Synthesis method of dihydrocapsaicin

Abstract

The invention discloses a synthesis method of dihydrocapsaicin, which comprises the following steps: taking terminal halogenated fatty alcohol as an initial raw material, and protecting hydroxyl of the terminal halogenated fatty alcohol to obtain a hydroxyl-protected intermediate; carrying out coupling reaction on the hydroxyl protected intermediate and a Grignard reagent derived from halogenated hydrocarbon under the catalysis of a copper-based Lewis acid catalyst; or carrying out coupling reaction on the Grignard reagent derived from the hydroxyl protected intermediate and halogenated hydrocarbon under the catalysis of a copper-based Lewis acid catalyst to obtain 8-methyl nonanol, oxidizing the 8-methylnonanol into 8-methylnonanoic acid; the method comprises the following steps: reacting 8-methylnonanoic acid with an activating agent, and then reacting with vanillin amine to obtain dihydrocapsaicin. According to the present invention, the cheap and easily available bulk chemical product terminal halogenated fatty alcohol is adopted as the raw material, the high yield and high purity synthesis of the dihydrocapsaicin is successfully achieved through the conventional chemical reaction with characteristics of mild condition and simple operation, and the whole process has characteristics of strong practicality, low production cost and significant market competition advantage.

Description

Technical Field

[0001] This invention relates to the field of organic compound technology, and in particular to a method for synthesizing dihydrocapsaicin. Background Technology

[0002] Capsaicin is a class of amide compounds, mainly found in chili peppers. It is a natural capsaicin compound extracted from natural chili peppers, mainly composed of capsaicin (R=-(CH2)4CH=CHCHMe2, 69%), dihydrocapsaicin (R=-(CH2)6CHMe2, 22%), nordihydrocapsaicin (R=-(CH2)3CH=CHCHMe2, 7%), homodihydrocapsaicin (R=-(CH2)7CHMe2, 1%), and homocapsaicin (R=-(CH2)5CH=CHCHMe2, 1%). Among them, capsaicin and dihydrocapsaicin account for more than 90% of the total capsaicin content. The pungent spiciness of capsaicin substances can produce a series of physiological reactions and repellent effects in humans and animals, thus having many functions and applications.

[0003] In the medical field, capsaicin inhibits pain signal transmission by acting on TRPV1 receptors (transient receptor potential vanillic acid subtype 1), relieving neuralgia, arthritis, and muscle soreness, and can be used in topical analgesic ointments and patches. It can also alleviate symptoms by regulating neuropeptide release, treating psoriasis and pruritus. Capsaicin can activate brown adipose tissue, promoting energy consumption and fat oxidation, resulting in a high basal metabolic rate and thus aiding in weight loss. It also has potential anti-cancer and antibacterial effects. In marine antifouling applications, marine organisms such as barnacles, algae, and shellfish attach in large quantities to ship bottoms, buoys, docks, bridge piers, seawater pipelines, and aquaculture cages. Due to their large numbers and rapid growth, they can slow ship speeds, increase fuel consumption, accelerate metal corrosion, clog pipelines and cage meshes, and cause underwater facilities to become unbalanced, posing a significant threat to human marine development. Capsaicin, as a repellent, has a strong repellent effect without killing marine life, demonstrating significant ecological benefits. In the field of wires and cables, capsaicin can be used as a repellent for termites and rodents. Polyvinyl chloride and polyethylene are increasingly used in the wire and cable industry as insulation and sheathing materials. In addition to being damaged by oxygen, heat, light, force and chemical corrosion, they are also damaged by termites, rats or rabbits, which can lead to power outages, communication interruptions, or even short circuits that cause fires. The strong spiciness of capsaicin can strongly stimulate the oral mucosa and taste nerves of rodents, making them averse to chewing, while at the same time killing termites.

[0004] In summary, the application potential of capsaicin compounds in the fields of medicine, agriculture, and food has attracted widespread attention. Among them, medical applications, especially chronic pain management, are a current research focus; in addition, their applications in functional foods and agricultural biopesticides are also important directions for exploration.

[0005] Among natural capsaicin compounds, dihydrocapsaicin has a high degree of hydrogenation of its fatty acid chains, contains no unsaturated bonds, and is more stable at high temperatures, making it suitable for use in food processing requiring heat (such as spicy snacks and hot pot bases). It can also relieve neuropathic pain (such as diabetic neuropathy and arthritis) by consuming substance P (a pain neurotransmitter) and has a more lasting analgesic effect. The structural formula of dihydrocapsaicin is as follows: .

[0006] Even in highly spicy natural chilies (such as Bhut Jolokia and Chili Pepper), the capsaicin content is only 0.5% to 1.5%. The extracted compounds contain more than twenty capsaicin analogues, requiring techniques such as column chromatography to obtain high-purity capsaicin compounds. This process is inefficient, time-consuming, and extremely costly, making it difficult to produce large quantities of high-purity capsaicin compounds using traditional methods. Therefore, to produce high-purity capsaicin compounds, chemical synthesis is necessary to reduce costs, improve product purity, and ultimately meet consumer demand.

[0007] Each gram of dihydrocapsaicin has a spiciness level as high as 16.1 × 10⁻⁶. 3 SHU, with its superior stability due to structural saturation, is a highly valuable capsaicin analogue. However, the synthetic efficiency of this compound has long been limited by the preparation process of the key intermediate, 8-methylnonanoic acid. Existing methods face significant challenges in the large-scale production of this intermediate, resulting in low overall yields and high costs. Therefore, developing a novel and more efficient synthetic route for 8-methylnonanoic acid is crucial. Summary of the Invention

[0008] To address the aforementioned technical problems, the present invention aims to provide a method for synthesizing dihydrocapsaicin. This invention uses readily available and inexpensive terminal halogenated fatty alcohols as raw materials, and through a conventional chemical reaction under mild conditions and with simple operation, successfully achieves the high-yield and high-purity synthesis of dihydrocapsaicin. The overall process is highly practical, has low production costs, and possesses significant market competitive advantages.

[0009] To achieve the above-mentioned technical objectives and effects, the present invention is implemented through the following technical solution: A method for synthesizing dihydrocapsaicin includes the following steps: (1) Using the terminal haloalcohol shown in formula (Ⅰ) as the starting material, its hydroxyl groups are protected to obtain hydroxyl-protected intermediates; (2) The hydroxyl-protected intermediate is coupled with a Grignard reagent derived from the haloalkane shown in formula (II) under the catalysis of a copper-based Lewis acid catalyst; or, the Grignard reagent derived from the hydroxyl-protected intermediate is coupled with the haloalkane shown in formula (II) under the catalysis of a copper-based Lewis acid catalyst to obtain 8-methylnonanol shown in formula (III). (3) Oxidize the 8-methylnonanol obtained in step (2) to 8-methylnonanoic acid as shown in formula (IV); (4) After reacting the 8-methylnonanoic acid obtained in step (3) with an activator, it is then reacted with vanillinamine to obtain the target product dihydrocapsaicin shown in formula (V); The synthetic route of this method is as follows: ; Where X1 and X2 are independently selected from fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms; n is an integer from 1 to 5; and m is an integer from 1 to 5.

[0010] Further, in step (1), the protecting group used for the hydroxyl protection is selected from one of methyl, tert-butyl, methoxymethyl, 2-tetrahydropyranyl, benzyl, 4-methoxybenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

[0011] Further, in step (2), the coupling reaction is carried out in an organic solvent selected from at least one of toluene, trifluoromethylbenzene, fluorobenzene, diethyl ether, N-methylpyrrolidone, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, chloroform, and dichloromethane.

[0012] Further, in step (2), the copper-based Lewis acid catalyst is lithium tetrachlorocubic acid.

[0013] Furthermore, in step (2), the temperature of the coupling reaction is -60°C to -10°C.

[0014] Furthermore, in step (2), the molar ratio of the hydroxyl-protected intermediate, the haloalkane shown in formula (II), to the copper-based Lewis acid catalyst is 1:(1-1.2):(0.002-0.01).

[0015] Furthermore, in step (3), the oxidation system used is selected from at least one of nitric acid, potassium permanganate, sodium hypochlorite, ferric nitrate-potassium chloride-oxygen, potassium dichromate, and Jones' reagent.

[0016] Further, in step (4), the activator is a sulfonyl chloride, which is selected from at least one of trifluoromethanesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-toluenesulfonyl chloride, 3-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 4-butylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-ethoxybenzenesulfonyl chloride, 2,4,6-tribenzenesulfonyl chloride, 2,5-dibenzenesulfonyl chloride, 2,4-dibenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride.

[0017] Further, the reaction in step (4) is carried out in the presence of a base selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, strontium carbonate, lithium carbonate, triethylamine, pyridine, diisopropylethylamine, DBU, and DMAP.

[0018] Further, in step (4), the molar ratio of 8-methylnonanoic acid, activator and vanillinamine is 1:(1.1-1.3):(1.1-1.3).

[0019] The beneficial effects of this invention are as follows: This invention addresses the bottlenecks of the long and demanding synthetic route for 8-methylnonanoic acid in existing technologies by employing a Grignard coupling strategy catalyzed by copper-based Lewis acids, and successfully achieves the efficient construction of key intermediates. This invention utilizes terminal halogenated fatty alcohols, a cheap and readily available bulk chemical raw material, as starting material. Under mild conditions, it can achieve high-yield and high-purity synthesis of dihydrocapsaicin through conventional reactions, avoiding complex purification steps. It is convenient to operate, highly practical, and significantly reduces production costs, providing a feasible technical solution for the large-scale production of dihydrocapsaicin. Attached Figure Description

[0020] Figure 1 It is 8-methylnonanol 1 H-NMR spectrum; Figure 2 It is 8-methylnonanoic acid 1 H-NMR spectrum; Figure 3 dihydrocapsaicin 1 H-NMR spectrum. Detailed Implementation

[0021] The technical solutions of the present invention will be clearly and completely described below with reference to specific embodiments. Obviously, the described embodiments are only some embodiments of the present invention, and not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0022] This invention provides a method for synthesizing dihydrocapsaicin, and the synthetic route of this method is as follows: ; Wherein, X1 and X2 are independently selected from fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms, and are further preferably chlorine atoms and bromine atoms; n is an integer from 1 to 5; m is an integer from 1 to 5.

[0023] The synthesis method includes the following steps: (1) Using the terminal haloalcohol shown in formula (Ⅰ) as the starting material, its hydroxyl groups are protected to obtain hydroxyl-protected intermediates; The protecting group used for hydroxyl protection is selected from one of methyl, tert-butyl, methoxymethyl, 2-tetrahydropyranyl, benzyl, 4-methoxybenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl, or tert-butyldiphenylsilyl, more preferably one of methoxymethyl, 2-tetrahydropyranyl, or benzyl; the hydroxyl protection reaction is carried out in an organic solvent selected from one of toluene, trifluoromethylbenzene, fluorobenzene, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, chloroform, or dichloromethane, more preferably one of methyltetrahydrofuran, chloroform, or dichloromethane. A reaction promoter is also added in step (1), which is an acid catalyst or a base, preferably p-toluenesulfonic acid or triethylamine; the reaction temperature for hydroxyl protection is 0~60℃, more preferably 10~30℃.

[0024] (2) The hydroxyl-protected intermediate is coupled with a Grignard reagent derived from the haloalkane shown in formula (II) under the catalysis of a copper-based Lewis acid catalyst; or, the Grignard reagent derived from the hydroxyl-protected intermediate is coupled with the haloalkane shown in formula (II) under the catalysis of a copper-based Lewis acid catalyst to obtain 8-methylnonanol shown in formula (III). In step (2), the coupling reaction is carried out in an organic solvent, which is selected from at least one of toluene, trifluoromethylbenzene, fluorobenzene, diethyl ether, N-methylpyrrolidone, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, chloroform, and dichloromethane, and more preferably at least one of N-methylpyrrolidone, tetrahydrofuran, methyltetrahydrofuran, and methyl tert-butyl ether. The copper-based Lewis acid catalyst is preferably lithium tetrachlorocopper oxide. The temperature of the coupling reaction in step (2) is -60°C to -10°C, and more preferably -20°C to -10°C. In addition, in step (2), an initiator is added, which is selected from at least one of iodine, iodomethane, dibromoethane, trimethylchlorosilane, and DIBAL-H, and more preferably at least one of iodine, iodomethane, and DIBAL-H. The molar ratio of the hydroxyl-protected intermediate, the haloalkane shown in formula (II), to the copper-based Lewis acid catalyst is 1:(1-1.2):(0.002-0.01).

[0025] (3) Oxidize the 8-methylnonanol obtained in step (2) to 8-methylnonanoic acid as shown in formula (IV); the oxidation system used in this step is selected from at least one of nitric acid, potassium permanganate, sodium hypochlorite, ferric nitrate-potassium chloride-oxygen, potassium dichromate, and Jones' reagent, and is more preferably at least one of nitric acid, ferric nitrate-potassium chloride-oxygen, and Jones' reagent. The reaction temperature of this step is 0~100℃, and is more preferably 20~50℃.

[0026] (4) After reacting the 8-methylnonanoic acid obtained in step (3) with an activator, it is then reacted with vanillinamine to obtain the target product dihydrocapsaicin shown in formula (V); The activator is a sulfonyl chloride, which is selected from at least one of trifluoromethanesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-toluenesulfonyl chloride, 3-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 4-butylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-ethoxybenzenesulfonyl chloride, 2,4,6-tribenzenesulfonyl chloride, 2,5-dibenzenesulfonyl chloride, 2,4-dibenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride. More preferably, the sulfonyl chloride is at least one of methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, and 3-nitrobenzenesulfonyl chloride.

[0027] The reaction in step (4) is carried out in an organic solvent selected from at least one of benzene, toluene, xylene, acetonitrile, ethyl acetate, propyl acetate, butyl acetate, petroleum ether, ethylene glycol dimethyl ether, ethylene glycol dibutyl ether, ethylene glycol monomethyl ether, ethylene glycol monoethyl ether, ethylene glycol monobutyl ether, acetone, chloroform, dichloromethane, and 1,2-dichloroethane, and more preferably at least one of toluene, acetonitrile, ethyl acetate, chloroform, dichloromethane, and 1,2-dichloroethane.

[0028] The reaction in step (4) is carried out in the presence of an alkali, which is selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, strontium carbonate, lithium carbonate, triethylamine, pyridine, diisopropylethylamine, DBU, and DMAP, and is more preferably at least one of potassium carbonate, lithium carbonate, triethylamine, and pyridine.

[0029] The reaction temperature of step (4) is 0-60℃, and more preferably 20-30℃.

[0030] In step (4), the molar ratio of 8-methylnonanoic acid, activator and vanillinamine is 1:(1.1-1.3):(1.1-1.3).

[0031] The present invention will be further described below through specific embodiments.

[0032] Example 1 Synthesis of 2-(6-chlorohexyloxy)tetrahydro-2H-pyran: 6-Chlorohexanol (137 g, 1 mol), p-toluenesulfonic acid monohydrate (9.5 g, 0.05 mol), and 1000 mL of dichloromethane were added to a reaction flask. Under ice-water cooling, 2,3-dihydropyran (100.8 g, 1.2 mol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature. The reaction of the 6-chlorohexanol starting material was detected by gas chromatography. The reaction was quenched by adding 500 mL of saturated sodium bicarbonate aqueous solution. The mixture was separated into liquid and liquid phases. The organic phase was dried with anhydrous sodium carbonate, filtered, and the filtrate was concentrated. Excess solvent and water were removed by vacuum pumping under reduced pressure, yielding 216.6 g of product, with a yield of 98%.

[0033] Synthesis of 8-methylnonanol: Under nitrogen protection, add activated magnesium strip (2.64 g, 0.11 mol) and 100 mL tetrahydrofuran to the reaction flask, then add DIBAL-H (1 mL, 1 M) and iodine (0.25 g, 0.001 mol). While maintaining the temperature below 25 °C, add 2-(6-chlorohexyloxy)tetrahydro-2H-pyran (22.1 g, 0.1 mol) / 80 mL tetrahydrofuran solution dropwise. After the addition is complete, continue stirring the reaction until the Grignard reagent is completely obtained and set aside for later use.

[0034] Under nitrogen protection, bromoisobutane (15.1 g, 0.11 mol) and 100 mL tetrahydrofuran / 25 mL N-methylpyrrolidone were added to the reaction flask and stirred until homogeneous. Lithium tetrachlorocubic ether THF solution (2 mL, ~0.1 mol / L) was then added, and the mixture was cooled to -30°C. The Grignard reagent was added dropwise over 2 hours. After the addition was complete, the mixture was stirred at -30°C for 2 hours and then allowed to warm naturally to 25°C overnight. The mixture was then cooled with ice water, and 250 mL of saturated ammonium chloride aqueous solution was added dropwise. The mixture was concentrated to remove the low-boiling-point solvent, extracted twice with ethyl acetate, and the organic phases were combined, washed twice with brine, and concentrated. 250 mL of methanol and 1 g of p-toluenesulfonic acid monohydrate were added to the residue, and the mixture was heated under reflux for 2 hours. The methanol was concentrated to remove the methanol, and the residue was purified by vacuum distillation to give 14.5 g of a pale yellow liquid product (92% yield). Figure 1 As shown, 1 ¹H NMR (400 MHz, CDCl₃): δ 3.68–3.63 (m, 2H), 1.59–1.50 (m, 4H), 1.42–1.25 (m, 8H), 1.23–1.15 (m, 2H), 0.88 (d, J = 8 Hz, 6H). Prepare the required amount of 8-methylnonanol according to the above synthetic method for later use.

[0035] Synthesis of 8-methylnonanoic acid: 79 g (0.5 mol) of 8-methylnonanol was dissolved in 1 L of 10% sodium hydroxide solution and heated to 60 °C. Potassium permanganate (158 g, 1 mol) was added in portions. After addition, the mixture was stirred for 1 hour, heated under reflux for 2 hours, cooled, filtered, and the filtrate was concentrated to one-quarter of its original volume. The solution was then cooled, acidified with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was distilled under reduced pressure to obtain 78.3 g of 8-methylnonanic acid, with a yield of 91%. Figure 2 As shown, 1H NMR (400 MHz, CDCl3): δ2.37(t, J=8 Hz, 2H), 1.67-1.63(m, 2H), 1.55-1.49(m, 1H), 1.39-1.28(m, 6H), 1.20-1.14(m, 2H), 0.88(d, J=8 Hz, 6H).

[0036] Synthesis of dihydrocapsaicin: Under nitrogen protection, 8-methylnonanoic acid (3.44 g, 20 mmol), pyridine (4.74 g, 60 mmol), and 250 mL of acetonitrile were added to a reaction flask. The mixture was cooled with ice water and kept below 10 °C. Methylsulfonyl chloride (2.53 g, 22 mmol) / 25 mL acetonitrile solution was added dropwise. After the addition was complete, the reaction was stirred for 1 hour. Vanillinamine (3.37 g, 22 mmol) / 50 mL acetonitrile solution was added dropwise, and the mixture was stirred at room temperature for 2 hours. The reaction was quenched with 50 mL of dilute hydrochloric acid, the solvent was removed by concentration, and the mixture was extracted twice with ethyl acetate. The organic phase was dried over anhydrous magnesium sulfate, concentrated, and the residue was purified by silica gel column chromatography (eluting buffer: ethyl acetate: petroleum ether = 15:1-8:1) to give 5.83 g of dihydrocapsaicin, yield 95%, melting point: 63-64 °C. Figure 3 As shown, 1 H NMR (400 MHz, d 6- DMSO): δ 8.81(s, 1H), 8.18 (t, J=6 Hz, 1H), 6.81(s, lH), 6.70(d, J=4 Hz, lH), 6.63(d, J=6Hz, lH), 4.16(d, J=2 Hz, 2H), 3.76 (s, 3H), 2.11(t, J=6 Hz, 2H), 1.51(m, 2H), 1.25(m, 8H), 1.14(m, 1H), 0.86(t, J=4 Hz, 6H).

[0037] Example 2 Synthesis of 6-chloro-1-trimethylsilyloxyhexane: 6-Chlorohexanol (68.5 g, 0.5 mol), triethylamine (60.6 g, 0.6 mol), and 500 mL of dichloromethane were added to a reaction flask. Under ice-water cooling, trimethylchlorosilane (65.4 g, 0.6 mol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature. The reaction of the 6-chlorohexanol starting material was detected by gas phase. The reaction was quenched by adding 250 mL of saturated sodium bicarbonate aqueous solution. The mixture was separated, and the organic phase was dried with anhydrous sodium carbonate. The mixture was filtered, and the filtrate was concentrated. Excess solvent and water were removed by vacuum pumping under reduced pressure to obtain 99.3 g of product, with a yield of 95%.

[0038] Synthesis of 8-methylnonanol: Under nitrogen protection, add activated magnesium strip (2.64 g, 0.11 mol) and a small amount of iodine to the reaction flask. Add bromoisobutane (13.7 g, 0.1 mol) / 600 mL tetrahydrofuran solution to the constant pressure funnel. Add about 10 mL of bromoisobutane solution dropwise, heat to initiate the reaction, maintain a gentle boil, and add the remaining bromoisohexane solution dropwise. After the addition is complete, maintain a gentle boil for 30 minutes, cool to obtain Grignard reagent, and set aside for later use.

[0039] Under nitrogen protection, 20.9 g (0.1 mol) of 6-chloro-1-trimethylsilyloxyhexane and 250 mL of tetrahydrofuran were added to the reaction flask and stirred until homogeneous. Then, 2 mL of lithium tetrachlorocubic oxyhydrogenate (THF) solution (~0.1 mol / L) was added, and the mixture was cooled to -10°C. The Grignard reagent was added dropwise over 2 hours. After the addition was complete, the mixture was stirred at 0°C for 2 hours and then allowed to warm naturally to 25°C overnight. The mixture was cooled with ice water, and 6N hydrochloric acid was added dropwise to pH ~1. The mixture was heated to reflux for 1 hour, concentrated to remove the low-boiling solvent, extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed twice with saturated brine, concentrated, and the residue was purified by vacuum distillation to give 14.2 g of a pale yellow liquid product (90% yield). The required amount of 8-methylnonanol was prepared according to the above synthetic method for later use.

[0040] The synthesis steps for 8-methylnonanoic acid and dihydrocapsaicin are the same as in Example 1.

[0041] Example 3 Synthesis of 1-bromo-4-methoxymethylbutane: 4-Bromobutanol (76.5 g, 0.5 mol), triethylamine (55.6 g, 0.55 mol), and 500 mL of ethyl acetate were added to a reaction flask. Under ice-water cooling, a solution of (chloromethyl)methyl ether (48 g, 0.6 mol) / 100 mL of ethyl acetate was added dropwise. After the addition was complete, the mixture was stirred overnight at room temperature. The reaction of the starting material 3-bromopropanol was detected by gas chromatography. The reaction was quenched by adding 250 mL of saturated sodium bicarbonate aqueous solution. The mixture was separated, and the organic phase was dried over anhydrous sodium carbonate. The solution was filtered, and the filtrate was concentrated. Excess solvent and water were removed by vacuum pumping under reduced pressure to obtain 92.6 g of product, with a yield of 94%.

[0042] Synthesis of 8-methylnonanol: Under nitrogen protection, add activated magnesium strip (2.64 g, 0.11 mol) and a small amount of iodine to the reaction flask. Add bromoisohexane (16.5 g, 0.1 mol) / 600 mL tetrahydrofuran solution to the constant pressure funnel. Add about 10 mL of bromoisohexane solution dropwise, heat to initiate the reaction, maintain a gentle boil, and add the remaining bromoisohexane solution dropwise. After the addition is complete, maintain heating at a gentle boil for 30 minutes, cool to obtain Grignard reagent, and set aside for later use.

[0043] Under nitrogen protection, 15.1 g (0.1 mol) of 1-bromo-4-methoxymethylbutane and 250 mL of tetrahydrofuran were added to the reaction flask and stirred until homogeneous. Then, 2 mL of lithium tetrachlorocubic ether THF solution (~0.1 mol / L) was added, and the mixture was cooled to -20°C. The Grignard reagent was added dropwise over 2 hours. After the addition was complete, the mixture was stirred at -20°C for 2 hours and then allowed to warm naturally to 25°C overnight. The mixture was cooled with ice water, and 6N hydrochloric acid was added dropwise to pH ~1. The mixture was heated to reflux for 1 hour, concentrated to remove the low-boiling-point solvent, extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed twice with saturated brine, concentrated, and the residue was purified by vacuum distillation to obtain 13.9 g of a pale yellow liquid product (88% yield). The required amount of 8-methylnonanol was prepared according to the above synthetic method and set aside for later use.

[0044] Synthesis of 8-methylnonanoic acid: 79 g (0.5 mol) of 8-methylnonanol was dissolved in 2 L of acetone, cooled with an ice-salt solution, and the temperature was controlled at 0-5 °C. Jones' reagent (500 mL, 2 M, 1 mol) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour. Gas chromatography confirmed that the 8-methylnonanol reaction was complete. 100 mL of isopropanol was added dropwise to quench the reaction. The solvent was removed by concentration to obtain a syrupy reaction product. The product was cooled, acidified with concentrated hydrochloric acid, and extracted three times with ethyl acetate. The organic phase was dried over anhydrous sodium sulfate, concentrated, and the residue was distilled under reduced pressure to obtain 73.1 g of 8-methylnonanic acid, with a yield of 85%. The required amount of 8-methylnonanic acid was prepared according to the above synthetic method for later use.

[0045] Synthesis of dihydrocapsaicin: Under nitrogen protection, 172 g (1 mol) of 8-methylnonanoic acid, 303 g (3 mol) of triethylamine, and 1200 mL of dichloromethane were added to a 2 L reaction flask. The mixture was cooled with cold water and kept below 25 °C. A solution of benzenesulfonyl chloride (195 g, 1.1 mol) in 250 mL of dichloromethane was added dropwise. After the addition was complete, the mixture was stirred for 1 hour. A solution of vanillinamine (168.3 g, 1.1 mol) in 250 mL of dichloromethane was then added dropwise, and the mixture was stirred at room temperature until the reaction was complete (gas phase detection). The reaction was quenched with 500 mL of dilute hydrochloric acid. The mixture was separated, and the organic phase was washed twice with saturated brine. The organic phase was dried over anhydrous magnesium sulfate, concentrated, and the residue was recrystallized from the residue using an ethyl acetate-petroleum ether mixture to obtain 294.72 g of dihydrocapsaicin, with a yield of 96%.

[0046] It will be apparent to those skilled in the art that the present invention is not limited to the details of the exemplary embodiments described above, and that the invention can be implemented in other specific forms without departing from the spirit or essential characteristics of the invention. Therefore, the embodiments should be considered in all respects as exemplary and non-limiting, and the scope of the invention is defined by the appended claims rather than the foregoing description. Thus, it is intended that all variations falling within the meaning and scope of equivalents of the claims be included within the present invention.

[0047] Furthermore, it should be understood that although this specification describes embodiments, not every embodiment contains only one independent technical solution. This narrative style is merely for clarity. Those skilled in the art should consider the specification as a whole, and the technical solutions in each embodiment can also be appropriately combined to form other embodiments that can be understood by those skilled in the art.

Claims

1. A method for synthesizing dihydrocapsaicin, characterized in that, Includes the following steps: (1) Using the terminal haloalcohol shown in formula (Ⅰ) as the starting material, its hydroxyl groups are protected to obtain hydroxyl-protected intermediates; (2) The hydroxyl-protected intermediate is coupled with a Grignard reagent derived from the haloalkane shown in formula (II) under the catalysis of a copper-based Lewis acid catalyst; or, the Grignard reagent derived from the hydroxyl-protected intermediate is coupled with the haloalkane shown in formula (II) under the catalysis of a copper-based Lewis acid catalyst to obtain 8-methylnonanol shown in formula (III). (3) Oxidize the 8-methylnonanol obtained in step (2) to 8-methylnonanoic acid as shown in formula (IV); (4) After reacting the 8-methylnonanoic acid obtained in step (3) with an activator, it is then reacted with vanillinamine to obtain the target product dihydrocapsaicin shown in formula (V); The synthetic route of this method is as follows: ； Where X1 and X2 are independently selected from fluorine atoms, chlorine atoms, bromine atoms, and iodine atoms; n is an integer from 1 to 5; and m is an integer from 1 to 5.

2. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (1), the protecting group used for the hydroxyl protection is selected from one of methyl, tert-butyl, methoxymethyl, 2-tetrahydropyranyl, benzyl, 4-methoxybenzyl, trimethylsilyl, triethylsilyl, triisopropylsilyl, tert-butyldimethylsilyl or tert-butyldiphenylsilyl.

3. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (2), the coupling reaction is carried out in an organic solvent selected from at least one of toluene, trifluoromethylbenzene, fluorobenzene, diethyl ether, N-methylpyrrolidone, tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, ethylene glycol dimethyl ether, chloroform, and dichloromethane.

4. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (2), the copper-based Lewis acid catalyst is lithium tetrachlorocopper oxide.

5. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (2), the temperature of the coupling reaction is -60°C to -10°C.

6. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (2), the molar ratio of the hydroxyl-protected intermediate, the haloalkane shown in formula (II), and the copper-based Lewis acid catalyst is 1:(1-1.2):(0.002-0.01).

7. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (3), the oxidation system used is selected from at least one of nitric acid, potassium permanganate, sodium hypochlorite, ferric nitrate-potassium chloride-oxygen, potassium dichromate, and Jones' reagent.

8. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (4), the activator is a sulfonyl chloride, which is selected from at least one of trifluoromethanesulfonyl chloride, methanesulfonyl chloride, benzenesulfonyl chloride, p-toluenesulfonyl chloride, 2-toluenesulfonyl chloride, 3-toluenesulfonyl chloride, 4-ethylbenzenesulfonyl chloride, 4-butylbenzenesulfonyl chloride, 4-methoxybenzenesulfonyl chloride, 4-ethoxybenzenesulfonyl chloride, 2,4,6-tribenzenesulfonyl chloride, 2,5-dibenzenesulfonyl chloride, 2,4-dibenzenesulfonyl chloride, 4-fluorobenzenesulfonyl chloride, 4-chlorobenzenesulfonyl chloride, 4-bromobenzenesulfonyl chloride, 4-iodobenzenesulfonyl chloride, 2,4,6-triisopropylbenzenesulfonyl chloride, 2-naphthalenesulfonyl chloride, 2-nitrobenzenesulfonyl chloride, 3-nitrobenzenesulfonyl chloride, and 4-nitrobenzenesulfonyl chloride.

9. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, The reaction in step (4) is carried out in the presence of a base selected from at least one of sodium hydroxide, potassium hydroxide, lithium hydroxide, cesium hydroxide, calcium hydroxide, magnesium hydroxide, zinc hydroxide, sodium carbonate, potassium carbonate, strontium carbonate, lithium carbonate, triethylamine, pyridine, diisopropylethylamine, DBU, and DMAP.

10. The method for synthesizing dihydrocapsaicin according to claim 1, characterized in that, In step (4), the molar ratio of 8-methylnonanoic acid, activator and vanillinamine is 1:(1.1-1.3):(1.1-1.3).

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