Method for producing 3, 5-diether amylbenzene and application of 3, 5-diether amylbenzene in preparation of 3, 5-dihydroxy amylbenzene

Abstract

The invention belongs to the technical field of organic synthesis, and particularly relates to a method for producing 3, 5-diether amylbenzene and application of the 3, 5-diether amylbenzene to preparation of 3, 5-dihydroxy amylbenzene, and the method comprises the step that halogenated n-pentane, a ligand, a compound shown in the formula 2 and a reducing agent are subjected to a coupling reaction in the presence of a nickel catalyst, preferably, the method also comprises the step of carrying out nucleophilic aromatic substitution reaction on 3, 5-difluoro halogenated benzene and a compound R-OH in the presence of strong base to obtain the compound shown in the formula 2. The method for preparing the 3, 5-dihydroxy amylbenzene comprises the following steps: producing the 3, 5-diether amylbenzene, and carrying out an R group removal protection reaction on the 3, 5-diether amylbenzene. The method disclosed by the invention has the characteristics of simplicity in operation, high production safety, high product yield and the like, and industrial production of 3, 5-diether amylbenzene and 3, 5-dihydroxy amylbenzene is favorably realized.

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 thereof 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 this method is low. Later studies found that the compound has a good inhibitory effect on human immune system diseases, and therefore has been rapidly and widely applied in the pharmaceutical 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 thereof 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 industrial production of 3,5-diether pentylbenzene and 3,5-dihydroxypentylbenzene.

[0004] The application is achieved by the following technical solutions.

[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] R in formula 3 is the same as R in formula 2, and both are substituted or unsubstituted methylenecycloarenyl; X in formula 2 is fluorine, chlorine, bromine or iodine.

[0007] In some embodiments of the application, the substituted or unsubstituted methylenecycloarenyl is Ar-CH2-, wherein Ar is Ph, 4-OMePh, 4-NO2Ph, 4-MePh, 1-naphthyl or 9-anthryl.

[0008] In some embodiments of the present application, the nickel catalyst is selected from at least one of nickel acetylacetonate, nickel fluoride, nickel bromide, nickel iodide, nickel chloride bis(triphenylphosphine), nickel acetate, nickel chloride dimethoxyethane, nickel bromide dimethoxyethane, and the like.

[0009] In some embodiments of the present application, the n-halogenopentane is selected from at least one of n-iodopentane, n-chloropentane, n-bromopentane.

[0010] In some embodiments of the present application, the ligand is selected from at least one of compounds containing at least one pyridyl group.

[0011] In some embodiments of the present application, the ligand is selected from at least one of compounds represented by the following formulae I to XII: ; wherein R' in formula I, formula II, formula III is independently selected from methyl, methoxy, butyl.

[0012] In some embodiments of the present application, the ligand is selected from at least one of compounds represented by formula IV (bipyridine), formula VII (1,10-phenanthroline), formula X (picolinimide).

[0013] 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.

[0014] 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).

[0015] 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 within the range consisting of any two of them: 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.

[0016] In some embodiments of the present application, the molar ratio of the compound represented by formula 2 to the n-halogenopentane in the coupling reaction is 1: (1-3), preferably 1: (1.5-2.5).

[0017] 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), which means that the molar ratio of the compound of formula 2 to halogenated n-pentane can be selected from any value or any range consisting of any two values from 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.

[0018] 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).

[0019] 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), which means that the molar ratio of the compound of formula 2 to ligand can be selected from any value or any range consisting of any two values from 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 reducing agent 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 reducing agent in the coupling reaction is 1:(1-3), which means that the molar ratio of the compound of formula 2 to reducing agent can be selected from any value or any range consisting of any two values from 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 reaction temperature of the coupling reaction is selected from 0-100°C, preferably from 30-60°C.

[0023] In some embodiments of the present invention, the reaction temperature of the coupling reaction being 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 combination thereof: 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.

[0024] In some embodiments of the present invention, the reaction time of the coupling reaction is selected from 1 to 24 hours, preferably from 10 to 15 hours.

[0025] In some embodiments of the present invention, the reaction time of the coupling reaction being selected from 1 to 24 hours means that the reaction time of the coupling reaction can be selected from any value of the following durations or any combination thereof: 1h, 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h, 20h, 21h, 22h, 23h, 24h.

[0026] In some embodiments of the present invention, the coupling reaction is carried out in the presence of a solvent.

[0027] In some embodiments of the present invention, the solvent used in the coupling reaction includes at least one of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone.

[0028] In some embodiments of the present invention, the ratio of the solvent used in the coupling reaction to the compound shown in Formula 2 is (5-10) mL:1 g.

[0029] In some embodiments of the present invention, the ratio of the solvent used in the coupling reaction to the compound shown in Formula 2 is (5-10) mL:1g, which means that the ratio of the solvent used in the coupling reaction to the compound shown in Formula 2 can be selected from any value of the following ratios or any combination thereof: 5 mL:1g, 5.5 mL:1g, 6 mL:1g, 6.5 mL:1g, 7 mL:1g, 7.5 mL:1g, 8 mL:1g, 8.5 mL:1g, 9 mL:1g, 9.5 mL:1g, 10 mL:1g.

[0030] In some embodiments of the present invention, the coupling reaction is carried out in the presence of an additive; the additive is selected from at least one of sodium iodide, magnesium chloride, potassium iodide, lithium chloride, pyridine, triethylamine, diisopropylethylenediamine, 4-dimethylaminopyridine, trimethylchlorosilane, etc.

[0031] In some embodiments of the present invention, the molar ratio of the compound represented by Formula 2 to the additive in the coupling reaction is 1:(0.1 to 1.5), preferably 1:(0.6 to 1.2).

[0032] In some embodiments of the present invention, the molar ratio of the compound represented by Formula 2 to the additive in the coupling reaction being 1:(0.1 to 1.5) means that the molar ratio of the compound represented by Formula 2 to the additive can be selected from any value of the following molar ratios or any combination thereof: 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.

[0033] In some embodiments of the present invention, the method further includes reacting 3,5-difluorohalobenzene with compound R-OH in the presence of a strong base to undergo a nucleophilic aromatic substitution reaction to obtain the compound shown in Formula 2; wherein, R in compound R-OH is the same as R in Formula 2, that is, both are substituted or unsubstituted methylene cycloaromatic groups.

[0034] In some embodiments of the present invention, the 3,5-difluorohalobenzene is selected from at least one of 1,3,5-trifluorobenzene, 3,5-difluorochlorobenzene, 3,5-difluorobromobenzene, and 3,5-difluoroiodobenzene.

[0035] In some embodiments of the present invention, the compound R-OH is selected from at least one of benzyl alcohol, p-methoxybenzyl alcohol, p-nitrobenzyl alcohol, p-methylbenzyl alcohol, 9-anthrayl alcohol, 1-naphthyl alcohol, etc.

[0036] In the nucleophilic aromatic substitution reaction of this invention, the role of the strong base is to deprotonate the compound R-OH, forming an alkoxy anion, which then undergoes an aromatic nucleophilic substitution reaction with the electron-deficient aromatic ring to obtain the compound shown in Formula 2. That is, the strong base can be any compound or composition capable of deprotonating the compound R-OH.

[0037] In some embodiments of the present invention, the strong base includes inorganic strong bases and / or organic strong bases, preferably selected from at least one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium hydride, lithium diisopropylamino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, 1,8-diazabicycloundec-7-ene, sodium hydroxide, potassium hydroxide, etc.

[0038] In some embodiments of the present invention, the molar ratio of the 3,5-difluorohalobenzene to compound R-OH in the nucleophilic aromatic substitution reaction is 1:(2-3).

[0039] In some embodiments of the present invention, the molar ratio of the strong base to compound R-OH in the nucleophilic aromatic substitution reaction is 1:(0.9 to 1.1).

[0040] In some embodiments of the present invention, the reaction temperature of the nucleophilic aromatic substitution reaction is selected from 20 to 110°C, preferably from 70 to 100°C.

[0041] In some embodiments of the present invention, the reaction temperature of the nucleophilic aromatic substitution reaction being selected from 20 to 110°C means that the reaction temperature of the nucleophilic aromatic substitution reaction can be selected from any value of the following temperatures or any combination thereof: 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.

[0042] In some embodiments of the present invention, the reaction time of the nucleophilic aromatic substitution reaction is selected from 2 to 12 hours, preferably from 4 to 8 hours.

[0043] In some embodiments of the present invention, the reaction time of the nucleophilic aromatic substitution reaction is selected from 2 to 12 h, which means that the reaction time of the nucleophilic aromatic substitution reaction can be selected from any value of the following durations or any combination thereof: 2h, 3h, 4h, 5h, 6h, 7h, 8h, 9h, 10h, 11h, 12h.

[0044] In some embodiments of the present invention, the nucleophilic aromatic substitution reaction is carried out in the presence of a solvent.

[0045] In some embodiments of the present invention, 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, and N-methylpyrrolidone.

[0046] In some embodiments of the present invention, the ratio of the solvent used in the nucleophilic aromatic substitution reaction to the amount of the 3,5-difluorohalobenzene is (5-20) mL: 1 g.

[0047] In some embodiments of the present invention, the ratio of the solvent used in the nucleophilic aromatic substitution reaction to the 3,5-difluorohalobenzene is (5-20) mL:1g. This means that the ratio of the solvent used in the coupling reaction to the compound shown in Formula 2 can be selected from any value of the following ratios or any combination thereof: 5 mL:1g, 5.5 mL:1g, 6 mL:1g, 6.5 mL:1g, 7 mL:1g, 7.5 mL:1g, 8 mL:1g, 8.5 mL:1g, 9 mL:1g, 9. 5mL:1g, 10mL:1g, 11mL:1g, 11.5mL:1g, 12mL:1g, 12.5mL:1g, 13mL:1g, 13.5mL:1g, 14mL:1g, 14.5mL:1g, 15mL: 1g, 15.5mL:1g, 16mL:1g, 16.5mL:1g, 17mL:1g, 17.5mL:1g, 18mL:1g, 18.5mL:1g, 19mL:1g, 19.5mL:1g, 20mL:1g.

[0048] In some embodiments of the present invention, the method for producing 3,5-dietherpentylene includes the following steps: (1) 3,5-difluorohalobenzene reacts with compound R-OH in the presence of a strong base to undergo a nucleophilic aromatic substitution reaction to obtain the compound shown in Formula 2; (2) The halopentane, ligand, compound of formula 2 and reducing agent are coupled in the presence of nickel catalyst to obtain 3,5-dietherpentene.

[0049] In some embodiments of the present invention, the method further includes purifying the crude product obtained in step (1).

[0050] In some embodiments of the present invention, the crude product purification in step (1) includes extraction and column elution; preferably, extraction and column elution are performed sequentially.

[0051] In some embodiments of the present invention, the method further includes purifying the crude product obtained in step (2).

[0052] In some embodiments of the present invention, the crude product purification in step (2) includes extraction and column elution; preferably, extraction and column elution are performed sequentially.

[0053] Secondly, the present invention provides a method for preparing 3,5-dihydroxypentane, the method comprising the following steps: performing a de-R-group protection reaction on 3,5-dietherpentane, wherein the 3,5-dietherpentane has the chemical structure shown in Formula 3. The de-R-group protection reaction is a reaction that reduces all -OR groups in the 3,5-dietherpentane to -OH groups.

[0054]

[0055] In Formula 3, R is a substituted or unsubstituted methylene cycloaromatic group.

[0056] In some embodiments of the present invention, the substituted or unsubstituted methylene cycloaromatic group is Ar-CH2-, wherein Ar is Ph, 4-OMePh, 4-NO2Ph, 4-MePh, 1-naphthyl or 9-anthrayl.

[0057] In some embodiments of the present invention, the reagents used in the de-R group protection reaction include Pd / C and hydrogen, Raney nickel and hydrogen, elemental iodine and triethylsilane, sodium borohydride and nickel chloride, trimethyliodosilane, boron trichloride, aluminum trichloride, boron trifluoride ether, or 2,3-dichloro-5,6-dicyanobenzoquinone, etc. In some embodiments of the present invention, the reagents used in the deprotection reaction can be classified according to the system as follows: 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 to remove various R-group protecting groups.

[0058] 2) Lewis acid system: elemental iodine and triethylsilyl methyl iodide, boron trichloride, aluminum trichloride, boron trifluoride diethyl ether; this system is applicable to 4-OMePh-CH2- (p-methoxybenzyl, PMB) and Ph-CH2- (benzyl, Bn).

[0059] 3) Oxidation system: For electron-rich benzyl groups, such as 4-OMePh-CH2- (p-methoxybenzyl, PMB), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) can be used for removal.

[0060] In some embodiments of the present invention, the reaction temperature of the de-R group protection reaction is selected from 0 to 50°C, preferably 20 to 30°C.

[0061] In some embodiments of the present invention, the reaction temperature of the de-R group protection reaction is selected from 0 to 50°C, which means that the reaction temperature of the de-R group protection reaction can be selected from any value of the following temperatures or any combination thereof: 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.

[0062] In some embodiments of the present invention, the reaction time for the de-R group protection reaction is selected from 1 to 12 hours.

[0063] In some embodiments of the present invention, the reaction time of the R-group removal protection reaction is selected from 1 to 12 h, which means that the reaction time of the R-group removal protection reaction can be selected from any value of the following durations or any combination thereof: 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h.

[0064] In some embodiments of the present invention, 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, and N-methylpyrrolidone.

[0065] In some embodiments of the present invention, the solvent used in the de-R group protection reaction is in a ratio of (5-10) mL to 1 g to 3,5-dietherpentylene.

[0066] In some embodiments of the present invention, the ratio of solvent to 3,5-dietherpentylbenzene used in the de-R group protection reaction is (5-10) mL: 1 g, meaning that the ratio of solvent to 3,5-dietherpentylbenzene can be selected from any value of the following ratios or any combination thereof: 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.

[0067] In some embodiments of the present invention, the method further includes producing 3,5-dietherpentylbenzene by the method described in the first aspect.

[0068] Thirdly, the present invention provides a method for preparing 3,5-dihydroxypentane, the method comprising producing 3,5-dietherpentane by means of the method described in the first aspect.

[0069] In some embodiments of the present invention, the method for preparing 3,5-dihydroxypentane further includes the following step: performing a de-R-group protection reaction on 3,5-dietherpentane. The de-R-group protection reaction is a reaction that reduces all -OR groups in 3,5-dietherpentane to -OH groups.

[0070] In some embodiments of the present invention, the reagents used in the de-R group protection reaction include Pd / C and hydrogen, Raney nickel and hydrogen, elemental iodine and triethylsilane, sodium borohydride and nickel chloride, trimethyliodosilane, boron trichloride, aluminum trichloride, boron trifluoride ether, or 2,3-dichloro-5,6-dicyanobenzoquinone, etc. In some embodiments of the present invention, the reagents used in the deprotection reaction can be classified according to the system as follows: 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 to remove various R-group protecting groups.

[0071] 2) Lewis acid system: elemental iodine and triethylsilyl methyl iodide, boron trichloride, aluminum trichloride, boron trifluoride diethyl ether; this system is applicable to 4-OMePh-CH2- (p-methoxybenzyl, PMB) and Ph-CH2- (benzyl, Bn).

[0072] 3) Oxidation system: For electron-rich benzyl groups, such as 4-OMePh-CH2- (p-methoxybenzyl, PMB), 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ) can be used for removal.

[0073] In some embodiments of the present invention, the reaction temperature of the de-R group protection reaction is selected from 0 to 50°C, preferably 20 to 30°C.

[0074] In some embodiments of the present invention, the reaction temperature of the de-R group protection reaction is selected from 0 to 50°C, which means that the reaction temperature of the de-R group protection reaction can be selected from any value of the following temperatures or any combination thereof: 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.

[0075] In some embodiments of the present invention, the reaction time for the de-R group protection reaction is selected from 1 to 12 hours.

[0076] In some embodiments of the present invention, the reaction time of the R-group removal protection reaction is selected from 1 to 12 h, which means that the reaction time of the R-group removal protection reaction can be selected from any value of the following durations or any combination thereof: 1 h, 2 h, 3 h, 4 h, 5 h, 6 h, 7 h, 8 h, 9 h, 10 h, 11 h, 12 h.

[0077] In some embodiments of the present invention, the de-R group protection reaction is carried out in the presence of a solvent; said 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, and N-methylpyrrolidone.

[0078] In some embodiments of the present invention, the solvent used in the de-R group protection reaction is in a ratio of (5-10) mL to 1 g to 3,5-dietherpentylene.

[0079] In some embodiments of the present invention, the ratio of solvent to 3,5-dietherpentylbenzene used in the de-R group protection reaction is (5-10) mL: 1 g, meaning that the ratio of solvent to 3,5-dietherpentylbenzene can be selected from any value of the following ratios or any combination thereof: 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.

[0080] In some embodiments of the present invention, the method for preparing 3,5-dihydroxypentane includes the following steps: (1) 3,5-difluorohalobenzene reacts with compound R-OH in the presence of a strong base to undergo a nucleophilic aromatic substitution reaction to obtain the compound shown in Formula 2; (2) The halopentane, ligand, compound of formula 2 and reducing agent are coupled in the presence of nickel catalyst to give 3,5-dietherpentene; (3) Deprotection reaction of 3,5-dietherpentene. In some embodiments of the present invention, the method further includes purifying the crude product obtained in step (3).

[0081] In some embodiments of the present invention, the purification method includes extraction and column elution; preferably, extraction and column elution are performed sequentially.

[0082] The technical approach of a specific embodiment of the present invention is as follows:

[0083] In the technical route of this invention, in the reaction for synthesizing compound 2a, the presence of a strong base causes benzyl alcohol to lose a proton, forming an alkoxy anion, which then undergoes an 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, a cross-electrophilic coupling reaction between aryl bromides and alkyl bromides is catalyzed by a nickel catalyst, achieving direct coupling of the pentyl group to the 1-site of the benzene ring in a one-step reaction to obtain compound 3a. The specific mechanism of this reaction is as follows: divalent nickel is first reduced to zero-valent nickel by a reducing agent, and then undergoes oxidative addition with the aryl bromide to form an aryl divalent nickel species; this species combines with an alkyl radical to generate an alkylaryl trivalent nickel intermediate, which is then reductively eliminated to obtain the target product compound 3a and a monovalent nickel species; the monovalent nickel species further undergoes a single-electron transfer process with the alkyl bromide to generate a divalent nickel species and an alkyl radical, thereby completing the catalytic cycle. After synthesizing compound 3a, only a deprotection reaction is needed to remove the benzyl group to obtain the target product 3,5-dihydroxypentane. The entire technical route is simple and easy to implement.

[0084] Fourthly, the present invention provides 3,5-dihydroxypentane prepared by the method for preparing 3,5-dihydroxypentane described in the second or third aspect.

[0085] Fifthly, the present invention provides the use of the 3,5-dihydroxypentane described in the fourth aspect in the production of chemical drugs such as cannabidiol.

[0086] In a sixth aspect, the present invention provides a method for producing cannabidiol, the method comprising preparing 3,5-dihydroxypentane by the method for preparing 3,5-dihydroxypentane described in the second or third aspect.

[0087] In some embodiments of the present invention, the method for producing cannabidiol further includes alkylating trans-menthyl-2,8-dien-1-ol with the 3,5-dihydroxypentane in the presence of a Lewis acid or a Brønsted acid.

[0088] In some embodiments of the present invention, the Lewis acid is selected from at least one of cerium trichloride, aluminum trichloride, ferric trichloride, titanium tetrachloride, zinc dichloride, boron trifluoride ether, etc.

[0089] In some embodiments of the present invention, the Brønsted acid is selected from at least one of hydrochloric acid, hydrobromic acid, trifluoromethanesulfonic acid, trifluoroacetic acid, acetic acid, formic acid, citric acid, etc.

[0090] In some embodiments of the present invention, the alkylation reaction is carried out in the presence of a solvent selected from at least one of haloalkanes, esters, alcohols, ethers, furans, aromatics, nitrile compounds, etc.; 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, etc.

[0091] In some embodiments of the present invention, the reaction temperature of the alkylation reaction is selected from 30 to 50°C, preferably from 35 to 45°C.

[0092] In some embodiments of the present invention, the reaction time of the alkylation reaction is 2 to 5 minutes.

[0093] In some embodiments of the present invention, the alkylation reaction is carried out under stirring.

[0094] The beneficial effects of this invention are as follows: This invention proposes a method for producing 3,5-dietherpentane, which includes coupling a halopentane, a ligand, a compound of Formula 2, and a reducing agent in the presence of a nickel catalyst. The coupling reaction is carried out under mild conditions and is simple to operate. Since no harsh reaction conditions are required, energy consumption and reaction safety can be effectively reduced.

[0095] This invention also proposes a method for preparing the compound shown in Formula 2 by reacting 3,5-difluorohalobenzene with compound R-OH in the presence of a strong base through a nucleophilic aromatic substitution reaction. This method has the advantages of mild conditions, simple operation, and low raw material cost. By using this method to first prepare the compound shown in Formula 2, and then using the compound shown in Formula 2 to produce 3,5-dietherpentene, the cost of producing 3,5-dietherpentene can be effectively reduced.

[0096] This invention also proposes a method for preparing 3,5-dihydroxypentane, which can be obtained by deprotecting 3,5-dietherpentane with an R-group. The method is mild, simple to operate, and can achieve a high product yield, which is conducive to industrial production and meets the market demand for 3,5-dihydroxypentane products.

[0097] The present invention also proposes a method for preparing 3,5-dihydroxypentylbenzene using the method of the present invention, first preparing 3,5-dihydroxypentylbenzene, and then using the obtained 3,5-dihydroxypentylbenzene as one of the main raw materials to produce cannabidiol. This method is simple to operate and is conducive to realizing the industrial production of cannabidiol. Attached Figure Description

[0098] Figure 1The hydrogen nuclear magnetic resonance spectrum of 3,5-dihydroxypentane was obtained by hydrogen nuclear magnetic resonance analysis of the yellow liquid obtained in Example 15.

[0099] Figure 2 The hydrogen nuclear magnetic resonance spectrum of cannabidiol was obtained by hydrogen nuclear magnetic resonance analysis of the white crystalline cannabidiol obtained in the application examples. Detailed Implementation

[0100] The following embodiments further illustrate the technology of the present invention. It should be noted that the specific embodiments below are only for explaining the present invention and do not constitute any limitation on the present invention. The present invention has been described with reference to typical embodiments, but it should be understood that the terms used herein are descriptive and explanatory, not limiting. Modifications can be made to the present invention within the scope of the claims, and revisions can be made to the present invention without departing from the scope and spirit of the present invention. Although the present invention described herein relates to specific methods, materials, and embodiments, it does not mean that the present invention is limited to the specific examples disclosed herein; on the contrary, the present invention can be extended to all other methods and applications having the same function.

[0101] The endpoints and any values ​​of the ranges disclosed in this invention are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the various ranges, the endpoint values ​​of the various ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this invention.

[0102] Example 1 The specific procedures for synthesizing the compound shown in Formula 2 (where R = benzyl and X = bromine; the corresponding compound is named compound 2a) are as follows: Sodium hydride (10 g, 0.25 mol) was added to N-methylpyrrolidone (156 mL), and benzyl alcohol (28.1 g, 0.26 mol) was slowly injected via syringe under an ice bath at 0°C. After the addition was complete, the ice bath was removed, and the mixture was stirred at room temperature for 1 h. Then, the mixture was placed back in an ice bath at 0°C to cool to 0°C, and 3,5-difluorobromobenzene (19.3 g, 0.1 mol) was added via syringe. The mixture was then heated in an oil bath at 75°C for 8 h. After the reaction was complete 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 extraction and separation, the organic phase was separated first, and the aqueous phase was extracted three times with diethyl ether (300 mL). The organic phases were combined and washed successively with potassium hydroxide solution (8 wt%) and saturated brine to separate the organic layer. After drying and concentrating the organic layer with anhydrous sodium sulfate, it was purified by silica gel column chromatography using n-hexane / ethyl acetate (30:1, v / v) as the eluent to give 34.0 g of product as a white solid. The yield of compound 2a was calculated to be 92%.

[0103] The obtained white solid was subjected to hydrogen nuclear magnetic resonance analysis, and the results are as follows: 1 H NMR (400 MHz, CDCl3) δ7.35-7.24 (m, 10H), 6.70 (d, J = 2.2 Hz, 2H), 6.47 (t, J = 2.2 Hz, 1H), 4.93 (s, 4H).

[0104] Example 2 The specific operation process for synthesizing the compound shown in Formula 2 (where R = benzyl and X = bromine; the corresponding compound is named compound 2a) is basically the same as in Example 1, except that sodium tert-butoxide (24 g, 0.25 mol) is used instead of sodium hydride (10 g, 0.25 mol). As a result, 31.2 g of product was obtained, and the yield of compound 2a was calculated to be 84%.

[0105] Example 3 The specific operation process for synthesizing the compound shown in Formula 2 (where R = 4-NO2Ph-CH2-, X = bromine; the corresponding compound is named compound 2b) is basically the same as in 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). As a result, 42.7 g of product was obtained, and the yield of compound 2b was calculated to be 93%.

[0106] Example 4 The specific operation process for synthesizing the compound shown in Formula 2 (where R = 4-OMePh-CH2-, X = bromine; the corresponding compound is named compound 2c) is basically the same as in 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), resulting in 38.6 g of product. The yield of compound 2c is calculated to be 90%.

[0107] Example 5 The specific operation process for synthesizing the compound shown in Formula 2 (where R = 1-naphthyl-CH2-, X = bromine; the corresponding compound is named compound 2d) is basically the same as in Example 1, except that 1-naphthylethanol (41.1 g, 0.26 mol) is used instead of benzyl alcohol (28.1 g, 0.26 mol), resulting in 41.2 g of product. The yield of compound 2d was calculated to be 88%.

[0108] Example 6 The specific operation of synthesizing the compound shown in Formula 2 (where R = 9-anthrayl-CH2-, X = bromine; the corresponding compound is named compound 2e) is basically the same as in Example 1, except that 9-anthrayl alcohol (54.1 g, 0.26 mol) is used instead of benzyl alcohol (28.1 g, 0.26 mol), resulting in 51.3 g of product. The yield of the synthesized compound 2e is calculated to be 91%.

[0109] Example 7 The specific steps for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) are as follows: Compound 2a (36.9 g, 0.1 mol) obtained in Example 1 was added to a 500 mL reaction flask along 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), bromopentane (30.2 g, 0.2 mol), and N-methylpyrrolidone (100 mL). The mixture was reacted at 40 °C for 12 h. After the reaction was complete and the reaction mixture was cooled, it was transferred to a separatory funnel, and ether (300 mL) and water (300 mL) were added. After extraction and layering, the organic phase was separated first, and the aqueous phase was extracted three times with ether (300 mL). The organic phases were combined and washed successively with potassium hydroxide solution (8 wt%) and saturated brine, and the organic layer was separated. After drying and concentrating the organic layer with anhydrous sodium sulfate, it was purified by silica gel column chromatography using n-hexane / ethyl acetate (30:1, v / v) as the eluent to obtain 32.4 g of product, which was a white liquid. The yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 90%.

[0110] The obtained white liquid was analyzed by hydrogen nuclear magnetic resonance, and the results are 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).

[0111] Example 8 The specific operation process for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) is basically the same as in Example 7, except that nickel bromide dimethoxyethane (3.08 g, 0.01 mol) is used instead of nickel iodide (3.1 g, 0.01 mol). As a result, 30.8 g of product was obtained. The yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 85.5%.

[0112] Example 9 The specific operation process for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) is basically the same as in Example 7, except that n-iodopentane (39.6 g, 0.2 mol) is used instead of n-bromopentane (30.2 g, 0.2 mol), resulting in 31.9 g of product. The yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 88.6%.

[0113] Example 10 The specific operation process for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) is basically the same as in Example 7, except that the reaction time of the mixture at 40°C is extended from 12h to 18h. As a result, 32.6 g of product was obtained. The yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 90%.

[0114] Example 11 The specific operation process for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) is basically the same as in Example 7, except that bipyridine (1.56 g, 0.01 mol) is used instead of 1,10-phenanthroline (1.8 g, 0.01 mol). As a result, 23.2 g of product was obtained. The yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 64.4%.

[0115] Example 12 The specific procedure for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) is basically the same as in Example 7, except that pyridineimide (1.21 g, 0.01 mol) is used instead of 1,10-phenanthroline (1.8 g, 0.01 mol). As a result, 18.6 g of product was obtained, and the yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 51.6%.

[0116] Example 13 The specific operation process for synthesizing 3,5-dibenzyl ether pentylbenzene (i.e., R = benzyl in Formula 3) is basically the same as in Example 7, except that pyridine is not added. As a result, 16.66 g of product was obtained. The yield of 3,5-dibenzyl ether pentylbenzene was calculated to be 46.2%.

[0117] Example 14 The specific procedure for synthesizing 3,5-bis(4-methoxybenzyl ether)pentene (i.e., R=4-OMePh-CH2- in Formula 3) is basically the same as in Example 7, except that compound 2c (42.9 g, 0.1 mol) obtained in Example 2 is 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. The yield of 3,5-bis(4-methoxybenzyl ether)pentene was calculated to be 91%.

[0118] Example 15 The specific steps for preparing 3,5-dihydroxypentane are as follows: The product 3,5-dibenzyl ether pentylbenzene (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 elemental iodine (50.8 g, 0.2 mol) were added sequentially. The mixture was reacted at 20–30 °C for 2 h. After the reaction mixture cooled, it was transferred to a separatory funnel, and saturated sodium sulfite (300 mL) was added. After extraction and separation, the organic phase was separated first, and the aqueous phase was extracted three times with ethyl acetate (100 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography using n-hexane / ethyl acetate (10:1, v / v) as the eluent to give 3,5-dihydroxypentylbenzene (Olivetol) (16.9 g, yield 94%) as a pale yellow liquid.

[0119] The obtained yellow liquid was subjected to hydrogen nuclear magnetic resonance analysis, and the hydrogen nuclear magnetic resonance spectrum is as follows: Figure 1 As shown, Figure 1 The results show: 1H 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).

[0120] Example 16 The specific steps for preparing 3,5-dihydroxypentane are as follows: The product 3,5-bis(4-methoxybenzyl ether)pentylbenzene (42.1 g, 0.1 mol) obtained in Example 14 was dissolved in dichloromethane (100 mL), and purified water (20 mL) and 2,3-dichloro-5,6-dicyanobenzoquinone (45.4 g, 0.2 mol) were added. The mixture was reacted at 20–30 °C for 2 h. After the reaction mixture cooled, it was transferred to a separatory funnel, and saturated sodium sulfite (300 mL) was added. After extraction and separation, the organic phase was separated first, and the aqueous phase was extracted three times with dichloromethane (80 mL). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by silica gel column chromatography using n-hexane / ethyl acetate (10:1, v / v) as the eluent to give 3,5-dihydroxypentylbenzene (Olivetol) (16.0 g, yield 89%) as a pale yellow liquid.

[0121] Application Examples Cannabidiol was prepared using 3,5-dihydroxypentane obtained in Example 15. The specific procedure is as follows: Trans-menthyl-2,8-dien-1-ol (2.0 g, 13.1 mmol, 1 eq) and 3,5-dihydroxypentane (2.4 g, 13.1 mmol, 1 eq) prepared in Example 15 were sequentially dissolved in chloroform (50 mL), heated to 40 °C, and boron trifluoride diethyl ether (185 mg, 1.3 mmol, 0.1 eq) was added. The reaction mixture was stirred at 40 °C for 3 min. Subsequently, saturated sodium bicarbonate solution (30 mL) was added to quench the reaction, and the mixture was allowed to stand and separated. The chloroform layer was collected, and the aqueous phase was extracted once again with dichloromethane (30 mL). The organic phases were combined, dried over anhydrous sodium sulfate, filtered, and the filter cake was washed with dichloromethane. The filtrate was concentrated under reduced pressure to a light buttery consistency. 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 colorless oily cannabidiol (1.52 g, yield 37%) and byproduct (1.45 g, yield 35%).

[0122] Under heating conditions, the obtained colorless oily cannabidiol was dissolved in n-heptane (3.0 mL), cooled to 0°C, and a small amount of seed crystals were added. The mixture was then continuously cooled to -20°C and allowed to crystallize overnight. The crystals were filtered under reduced pressure, and washed twice with a small amount of n-heptane. The crystals were collected and dried under reduced pressure to obtain white crystalline cannabidiol (1.14 g, yield 27%).

[0123] The obtained white crystalline cannabidiol was subjected to proton NMR analysis, and the proton NMR spectrum is shown below. Figure 2 As shown, Figure 2 The results show: 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.

[0124] The technical solutions proposed in this invention are merely preferred embodiments of the invention. The scope of protection of this invention is not limited thereto. Any simple variations or equivalent substitutions of the technical solutions that can be obviously obtained by those skilled in the art within the scope of the technology disclosed in this invention shall fall within the scope of protection of this invention.

Claims

1. A method for producing 3,5-dietherpentane, characterized in that, The 3,5-dietherpentanebenzene has the chemical structure shown in Formula 3, and the method comprises coupling a halopentane, a ligand, a compound shown in Formula 2, and a reducing agent in the presence of a nickel catalyst; Formulas 3 and 2 are shown below: The R in Formula 3 is the same as the R in Formula 2, both being substituted or unsubstituted methylene cycloaromatic groups; In Formula 2, X is fluorine, chlorine, bromine, or iodine.

2. The method according to claim 1, characterized in that, The substituted or unsubstituted methylene cycloaromatic group is Ar-CH2-, wherein Ar is Ph, 4-OMePh, 4-NO2Ph, 4-MePh, 1-naphthyl or 9-anthrayl.

3. The method according to claim 1 or 2, characterized in that, The nickel catalyst is selected from at least one of nickel acetylacetonate, nickel fluoride, nickel bromide, nickel iodide, bis(triphenylphosphine) nickel chloride, nickel acetate, nickel chloride dimethoxyethane, and nickel bromide dimethoxyethane. And / or, the halopentane is selected from at least one of iodopentane, chloropentane, and bromopentane; And / or, the ligand is selected from at least one of compounds containing at least one pyridinium group; And / or, the reducing agent is selected from at least one of zinc powder, manganese powder, and magnesium powder; And / or, in the coupling reaction, the molar ratio of the compound represented by Formula 2 to the nickel catalyst is 1:(0.05 to 0.5). And / or, in the coupling reaction, the molar ratio of the compound represented by Formula 2 to the halopentane is 1:(1-3). And / or, in the coupling reaction, the molar ratio of the compound represented by Formula 2 to the ligand is 1:(0.05 to 0.5). And / or, in the coupling reaction, the molar ratio of the compound represented by Formula 2 to the reducing agent is 1:(1-3). And / or, the reaction temperature of the coupling reaction is selected from 0 to 100°C; And / or, the reaction time of the coupling reaction is selected from 1 to 24 hours.

4. The method according to claim 3, characterized in that, The ligand is selected from at least one of the compounds represented by formulas I to XII: ； In formulas I, II, and III, R' is independently selected from methyl, methoxy, and butyl; And / or, the coupling reaction is carried out in the presence of a solvent; And / or, the coupling reaction is carried out in the presence of an additive; the additive is selected from at least one of sodium iodide, magnesium chloride, potassium iodide, lithium chloride, pyridine, triethylamine, diisopropylethylenediamine, 4-dimethylaminopyridine, and trimethylchlorosilane. And / or, the method further includes reacting 3,5-difluorohalobenzene with compound R-OH in the presence of a strong base to undergo a nucleophilic aromatic substitution reaction to obtain the compound shown in Formula 2; wherein, R in compound R-OH is the same as R in Formula 2.

5. The method according to claim 4, characterized in that, The ligand is selected from at least one of the compounds shown in Formula IV, Formula VII, and Formula X; And / or, the solvent used in the coupling reaction includes at least one of N,N-dimethylformamide, dimethyl sulfoxide, N,N-dimethylacetamide, and N-methylpyrrolidone; And / or, the ratio of the solvent used in the coupling reaction to the compound shown in Formula 2 is (5-10) mL: 1 g; And / or, in the coupling reaction, the molar ratio of the compound represented by Formula 2 to the additive is 1:(0.1 to 1.5). And / or, the 3,5-difluorohalobenzene is selected from at least one of 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-anthrayl alcohol, and 1-naphthyl alcohol; And / or, the strong base is selected from at least one of potassium tert-butoxide, sodium tert-butoxide, sodium methoxide, sodium hydride, lithium diisopropylamino, sodium bis(trimethylsilyl)amino, potassium bis(trimethylsilyl)amino, lithium bis(trimethylsilyl)amino, 1,8-diazabicycloundec-7-ene, sodium hydroxide, and potassium hydroxide. And / or, in the nucleophilic aromatic substitution reaction, the molar ratio of the 3,5-difluorohalobenzene to compound R-OH is 1:(2-3). And / or, in the nucleophilic aromatic substitution reaction, the molar ratio of the strong base to compound R-OH is 1:(0.9 to 1.1). And / or, the reaction temperature of the nucleophilic aromatic substitution reaction is selected from 20 to 110 °C; And / or, the reaction time of the nucleophilic aromatic substitution reaction is selected from 2 to 12 hours; And / or, the nucleophilic aromatic substitution reaction is carried out in the presence of a solvent.

6. The method according to claim 5, characterized in that, 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, and N-methylpyrrolidone. And / or, the ratio of the solvent used in the nucleophilic aromatic substitution reaction to the amount of the 3,5-difluorohalobenzene is (5-20) mL:1 g.

7. A method for preparing 3,5-dihydroxypentane, characterized in that, The method includes producing 3,5-dietherpentylbenzene by any one of claims 1 to 6.

8. The method for preparing 3,5-dihydroxypentane according to claim 7, characterized in that, The method for preparing 3,5-dihydroxypentane includes the following steps: performing a de-R-group protection reaction on 3,5-dietherpentane; wherein the reagents used in the de-R-group protection reaction include Pd / C and hydrogen, Raney nickel and hydrogen, elemental iodine and triethylsilane, sodium borohydride and nickel chloride, trimethyliodosilane, boron trichloride, aluminum trichloride, boron trifluoride ether, or 2,3-dichloro-5,6-dicyanobenzoquinone.

9. The method for preparing 3,5-dihydroxypentane according to claim 8, characterized in that, The reaction temperature for the de-R group protection reaction is selected from 0 to 50°C; And / or, the reaction time for the de-R group protection reaction is selected from 1 to 12 hours; 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, and N-methylpyrrolidone.

10. A method for producing cannabidiol, characterized in that, The method comprises preparing 3,5-dihydroxypentane by the method for preparing 3,5-dihydroxypentane according to any one of claims 7 to 9.

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