained. Nuclear magnetic data ：1H NMR(400MHz,Chloroform-d)δ7.30-7.25(m,2H),7.23-7.15(m,3H),6.29-6.26(m,2H),5.34-5.25(m,1H),5.15-5.02(m,3H),3.48-3.44(m,2H),2.93-2.77(m,4H),2.20-2.08(m,4H),1.91(s,3H),1.68(s,3H),1.55(s,3H).
Example 4
Synthesis of Compound 2d
N-iodosuccinimide (NIS, 102 mmol) was added to a mixture of dimethyl sulfoxide of compound 1a (100 mmol) at-10deg.C, and the mixture was stirred for 1.5 hours at 20deg.C. The reaction mixture was quenched with saturated aqueous solution of sodium thiosulfate, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give compound 2d,85mmol as a pale yellow solid with a purity of 97% and a yield of 85%, MS (ESI) m/z 423.22[ M+H ] +.
Synthesis of Compound 3d
Compound 2d (85 mmol), compound 2d-1 (93.5 mmol), chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos-Pd-G2, 0.85 mmol) and cesium carbonate aqueous solution (1M) were added sequentially to a reaction flask containing toluene (3V) and reacted at 80℃for 6 hours. The reaction was cooled to room temperature, extracted with water, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, concentrated, and the crude product was crystallized from a mixed solvent of toluene and n-heptane to give 3d,76.5mmol, an off-white solid, 95% purity, 90% yield, MS (ESI) m/z 365.45[ M+H ] +.
Synthesis of Compound 4d
Aqueous sodium hydroxide (770 mmol,20% w/w) and compound 3d (76.5 mmol) were added sequentially to the reaction flask and incubated at 80℃for 5 hours until the reaction was complete. Cooling to room temperature, adding concentrated hydrochloric acid (920 mmol) to adjust the pH of the reaction solution to 1-2, controlling the temperature to be within-5 ℃ and stirring for 2 hours, wherein a large amount of solids are separated out. The filter cake obtained by filtration was recrystallized from a mixed solvent of toluene and n-heptane, and after air-drying, compound 4d, a pale yellow solid, 69.2mmol, purity 98%, yield 90.5%, MS (ESI) m/z 249.37[ M+H ] + were obtained. Nuclear magnetic data ：1H NMR(400MHz,Chloroform-d):δ＝6.29(s,2H),5.27(dt,1H,J＝7.1Hz),4.93(s,2H),3.38(d,2H,J＝7.5Hz),2.47(t,2H),1.81(s,3H),1.73(s,3H),1.65-1.54(m,2H),1.37-1.20(m,4H),0.87(t,3H).
Comparative example
Synthesis of Compound 2e
Dibromocyanoacetamide (DBNPA, 51 mmol) was added to a tetrahydrofuran mixture of compound 1a (100 mmol) at-10℃and stirred for 5 hours at-5 ℃. The reaction mixture was quenched with saturated aqueous solution of sodium thiosulfate, then extracted with ethyl acetate, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated to give compound 2e,70mmol, as a yellow oily liquid having a purity of 85% and a yield of 70%, MS (ESI) m/z 290.18[ M+H ] +.
Synthesis of Compound 3e
Compound 2e (70 mmol), compound 2e-1 (77 mmol), chloro (2-dicyclohexylphosphino-2 ',4',6 '-triisopropyl-1, 1' -biphenyl) [2- (2 '-amino-1, 1' -biphenyl) ] palladium (II) (XPhos-Pd-G2, 0.7 mmol) and tripotassium phosphate aqueous solution (1M) were added sequentially to a reaction flask containing THF (3V) and reacted at 80 ℃ for 15 hours. The reaction was cooled to room temperature, extracted with water, the organic phase was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated, and the crude product obtained was purified by column chromatography to give compound 3a,41mmol, as a pale yellow solid, 93% pure, 58.6% yield, MS (ESI) m/z 347.52[ M+H ] +.
Synthesis of Compound 4a
Concentrated sulfuric acid was slowly added to a reaction flask containing compound 3e (41 mmol) and ethanol (10V), stirred at 80 ℃ for 1 hour, cooled to 0 ℃, slowly added dropwise with an aqueous solution of sodium nitrite (410 mmol), stirred at 0 ℃ for 1 hour after the addition, and then stirred at 80 ℃ for 12 hours. Ethanol was removed by concentration under reduced pressure, extraction was performed with ethyl acetate, and the organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated. The crude product was recrystallized to give compound 4a as pale yellow solid, 28.7mmol, purity 70%, yield 96.3%, MS (ESI) m/z 317.49[ M+H ] +. Nuclear magnetic data ：1H NMR(400MHz,Chloroform-d)δ6.27(s,2H),5.34-5.26(m,1H),5.15(s,2H),5.11-5.05(m,1H),3.42(d,J＝7.1Hz,2H),2.55-2.43(m,2H),2.10(dq,J＝12.2,6.2Hz,4H),1.84(d,J＝1.4Hz,3H),1.72-1.68(s,3H),1.65-1.54(m,5H),1.33(tq,J＝6.6,4.1,3.2Hz,4H),0.91(t,J＝6.8Hz,3H).
While the methods of this invention have been described in terms of preferred embodiments, it will be apparent to those of skill in the art that variations and combinations of the methods and applications described herein can be made and applied within the spirit and scope of the invention. Those skilled in the art can, with the benefit of this disclosure, suitably modify the process parameters to achieve this. It is expressly noted that all such similar substitutions and modifications will be apparent to those skilled in the art, and are deemed to be included within the present invention.

Claims (9)

1. A method for synthesizing cannabigerol and analogues thereof, comprising the steps of:
S1: compound 1 is reacted with a halogenating agent to form compound 2;
s2: the compound 2 and the compound 2-1 are subjected to a coupling reaction to generate a compound 3;
S3: decarboxylation reaction of the compound 3 to obtain a compound 4;
wherein, the cannabigerol and analogues thereof have the structure shown in the compound 4;
R 1 and R 2 are each independently C 1-10 alkyl or C 3-6 cycloalkyl;
r 3 is C 1-12 alkyl, C 2-10 alkynyl, C 2-10 alkenyl, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, 5-to 10-membered heteroaryl or C 6-10 aryl; optionally, C 1-12 alkyl, C 2-10 alkynyl, C 2-10 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 6-10 aryl are each independently substituted with 1, 2, 3, or 4 substituents selected from C 1-6 alkyl, C 3-6 cycloalkyl, C 6-10 aryl, 5-6 membered heteroaryl, or 3-6 membered heterocyclyl;
x is halogen; preferably bromine or iodine;
n is 1, 2 or 3.
2. The synthesis method according to claim 1, wherein,
R 1 and R 2 are each independently C 1-6 alkyl or C 3-6 cycloalkyl; preferably, R 1 and R 2 are each independently methyl, ethyl, propyl, isopropyl, tert-butyl, cyclopropyl, cyclohexyl or cyclopentyl;
R 3 is C 1-10 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, C 3-6 cycloalkyl, 3-to 6-membered heterocyclyl, 5-to 10-membered heteroaryl or C 6-10 aryl; optionally, C 1-10 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, and C 6-10 aryl are each independently substituted with 1, 2, 3, or 4 substituents selected from C 1-10 alkyl, C 2-8 alkynyl, C 2-8 alkenyl, C 3-6 cycloalkyl, 3-6 membered heterocyclyl, 5-10 membered heteroaryl, or C 6-10 aryl; preferably, R 3 is methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, propenyl, butenyl, propynyl or butynyl; optionally, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, propenyl, butenyl, propynyl and butynyl are each independently substituted with 1, 2, 3 or 4 substituents selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenyl, propenyl, butenyl, propynyl and butynyl.
3. The synthetic method of claim 1, wherein the cannabigerol and its analogues are selected from the structures:
4. a synthetic method according to any one of claim 1 to 3 wherein,
The molar ratio of compound 1 to halogenated agent is 1: (0.4-1.5); preferably, the molar ratio of compound 1 to halogenated agent is 1: (0.5-1.2).
5. A synthetic method according to any one of claim 1 to 3 wherein,
The halogenating agent is selected from a chlorinating agent, a brominating agent or an iodinating agent; preferably, the halogenating reagent is selected from chlorine, N-chlorosuccinimide (NCS), thionyl chloride, phosphorus pentachloride, carbon tetrachloride, dichlorohydantoin (DCDMH), hydrobromic acid, bromine, N-bromosuccinimide (NBS), N-bromophthalimide (NBSac), dibromohydantoin (DBH), pyridinium tribromide (PyHBr 3), carbon tetrabromide, dibromocyanoacetamide (DBNPA), 1, 3-dibromo-1, 3, 5-triazine-2, 4, 6-trione (DBI), N-bromophthalimide (NBP), elemental iodine, N-iodosuccinimide (NIS), iodine chloride (ICl), potassium iodide or cuprous iodide.
6. A synthetic method according to any one of claim 1 to 3 wherein,
The molar ratio of compound 2 to compound 2-1 is 1: (1.0-2.0); preferably, the molar ratio of compound 2 to compound 2-1 is 1: (1.1-1.5).
7. A synthetic method according to any one of claim 1 to 3 wherein,
The coupling reaction is carried out in an organic solvent under the action of a palladium catalyst and a first base;
Wherein the palladium catalyst is selected from the group consisting of chloro (2-dicyclohexylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) [2- (2 ' -amino-1, 1' -biphenyl) ] palladium (II) (XPhos-Pd-G2), methanesulfonic acid (2-di-tert-butylphosphino-2 ',4',6' -triisopropyl-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (tBuXPhos-Pd-G3), chloro (2-dicyclohexylphosphino-2 ',6' -di-isopropoxy-1, 1' -biphenyl) (2-amino-1, 1' -biphenyl-2-yl) palladium (II) (RuPhos-Pd-G2), chloro (2-dicyclohexylphosphino-2 ',6' -dimethoxy-1, 1' -biphenyl) (2 ' -amino-1, 1' -biphenyl-2-yl) palladium (II) (SPhos-Pd-G2), methanesulfonic acid (2-dicyclohexylphosphino-3, 6' -dimethoxy-2 ',4' -biphenyl-2 ',6 '-triisopropyl-1, 1' -biphenyl) (2 '-amino-1, 1' -biphenyl-2-yl) palladium (II) (BrettPhos-Pd-G3) and chloro [ (tricyclohexylphosphine) -2- (2-aminobiphenyl) ] palladium (II) (PCy 3-Pd-G2);
The first base is selected from potassium tert-butoxide, sodium tert-butoxide, cesium carbonate, potassium hydroxide, sodium hydroxide, potassium acetate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, tripotassium phosphate or sodium hydride;
The organic solvent is selected from 1, 4-dioxane, tetrahydrofuran, 2-methyltetrahydrofuran, N-methylpyrrolidone, acetonitrile, toluene, tertiary butanol, ethanol, ethylene glycol dimethyl ether, N-dimethylformamide, N-dimethylacetamide, dimethyl sulfoxide, sulfolane or cyclopentyl methyl ether.
8. A synthetic method according to any one of claim 1 to 3 wherein,
Compound 3 is hydrolyzed in a second alkali aqueous solution, and then decarboxylated under the action of acid.
9. The synthesis method according to claim 8, wherein,
The second alkali aqueous solution is one or a mixture of any proportion of aqueous solution of potassium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate and potassium bicarbonate; the molar ratio of compound 3 to the second base is 1: (8-15);
The acid is one or a mixture of hydrochloric acid, sulfuric acid and phosphoric acid in any proportion; the molar ratio of compound 3 to the acid is 1: (10-20).
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