Process for the production of 3,5-dietherpentaphene and its use in the preparation of 3,5-dihydroxypentaphene

Abstract

The application belongs to the technical field of organic synthesis, and particularly relates to a method for producing 3,5-diether pentylbenzene and application of the method in preparation of 3,5-dihydroxypentylbenzene, the method comprising coupling reaction of halogenated n-pentane, a ligand, a compound shown in formula 2 and a reducing agent in the presence of a nickel catalyst; preferably, the method further comprises nucleophilic aromatic substitution reaction of 3,5-difluorohalobenzene and a compound R-OH in the presence of a strong base to obtain the compound shown in formula 2. The method for preparing 3,5-dihydroxypentylbenzene comprises producing 3,5-diether pentylbenzene and performing de-R group protection reaction on the 3,5-diether pentylbenzene. The method has the characteristics of simple operation, high production safety and high product yield, and is conducive to industrial production of 3,5-diether pentylbenzene and 3,5-dihydroxypentylbenzene.

Description

TECHNICAL FIELD

[0001] The application belongs to the technical field of organic synthesis, and particularly relates to a method for producing 3,5-diether pentylbenzene and application of the method in preparation of 3,5-dihydroxypentylbenzene. BACKGROUND

[0002] 3,5-dihydroxypentylbenzene is an important pharmaceutical intermediate. Olivetol In the early stage, 3,5-dihydroxypentylbenzene was obtained by extracting lichenic acid from lichen plants and further degrading, but the yield of the method is low. Later, it was found that the compound has a good inhibitory effect on human immune system diseases, and therefore has been rapidly and widely applied in the medical field. 3,5-dihydroxypentylbenzene can be combined with other drugs with immunosuppressive activity to synthesize a variety of drugs for treating human immunodeficiency caused by reverse transcriptase virus, cancer and other malignant tumors. In addition, it can also be used to synthesize analgesic, sedative, anti-inflammatory, digestion-aiding and antihypertensive drugs, for example, a key intermediate for synthesizing cannabidiol. Due to its unique pharmacological effect, the market demand for 3,5-dihydroxypentylbenzene has sharply increased. However, the existing synthesis process cannot meet the demand of large-scale production, and it is urgent to develop a series of new routes with simple process and economic feasibility. SUMMARY

[0003] The application aims to provide a method for producing 3,5-diether pentylbenzene and application of the method in preparation of 3,5-dihydroxypentylbenzene. The method has the characteristics of simple operation, high production safety and high product yield, and is beneficial to realize industrialized production of 3,5-diether pentylbenzene and 3,5-dihydroxypentylbenzene.

[0004] The application achieves the above-mentioned purpose by the following technical scheme.

[0005] In a first aspect, the application provides a method for producing 3,5-diether pentylbenzene, the 3,5-diether pentylbenzene having a chemical structure shown in formula 3, the method comprising coupling halogenated n-pentane, a ligand, a compound shown in formula 2 and a reducing agent in the presence of a nickel catalyst; wherein formula 3 and formula 2 are as follows:

[0006]

[0007] R in formula 3 is the same as R in formula 2, and both are substituted or unsubstituted methylenecycloarylene;

[0008] X in formula 2 is fluorine, chlorine, bromine or iodine.

[0009] In some embodiments of the present application, the substituted or unsubstituted methylenecycloaromatic group is Ar-CH2-, wherein Ar is Ph, 4-OMePh, 4-NO2Ph, 4-MePh, 1-naphthyl or 9-anthryl.

[0010] In some embodiments of the present application, the nickel catalyst is selected from at least one of acetylacetone nickel, nickel fluoride, nickel bromide, nickel iodide, bis(triphenylphosphine) nickel chloride, nickel acetate, nickel chloride dimethoxyethane, nickel bromide dimethoxyethane and the like.

[0011] In some embodiments of the present application, the halogenated n-pentane is selected from at least one of iodinated n-pentane, chlorinated n-pentane, brominated n-pentane.

[0012] In some embodiments of the present application, the ligand is selected from at least one of the compounds containing at least one pyridyl group.

[0013] In some embodiments of the present application, the ligand is selected from at least one of the compounds represented by the following formulae I to XII:

[0014] ;

[0015] wherein R' in formula I, formula II and formula III is each independently selected from methyl, methoxy, butyl.

[0016] In some embodiments of the present application, the ligand is selected from at least one of the compounds represented by formula IV (bipyridine), formula VII (1,10-phenanthroline) and formula X (picolinimide).

[0017] In some embodiments of the present application, the reducing agent is selected from at least one of zinc powder, manganese powder, magnesium powder and the like; preferably zinc powder.

[0018] In some embodiments of the present application, the molar ratio of the compound represented by formula 2 to the nickel catalyst in the coupling reaction is 1: (0.05-0.5), preferably 1: (0.08-0.2).

[0019] In some embodiments of the present application, the molar ratio of the compound represented by formula 2 to the nickel catalyst in the coupling reaction is 1: (0.05-0.5) means that the molar ratio of the compound represented by formula 2 to the nickel catalyst can be selected from any value in the following molar ratios or any value in the range consisting of any two of the following molar ratios: 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5.

[0020] In some embodiments of the present application, the molar ratio of the compound of formula 2 to halogenated n-pentane in the coupling reaction is 1:(1-3), preferably 1:(1.5-2.5).

[0021] In some embodiments of the present application, the molar ratio of the compound of formula 2 to halogenated n-pentane in the coupling reaction is 1:(1-3) means that the molar ratio of the compound of formula 2 to halogenated n-pentane can be any value selected from the following molar ratios or any value within the range consisting of any two of the following molar ratios: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.

[0022] In some embodiments of the present application, the molar ratio of the compound of formula 2 to ligand in the coupling reaction is 1:(0.05-0.5), preferably 1:(0.08-0.2).

[0023] In some embodiments of the present application, the molar ratio of the compound of formula 2 to ligand in the coupling reaction is 1:(0.05-0.5) means that the molar ratio of the compound of formula 2 to ligand can be any value selected from the following molar ratios or any value within the range consisting of any two of the following molar ratios: 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5.

[0024] In some embodiments of the present application, the molar ratio of the compound of formula 2 to reducing agent in the coupling reaction is 1:(1-3), preferably 1:(1.5-2.5).

[0025] In some embodiments of the present application, the molar ratio of the compound of formula 2 to reducing agent in the coupling reaction is 1:(1-3) means that the molar ratio of the compound of formula 2 to reducing agent can be any value selected from the following molar ratios or any value within the range consisting of any two of the following molar ratios: 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3.

[0026] In some embodiments of the present application, the reaction temperature of the coupling reaction is selected from 0 to 100°C, preferably from 30 to 60°C.

[0027] In some embodiments of the present application, the reaction temperature of the coupling reaction is selected from 0 to 100°C means that the reaction temperature of the coupling reaction can be selected from any value of the following temperatures or any range consisting of any two of them: 0°C, 3°C, 5°C, 8°C, 10°C, 13°C, 15°C, 18°C, 20°C, 23°C, 25°C, 28°C, 30°C, 33°C, 35°C, 38°C, 40°C, 43°C, 45°C, 48°C, 50°C, 53°C, 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C, 78°C, 80°C, 83°C, 85°C, 88°C, 90°C, 93°C, 95°C, 98°C, 100°C.

[0028] In some embodiments of the present application, the reaction time of the coupling reaction is selected from 1 to 24h, preferably from 10 to 15h.

[0029] In some embodiments of the present application, the reaction time of the coupling reaction is selected from 1 to 24h means that the reaction time of the coupling reaction can be selected from any value of the following time lengths or any range consisting of any two of them: 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h.

[0030] In some embodiments of the present application, the coupling reaction is carried out in the presence of a solvent.

[0031] In some embodiments of the present application, the solvent used in the coupling reaction comprises at least one of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.

[0032] In some embodiments of the present application, the solvent used in the coupling reaction is used in a ratio of (5 to 10) mL: 1g to the compound shown in formula 2.

[0033] In some embodiments of the present application, the ratio of the solvent used in the coupling reaction to the compound of formula 2 is (5-10) mL:1 g, which means that the ratio of the solvent used in the coupling reaction to the compound of formula 2 can be selected from any value in the following ratio or any range formed by any two of the following ratios: 5 mL:1 g, 5.5 mL:1 g, 6 mL:1 g, 6.5 mL:1 g, 7 mL:1 g, 7.5 mL:1 g, 8 mL:1 g, 8.5 mL:1 g, 9 mL:1 g, 9.5 mL:1 g, 10 mL:1 g.

[0034] In some embodiments of the present application, the coupling reaction is carried out in the presence of an additive selected from at least one of sodium iodide, magnesium chloride, potassium iodide, lithium chloride, pyridine, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, trimethylchlorosilane, and the like.

[0035] In some embodiments of the present application, the molar ratio of the compound of formula 2 to the additive in the coupling reaction is 1:(0.1-1.5), preferably 1:(0.6-1.2).

[0036] In some embodiments of the present application, the molar ratio of the compound of formula 2 to the additive in the coupling reaction is 1:(0.1-1.5), which means that the molar ratio of the compound of formula 2 to the additive can be selected from any value in the following molar ratio or any range formed by any two of the following molar ratios: 1:0.1, 1:0.15, 1:0.2, 1:0.25, 1:0.3, 1:0.35, 1:0.4, 1:0.45, 1:0.5, 1:0.55, 1:0.6, 1:0.65, 1:0.7, 1:0.75, 1:0.8, 1:0.85, 1:0.9, 1:0.95, 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5.

[0037] In some embodiments of the present application, the method further comprises subjecting 3,5-difluorohalobenzene to a nucleophilic aromatic substitution reaction with a compound R-OH in the presence of a strong base to obtain the compound of formula 2; wherein R in the compound R-OH is the same as R in formula 2, i.e., both are substituted or unsubstituted methylenecycloarylene groups.

[0038] In some embodiments of the present application, the 3,5-difluorohalobenzene is selected from at least one of 1,3,5-trifluorobenzene, 3,5-difluorochlorobenzene, 3,5-difluorobromobenzene, 3,5-difluoroiodobenzene, and the like.

[0039] In some embodiments of the present application, the compound R-OH is selected from at least one of benzyl alcohol, p-methoxybenzyl alcohol, p-nitrobenzyl alcohol, p-methylbenzyl alcohol, 9-anthryl alcohol, 1-naphthalenemethyl alcohol, and the like.

[0040] In the present application, the strong base in the nucleophilic aromatic substitution reaction is to deprotonate the compound R-OH to form an alkoxy anion, and then to react with an electron-deficient aromatic ring to form a compound shown in Formula 2. That is, the strong base can be any compound or composition that can deprotonate the compound R-OH.

[0041] In some embodiments of the present application, the strong base comprises an inorganic strong base and / or an organic strong base, preferably selected from at least one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium hydride, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, 1,8-diazabicycloundec-7-ene, sodium hydroxide, potassium hydroxide, and the like.

[0042] In some embodiments of the present application, the molar ratio of the 3,5-difluorohalobenzene to the compound R-OH in the nucleophilic aromatic substitution reaction is 1: (2-3).

[0043] In some embodiments of the present application, the molar ratio of the strong base to the compound R-OH in the nucleophilic aromatic substitution reaction is 1: (0.9-1.1).

[0044] In some embodiments of the present application, the reaction temperature of the nucleophilic aromatic substitution reaction is selected from 20-110°C, preferably selected from 70-100°C.

[0045] In some embodiments of the present application, the reaction temperature of the nucleophilic aromatic substitution reaction selected from 20-110°C means that the reaction temperature of the nucleophilic aromatic substitution reaction can be selected from any value or any range consisting of any two values selected from the following temperatures: 20°C, 23°C, 25°C, 28°C, 30°C, 33°C, 35°C, 38°C, 40°C, 43°C, 45°C, 48°C, 50°C, 53°C, 55°C, 58°C, 60°C, 63°C, 65°C, 68°C, 70°C, 73°C, 75°C, 78°C, 80°C, 83°C, 85°C, 88°C, 90°C, 93°C, 95°C, 98°C, 100°C, 103°C, 105°C, 110°C.

[0046] In some embodiments of the present application, the reaction time of the nucleophilic aromatic substitution reaction is selected from 2-12h, preferably selected from 4-8h.

[0047] In some embodiments of the present application, the reaction time of the nucleophilic aromatic substitution reaction is selected from 2 to 12 hours. The reaction time of the nucleophilic aromatic substitution reaction can be selected from any value or any range consisting of two of the following values: 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, and 12 hours.

[0048] In some embodiments of the present application, the nucleophilic aromatic substitution reaction is carried out in the presence of a solvent.

[0049] In some embodiments of the present application, the solvent used in the nucleophilic aromatic substitution reaction includes at least one of methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, and the like.

[0050] In some embodiments of the present application, the ratio of the amount of the solvent used in the nucleophilic aromatic substitution reaction to the amount of 3,5-difluorohalobenzene is (5 to 20) mL: 1 g.

[0051] In some embodiments of the present application, the ratio of the amount of the solvent used in the nucleophilic aromatic substitution reaction to the amount of 3,5-difluorohalobenzene is (5 to 20) mL: 1 g. The ratio of the amount of the solvent used in the coupling reaction to the amount of the compound of formula 2 can be selected from any value or any range consisting of two of the following values: 5 mL: 1 g, 5.5 mL: 1 g, 6 mL: 1 g, 6.5 mL: 1 g, 7 mL: 1 g, 7.5 mL: 1 g, 8 mL: 1 g, 8.5 mL: 1 g, 9 mL: 1 g, 9.5 mL: 1 g, 10 mL: 1 g, 11 mL: 1 g, 11.5 mL: 1 g, 12 mL: 1 g, 12.5 mL: 1 g, 13 mL: 1 g, 13.5 mL: 1 g, 14 mL: 1 g, 14.5 mL: 1 g, 15 mL: 1 g, 15.5 mL: 1 g, 16 mL: 1 g, 16.5 mL: 1 g, 17 mL: 1 g, 17.5 mL: 1 g, 18 mL: 1 g, 18.5 mL: 1 g, 19 mL: 1 g, 19.5 mL: 1 g, and 20 mL: 1 g.

[0052] In some embodiments of the present application, the method for producing 3,5-diether pentaphene includes the following steps:

[0053] (1) allowing 3,5-difluorohalobenzene to undergo a nucleophilic aromatic substitution reaction with a compound R-OH in the presence of a strong base to obtain a compound of formula 2;

[0054] (2) coupling reaction of halogenated n-pentane, ligand, compound shown in formula 2 and reducing agent in the presence of nickel catalyst to obtain 3,5-diether pentabenzene.

[0055] In some embodiments of the present application, the method further comprises purifying the crude product obtained in step (1).

[0056] In some embodiments of the present application, the purification method of the crude product in step (1) comprises extraction and column chromatography elution; preferably, the extraction and column chromatography elution are performed sequentially.

[0057] In some embodiments of the present application, the method further comprises purifying the crude product obtained in step (2).

[0058] In some embodiments of the present application, the purification method of the crude product in step (2) comprises extraction and column chromatography elution; preferably, the extraction and column chromatography elution are performed sequentially.

[0059] In the second aspect, the present application provides a method for preparing 3,5-dihydroxypentabenzene, comprising the following step: performing a de-R group protection reaction on 3,5-diether pentabenzene, wherein the 3,5-diether pentabenzene has a chemical structure shown in formula 3. The de-R group protection reaction is a reaction of reducing -OR groups in 3,5-diether pentabenzene to -OH groups.

[0060]

[0061] R in formula 3 is a substituted or unsubstituted methylenecycloarenyl group.

[0062] In some embodiments of the present application, the substituted or unsubstituted methylenecycloarenyl group is Ar-CH2-, wherein Ar is Ph, 4-OMePh, 4-NO2Ph, 4-MePh, 1-naphthyl or 9-anthryl.

[0063] In some embodiments of the present application, the reagent used in the de-R group protection reaction comprises Pd / C and hydrogen, Raney nickel and hydrogen, elemental iodine and triethylsilane, sodium borohydride and nickel chloride, trimethyl iodide silane, boron trichloride, aluminum trichloride, boron trifluoride ether or 2,3-dichloro-5,6-dicyanoquinone, etc.

[0064] In some embodiments of the present application, the reagent used in the de-R group protection reaction can be classified into the following systems:

[0065] 1) metal hydride system: palladium on carbon (Pd / C) and hydrogen, Raney nickel and hydrogen, sodium borohydride and nickel chloride; this system can be used for deprotection of each R group.

[0066] 2) Lewis acid system: elemental iodine and triethylsilane, boron trichloride, aluminum trichloride, boron trifluoride diethyl ether; this system is suitable for 4-OMePh-CH2- (p-methoxybenzyl, PMB), Ph-CH2- (benzyl, Bn).

[0067] 3) Oxidation system: for electron-rich benzyl groups, such as 4-OMePh-CH2- (p-methoxybenzyl, PMB), 2,3-dichloro-5,6-dicyanoquinone (DDQ) can be used for removal.

[0068] In some embodiments of the present application, the reaction temperature of the de-R group protection reaction is selected from 0-50°C, preferably 20-30°C.

[0069] In some embodiments of the present application, the reaction temperature of the de-R group protection reaction selected from 0-50°C means that the reaction temperature of the de-R group protection reaction can be selected from any value or any range consisting of two of the following values: 0°C, 3°C, 5°C, 8°C, 10°C, 13°C, 15°C, 18°C, 20°C, 23°C, 25°C, 28°C, 30°C, 33°C, 35°C, 38°C, 40°C, 43°C, 45°C, 48°C, 50°C.

[0070] In some embodiments of the present application, the reaction time of the de-R group protection reaction is selected from 1-12h.

[0071] In some embodiments of the present application, the reaction time of the de-R group protection reaction selected from 1-12h means that the reaction time of the de-R group protection reaction can be selected from any value or any range consisting of two of the following values: 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h.

[0072] In some embodiments of the present application, the de-R group protection reaction is carried out in the presence of a solvent; the solvent includes at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.

[0073] In some embodiments of the present application, the solvent used in the de-R group protection reaction is used in an amount of (5-10) mL: 1g relative to 3,5-diether pentaphene.

[0074] In some embodiments of the present application, the ratio of the solvent used in the de-R group protection reaction to 3,5-diether pentaphene is (5-10) mL: 1 g, which means that the ratio of the solvent to 3,5-diether pentaphene can be selected from any value in the following ratio or any value within the range formed by any two of the following ratios: 5 mL: 1 g, 5.5 mL: 1 g, 6 mL: 1 g, 6.5 mL: 1 g, 7 mL: 1 g, 7.5 mL: 1 g, 8 mL: 1 g, 8.5 mL: 1 g, 9 mL: 1 g, 9.5 mL: 1 g, 10 mL: 1 g.

[0075] In some embodiments of the present application, the method further comprises producing 3,5-diether pentaphene by the method of the first aspect.

[0076] In the third aspect, the present application provides a method for preparing 3,5-dihydroxypentaphene, which comprises producing 3,5-diether pentaphene by the method of the first aspect.

[0077] In some embodiments of the present application, the method for preparing 3,5-dihydroxypentaphene further comprises the step of subjecting 3,5-diether pentaphene to a de-R group protection reaction. The de-R group protection reaction is a reaction in which the -OR group in 3,5-diether pentaphene is reduced to an -OH group.

[0078] In some embodiments of the present application, the reagent used in the de-R group protection reaction includes Pd / C and hydrogen, Raney nickel and hydrogen, elemental iodine and triethylsilane, sodium borohydride and nickel chloride, trimethyl iodide silane, boron trichloride, aluminum trichloride, boron trifluoride ether, or 2,3-dichloro-5,6-dicyanoquinone, etc.

[0079] In some embodiments of the present application, the reagent used in the de-R group protection reaction can be divided into the following systems:

[0080] 1) Metal hydride system: palladium on carbon (Pd / C) and hydrogen, Raney nickel and hydrogen, sodium borohydride and nickel chloride; this system is applicable to the removal of various R group protection groups.

[0081] 2) Lewis acid system: elemental iodine and triethylsilane, trimethyl iodide silane, boron trichloride, aluminum trichloride, boron trifluoride ether; this system is applicable to 4-OMePh-CH2- (p-methoxybenzyl, PMB), Ph-CH2- (benzyl, Bn).

[0082] 3) Oxidation system: for electron-rich benzyl groups, such as 4-OMePh-CH2- (p-methoxybenzyl, PMB), 2,3-dichloro-5,6-dicyanoquinone (DDQ) can be used for removal.

[0083] In some embodiments of the present application, the reaction temperature of the de-R group protection reaction is selected from 0-50℃, preferably 20-30℃.

[0084] In some embodiments of the present application, the reaction temperature of the de-R group protection reaction selected from 0-50℃ means that the reaction temperature of the de-R group protection reaction can be selected from any value in the following temperature or any range consisting of any two of them: 0℃, 3℃, 5℃, 8℃, 10℃, 13℃, 15℃, 18℃, 20℃, 23℃, 25℃, 28℃, 30℃, 33℃, 35℃, 38℃, 40℃, 43℃, 45℃, 48℃, 50℃.

[0085] In some embodiments of the present application, the reaction time of the de-R group protection reaction is selected from 1-12h.

[0086] In some embodiments of the present application, the reaction time of the de-R group protection reaction selected from 1-12h means that the reaction time of the de-R group protection reaction can be selected from any value in the following time length or any range consisting of any two of them: 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h.

[0087] In some embodiments of the present application, the de-R group protection reaction is carried out in the presence of a solvent; the solvent includes at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone, etc.

[0088] In some embodiments of the present application, the amount ratio of the solvent used in the de-R group protection reaction to 3,5-diether pentaphene is (5-10) mL: 1g.

[0089] In some embodiments of the present application, the amount ratio of the solvent used in the de-R group protection reaction to 3,5-diether pentaphene is (5-10) mL: 1g means that the amount ratio of the solvent to 3,5-diether pentaphene can be selected from any value in the following amount ratio or any range consisting of any two of them: 5mL:1g, 5.5mL:1g, 6mL:1g, 6.5mL:1g, 7mL:1g, 7.5mL:1g, 8mL:1g, 8.5mL:1g, 9mL:1g, 9.5mL:1g, 10mL:1g.

[0090] In some embodiments of the present application, the method for preparing 3,5-dihydroxypentaphene comprises the following steps:

[0091] (1) making 3,5-difluorohalobenzene and compound R-OH in the presence of a strong base to undergo nucleophilic aromatic substitution reaction to obtain the compound shown in formula 2;

[0092] (2) making halogenated n-pentane, ligand, compound shown in formula 2 and reducing agent to undergo coupling reaction in the presence of a nickel catalyst to obtain 3,5-diether pentylbenzene;

[0093] (3) performing deprotection reaction on 3,5-diether pentylbenzene.

[0094] In some embodiments of the present application, the method further comprises purifying the crude product obtained in step (3).

[0095] In some embodiments of the present application, the purification method comprises extraction and column elution; preferably, extraction and column elution are performed in sequence.

[0096] The technical route of a specific embodiment of the present application is shown as follows:

[0097]

[0098] In the technical route of the present application, in the reaction for synthesizing compound 2a, the presence of a strong base makes benzyl alcohol lose a proton to form an alkoxy anion, which can further undergo aromatic nucleophilic substitution reaction (i.e. SNAr reaction) with the electron-deficient aromatic ring of 3,5-difluorobromobenzene to synthesize compound 2a. In the reaction for synthesizing compound 3a, cross-electrophilic coupling reaction between aryl bromide and alkyl bromide is catalyzed by a nickel catalyst to realize direct coupling of a pentyl group to the 1 position of a benzene ring through one-step reaction to obtain compound 3a; the specific mechanism of the reaction is as follows: divalent nickel is first reduced to zero-valent nickel by a reducing agent, and then undergoes oxidative addition with aryl bromide to form an aryl divalent nickel species; the species combines with an alkyl radical to produce an alkyl aryl trivalent nickel intermediate, which then undergoes reductive elimination to obtain target product compound 3a and a monovalent nickel species; the monovalent nickel species further undergoes single electron transfer process with alkyl bromide to generate divalent nickel species and an alkyl radical, thereby completing the catalytic cycle. After synthesizing compound 3a, only the deprotection reaction of compound 3a to remove the benzyl group is needed to obtain target product 3,5-dihydroxypentylbenzene. The entire technical route is simple and easy to implement.

[0099] In a fourth aspect, the present application provides 3,5-dihydroxypentylbenzene prepared by the method of the second aspect or the third aspect.

[0100] In a fifth aspect, the present application provides use of 3,5-dihydroxypentylbenzene of the fourth aspect in the production of pharmaceuticals such as cannabidiol.

[0101] In a sixth aspect, the present application provides a method for producing cannabidiol, the method comprising preparing 3,5-dihydroxy pentylbenzene by the method for preparing 3,5-dihydroxy pentylbenzene according to the second aspect or the third aspect.

[0102] In some embodiments of the present application, the method for producing cannabidiol further comprises subjecting trans-menthyl-2,8-dien-1-ol to an alkylation reaction with the 3,5-dihydroxy pentylbenzene in the presence of a Lewis acid or a Brønsted acid.

[0103] In some embodiments of the present application, the Lewis acid is selected from at least one of cerium trichloride, aluminum trichloride, iron trichloride, titanium tetrachloride, zinc dichloride, boron trifluoride etherate, and the like.

[0104] In some embodiments of the present application, the Brønsted acid is selected from at least one of hydrochloric acid, hydrobromic acid, triflic acid, trifluoroacetic acid, acetic acid, formic acid, citric acid, and the like.

[0105] In some embodiments of the present application, the alkylation reaction is carried out in the presence of a solvent selected from at least one of halogenated alkanes, ester compounds, alcohol compounds, ether compounds, furan compounds, aromatic hydrocarbons, nitrile compounds, and the like; preferably selected from at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, and the like.

[0106] In some embodiments of the present application, the reaction temperature of the alkylation reaction is selected from 30-50°C, preferably selected from 35-45°C.

[0107] In some embodiments of the present application, the reaction time of the alkylation reaction is 2-5 min.

[0108] In some embodiments of the present application, the alkylation reaction is carried out under stirring.

[0109] The beneficial effects of the present application are as follows:

[0110] The present application provides a method for producing 3,5-dihydroxy pentylbenzene, the method comprising subjecting halogenated n-pentane, a ligand, a compound shown in formula 2, and a reducing agent to a coupling reaction in the presence of a nickel catalyst, the coupling reaction is carried out under mild conditions and is simple to operate, and since there is no need to provide harsh reaction conditions, the energy consumption and reaction safety can be effectively reduced.

[0111] The application further provides a method for preparing the compound shown in formula 2 by subjecting 3,5-difluorohalobenzene to nucleophilic aromatic substitution reaction with a compound R-OH in the presence of a strong base; the method has the advantages of mild conditions, simple operation and low cost of raw materials, and by using the method to first prepare the compound shown in formula 2, then using the compound shown in formula 2 to produce 3,5-dioxy-pentaphene, the cost of producing 3,5-dioxy-pentaphene can be effectively reduced.

[0112] The application further provides a method for preparing 3,5-dihydroxypentaphene by subjecting 3,5-dioxy-pentaphene to R group protection reaction, which has the advantages of mild conditions, simple operation and high product yield, and is conducive to realizing industrialized production and meeting the market demand for 3,5-dihydroxypentaphene products.

[0113] The application further provides a method for producing cannabidiol by using the method for preparing 3,5-dihydroxypentaphene to first prepare 3,5-dihydroxypentaphene, and then using the obtained 3,5-dihydroxypentaphene as one of main raw materials, which has the advantage of simple operation and is conducive to realizing industrialized production of cannabidiol. BRIEF DESCRIPTION OF DRAWINGS

[0114] Figure 1 The hydrogen nuclear magnetic resonance spectrum of 3,5-dihydroxypentaphene is shown, which is obtained by subjecting the yellow liquid obtained in Example 15 to hydrogen nuclear magnetic resonance analysis.

[0115] Figure 2 The hydrogen nuclear magnetic resonance spectrum of cannabidiol is shown, which is obtained by subjecting the white crystalline cannabidiol obtained in the application example to hydrogen nuclear magnetic resonance analysis. DETAILED DESCRIPTION

[0116] The application is further described by the following examples. It should be noted that the following specific examples are only used to explain the application and do not constitute any limitation on the application. The application is described by referring to typical examples, but it should be understood that the words used therein are descriptive and explanatory words, rather than limiting words. The application can be modified as specified within the scope of the claims of the application, and the application can be revised without departing from the scope and spirit of the application. Although the application described therein relates to specific methods, materials and examples, it does not mean that the application is limited to the specific examples disclosed therein, on the contrary, the application can be extended to all other methods and applications with the same function.

[0117] The endpoints of the ranges and any values disclosed herein are not limited to the precise values recited as the exact dimensions are not considered critical for the invention. Any numeric range recited is intended to include all values from the lower value to the upper value, inclusive of both values, and to also include any value approximately or about the infrastructure of that range, even if the value is outside the stated range. Numeric ranges include endpoints between the individual numeric values, between the endpoints of the numeric values, and between the individual numeric values and the endpoints of the numeric values, and any new numeric range created by combining the endpoints and individual numeric values should be considered as being specifically disclosed herein.

[0118] Example 1

[0119] The compound shown in Formula 2 (R = benzyl, X = bromine in Formula 2; the corresponding compound is named as Compound 2a) was synthesized according to the following procedure:

[0120] Sodium hydride (10 g, 0.25 mol) was added to N-methylpyrrolidone (156 mL) and slowly injected into benzyl alcohol (28.1 g, 0.26 mol) via a needle tube at 0 °C in an ice bath. After the addition was completed, the ice bath was removed and the mixture was stirred at room temperature for 1 h. The mixture was then cooled to 0 °C in an ice bath and 3,5-difluorobromobenzene (19.3 g, 0.1 mol) was added via a needle tube. The mixture was then heated in an oil bath at 75 °C for 8 h. After the reaction was completed and the reaction mixture was cooled, it was transferred to a separatory funnel and diethyl ether (300 mL) and water (300 mL) were added. After the extraction was separated into layers, the aqueous phase was extracted with diethyl ether (300 mL) three times. The organic phases were combined and washed with potassium hydroxide solution (8 wt% potassium hydroxide) and saturated brine, and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography using n-hexane / ethyl acetate (30:1, v / v) as the eluent to give 34.0 g of the product as a white solid. The yield of the synthesized compound 2a was calculated to be 92%.

[0121] The white solid was analyzed by hydrogen nuclear magnetic resonance and the results were as follows: 1 H NMR (400 MHz, CDCl3) δ 7.35-7.24 (m, 10H), 6.70 (d, J = 2.2 Hz, 2H), 6.47 (t, J = 2.2 Hz, 1H), 4.93 (s, 4H).

[0122] Example 2

[0123] The procedure for synthesizing the compound of Formula 2 (Formula 2, R = benzyl, X = bromo; the corresponding compound is named as compound 2a) is essentially the same as that of Example 1, except that sodium tert-butoxide (24 g, 0.25 mol) is used instead of sodium hydride (10 g, 0.25 mol), which results in 31.2 g of product, which is calculated to be 84% yield of compound 2a.

[0124] Example 3

[0125] The procedure for synthesizing the compound of Formula 2 (Formula 2, R = 4-NO2Ph-CH2-, X = bromo; the corresponding compound is named as compound 2b) is essentially the same as that of Example 1, except that p-nitrobenzyl alcohol (39.8 g, 0.26 mol) is used instead of benzyl alcohol (28.1 g, 0.26 mol), which results in 42.7 g of product, which is calculated to be 93% yield of compound 2b.

[0126] Example 4

[0127] The procedure for synthesizing the compound of Formula 2 (Formula 2, R = 4-OMePh-CH2-, X = bromo; the corresponding compound is named as compound 2c) is essentially the same as that of Example 1, except that p-methoxybenzyl alcohol (35.9 g, 0.26 mol) is used instead of benzyl alcohol (28.1 g, 0.26 mol), which results in 38.6 g of product, which is calculated to be 90% yield of compound 2c.

[0128] Example 5

[0129] The procedure for synthesizing the compound of Formula 2 (Formula 2, R = 1-naphthyl-CH2-, X = bromo; the corresponding compound is named as compound 2d) is essentially the same as that of Example 1, except that 1-naphthalenemethanol (41.1 g, 0.26 mol) is used instead of benzyl alcohol (28.1 g, 0.26 mol), which results in 41.2 g of product, which is calculated to be 88% yield of compound 2d.

[0130] Example 6

[0131] The procedure for synthesizing the compound of Formula 2 (Formula 2, R = 9-anthryl-CH2-, X = bromo; the corresponding compound is named as compound 2e) is essentially the same as that of Example 1, except that 9-anthracenemethanol (54.1 g, 0.26 mol) is used instead of benzyl alcohol (28.1 g, 0.26 mol), which results in 51.3 g of product, which is calculated to be 91% yield of compound 2e.

[0132] Example 7

[0133] Synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was carried out as follows:

[0134] The compound 2a (36.9 g, 0.1 mol) obtained from Example 1 was added to a 500 mL reaction flask together with nickel iodide (3.1 g, 0.01 mol), 1,10-phenanthroline (1.8 g, 0.01 mol), pyridine (7.9 g, 0.1 mol), zinc powder (13 g, 0.2 mol), n-pentyl bromide (30.2 g, 0.2 mol) and N-methyl pyrrolidone (100 mL). The mixture was allowed to react at 40°C for 12 h. After the reaction was completed and the reaction mixture was cooled, it was transferred to a separatory funnel and diethyl ether (300 mL) and water (300 mL) were added. After the extraction was completed, the organic phase was separated first and the aqueous phase was extracted with diethyl ether (300 mL) three times. The organic phases were combined and washed with potassium hydroxide solution (8 wt% of potassium hydroxide) and saturated brine successively and the organic layer was separated. The organic layer was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography using n-hexane / ethyl acetate (30:1, v / v) as the eluent to give 32.4 g of the product as a white liquid. The yield of the synthesis of 3,5-dibenzyl ether pentaphene was 90% by calculation.

[0135] The white liquid obtained was analyzed by hydrogen nuclear magnetic resonance and the results were as follows: 1 H NMR (400 MHz, CDCl3) delta 7.47-7.30 (m, 10H), 6.49-6.44 (m, 3H), 5.03 (s, 4H), 2.55 (dd, J = 8.7, 6.8 Hz,2H), 1.66-1.55 (m, 3H), 1.40-1.24 (m, 5H), 0.90 (t, J = 6.8 Hz, 3H)。

[0136] Example 8

[0137] The synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was carried out as in Example 7 except that nickel bromide dimethoxyethane (3.08 g, 0.01 mol) was used instead of nickel iodide (3.1 g, 0.01 mol) to give 30.8 g of the product. The yield of the synthesis of 3,5-dibenzyl ether pentaphene was 85.5% by calculation.

[0138] Example 9

[0139] The procedure for the synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was essentially the same as in Example 7, except that the reaction mixture was allowed to react at 40 °C for 18 h instead of 12 h. This resulted in 32.6 g of product, which corresponds to a yield of 90% for the synthesis of 3,5-dibenzyl ether pentaphene.

[0140] Example 10

[0141] The procedure for the synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was essentially the same as in Example 7, except that the reaction mixture was allowed to react at 40 °C for 18 h instead of 12 h. This resulted in 32.6 g of product, which corresponds to a yield of 90% for the synthesis of 3,5-dibenzyl ether pentaphene.

[0142] Example 11

[0143] The procedure for the synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was essentially the same as in Example 7, except that 2,2'-bipyridine (1.56 g, 0.01 mol) was used instead of 1,10-phenanthroline (1.8 g, 0.01 mol). This resulted in 23.2 g of product, which corresponds to a yield of 64.4% for the synthesis of 3,5-dibenzyl ether pentaphene.

[0144] Example 12

[0145] The procedure for the synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was essentially the same as in Example 7, except that picolinimide (1.21 g, 0.01 mol) was used instead of 1,10-phenanthroline (1.8 g, 0.01 mol). This resulted in 18.6 g of product, which corresponds to a yield of 51.6% for the synthesis of 3,5-dibenzyl ether pentaphene.

[0146] Example 13

[0147] The procedure for the synthesis of 3,5-dibenzyl ether pentaphene (i.e. R = benzyl in Formula 3) was essentially the same as in Example 7, except that no pyridine was added. This resulted in 16.66 g of product, which corresponds to a yield of 46.2% for the synthesis of 3,5-dibenzyl ether pentaphene.

[0148] Example 14

[0149] The procedure for synthesizing 3,5-bis(4-methoxybenzyl ether)amylbenzene (i.e., R = 4-OMePh-CH2- in Formula 3) was essentially the same as in Example 7, except that compound 2c (42.9 g, 0.1 mol) obtained in Example 2 was used instead of compound 2a (36.9 g, 0.1 mol) obtained in Example 1. As a result, 38.3 g of product was obtained, which corresponded to a yield of 91% for the synthesis of 3,5-bis(4-methoxybenzyl ether)amylbenzene.

[0150] Example 15

[0151] The procedure for synthesizing 3,5-bis(4-methoxybenzyl ether)amylbenzene (i.e., R = 4-OMePh-CH2- in Formula 3) was essentially the same as in Example 7, except that compound 2c (42.9 g, 0.1 mol) obtained in Example 2 was used instead of compound 2a (36.9 g, 0.1 mol) obtained in Example 1. As a result, 38.3 g of product was obtained, which corresponded to a yield of 91% for the synthesis of 3,5-bis(4-methoxybenzyl ether)amylbenzene.

[0152] The product 3,5-bis(benzyl ether)amylbenzene (36.0 g, 0.1 mol) obtained in Example 7 was dissolved in ethyl acetate (100 mL), and triethylsilane (23.2 g, 0.2 mol) and iodine (50.8 g, 0.2 mol) were added sequentially. The mixture was allowed to react at 20-30 °C for 2 h, and then transferred to a separatory funnel after the reaction mixture was cooled. Saturated sodium sulfite (300 mL) was added. After the aqueous phase was extracted with ethyl acetate (100 mL) three times, the organic phase was separated. The combined organic phase was dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography using n-hexane / ethyl acetate (10:1, v / v) as the eluent to obtain 3,5-dihydroxyamylbenzene (Olivetol) (16.9 g, yield 94%) as a light yellow liquid.

[0153] The yellow liquid obtained was analyzed by1H NMR, and the1H NMR spectrum is shown in Figure 1 Figure 1 The results showed that: 1 H NMR (400 MHz, CDCl3) δ 6.25 (d, J = 2.2 Hz, 2H), 6.18 (t, J = 2.2 Hz,1H), 4.91 (s, 2H), 2.48 (dd, J = 8.8, 6.7 Hz, 2H), 1.65-1.49 (m, 2H), 1.36-1.27 (m, 4H), 0.88 (t, J = 6.8 Hz, 3H).

[0154] Example 16

[0155] The procedure for synthesizing 3,5-bis(4-methoxybenzyl ether)amylbenzene (i.e., R = 4-OMePh-CH2- in Formula 3) was essentially the same as in Example 7, except that compound 2c (42.9 g, 0.1 mol) obtained in Example 2 was used instead of compound 2a (36.9 g, 0.1 mol) obtained in Example 1. As a result, 38.3 g of product was obtained, which corresponded to a yield of 91% for the synthesis of 3,5-bis(4-methoxybenzyl ether)amylbenzene.

[0156] ​The product obtained in Example 14, 3,5-di(4-methoxybenzyl ether)pentaphene (42.1 g, 0.1 mol) was dissolved in dichloromethane (100 mL), purified water (20 mL), 2,3-dichloro-5,6-dicyano-benzoquinone (45.4 g, 0.2 mol) were added, and the mixture was reacted at 20-30 °C for 2 h. After the reaction mixture was cooled, it was transferred to a separatory funnel, and saturated sodium sulfite (300 mL) was added. After the extraction was separated into layers, the organic phase was first separated, and the aqueous phase was extracted three times with dichloromethane (80 mL). The combined organic phases were dried over anhydrous sodium sulfate and concentrated, and then purified by silica gel column chromatography, eluted with n-hexane / ethyl acetate (10:1, v / v) as an eluent, to obtain 3,5-dihydroxypentaphene (Olivetol) (16.0 g, yield 89%) as a light yellow liquid.

[0157] Application Example

[0158] Cannabidiol was prepared using 3,5-dihydroxypentaphene prepared in Example 15, according to the following procedure:

[0159] Trans-menthyl-2,8-dien-1-ol (2.0 g, 13.1 mmol, 1 eq) and 3,5-dihydroxypentaphene (2.4 g, 13.1 mmol, 1 eq) prepared in Example 15 were sequentially dissolved in chloroform (50 mL), heated to 40 °C, and then boron trifluoride etherate (185 mg, 1.3 mmol, 0.1 eq) was added, and the reaction mixture was stirred at 40 °C for 3 min. Subsequently, saturated sodium bicarbonate solution (30 mL) was added to quench, and then it was allowed to stand to separate into layers, and the chloroform layer was collected, and the aqueous phase was extracted once more with dichloromethane (30 mL), and the combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated to a light yellow oily substance under reduced pressure. The oily substance was dissolved in an appropriate amount of petroleum ether, and then loaded onto a silica gel column for separation and purification, to obtain cannabidiol (1.52 g, yield 37%) and a byproduct (1.45 g, yield 35%) as colorless oily substances.

[0160] The obtained cannabidiol as a colorless oily substance was dissolved in n-heptane (3.0 mL), cooled to 0 °C, and then a small amount of seed crystals was added, and then the temperature was continuously lowered to -20 °C overnight to crystallize. The crystals were filtered under reduced pressure, and then washed with a small amount of n-heptane twice. The crystals were collected and dried under reduced pressure to obtain white crystalline cannabidiol (1.14 g, yield 27%).

[0161] The obtained white crystalline cannabidiol was analyzed by hydrogen nuclear magnetic resonance, and the hydrogen nuclear magnetic resonance spectrum is shown in FIG. 1. Figure 2 Figure 2 The results showed that: 1 ​H NMR (600 MHz, CDCl3) δ 6.29 (s, 1H), 6.16 (s, 1H), 5.98 (s,1H), 5.57 (s,1H), 4.67 (s, 1H), 4.66-4.58 (m, 1H), 4.56 (s, 1H), 3.85 (ddq, J= 9.0, 4.8, 2.4 Hz, 1H), 2.44 (t, J = 7.8 Hz, 2H), 2.40 (td, J = 11.0, 10.6,3.2 Hz, 1H), 2.28 -2.19 (m, 1H), 2.10 (ddt, J = 17.8, 5.0, 2.4 Hz, 1H), 1.86-1.73 (m, 5H), 1.66 (s, 3H), 1.58-1.54 (m, 2H), 1.35-1.25 (m, 4H), 0.88 (t, J= 7.2 Hz, 3H) 13C NMR (150 MHz, Methanol-d4) δ 156.00, 148.83, 141.30,133.06, 125.88, 114.53, 109.23, 106.96, 45.02, 36.05, 35.24, 31.29, 30.65,30.31, 29.30, 22.42, 22.24, 18.17, 13.12; MS (m / z):[M+H] + calcd. for C 21 H 31 O2,315; found, 314.9。

[0162] The above-described technical solutions of the present application are merely preferred specific embodiments of the present application, and the protection scope of the present application is not limited thereto. Any simple change or equivalent replacement of the technical solutions within the technical scope disclosed by the present application can fall within the protection scope of the present application.

Claims

1. A process for the preparation of 3,5-dihydroxypentylbenzene, characterized in that, The method comprises producing 3,5-diether pentaphene, and then performing a de-R group protection reaction on the 3,5-diether pentaphene; wherein the reagent used in the de-R group protection reaction comprises elemental iodine and triethylsilane, sodium borohydride and nickel chloride, trimethyl iodide silane, boron trichloride, aluminum trichloride, boron trifluoride diethyl ether, or 2,3-dichloro-5,6-dicyano-1,4-benzoquinone; the 3,5-diether pentaphene has a chemical structure as shown in formula 3, and the method for producing the 3,5-diether pentaphene comprises coupling halogenated n-pentane, a ligand, a compound as shown in formula 2, and a reducing agent in the presence of a nickel catalyst; formula 3 and formula 2 are as follows: R in formula 3 is the same as R in formula 2, and both are substituted or unsubstituted methylenecycloaromatic groups; X in formula 2 is chlorine, bromine or iodine; the ligand is 1,10-phenanthroline; the coupling reaction is performed in the presence of pyridine; the nickel catalyst is at least one selected from acetylacetone nickel, nickel fluoride, nickel bromide, nickel iodide, bis(triphenylphosphine) nickel chloride, nickel acetate, nickel chloride dimethoxyethane, and nickel bromide dimethoxyethane; the reducing agent is at least one selected from zinc powder and manganese powder.

2. The method of claim 1, wherein, the substituted or unsubstituted methylenecycloaromatic group is Ar-CH2-, wherein Ar is Ph, 4-OMePh, 4-NO2Ph, 4-MePh, 1-naphthyl or 9-anthryl.

3. The method of claim 2, wherein, the halogenated n-pentane is at least one selected from iodinated n-pentane, chlorinated n-pentane and brominated n-pentane; and / or, the molar ratio of the compound as shown in formula 2 to the nickel catalyst in the coupling reaction is 1:(0.05-0.5); and / or, the molar ratio of the compound as shown in formula 2 to the halogenated n-pentane in the coupling reaction is 1:(1-3); and / or, the molar ratio of the compound as shown in formula 2 to the ligand in the coupling reaction is 1:(0.05-0.5); and / or, the molar ratio of the compound as shown in formula 2 to the reducing agent in the coupling reaction is 1:(1-3); and / or, the molar ratio of the compound as shown in formula 2 to pyridine in the coupling reaction is 1:(0.1-1.5); and / or, the reaction temperature of the coupling reaction is selected from 0-100°C; and / or, the reaction time of the coupling reaction is selected from 1-24h.

4. The method of claim 1, wherein, the coupling reaction is performed in the presence of a solvent.

5. The method of claim 4, wherein, the solvent used in the coupling reaction comprises at least one selected from N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide and N-methyl pyrrolidone; and / or, the amount ratio of the solvent used in the coupling reaction to the compound as shown in formula 2 is (5-10) mL:1g.

6. The method of claim 1, wherein, The method further comprises performing a nucleophilic aromatic substitution reaction on 3,5-difluorohalobenzene and a compound R-OH in the presence of a strong base to obtain the compound as shown in formula 2; wherein R in the compound R-OH is the same as R in formula 2.

7. The method of claim 6, wherein, the 3,5-difluorohalobenzene is at least one selected from 1,3,5-trifluorobenzene, 3,5-difluorochlorobenzene, 3,5-difluorobromobenzene and 3,5-difluoroiodobenzene; and / or, the compound R-OH is selected from at least one of benzyl alcohol, p-methoxybenzyl alcohol, p-nitrobenzyl alcohol, p-methylbenzyl alcohol, 9-anthryl alcohol, 1-naphthalenemethyl alcohol; and / or, the strong base is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium hydride, lithium diisopropylamide, sodium bis(trimethylsilyl)amide, potassium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, 1,8-diazabicycloundec-7-ene, sodium hydroxide, potassium hydroxide; and / or, the molar ratio of the 3,5-difluorohalobenzene to the compound R-OH in the nucleophilic aromatic substitution reaction is 1:(2-3); and / or, the molar ratio of the strong base to the compound R-OH in the nucleophilic aromatic substitution reaction is 1:(0.9-1.1); and / or, the reaction temperature of the nucleophilic aromatic substitution reaction is selected from 20-110°C; and / or, the reaction time of the nucleophilic aromatic substitution reaction is selected from 2-12h; and / or, the nucleophilic aromatic substitution reaction is carried out in the presence of a solvent.

8. The method of claim 7, wherein, The solvent used in the nucleophilic aromatic substitution reaction includes at least one of methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone; and / or, the amount ratio of the solvent used in the nucleophilic aromatic substitution reaction to the 3,5-difluorohalobenzene is (5-20)mL:1g.

9. The method according to any one of claims 1 to 8, characterized in that, The reaction temperature of the de-R group protection reaction is selected from 0-50°C; and / or, the reaction time of the de-R group protection reaction is selected from 1-12h; and / or, the de-R group protection reaction is carried out in the presence of a solvent; the solvent includes at least one of dichloromethane, chloroform, 1,2-dichloroethane, ethyl acetate, methanol, ethanol, isopropanol, n-butanol, tert-butanol, methyl tert-butyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, toluene, acetonitrile, 1,4-dioxane, N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, N-methylpyrrolidone.

10. A method of producing cannabidiol, characterized by, The method comprises preparing 3,5-dihydroxypentylbenzene by the method for preparing 3,5-dihydroxypentylbenzene according to any one of claims 1-9, and then using the prepared 3,5-dihydroxypentylbenzene to prepare cannabidiol.

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