Preparation method and application of high-purity cannabidiol heptyl derivative CBDP

Abstract

The invention discloses a preparation method and application of a high-purity cannabidiol heptyl derivative CBDP, and belongs to the technical field of organic synthesis compounds. In order to solve the technical problems of low purity, complex process and high cost of cannabidiol heptyl derivatives in the prior art, the invention provides a preparation method with high purity and simple preparation process. The key points of the technical scheme are as follows: (1) 5-heptylresorcinol and (1S, 4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexene-1-alcohol are dissolved in a solvent and react under the action of a Lewis acid catalyst, and a cannabidiol heptyl derivative CBDP is obtained; (2) dissolving a cannabidiol heptyl derivative CBDP in a solvent, reacting with a derivatization reagent, and purifying to obtain an intermediate 7; and (3) dissolving the intermediate 7 in a solvent, and purifying through an enzyme hydrolysis reaction to obtain the high-purity cannabidiol heptyl derivative CBDP.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis compound technology, specifically to a method for preparing and applying a high-purity cannabidiol heptyl derivative CBDP. Background Technology

[0002] For understanding the technical content of this invention: Cannabidiol heptyl derivative CBDP is a close relative of cannabidiol (CBD). Given CBD's remarkable efficacy in treating epilepsy (e.g., Epidiolex), it is inferred that CBDP also possesses similar potential. The chemical name of CBDP is (-)-2-[(3R,4R)-p-menthyl-1,8-dien-3-yl]-5-heptylresorcinol, and its structural formula is:

[0003] Enzymes, as green catalysts capable of catalysis under mild conditions, have catalyzed many atom-economical chemical reactions and exhibited very broad substrate adaptability and high stereoselectivity, thus their catalytic ability has been fully affirmed. Hydrolases have received the most extensive attention and research over the past 15 years. A series of studies have shown that the formation of many carbon-carbon bonds and carbon-heterobonds, oxidation processes, and novel hydrolytic transformations catalyzed by hydrolases represent a significant breakthrough and expansion compared to the catalytic transformations (hydrolysis, esterification, amidation, acylation, etc.) of traditional hydrolases.

[0004] Currently, there are two main routes reported both domestically and internationally for purifying the heptyl cannabidiol derivative CBDP.

[0005] Publication number: WO2011006099, publication date: January 13, 2011. This document describes an early synthetic route involving the direct docking of 5-heptylresorcinol with (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol to the heptyl cannabidiol derivative CBDP. The synthetic route is as follows:

[0006] Publication number WO2020232545, published on November 26, 2020, describes a recent synthetic route involving the docking of phloroglucinol with (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol, followed by protection of the para-hydroxyl group with N-phenylbis(trifluoromethanesulfonyl)imide and the ortho-hydroxyl group with trimethylsilyl ether. Finally, the mixture is docked with a Grignard reagent and hydrolyzed to yield the heptyl cannabidiol derivative CBDP. The process route is shown below:

[0007] The prior art represented by the aforementioned documents has at least the following unresolved technical problems or defects: (1) Column chromatography purification is inconvenient to use in industrial production. The relevant evidence is: Publication No. WO2011006099. The synthetic route disclosed in this document is short, but the post-processing requires column chromatography purification, which limits industrial production.

[0008] (2) The process route is complicated and costly. The relevant evidence is: Publication No. WO2020232545. The synthetic route disclosed in this document is too long and the post-processing is extremely complicated, resulting in high production costs and making it unsuitable for industrial production. Summary of the Invention

[0009] The purpose of this invention is to provide: A method for preparing high-purity cannabidiol heptyl derivative CBDP, and related technologies, to solve technical problems such as improving product purity, reducing production costs, and suitability for industrial production, or combinations thereof.

[0010] Terminology Explanation: Unless otherwise defined, all technical terms in this document have the same meanings as commonly understood by one of ordinary skill in the art to which the subject matter of the claims pertains. Unless otherwise stated, all patents, patent inventions, and publications cited in this document are incorporated herein by reference in their entirety. If multiple definitions exist for terms in this document, the definitions in this chapter shall prevail.

[0011] It should be understood that the above brief description and the following detailed description are exemplary and for illustrative purposes only, and do not limit the subject matter of the invention in any way. In this invention, the singular is used in conjunction with the plural unless otherwise specifically stated. It should also be noted that, unless otherwise stated, the use of “or” or “or” means “and / or”. Furthermore, the use of the term “comprising” and other forms such as “including,” “containing,” and “contains” are not limiting.

[0012] Definitions of standard chemical terms can be found in the references "Organic Chemistry" and "Oxford Dictionary of Organic Chemistry".

[0013] Unless otherwise stated, conventional methods within the scope of the art, such as carbon NMR spectroscopy, hydrogen NMR spectroscopy, ion chromatography, and gas chromatography, shall be used.

[0014] Unless specifically defined herein, the use of all commercially available products herein employs standard techniques. For example, it may be carried out using the manufacturer's instructions for use with the kit, or in accordance with methods known in the art or the description of this invention. The techniques and methods described herein can generally be implemented according to conventional methods well known in the art, based on the descriptions in the various summary and more specific documents cited and discussed in this specification.

[0015] The term "cannabidiol" as used in this article refers to: [C64]C64. 21 H 30 O2, abbreviated as CBD, has a benzene ring in its structural formula with a 5-carbon alkyl side chain (pentyl, -C5H). 11 Cannabinoids are natural, non-psychoactive cannabinoids extracted from cannabis plants (such as hemp and industrial hemp). Because they do not have hallucinogenic or addictive properties and have a variety of potential physiological activities, they are widely used in the fields of medicine, health and daily chemical products.

[0016] The terms "cannabidiol heptyl derivative CBDP" and "compound 0" used in this article refer to compounds with the molecular formula C 23 H 34 O2, abbreviated as CBDP, is an alkyl side chain (heptyl, -C7H) with 7 carbon atoms attached to the benzene ring in its structural formula. 15 ), CAS No.: 55824-13-0, extremely low natural content, relies on semi-synthetic.

[0017] The term "p-nitrobenzenesulfonyl chloride" used in this article refers to p-NsCl or p-NBSCl, an aromatic organic reagent containing nitro and sulfonyl chloride functional groups. Due to its high reactivity and site selectivity, it is widely used in the fields of functional group modification and protection in organic synthesis and analytical chemistry, and is a key raw material for the synthesis of pharmaceutical and dye intermediates.

[0018] The term "DCM" used in this article refers to dichloromethane, a colorless, transparent, volatile liquid with a pungent odor similar to ether. It is a commonly used organic solvent in organic chemistry experiments. Due to its good solubility in many organic compounds and its low boiling point (approximately 40°C), it is easily separated by distillation and is therefore widely used in organic synthesis, extraction, and cleaning processes. It can also be used as a chemical raw material in pharmaceuticals, metal degreasing, and other fields.

[0019] The term "derivative" as used in this article refers to, in organic chemistry, a reagent that can react chemically with a target compound to generate a derivative with specific properties (such as easy detection and separation). Through derivatization, the volatility, stability, solubility, or detection sensitivity of the target compound can be improved.

[0020] The term "hydrolysis reagent" used in this article refers to a reagent that can induce a hydrolysis reaction in a compound. Hydrolysis reaction usually refers to a double displacement reaction between a compound and water, and can be classified into acid hydrolysis, alkaline hydrolysis, and enzyme-catalyzed hydrolysis.

[0021] The term "alkaline phosphatase HC-ALP" as used in this article refers to an enzyme that catalyzes the hydrolysis of phosphate esters in an alkaline environment, releasing inorganic phosphate.

[0022] The term "Et3N" used in this article refers to triethylamine, with the chemical formula (C2H5)3N. It is an organic tertiary amine with a strong ammonia odor, is volatile, and is alkaline. In organic synthesis, it is commonly used as an acid-binding agent to neutralize acidic substances (such as hydrochloric acid and sulfuric acid) generated in the reaction, thus promoting the forward reaction.

[0023] The terms "5-heptylresorcinol" and "compound 6" used in this article refer to: CAS No. 500-67-4, molecular formula C 13 H 20 O2, a white to off-white solid powder at room temperature, is a resorcinol derivative containing a heptyl side chain. It belongs to the phenolic aromatic compounds and is widely used in the fields of medicine, cosmetics, food preservation and industrial preservation due to its antibacterial, antioxidant and whitening activities. It is an organic synthesis intermediate with both multifunctionality and safety.

[0024] The terms “(1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol” and “Compound 2” as used herein refer to: CAS No. 22972-51-6, molecular formula C 10 H 16 O, the core is a "cyclohexene ring" (containing a carbon-carbon double bond), carbon 1 is connected to a methyl group and a hydroxyl group, carbon 4 is connected to a 1-methyl vinyl group, and carbons 1 and 4 are chiral centers (forming a specific spatial configuration). This "cycloene + alcohol hydroxyl + unsaturated side chain" structure is the key to its chemical activity.

[0025] The term "Lewis acid catalyst" used in this article refers to a class of substances that follow the Lewis acid-base theory, can accept electron pairs, and activate the substrate by forming coordinate bonds with the reaction substrate, thereby accelerating organic chemical reactions (such as addition, substitution, cyclization, etc.). It is one of the most widely used catalyst types in organic synthesis and chemical production, and has both high activity and reaction selectivity.

[0026] The term "acid-binding agent" as used in this article refers to a class of reagents used in organic synthesis to neutralize acids generated in reactions (such as hydrochloric acid, sulfonic acid, etc.), adjust the pH of the system, and reduce the influence of acids on products or catalysts.

[0027] The term "quenching reagent" used in this article refers to a class of reagents used in organic synthesis to rapidly terminate reactions, neutralize or destroy active substances (such as catalysts, unreacted raw materials, and intermediates) in the reaction system, thereby preventing side reactions and ensuring operational safety. Its core function is to "inactivate the reaction system and stabilize the product".

[0028] The term "hydrolytic enzyme" used in this article refers to a class of enzymes that catalyze the hydrolysis of compounds in the interdisciplinary field of organic chemistry and biochemistry. Their core function is to break chemical bonds (such as ester bonds, ether bonds, amide bonds, etc.) and introduce water molecules to decompose the substrate into two or more small molecule products. They are widely used in organic synthesis and biotransformation.

[0029] In a first aspect, the present invention provides: a method for preparing a high-purity cannabidiol heptyl derivative CBDP, comprising the steps of: (1) 5-Heptylresorcinol and (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol were dissolved in a solvent and reacted under the action of Lewis acid catalyst to obtain low-purity cannabidiol heptyl derivative CBDP. (2) Dissolve the low-purity cannabidiol heptyl derivative CBDP obtained in step (1) in a solvent, react with a derivatizing reagent, and purify to obtain intermediate 7; (3) The intermediate 7 obtained in step (2) is dissolved in a solvent and purified by enzymatic hydrolysis to obtain the high-purity cannabidiol heptyl derivative CBDP.

[0030] The reaction route for the high-purity cannabidiol heptayl derivative CBDP is as follows:

[0031] The technical features include: Lewis acid catalysts, derivatizing reagents, and enzymes.

[0032] The solvent in step (1) is selected from at least one of the following: a mixed solution of dichloroethane, dichloromethane, chloroform, ethyl acetate and water; The solvent in step (1) is preferably at least one of a mixed solution of dichloroethane, dichloromethane, ethyl acetate and water; The solvent in step (1) is further preferably dichloromethane.

[0033] Wherein, the Lewis acid catalyst type in step (1) is selected from at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), ferric trichloride (FeCl3), and zinc chloride (ZnCl2); The Lewis acid catalyst used in step (1) is preferably at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), and zinc chloride (ZnCl2); The Lewis acid catalyst type in step (1) is further preferably at least one of p-toluenesulfonic acid and zinc chloride (ZnCl2); The Lewis acid catalyst type in step (1) is more preferably p-toluenesulfonic acid.

[0034] In step (1), the molar ratio of 5-heptylresorcinol to (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol is selected from 1:1.1-1.3; The preferred molar ratio of 5-heptylresorcinol to (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol in step (1) is 1:1.15-1.25; The molar ratio of 5-heptylresorcinol to (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol in step (1) is further preferably 1:1.2.

[0035] The amount of Lewis acid catalyst used in step (1) is 5 mol%-15 mol% of 5-heptylresorcinol. The amount of Lewis acid catalyst used in step (1) is preferably 8 mol%-13 mol% of 5-heptylresorcinol. The amount of Lewis acid catalyst used in step (1) is further preferably 10 mol% of 5-heptylresorcinol. Preferably, the order of adding the solvent in step (1) is to first dissolve 5-heptylresorcinol and Lewis acid catalyst in the solvent, and then add (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol; More preferably, the process of nitrogen protection and cooling is further included before the addition of (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol; More preferably, the cooling temperature is 0°C.

[0036] Preferably, the mixing method of the raw material dissolved in the solvent in step (1) is selected from at least one of mechanical stirring and ultrasonic mixing; More preferably, the mixing method is mechanical stirring.

[0037] The reaction temperature in step (1) is 10-30℃ and the reaction time is 1-3h. The preferred reaction temperature in step (1) is 15-30℃, and the reaction time is 2-3h. The reaction temperature in step (1) is further preferably 20°C, and the reaction time is 2.5h.

[0038] Preferably, step (1) further includes a step of quenching the reaction after the reaction; More preferably, the quenching agent is at least one selected from saturated sodium bicarbonate, sodium carbonate solution, potassium bicarbonate solution, ammonia, and triethylamine; More preferably, the quenching agent is at least one of saturated sodium bicarbonate and sodium carbonate solution; The preferred choice is saturated sodium bicarbonate.

[0039] Preferably, the quenching process further includes separation and extraction, and washing steps; More preferably, the separation and extraction involves separating the organic layer and extracting the aqueous phase; More preferably, the extraction solvent of the aqueous phase is selected from at least one of dichloromethane, dichloroethane, chloroform, and ethyl acetate; The preferred option is dichloromethane; More preferably, the washing solvent is at least one of a saturated sodium chloride solution, a saturated ammonium chloride solution, and water; The optimal solution is a saturated sodium chloride solution.

[0040] More preferably, the washing step further includes a solvent removal step; More preferably, the solvent removal method is selected from at least one of vacuum rotary evaporation, vacuum distillation, vacuum drying, and nitrogen purging; More preferably, the solvent removal method is selected from at least one of vacuum rotary evaporation and vacuum distillation; The optimal method is rotary evaporation under reduced pressure.

[0041] The derivatizing reagent in step (2) is selected from at least one of benzoyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; The derivatizing reagent in step (2) is preferably at least one of benzoyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; The derivatizing reagent in step (2) is further preferably p-nitrobenzenesulfonyl chloride.

[0042] The solvent in step (2) is selected from at least one of the following: a mixed solution of dichloroethane, dichloromethane, chloroform, ethyl acetate, and water; The solvent in step (2) is preferably at least one of a mixed solution of dichloroethane, dichloromethane, ethyl acetate and water; The solvent in step (2) is further preferably dichloromethane; Preferably, the raw materials in step (2) further include an acid-binding agent; More preferably, the acid-binding agent is selected from at least one of triethylamine, pyridine, diethylamine, and N,N-diisopropylethylamine; More preferably, the acid-binding agent is selected from at least one of triethylamine and pyridine; Most preferably, the acid-binding agent is triethylamine; In step (2), the molar ratio of low-purity cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-3. The preferred molar ratio of the low-purity cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-2.5; The molar ratio of the low-purity cannabidiol heptyl derivative CBDP to the derivatizing reagent is further preferably 1:2.15.

[0043] Preferably, the molar percentage of the acid-binding agent is 200%-250% of the low-purity cannabidiol heptayl derivative CBDP; More preferably, the molar percentage is 220% of the low-purity cannabidiol heptayl derivative CBDP; Preferably, the order of adding the solvent in step (2) is to first dissolve the low-purity cannabidiol heptyl derivative CBDP and the acid-binding agent obtained in step (1) in the solvent, and then add the derivatizing reagent; More preferably, the process of nitrogen protection and cooling is also included before adding the derivatizing reagent; More preferably, the cooling temperature is 0°C.

[0044] Preferably, the mixing method of the raw material in step (2) is selected from at least one of mechanical stirring and ultrasonic mixing; More preferably, the mixing method is mechanical stirring.

[0045] The reaction temperature in step (2) is 10-30℃ and the reaction time is 4-6h. The preferred reaction temperature in step (2) is 15-30℃, and the reaction time is 4-5h. The reaction temperature in step (2) is further preferably 25°C, and the reaction time is 4.5h.

[0046] The purification methods described in step (2) include, but are not limited to, extraction, concentration and recrystallization. Preferably, the extraction solvent is selected from at least one of 1% hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, and dilute phosphoric acid aqueous solution; More preferably, at least one of 1% hydrochloric acid aqueous solution and dilute sulfuric acid aqueous solution; A further preferred option is a 1% hydrochloric acid aqueous solution; Preferably, the concentration is an organic phase concentration; More preferably, the concentration method is selected from at least one of vacuum rotary evaporation, vacuum distillation, thin-film evaporation, and freeze drying; More preferably, at least one of vacuum rotary evaporation and vacuum distillation; The optimal method is rotary evaporation under reduced pressure; Preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, ethyl acetate, diethyl ether, isopropanol, and dichloromethane; More preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, and ethyl acetate; A further preferred method is the use of a combination of methyl tert-butyl ether (MTBE) and n-heptane; The preferred combination is methyl tert-butyl ether (MTBE) and n-heptane in a volume ratio of 2:1. Preferably, the recrystallization reaction temperature is 60-90℃, and the cooling temperature is -10-10℃; More preferably, the recrystallization reaction temperature is 70°C and the cooling temperature is 0°C; Preferably, the recrystallization step is followed by a drying process; More preferably, the drying method includes, but is not limited to, at least one of natural air drying, oven drying, freeze drying, infrared drying, and microwave drying; More preferably, the drying method is at least one of natural air drying, oven drying, and freeze drying; The best method is oven drying.

[0047] The solvent in step (3) is selected from at least one of methanol, ethylene glycol, isopropanol, a mixed solution of phosphate buffer and ethanol, and tetrahydrofuran; The solvent used in step (3) is preferably at least one of a mixed solution of methanol, ethylene glycol, phosphate buffer, and ethanol; The solvent used in step (3) is preferably a mixture of phosphate buffer and ethanol; The solvent used in step (3) is more preferably a mixture of phosphate buffer and ethanol in a volume ratio of 1:2; The hydrolytic enzyme mentioned in step (3) is selected from at least one of alkaline phosphatase (HC-ALP), phospholipase (PLA2IIL), and phospholipase (D PLDII). The enzyme mentioned in step (3) is preferably at least one of alkaline phosphatase (HC-ALP) and phospholipase (PLA2IIL); The enzyme type mentioned in step (3) is further preferably alkaline phosphatase (HC-ALP).

[0048] The amount of hydrolytic enzyme used in step (3) is 2%-3% of the mass of intermediate 7; The preferred amount of hydrolytic enzyme used in step (3) is 2.5%-3% of the mass of intermediate 7; The amount of hydrolytic enzyme used in step (3) is further preferably 2.8% of the mass of intermediate 7; The reaction temperature in step (3) is 15-40℃ and the reaction time is 12-36h. The preferred reaction temperature in step (3) is 15-25℃, and the reaction time is 12-20h; The reaction temperature in step (3) is further preferably 20-25℃, and the reaction time is 16h.

[0049] The purification process described in step (3) includes, but is not limited to, extraction and concentration. Preferably, the extraction reagent is selected from at least one of n-heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, and isopropyl acetate; More preferably, the extraction reagent is selected from at least one of n-heptane, n-hexane, and cyclohexane; More preferably, the extraction reagent is n-heptane; Preferably, the concentration is an organic phase concentration; More preferably, the concentration method is selected from at least one of vacuum rotary evaporation, vacuum distillation, thin-film evaporation, and freeze drying; More preferably, at least one of vacuum rotary evaporation and vacuum distillation; The optimal method is rotary evaporation under reduced pressure.

[0050] Preferably, the method for preparing the high-purity cannabidiol heptayl derivative CBDP includes the following steps: (1) 5-Heptylresorcinol reacts with (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol under Lewis acid catalysis. 5-Heptylresorcinol, p-toluenesulfonic acid, and dichloromethane are mixed, cooled to 0°C under nitrogen protection, and (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol is added. The mixture is heated to 20°C and stirred for about 1-3 hours. The reaction is quenched by adding saturated sodium bicarbonate solution. After extraction and washing, the solvent is removed under reduced pressure to obtain a low-purity cannabidiol heptyl derivative CBDP. (2) Dichloromethane and triethylamine were added to the low-purity cannabidiol heptyl derivative CBDP obtained in step (1), and the temperature was lowered to 0°C under nitrogen protection. p-nitrobenzenesulfonyl chloride was added, and the temperature was raised to 25°C. The reaction was carried out for 4-6 hours. The mixture was extracted and separated, and the solvent was removed by vacuum concentration. MTBE and n-heptane were added, and the temperature was raised to 70°C to dissolve the solvent. The temperature was then lowered to 0°C, filtered and dried to obtain intermediate 7. (3) Add phosphate buffer solution, ethanol and alkaline phosphatase (HC-ALP) to intermediate 7 obtained in step (2), stir and react at 20-25℃ for 16h, extract and separate the liquid, concentrate the organic phase under reduced pressure to obtain the high-purity cannabidiol heptyl derivative CBDP.

[0051] The reaction route for preparing the cannabidiol heptayl derivative CBDP is as follows:

[0052] Based on further solutions to the technical problems of the present invention, or simultaneous solutions to multiple technical problems, the preferred solution in the technical solution provided in the first aspect of the present invention includes: The first preferred option is as follows: the Lewis acid catalyst in step (1) is selected from at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), ferric chloride (FeCl3), and zinc chloride (ZnCl2); preferably at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), and zinc chloride (ZnCl2); further preferably at least one of p-toluenesulfonic acid and zinc chloride (ZnCl2); and even more preferably p-toluenesulfonic acid. This technical solution, while solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0053] The second preferred embodiment: the molar ratio of 5-heptylresorcinol to (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol in step (1) is selected from 1:1.1-1.3; preferably 1:1.15-1.25; and more preferably 1:1.2. This technical solution, based on solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0054] The third preferred option is that the amount of Lewis acid catalyst used in step (1) is 5 mol%-15 mol% of 5-heptylresorcinol; preferably 8 mol%-13 mol% of 5-heptylresorcinol; and even more preferably 10 mol% of 5-heptylresorcinol. This technical solution not only solves the technical problem of "improving product purity", but also further solves the technical problem of "further improving product purity".

[0055] The fourth preferred embodiment: the quenching agent is at least one selected from saturated sodium bicarbonate, sodium carbonate solution, potassium bicarbonate solution, ammonia, and triethylamine; preferably, the quenching agent is at least one selected from saturated sodium bicarbonate and sodium carbonate solution; more preferably, it is saturated sodium bicarbonate. This technical solution, while solving the technical problem of "improving product purity," further solves the technical problem of "further improving product purity."

[0056] The fifth preferred embodiment: the separation and extraction involves separating the organic layer and extracting the aqueous phase; preferably, the extraction solvent for the aqueous phase is selected from at least one of dichloromethane, dichloroethane, chloroform, and ethyl acetate; more preferably, dichloromethane; preferably, the washing solvent is at least one of a saturated sodium chloride solution, a saturated ammonium chloride solution, and water; more preferably, a saturated sodium chloride solution. This technical solution, while solving the technical problem of "improving product purity," further solves the technical problem of "further improving product purity."

[0057] The sixth preferred option: The derivatizing reagent in step (2) is selected from at least one of benzoyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; preferably at least one of benzoyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; and more preferably p-nitrobenzenesulfonyl chloride. This technical solution, based on solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0058] The seventh preferred embodiment: the acid-binding agent is selected from at least one of triethylamine, pyridine, diethylamine, and N,N-diisopropylethylamine; preferably at least one of triethylamine and pyridine; more preferably triethylamine. This technical solution, while solving the technical problem of "improving product purity," further solves the technical problem of "further improving product purity."

[0059] The eighth preferred embodiment: In step (2), the molar ratio of low-purity cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-3; preferably 1:2-2.5; and even more preferably 1:2.15. This technical solution, based on solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0060] The ninth preferred embodiment: the molar percentage of the acid-binding agent is 200%-250% of the low-purity cannabidiol heptyl derivative CBDP; preferably 220% of the low-purity cannabidiol heptyl derivative CBDP. This technical solution, based on solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0061] The tenth preferred solution: the reaction temperature in step (2) is 10-30℃ and the reaction time is 4-6h; preferably 15-30℃ and the reaction time is 4-5h; more preferably 25℃ and the reaction time is 4.5h. This technical solution solves the technical problem of "improving product purity" and further solves the technical problem of "further improving product purity".

[0062] Eleventh preferred embodiment: The extraction solvent in step (2) is selected from at least one of 1% hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, and dilute phosphoric acid aqueous solution; preferably at least one of 1% hydrochloric acid aqueous solution and dilute sulfuric acid aqueous solution; more preferably 1% hydrochloric acid aqueous solution. This technical solution solves the technical problem of "improving product purity" and further solves the technical problem of "further improving product purity".

[0063] The twelfth preferred embodiment: the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, ethyl acetate, diethyl ether, isopropanol, and dichloromethane; preferably at least one of methyl tert-butyl ether (MTBE), n-heptane, and ethyl acetate; more preferably a combination of methyl tert-butyl ether (MTBE) and n-heptane; even more preferably a combination of methyl tert-butyl ether (MTBE) and n-heptane in a volume ratio of 2:1. This technical solution, while addressing the technical problem of "improving product purity," further addresses the technical problem of "further improving product purity."

[0064] The thirteenth preferred embodiment: the hydrolytic enzyme in step (3) is selected from at least one of alkaline phosphatase (HC-ALP), phospholipase (PLA2IIL), and phospholipase (D PLDII); preferably at least one of alkaline phosphatase (HC-ALP) and phospholipase (PLA2IIL); and more preferably alkaline phosphatase (HC-ALP). This technical solution, based on solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0065] The fourteenth preferred option: the amount of hydrolytic enzyme used in step (3) is 2%-3% of the mass of intermediate 7; preferably 2.5%-3% of the mass of intermediate 7; and even more preferably 2.8% of the mass of intermediate 7. This technical solution solves the technical problem of "improving product purity" and further solves the technical problem of "further improving product purity".

[0066] The fifteenth preferred embodiment: The reaction temperature in step (3) is 15-40℃, and the reaction time is 12-36h; preferably 15-25℃, and the reaction time is 12-20h; further preferably 20-25℃, and the reaction time is 16h. This technical solution, based on solving the technical problem of "improving product purity", further solves the technical problem of "further improving product purity".

[0067] Secondly, the present invention provides: an intermediate 7 in the preparation process of a high-purity cannabidiol heptyl derivative CBDP, the chemical name of which is (1'R,2'R)-4-heptyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-dibis(4-nitrobenzenesulfonate), and the structural formula is as follows:

[0068] Thirdly, the present invention provides a method for preparing the intermediate 7, comprising the steps of: dissolving the cannabidiol heptyl derivative CBDP in a solvent, reacting it with a derivatizing reagent, and purifying it to obtain the intermediate 7.

[0069] This includes technical features: solvents and derivatizing reagents.

[0070] The derivatizing reagent is selected from at least one of benzoyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; The derivatizing reagent is preferably at least one of benzoyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; The derivatizing reagent is further preferably p-nitrobenzenesulfonyl chloride.

[0071] The solvent is selected from at least one of the following: a mixed solution of dichloroethane, dichloromethane, chloroform, ethyl acetate, and water; The solvent is preferably at least one of a mixed solution of dichloroethane, dichloromethane, ethyl acetate and water; The solvent is further preferably dichloromethane; Preferably, the raw material also contains an acid-binding agent; More preferably, the acid-binding agent is selected from at least one of triethylamine, pyridine, diethylamine, and N,N-diisopropylethylamine; More preferably, the acid-binding agent is selected from at least one of triethylamine and pyridine; Most preferably, the acid-binding agent is triethylamine; The molar ratio of cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-3; The preferred molar ratio of the cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-2.5; The molar ratio of the cannabidiol heptyl derivative CBDP to the derivatizing reagent is further preferably 1:2.15.

[0072] Preferably, the molar percentage of the acid-binding agent is 200%-250% of the cannabidiol heptayl derivative CBDP; More preferably, the molar percentage is 220% of the cannabidiol heptyl derivative CBDP; Preferably, the order of adding the solvent-soluble ingredients is as follows: first, dissolve the cannabidiol heptyl derivative CBDP and the acid-binding agent in the solvent, and then add the derivatizing reagent; More preferably, the process of nitrogen protection and cooling is also included before adding the derivatizing reagent; More preferably, the cooling temperature is 0°C.

[0073] Preferably, the mixing method of the raw material in the solvent is selected from at least one of mechanical stirring and ultrasonic mixing; More preferably, the mixing method is mechanical stirring.

[0074] The reaction temperature is 10-30℃, and the reaction time is 4-6h. The preferred reaction temperature is 15-30℃, and the reaction time is 4-5 hours. The reaction temperature is further preferably 25°C, and the reaction time is 4.5 h.

[0075] The purification methods include, but are not limited to, extraction, concentration and recrystallization. Preferably, the extraction solvent is selected from at least one of 1% hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, and dilute phosphoric acid aqueous solution; More preferably, at least one of 1% hydrochloric acid aqueous solution and dilute sulfuric acid aqueous solution; A further preferred option is a 1% hydrochloric acid aqueous solution; Preferably, the concentration is an organic phase concentration; More preferably, the concentration method is selected from at least one of vacuum rotary evaporation, vacuum distillation, thin-film evaporation, and freeze drying; More preferably, at least one of vacuum rotary evaporation and vacuum distillation; The optimal method is rotary evaporation under reduced pressure; Preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, ethyl acetate, diethyl ether, isopropanol, and dichloromethane; More preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, and ethyl acetate; A further preferred method is the use of a combination of methyl tert-butyl ether (MTBE) and n-heptane; The preferred combination is methyl tert-butyl ether (MTBE) and n-heptane in a volume ratio of 2:1. Preferably, the recrystallization reaction temperature is 60-90℃, and the cooling temperature is -10-10℃; More preferably, the recrystallization reaction temperature is 70°C and the cooling temperature is 0°C; Preferably, the recrystallization step is followed by a drying process; More preferably, the drying method includes, but is not limited to, at least one of natural air drying, oven drying, freeze drying, infrared drying, and microwave drying; More preferably, the drying method is at least one of natural air drying, oven drying, and freeze drying; The best method is oven drying.

[0076] Fourthly, the present invention provides the application of the intermediate 7 in the preparation of high-purity cannabidiol heptyl derivative CBDP.

[0077] This includes the technical feature of the application of the intermediate 7.

[0078] Preferably, the intermediate 7 can be recrystallized to obtain a high-purity solid, avoiding column chromatography and making the preparation process of cannabidiol heptyl derivative CBDP suitable for industrial production.

[0079] Embodiments 1-6 of this invention at least support the protection scope of claims 1-9.

[0080] For claims 1-9: Lewis acid catalysts, derivatizing reagents, and enzymes.

[0081] The technical feature "Lewis acid catalyst" is derived from the aforementioned explanation and / or the corresponding technical feature in Examples 1-6, such as "the type of Lewis acid catalyst is selected from at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), ferric chloride (FeCl3), and zinc chloride (ZnCl2)," through the common feature "a class of substances that follow the Lewis acid-base theory and can accept electron pairs, activating the substrate by forming a coordinate bond with the reaction substrate." Therefore, those skilled in the art can reasonably infer that the technical feature "Lewis acid catalyst," its subordinate concepts, its substantially equivalent technical means, and technical means that can replace "Lewis acid catalyst" based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of claims 1-9. For example, replacing "Lewis acid catalyst" with "p-toluenesulfonic acid," "aluminum trichloride," etc., while keeping other technical features unchanged, still falls within the protection scope of claims 1-9 of this invention.

[0082] The technical feature "derivative" is derived from the aforementioned explanation and / or the corresponding technical features "at least one of benzoyl chloride, p-toluenesulfonyl chloride, p-nitrophenylcyclooxygenyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride" in Examples 1-6, and is summarized by the common feature "in organic chemistry, refers to a reagent that can chemically react with a target compound to generate a derivative with specific properties (such as easy detection and easy separation)". Therefore, those skilled in the art can reasonably presume that the technical feature "derivative", its subordinate concepts, its substantially equivalent technical means, and technical means that can replace "derivative" based on the existing level of technology and conventional technical means and common knowledge should all fall within the protection scope of claims 1-9. For example, replacing "derivative" with "p-toluenesulfonyl chloride" while keeping other technical features unchanged still falls within the protection scope of claims 1-9 of this invention.

[0083] The technical feature "enzyme" is derived from the aforementioned explanation and / or the corresponding technical feature in Examples 1-6, such as "the hydrolytic enzyme is selected from at least one of alkaline phosphatase (HC-ALP), phospholipase (PLA2IIL), and phospholipase (D PLDII)," and is summarized by the common feature "in the interdisciplinary field of organic chemistry and biochemistry, an enzyme that can catalyze the hydrolysis of compounds, whose core function is to break chemical bonds (such as ester bonds, ether bonds, amide bonds, etc.) and introduce water molecules to decompose the substrate into two or more small molecule products, and is widely used in organic synthesis and biotransformation." Therefore, those skilled in the art can reasonably presume that the technical feature "enzyme," its subordinate concepts, its essentially equivalent technical means, and technical means that can replace "enzyme" based on the existing level of technology and conventional technical means and common knowledge should all fall within the protection scope of claims 1-9. For example, if other technical features remain unchanged, replacing "enzyme" with "alkaline phosphatase (HC-ALP)," "phospholipase," etc., still falls within the protection scope of claims 1-9 of this invention.

[0084] Embodiments 1-6 of this invention at least support the protection scope of claim 10.

[0085] Regarding the application involved in claim 10:

[0086] The technical feature "application" is summarized from the foregoing explanation and / or the corresponding technical feature in Examples 1-6, such as "the intermediate 7 can be recrystallized to obtain a high-purity solid, avoiding column chromatography, thus making the preparation process of the cannabidiol heptyl derivative CBDP suitable for industrial production." Therefore, those skilled in the art can reasonably presume that the technical feature "application," its subordinate concepts, its substantially equivalent technical means, and technical means that can replace "application" based on existing technology and conventional technical means and common knowledge should all fall within the protection scope of claim 10.

[0087] The beneficial effects of this invention are as follows: The present invention has at least the following beneficial effects: (1) The present invention uses p-nitrosulfonyl chloride derivative to prepare intermediate 7. This intermediate can be recrystallized to obtain a high-purity solid, avoiding column chromatography operation, so that the cannabidiol heptyl derivative CBDP can be used for industrial production.

[0088] (2) Alkaline phosphatase (HC-ALP) is a catalyst that is easy to operate, has mild reaction conditions, and high yield, thus avoiding environmental pollution caused by thiophenol and other strong acids and bases.

[0089] (3) In this invention, p-nitrosulfonyl chloride derivatization and alkaline phosphatase (HC-ALP) are used as catalysts. The chemical purity of the produced cannabidiol heptyl derivative CBDP is close to 100%, and the unknown single impurities are all less than 0.10%.

[0090] (4) Compared with the prior art, the present invention has better technical effect in improving product yield.

[0091] According to experimental tests, this invention increases the purity of CBDP from about 98% in the prior art to over 99.8%.

[0092] Furthermore, based on the present invention: Based on the comparison of Examples 1-6 and Comparative Examples 1-2, the present invention employs a combination of technical means such as "derivation" and "enzymatic hydrolysis" to achieve a new technical effect: "significantly improving the purity of the cannabidiol heptayl derivative CBDP." The combined technical effect is superior to the sum of the effects of each individual technical means. Attached Figure Description

[0093] Figure 1 The HPLC chromatogram of the low-purity cannabidiol heptyl derivative CBDP prepared in Example 1 (RT 10.68 min). Figure 2 The HPLC spectrum of intermediate 7 prepared in Example 1 (RT 14.38 min). Figure 3 The HPLC spectrum of the high-purity cannabidiol heptyl derivative CBDP prepared in Example 1 (RT 10.68 min). Figure 4 The HPLC chromatogram of the cannabidiol heptyl derivative CBDP prepared in Comparative Example 1 (RT 10.62 min). Detailed Implementation

[0094] The following non-limiting embodiments are intended to enable those skilled in the art to gain a more comprehensive understanding of the present invention, but do not limit the invention in any way. The following content is merely an exemplary description of the scope of protection claimed by the present invention, and those skilled in the art can make various changes and modifications to the present invention based on the disclosed content, and such changes should also fall within the scope of protection claimed by the present invention.

[0095] The present invention will be further described below by way of specific embodiments. Unless otherwise specified, all instruments, devices, equipment, reagents, products, etc., used in the embodiments of the present invention are obtained through conventional commercial means.

[0096] Specific raw material information is shown in Table 1: Table 1. Raw Material Information

[0097] In the following embodiments, the detection method / calculation method is as follows: 1. Purity: Cannabidiol heptyl derivative CBDP was detected by high performance liquid chromatography (HPLC) and calculated using the area normalization method.

[0098] (1) Preparation: Prepare the mobile phase (water-acetonitrile = 60:40, sonicate for 10 minutes); activate the chromatographic column (wash with the mobile phase for 30 minutes, equilibrate the stationary phase); prepare the standard solution and sample solution.

[0099] (2) Sample injection: The autosampler sequentially injects blank solvent (water-acetonitrile), standard and sample.

[0100] (3) Separation and detection: The mobile phase carries the sample into the Agilent Proshell SB-C18 column at a column temperature of 35°C. The sample solution is retained in the column due to its hydrophobicity and is detected by a UV detector (λ=210 nm) after flowing out with the mobile phase, and the output signal is generated.

[0101] (4) Data analysis: The workstation generates a chromatogram, compares the retention time of the sample and the standard, and plots a standard curve using the peak area of ​​the standard.

[0102] 2. Yield: The formula for calculating yield is: Yield % = Actual product mass / Theoretical product mass × 100%. Example 1 (1) Preparation of low-purity cannabidiol heptyl derivative CBDP: Add 20.8 g of 5-heptylresorcinol and 1.7 g of p-toluenesulfonic acid to a 1 L four-necked reaction flask, then add 400 mL of dichloromethane. Under nitrogen protection, lower the temperature to 0 °C, then add 18.3 g of (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol. After the addition is complete, raise the reaction temperature to 20 °C and stir for about 1-3 hours. Quench the reaction with 200 mL of saturated sodium bicarbonate solution, separate the organic layer, and extract the aqueous phase with 200 mL of dichloromethane. Combine the organic layers and wash with 200 mL of saturated brine. Remove the solvent under reduced pressure to obtain 32.5 g of a light reddish-brown oil (HPLC purity, see [link]). Figure 1 ), with a yield of 95%.

[0103] (2) Preparation of intermediate 7 ((1'R,2'R)-4-heptyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-dibis(4-nitrobenzenesulfonate)): Add 32.5 g of low-purity cannabidiol heptyl derivative CBDP, 300 mL of dichloromethane, and 21.1 g of triethylamine to a 1 L four-necked reaction flask. Under nitrogen protection, cool to 0 °C, add 45.2 g of p-nitrobenzenesulfonyl chloride, and heat to 25 °C for 4-6 h. Extract with 200.0 mL of 1% hydrochloric acid aqueous solution, discard the aqueous phase, concentrate the organic phase under reduced pressure to remove the solvent, add 300.0 mL of MTBE and 150.0 mL of n-heptane, heat to 70 °C to dissolve, cool to 0 °C, filter and dry to obtain 57.5 g of off-white solid with HPLC purity of 99.8% (see [link to flask]). Figure 2 The yield was 85%.

[0104] (3) Preparation of high-purity cannabidiol heptyl derivative CBDP: Add 50.0 mL of phosphate buffer solution, 100.0 mL of ethanol, 280 mg of alkaline phosphatase (HC-ALP), and 10.0 g of intermediate 7 to a 500 mL reaction flask. Stir the mixture at 20-25°C for 16 h. Extract with 100.0 mL of n-heptane, discard the aqueous phase, and concentrate the organic phase under reduced pressure to remove n-heptane, yielding 4.7 g of a colorless oily substance with an HPLC purity of 99.8%. See [link to HPLC]. Figure 3 Yield: 98%.

[0105] Example 2 (1) Preparation of low-purity cannabidiol heptyl derivative CBDP: 1.04 kg of 5-heptylresorcinol, 85.0 g of p-toluenesulfonic acid, and 20 L of dichloromethane were added to a 50 L reactor. The mixture was cooled to 0 °C under nitrogen protection, and then 915.0 g of (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol was added. After the addition was complete, the reaction temperature was raised to 20 °C and stirred for approximately 1-3 hours. The reaction was quenched with 10 L of saturated sodium bicarbonate solution. The organic layer was separated, and the aqueous phase was extracted with 10 L of dichloromethane. The combined organic layers were washed with 10 L of saturated brine, and the solvent was removed under reduced pressure to obtain 1.64 kg of a light reddish-brown oily substance, with a yield of 96%.

[0106] (2) Preparation of intermediate 7 ((1'R,2'R)-4-heptyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-dibis(4-nitrobenzenesulfonate)): 1.64 kg of cannabidiol heptyl derivative CBDP, 16 L of dichloromethane, and 1.06 kg of triethylamine were added to a 50 L reactor. Under nitrogen protection, the mixture was cooled to 0 °C. 2.28 kg of p-nitrobenzenesulfonyl chloride was added, and the mixture was heated to 25 °C and reacted for 4-6 h. 10 L of 1% dilute hydrochloric acid aqueous solution was added for extraction, and the aqueous phase was discarded. The organic phase was concentrated under reduced pressure to remove the solvent. 15 L of MTBE and 7.5 L of n-heptane were added, and the mixture was heated to 70 °C to dissolve the solid. The mixture was then cooled to 0 °C, filtered, and dried to obtain 2.97 kg of an off-white solid, with a yield of 87%.

[0107] (3) Preparation of high-purity cannabidiol heptyl derivative CBDP: 15L of phosphate buffer solution, 30L of ethanol, 83.2g of alkaline phosphatase (HC-ALP), and 2.97kg of intermediate 7 were added to a 100L reactor and stirred at 20-25 degrees Celsius for 16h. 30L of n-heptane was added for extraction, the aqueous phase was discarded, and the organic phase was concentrated under reduced pressure to remove n-heptane, yielding 1.41kg of a colorless oily substance with a yield of 99% and a purity of 99.7%.

[0108] Example 3 Unlike Example 1, the mass of p-nitrobenzenesulfonyl chloride was 42.06 g, otherwise the same. The purity of the obtained product was 99.6%, and the yield was 85%.

[0109] Example 4 Unlike Example 1, the mass of p-nitrobenzenesulfonyl chloride was 63.09 g, otherwise the same. The purity of the obtained product was 99.8%, and the yield was 98%.

[0110] Example 5 Unlike Example 1, the mass of alkaline phosphatase (HC-ALP) used in step (3) was 200 mg, while all other steps were the same. The purity of the resulting product was 99.8%, and the yield was 98%.

[0111] Example 6 Unlike Example 1, the mass of alkaline phosphatase (HC-ALP) used in step (3) was 300 mg, while all other steps were the same. The purity of the resulting product was 99.7%, and the yield was 98%.

[0112] Comparative Example 1 Preparation of cannabidiol heptayl derivative CBDP: Under an argon atmosphere, 1.0 equivalent of resorcinol 1 and 0.1 equivalent of p-toluenesulfonic acid were added, followed by 20°C dichloromethane. The mixture was cooled to 0°C, and then 1.2 equivalent of (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol was added. After addition, the reaction temperature was raised to room temperature, and stirring was continued for approximately 1-3 hours. The reaction was quenched by adding saturated sodium bicarbonate solution, and the organic layer was separated. The aqueous phase was extracted with 10°C dichloromethane. The combined organic layers were washed with brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was separated by silica gel chromatography to obtain a colorless, viscous oil with a yield of 32% and an HPLC purity of 96.6% (see...). Figure 4 ).

[0113] Comparative Example 2 (1) Preparation of intermediate 3: Add 400 mL of anhydrous ethanol and 800 mL of dichloromethane to the reaction flask, along with 91.1 g of phloroglucinol and 100 g of anhydrous magnesium sulfate. Cool to 0°C. Add 7.0 g of diethyl tetrafluoroborate and slowly add a dichloromethane solution (100 g dissolved in 800 mL) of (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol while maintaining the temperature at 0°C. After the addition is complete, heat to room temperature and stir for 1.5 hours. Filter, rinse the filter cake with dichloromethane, and combine the filtrates. The product was washed once with sodium aqueous solution and once with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, filtered, and concentrated to obtain 168 g of a viscous oily substance. 470 mL of dichloromethane was added, and the mixture was stirred for 2 hours. After filtration and drying, 70.3 g of the product was obtained. The mother liquor was concentrated to remove the solvent, and 240 mL of dichloromethane was added. After stirring for 1.5 hours, the mixture was filtered and dried to obtain 18.0 g of the product. The mother liquor was concentrated to remove the solvent, and 125 mL of dichloromethane was added. After stirring for 2 hours, the mixture was filtered and dried to obtain 5.2 g of the product. A total of 93.5 g of product was obtained.

[0114] (2) Preparation of intermediate 4: Add 93.5 g of intermediate 3, 108.3 g of triethylamine, and 900 mL of dichloromethane to a reaction flask. Add 118.6 g of N-phenylbis(trifluoromethanesulfonyl)imide at room temperature. After the addition is complete, stir overnight at room temperature. Add 350 mL of water, and extract the aqueous phase with 3 x 100 mL of dichloromethane. Combine the organic phases and dry with anhydrous magnesium sulfate. Filter through a short silica gel column. Concentrate the filtrate to dryness, dissolve in 25 mL of n-hexane and 75 mL of dichloromethane, and filter again through a short silica gel column. Filter the filter cake. Wash until no product is detected by TLC, concentrate the filtrate to obtain 118g of crude product; add 120mL of n-hexane, stir for 2 hours, filter and dry to obtain 72.5g of product; concentrate the mother liquor to dryness, add 30mL of ethyl acetate and 40mL of n-hexane to dissolve, filter through a short silica gel column, wash the filter cake until no product is detected by TLC, concentrate the filtrate to dryness, add 40mL of n-hexane, stir for 1 hour, filter and dry to obtain 25.0g of product; concentrate the mother liquor to dryness and column chromatography to obtain 7.0g of product, for a total of 104.5g of product.

[0115] (3) Preparation of intermediate 5: Add 104 g of intermediate 4, 134 g of triethylamine, and 600 mL of dichloromethane to a reaction flask, cool to 0 degrees Celsius, and add 144 g of TMsCl. After the addition is complete, heat to room temperature, stir, and filter. Filter, and wash the filter cake with dichloromethane. Combine the filtrates, concentrate, add 800 mL of n-hexane, stir for 2 hours, filter, and concentrate the filtrate to dryness to obtain 135 g of a pale yellow oily substance.

[0116] (4) Preparation of cannabidiol heptyl derivative CBDP: Under nitrogen protection, 40 mL of tetrahydrofuran, 14 mL of 2 M n-heptylmagnesium bromide in diethyl ether solution, 6.3 g of zinc bromide, and 3.0 g of lithium bromide were added to the reaction flask. After stirring for 30 minutes, a mixed solution was added: 10.0 g of intermediate 5 and 140 mg of PdCl2 (dppf) dissolved in 40 mL of tetrahydrofuran. The mixture was stirred at room temperature for 2 hours, then 20 mL of water and 10 mL of 2 M sulfuric acid solution were added. The mixture was stirred at room temperature for 1 hour. The aqueous phase was discarded, and the organic phase was dried over anhydrous magnesium sulfate. The mixture was filtered, concentrated to dryness, and then hexane was added. The mixture was passed through a short silica gel column, and the filtrate was concentrated to dryness to obtain 5.25 g of an oily substance with a purity of 92.8%.

[0117] Comparative Example 3 Unlike Example 1, step (3) involved the hydrolysis of 4.6 g of thiophenol at a temperature of 20-25 degrees Celsius for 16 hours, with all other parameters remaining the same. The purity of the resulting product was 98.8%, and the yield was 78%.

[0118] Comparative Example 4 Unlike Example 1, step (3) used 4.0 g of hydrobromic acid for hydrolysis, the reaction temperature was 20-25 degrees Celsius, and the reaction time was 16 hours, all other steps were the same. The purity of the obtained product was 95.8%, and the yield was 80%.

[0119] Verification of technical effectiveness and / or analysis of technical problem solving By designing a process route for the derivatization of intermediate 7 and the enzymatic hydrolysis to remove the p-methylbenzenesulfonyl group, the chemical purity of the cannabidiol heptyl derivative CBDP was significantly improved, while avoiding post-treatment after column chromatography purification, making it suitable for large-scale industrial production.

[0120] Finally, it should be noted that the above content is only used to illustrate the technical solution of the present invention, and is not intended to limit the scope of protection of the present invention. Simple modifications or equivalent substitutions made by those skilled in the art to the technical solution of the present invention do not depart from the essence and scope of the technical solution of the present invention.

Claims

1. A method for preparing a high-purity cannabidiol heptyl derivative CBDP, characterized in that, Including the following steps: (1) 5-Heptylresorcinol and (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol were dissolved in a solvent and reacted under the action of Lewis acid catalyst to obtain low-purity cannabidiol heptyl derivative CBDP. (2) Dissolve the low-purity cannabidiol heptyl derivative CBDP obtained in step (1) in a solvent, react with a derivatizing reagent, and purify to obtain intermediate 7; (3) The intermediate 7 obtained in step (2) is dissolved in a solvent and purified by enzymatic hydrolysis to obtain the high-purity cannabidiol heptyl derivative CBDP. The reaction route for the high-purity cannabidiol heptayl derivative CBDP is as follows: 。 2. The preparation method according to claim 1, characterized in that, The solvent in step (1) is selected from at least one of a mixed solution of dichloroethane, dichloromethane, chloroform, ethyl acetate and water; preferably at least one of a mixed solution of dichloroethane, dichloromethane, ethyl acetate and water; more preferably dichloromethane; The Lewis acid catalyst in step (1) is selected from at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), ferric chloride (FeCl3), and zinc chloride (ZnCl2); preferably at least one of p-toluenesulfonic acid, aluminum trichloride (AlCl3), and zinc chloride (ZnCl2); more preferably at least one of p-toluenesulfonic acid and zinc chloride (ZnCl2); and even more preferably p-toluenesulfonic acid. The molar ratio of 5-heptylresorcinol to (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol in step (1) is selected from 1:1.1-1.3; preferably 1:1.15-1.25; more preferably 1:1.2; The amount of Lewis acid catalyst used in step (1) is 5 mol%-15 mol% of 5-heptylresorcinol; preferably 8 mol%-13 mol% of 5-heptylresorcinol; more preferably 10 mol% of 5-heptylresorcinol. The order of adding the solvent in step (1) is as follows: first, 5-heptylresorcinol and Lewis acid catalyst are dissolved in the solvent, and then (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol is added; Preferably, the process of nitrogen protection and cooling is further included before adding (1S,4R)-1-methyl-4-(1-methylvinyl)-2-cyclohexen-1-ol; More preferably, the cooling temperature is 0°C; The reaction temperature in step (1) is 10-30℃ and the reaction time is 1-3h; preferably 15-30℃ and the reaction time is 2-3h; more preferably 20℃ and the reaction time is 2.5h.

3. The preparation method according to any one of claims 1-2, characterized in that, The reaction described in step (1) is followed by a step of quenching the reaction; Preferably, the quenching agent is at least one selected from saturated sodium bicarbonate, sodium carbonate solution, potassium bicarbonate solution, ammonia, and triethylamine; more preferably, the quenching agent is at least one selected from saturated sodium bicarbonate and sodium carbonate solution; most preferably, saturated sodium bicarbonate. The quenching process also includes separation, extraction, and washing steps; Preferably, the separation and extraction involves separating the organic layer and extracting the aqueous phase; More preferably, the extraction solvent of the aqueous phase is selected from at least one of dichloromethane, dichloroethane, chloroform, and ethyl acetate; most preferably, it is dichloromethane. Preferably, the washing solvent is at least one of a saturated sodium chloride solution, a saturated ammonium chloride solution, and water; most preferably, it is a saturated sodium chloride solution. Preferably, the washing step further includes a solvent removal step; More preferably, the solvent removal method is selected from at least one of vacuum rotary evaporation, vacuum distillation, vacuum drying, and nitrogen purging; even more preferably, the solvent removal method is selected from at least one of vacuum rotary evaporation and vacuum distillation; most preferably, vacuum rotary evaporation.

4. The preparation method according to claim 1, characterized in that, The derivatizing reagent in step (2) is selected from at least one of benzoyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; preferably at least one of benzoyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; more preferably p-nitrobenzenesulfonyl chloride; The solvent in step (2) is selected from at least one of a mixed solution of dichloroethane, dichloromethane, chloroform, ethyl acetate and water; preferably at least one of a mixed solution of dichloroethane, dichloromethane, ethyl acetate and water; more preferably dichloromethane; Preferably, the raw materials in step (2) further include an acid-binding agent; More preferably, the acid-binding agent is selected from at least one of triethylamine, pyridine, diethylamine, and N,N-diisopropylethylamine; even more preferably, the acid-binding agent is selected from at least one of triethylamine and pyridine; most preferably, the acid-binding agent is triethylamine.

5. The preparation method according to claim 1 or 4, characterized in that, In step (2), the molar ratio of low-purity cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-3; preferably 1:2-2.5; more preferably 1:2.15; Preferably, the molar percentage of the acid-binding agent is 200%-250% of the low-purity cannabidiol heptayl derivative CBDP; more preferably, it is 220% of the low-purity cannabidiol heptayl derivative CBDP. Preferably, the order of adding the solvent in step (2) is to first dissolve the low-purity cannabidiol heptyl derivative CBDP and the acid-binding agent obtained in step (1) in the solvent, and then add the derivatizing reagent; more preferably, the process of nitrogen protection and cooling is included before adding the derivatizing reagent; even more preferably, the cooling temperature is 0°C. The reaction temperature in step (2) is 10-30℃ and the reaction time is 4-6h; preferably 15-30℃ and the reaction time is 4-5h; more preferably 25℃ and the reaction time is 4.5h. The purification methods described in step (2) include, but are not limited to, extraction, concentration, and recrystallization. Preferably, the extraction solvent is selected from at least one of 1% hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, and dilute phosphoric acid aqueous solution; more preferably, it is selected from at least one of 1% hydrochloric acid aqueous solution and dilute sulfuric acid aqueous solution; even more preferably, it is a 1% hydrochloric acid aqueous solution. Preferably, the concentration is an organic phase concentration; more preferably, the concentration method is selected from at least one of vacuum rotary evaporation, vacuum distillation, thin-film evaporation, and freeze drying; even more preferably, at least one of vacuum rotary evaporation and vacuum distillation; most preferably, vacuum rotary evaporation. Preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, ethyl acetate, diethyl ether, isopropanol, and dichloromethane; Preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, and ethyl acetate; more preferably, MTBE and n-heptane are used in combination; most preferably, MTBE and n-heptane are used in combination at a volume ratio of 2:

1. Preferably, the recrystallization reaction temperature is 60-90℃ and the cooling temperature is -10-10℃; more preferably, the recrystallization reaction temperature is 70℃ and the cooling temperature is 0℃. Preferably, the recrystallization step is followed by a drying process.

6. The preparation method according to claim 1, characterized in that, The solvent in step (3) is selected from at least one of methanol, ethylene glycol, isopropanol, a mixture of phosphate buffer and ethanol, and tetrahydrofuran; preferably at least one of methanol, ethylene glycol, phosphate buffer and ethanol; more preferably a mixture of phosphate buffer and ethanol; and even more preferably a mixture of phosphate buffer and ethanol in a volume ratio of 1:

2. The hydrolytic enzyme mentioned in step (3) is selected from at least one of alkaline phosphatase (HC-ALP), phospholipase (PLA2IIL), and phospholipase (DPLDII); preferably at least one of alkaline phosphatase (HC-ALP) and phospholipase (PLA2IIL); more preferably alkaline phosphatase (HC-ALP). The amount of hydrolytic enzyme used in step (3) is 2%-3% of the mass of intermediate 7; preferably 2.5%-3% of the mass of intermediate 7; more preferably 2.8% of the mass of intermediate 7. The reaction temperature in step (3) is 15-40℃ and the reaction time is 12-36h; preferably 15-25℃ and the reaction time is 12-20h; more preferably 20-25℃ and the reaction time is 16h. The purification process in step (3) includes, but is not limited to, extraction and concentration. Preferably, the extraction reagent is selected from at least one of n-heptane, n-hexane, cyclohexane, petroleum ether, ethyl acetate, and isopropyl acetate; more preferably, the extraction reagent is selected from at least one of n-heptane, n-hexane, and cyclohexane; even more preferably, the extraction reagent is n-heptane. Preferably, the concentration is an organic phase concentration; More preferably, the concentration method is selected from at least one of vacuum rotary evaporation, vacuum distillation, thin-film evaporation, and freeze drying; even more preferably, it is selected from at least one of vacuum rotary evaporation and vacuum distillation; most preferably, it is vacuum rotary evaporation.

7. An intermediate 7 in the preparation process of the high-purity cannabidiol heptayl derivative CBDP according to claim 1 or any one of claims 4-6, characterized in that, The intermediate 7 is chemically named (1'R,2'R)-4-heptyl-5'-methyl-2'-(prop-1-en-2-yl)-1',2',3',4'-tetrahydro-[1,1'-biphenyl]-2,6-dibis(4-nitrobenzenesulfonate), and its structural formula is as follows: 。 8. The method for preparing intermediate 7 according to claim 7, characterized in that, The steps include: dissolving the cannabidiol heptyl derivative CBDP in a solvent, reacting it with a derivatizing reagent, and purifying it to obtain intermediate 7.

9. The preparation method according to claim 8, characterized in that, The derivatizing reagent is selected from at least one of benzoyl chloride, p-toluenesulfonyl chloride, p-nitrobenzenesulfonyl chloride, methanesulfonyl chloride, and trifluoromethanesulfonyl chloride; preferably at least one of benzoyl chloride, p-toluenesulfonyl chloride, and p-nitrobenzenesulfonyl chloride; more preferably p-nitrobenzenesulfonyl chloride; The solvent is selected from at least one of a mixed solution of dichloroethane, dichloromethane, chloroform, ethyl acetate and water; preferably at least one of a mixed solution of dichloroethane, dichloromethane, ethyl acetate and water; more preferably dichloromethane; Preferably, the raw material further comprises an acid-binding agent; more preferably, the acid-binding agent is selected from at least one of triethylamine, pyridine, diethylamine, and N,N-diisopropylethylamine; even more preferably, the acid-binding agent is selected from at least one of triethylamine and pyridine; most preferably, the acid-binding agent is triethylamine. The molar ratio of the cannabidiol heptyl derivative CBDP to the derivatizing reagent is 1:2-3; preferably 1:2-2.5; more preferably 1:2.15; Preferably, the molar percentage of the acid-binding agent is 200%-250% of the cannabidiol heptayl derivative CBDP; more preferably, it is 220% of the cannabidiol heptayl derivative CBDP. Preferably, the order of adding the solvent-soluble ingredients is as follows: first, dissolve the cannabidiol heptyl derivative CBDP and the acid-binding agent in the solvent, and then add the derivatizing reagent; more preferably, the process of nitrogen protection and cooling is included before adding the derivatizing reagent; even more preferably, the cooling temperature is 0°C. The reaction temperature is 10-30℃, and the reaction time is 4-6h; preferably 15-30℃, and the reaction time is 4-5h; more preferably 25℃, and the reaction time is 4.5h. The purification methods include, but are not limited to, extraction, concentration and recrystallization. Preferably, the extraction solvent is selected from at least one of 1% hydrochloric acid aqueous solution, dilute sulfuric acid aqueous solution, and dilute phosphoric acid aqueous solution; more preferably, it is selected from at least one of 1% hydrochloric acid aqueous solution and dilute sulfuric acid aqueous solution; even more preferably, it is a 1% hydrochloric acid aqueous solution. Preferably, the concentration is an organic phase concentration; More preferably, the concentration method is selected from at least one of vacuum rotary evaporation, vacuum distillation, thin-film evaporation, and freeze drying; even more preferably, it is selected from at least one of vacuum rotary evaporation and vacuum distillation; most preferably, it is vacuum rotary evaporation. Preferably, the solvent for recrystallization is selected from at least one of methyl tert-butyl ether (MTBE), n-heptane, ethyl acetate, diethyl ether, isopropanol, and dichloromethane; more preferably, at least one of methyl tert-butyl ether (MTBE), n-heptane, and ethyl acetate; even more preferably, a combination of methyl tert-butyl ether (MTBE) and n-heptane; most preferably, a combination of methyl tert-butyl ether (MTBE) and n-heptane in a volume ratio of 2:

1. Preferably, the recrystallization reaction temperature is 60-90℃ and the cooling temperature is -10-10℃; more preferably, the recrystallization reaction temperature is 70℃ and the cooling temperature is 0℃. Preferably, the recrystallization step is followed by a drying process.

10. The use of intermediate 7 according to claim 7 in the preparation of high-purity cannabidiol heptyl derivative CBDP.

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