Preparation of arecoline and preparation of a pouch base material

Abstract

The application belongs to the technical field of heterocyclic compounds, and particularly relates to a preparation method of arecoline and a preparation method of a base material of a betel quid. 1,2,5,6-tetrahydropyridine and formic acid are dissolved in water, an aqueous formaldehyde solution is added after being heated, and then the mixture is kept warm, the pH is adjusted, and an organic layer is extracted. The organic layer is spin-dried to obtain N-methyl tetrahydropyridine. The N-methyl tetrahydropyridine is dissolved in N,N-dimethylacetamide, a palladium catalyst, a palladium catalyst ligand and an organic base catalyst are added, and then the mixture is heated after being replaced by nitrogen. Methyl chloroformate is added under the protection of nitrogen to react, and then the mixture is cooled and filtered to obtain a filtrate. Methyl sulfonic acid is added to the filtrate to react, and then the mixture is cooled and filtered to obtain arecoline methanesulfonate. The arecoline methanesulfonate is added to water, the pH is adjusted, and then the mixture is extracted. The obtained organic layer is concentrated to obtain arecoline crude product, and then the arecoline crude product is subjected to negative pressure rectification to obtain pure arecoline. The process flow is greatly simplified, the production conversion is facilitated, the yield of the prepared arecoline is high, and the purity of the prepared arecoline is high.

Description

Technical Field

[0001] The invention belongs to the technical field of heterocyclic compounds, and particularly relates to a preparation method of arecoline and an oral bag base material and a preparation method thereof. Background Art

[0002] Betel nut, the dried mature seed of the palm plant Areca catechu L, is one of the four major southern medicinal herbs commonly used in traditional Chinese medicine. The 2015 edition of the Chinese Pharmacopoeia states that betel nut (dried mature seeds of betel nut) possesses insecticidal, digestive, qi-promoting, diuretic, and antimalarial properties; while the dried pericarp (betel nut peel) has the properties of promoting qi, relieving fullness, promoting diuresis, and reducing swelling. Arecoline, a very important alkaloid in betel nut, is the primary component responsible for the satisfaction and pleasure it imparts to users of betel nut and related products.

[0003] Chinese patent CN117298207A discloses a method for pretreating betel nut and extracting arecoline. The method uses betel nut as a raw material, undergoes crushing and granulation to produce betel nut granules, which are then further processed to produce an arecoline extract. The product of this patent is still a mixture, making it unsuitable as a source of arecoline raw material for oral products.

[0004] Chinese patent CN114702435A discloses a method for preparing arecoline. The method uses an arecoline extract as the raw material, extracts it through an adsorbent, and then concentrates it to obtain an arecoline extract with an arecoline content of 65.6-85.8%. This patent still falls within the scope of naturally extracted arecoline, but the efficiency is low and the purity of the arecoline extract is not high.

[0005] Chinese patent CN118812418A discloses a method for preparing high-purity arecoline hydrobromide. The method uses methyl acrylate as the starting material, sequentially undergoing methylamine addition, sodium methoxide ring closure, sodium borohydride reduction, and dehydration under acidic conditions to purify the salt to obtain arecoline hydrobromide. This patent utilizes a four-step reaction process to prepare arecoline hydrobromide, which is lengthy and involves sodium borohydride reduction, posing a risk. Summary of the Invention

[0006] The purpose of the present invention is to provide a preparation method of arecoline, which greatly simplifies the process flow, facilitates production conversion, and has high yield and high purity of the prepared arecoline; the present invention also provides a base material for an oral bag and a preparation method thereof.

[0007] The preparation method of arecoline of the present invention comprises the following steps:

[0008] (1) Dissolve 1,2,5,6-tetrahydropyridine and formic acid in water, add formaldehyde aqueous solution after heating, keep warm, adjust pH, extract to obtain organic layer, and spin-dry the organic layer to obtain N-methyltetrahydropyridine;

[0009] (2) dissolving the N-methyltetrahydropyridine obtained in step (1) in N,N-dimethylacetamide, adding a palladium catalyst, a palladium catalyst ligand and an organic base catalyst, replacing the atmosphere with nitrogen, heating the mixture, adding methyl chloroformate under nitrogen protection to react, cooling the mixture and filtering the mixture to obtain a filtrate;

[0010] (3) adding methanesulfonic acid to the filtrate obtained in step (2) to react, cooling and filtering to obtain arecoline methanesulfonate;

[0011] (4) Adding the arecoline methanesulfonate obtained in step (3) to water, adjusting the pH, extracting, concentrating the obtained organic layer to obtain crude arecoline, and performing vacuum distillation to obtain pure arecoline.

[0012] In step (1), the mass ratio of 1,2,5,6-tetrahydropyridine, formic acid, water and formaldehyde aqueous solution is 1:1.05-1.15:3-5:3-3.5, the mass concentration of formaldehyde aqueous solution is 35-40%, the temperature is raised to 60-70°C, the insulation time is 3-6h, the pH is adjusted to 10.5-11, and the extraction is carried out using dichloromethane.

[0013] In step (2), the mass ratio of N-methyltetrahydropyridine to N,N-dimethylacetamide is 1:2-5.

[0014] In step (2), the palladium catalyst is one or both of Pd(OAc)2 or PdCl2, and the mass ratio of the palladium catalyst to the 1,2,5,6-tetrahydropyridine in step (1) is 0.001-0.003:1; the palladium catalyst ligand is one or both of tri(2-pyridyl)phosphine or triphenylphosphine, and the mass ratio of the palladium catalyst ligand to the 1,2,5,6-tetrahydropyridine in step (1) is 0.002-0.005:1; the organic base catalyst is one or more of triethylamine, diisopropylamine or diazabicyclic, and the mass ratio of the organic base catalyst to the 1,2,5,6-tetrahydropyridine in step (1) is 0.1-0.2:1.

[0015] The mass ratio of methyl chloroformate in step (2) to 1,2,5,6-tetrahydropyridine in step (1) is 1.08-1.15:1, the temperature is raised to 40-50°C, the reaction temperature is 90-105°C, the reaction time is 3-5h, and the temperature is lowered to 20-40°C.

[0016] The mass ratio of methanesulfonic acid in step (3) to 1,2,5,6-tetrahydropyridine in step (1) is 1.05-1.20:1, the reaction temperature is 20-40°C, the reaction time is 0.5-2h, and the temperature is lowered to below 5°C.

[0017] In step (4), the mass ratio of arecoline methanesulfonate to water is 1:3-4, the pH is adjusted to 10-10.5 by adding sodium hydroxide, and the extraction is performed using dichloromethane; the vacuum degree of the negative pressure distillation is ≤-0.097 MPa, and the temperature of the negative pressure distillation is 85-95°C.

[0018] The oral bag base material of the present invention comprises raw materials including arecoline prepared by the arecoline preparation method of the present invention, cation exchange resin, glycerol, ethanol, a binder, a sweetener and microcrystalline cellulose pellet cores.

[0019] The cation exchange resin is IRP64 hydrogen-type cation exchange resin, the binder is one or more of hydroxypropyl methylcellulose (HPMC), highly substituted hydroxypropyl cellulose (H-HPC) or polyvinyl pyrrolidone (PVP), the sweetener is one or more of xylitol, maltitol or sorbitol, the mass ratio of arecoline, cation exchange resin, glycerol, ethanol and binder is 1:2.2-3.0:2.0-4.0:6.0-15.0:1.5-2.5, and the mass ratio of arecoline, sweetener and microcrystalline cellulose pellet core is 1:20.5-25.5:35.0-38.0.

[0020] The particle size of the microcrystalline cellulose pellet core is 150-300 μm.

[0021] The method for preparing the oral bag base material of the present invention comprises the following steps:

[0022] (A) stirring and mixing arecoline, a cation exchange resin, and glycerol, and then adding ethanol and a binder and continuing to stir and mix to obtain an arecoline spray slurry;

[0023] (B) mixing a sweetener and microcrystalline cellulose pellet cores to obtain a mixture; spraying the arecoline spray slurry into the mixture, and drying and sieving the mixture to obtain an oral bag base material.

[0024] The mesh size of the sieving in step (B) is 60-80 mesh.

[0025] The present invention provides an oral bag base material that can evenly release arecoline and other flavor components, allowing arecoline to be released evenly, slowly, and persistently in the oral cavity, providing consumers with a long-lasting and peaceful physiological satisfaction while effectively reducing irritation to the digestive tract.

[0026] The beneficial effects of the present invention are as follows:

[0027] The present application takes 1,2,5,6-tetrahydropyridine as a starting material, and high-purity arecanine products are obtained through Eschweiler-Clarke methylation, Heck coupling, salt crystallization, free, and rectification purification, with a purity of 99.9% or more by HPLC and a total yield of 70% or more, which is higher in yield and purity compared with the traditional extraction process. Compared with the traditional methyl acrylate synthesis route (arecoline hydrobromide is prepared through multiple steps of methylamine addition, sodium alcohol ring closing, sodium borohydride reduction, dehydration, and salt formation), the present application greatly simplifies the process flow and is more conducive to production conversion.

[0028] The selected palladium catalyst, palladium catalyst ligand and organic base catalyst of the present application improve the reaction efficiency through a synergistic mechanism. In the HECK coupling reaction process, the palladium catalyst acts as a metal center, accepts the electron pair of the substrate through the empty orbital, initiates the oxidative addition to form a palladium complex intermediate; the palladium catalyst ligand improves the electron cloud density of the metal palladium through coordination with the palladium catalyst, accelerates the oxidative addition reaction rate; the organic base catalyst continuously captures the acidic substances HCl generated in the reaction, promotes the forward reaction, and accelerates the oxidative addition-olefin insertion-reduction elimination cycle process in the HECK reaction.

[0029] The present application selects tri(2-pyridyl)phosphine or triphenylphosphine as an organic phosphorus ligand as the palladium catalyst ligand. The phosphorus atom of the organic phosphorus ligand has a lone pair of electrons, which can form a strong coordination bond with the empty orbital of the palladium catalyst. This coordination not only improves the electron cloud density of the palladium center and reduces the activation energy of oxidative addition, but also regulates the electronic environment and steric hindrance of palladium, so that the palladium complex intermediate has specific reactivity and selectivity. The structural characteristics of the organic phosphorus ligand and the palladium catalyst produce an electronic effect synergistically. The aromatic groups such as pyridyl or phenyl perform π-π conjugation to delocalize the electron cloud, making the electron cloud distribution of the palladium center more uniform, which is conducive to the oxidative addition of the substrate molecule; at the same time, the steric hindrance effect of the organic phosphorus ligand can accurately control the direction and stereochemistry of the olefin insertion, avoiding side reactions.

[0030] The present application selects triethylamine, diisopropylamine or diazabicyclo as an organic base catalyst to quickly capture HCl generated in the reaction, maintain the alkaline environment of the system, and prevent the deactivation of the palladium catalyst due to acidic substances; more importantly, there is a weak interaction between the organic base catalyst such as triethylamine, diisopropylamine or diazabicyclo and the organic phosphorus ligand, which can fine-tune the coordination mode of the ligand and palladium, optimize the active conformation of the palladium complex, accelerate the olefin insertion and reduction elimination steps, and thus promote the efficient performance of the entire oxidative addition-olefin insertion-reduction elimination cycle.

[0031] Cationic exchange resins are cross-linked polymers (such as styrene-divinylbenzene copolymers) with a three-dimensional network structure. The backbone carries a large number of acidic functional groups such as sulfonic acid groups (-SO3H), forming a hierarchical porous structure with micron-scale macropores and nanometer-scale micropores. The tertiary amine group in the arecoline molecule is protonated under acidic conditions to generate cations ([arecoline-H] + ), H + Ion exchange occurs, forming an ion-pair complex (i.e., a complex salt) of "resin anion-arecoline cation" through electrostatic interactions. Simultaneously, the alkyl chains in the arecoline molecule bind to the resin's hydrophobic backbone through hydrophobic interactions, and the carbonyl groups form hydrogen bonds with the resin's hydroxyl groups, further stabilizing the complex. The three-dimensional network of the cation exchange resin acts as a "molecular cage," securing the complex salt within its pores. When exposed to an aqueous environment, the ion pairs gradually dissociate, releasing the arecoline. The diffusion resistance of the porous structure (micropores restrict diffusion and regulate swelling / contraction) and the resin's cross-linking density (higher cross-linking results in slower release) contribute to the sustained-release mechanism, creating a controllable three-dimensional sustained-release network. This invention constructs an oral arecoline delivery system. The unique porous structure of the cation exchange resin forms a complex salt with arecoline, creating a three-dimensional sustained-release network that achieves precise sustained-release delivery of arecoline in the oral cavity.

[0032] Arecoline in natural betel nut is immediately released in the mouth (pH can reach 10-11), directly corroding oral mucosal epithelial cells and disrupting the lipid bilayer of the cell membrane, leading to cell swelling and apoptosis. However, this invention allows for a slower release of arecoline in the mouth, reducing irritation. This invention provides consumers with a multi-dimensional sensory experience, maintaining the continuity of flavor release while significantly reducing the burning sensation in the oral mucosa and the risk of digestive tract irritation associated with traditional betel nut chewing.

[0033] Reaction equation of the present invention is as follows:

[0034]

[0035] 1,2,5,6-tetrahydropyridine, formic acid, and formaldehyde undergo an Eschweiler-Clarke methylation reaction to produce N-methyltetrahydropyridine; N-methyltetrahydropyridine and methyl chloroformate undergo a Heck coupling reaction to produce arecoline (content 80-90%) and isomeric impurity 1-methyl-1,2,3,6-tetrahydropyridine-4-carboxylic acid methyl ester (content 10-20%); arecoline and isomeric impurities are salted with methanesulfonic acid (MSA) and crystallized to separate from the system; the methanesulfonate of arecoline and the methanesulfonate of the isomeric impurities are dissolved and then neutralized with sodium hydroxide to release them, followed by extraction with dichloromethane (DCM) and concentration to obtain crude arecoline; arecoline and isomeric impurities are separated by distillation utilizing the difference in boiling points between arecoline and isomeric impurities; and pure arecoline is obtained by distillation and purification under vacuum conditions of ≤-0.097 MPa and 85-95°C. BRIEF DESCRIPTION OF THE DRAWINGS

[0036] Figure 1 It is the H NMR spectrum of arecoline prepared in Example 1.

[0037] Figure 2 It is the NMR carbon spectrum of arecoline prepared in Example 1. DETAILED DESCRIPTION

[0038] The present invention is further described below with reference to the following examples.

[0039] Example 1

[0040] The preparation method of arecoline comprises the following steps:

[0041] (1) Dissolve 50.0 g of 1,2,5,6-tetrahydropyridine and 52.5 g of formic acid in 150.0 g of water, heat to 60°C, add 150.0 g of 35% formaldehyde aqueous solution dropwise, keep warm for 3 h after the addition is complete, adjust the pH to 10.5, extract with dichloromethane to obtain an organic layer, and spin-dry the organic layer to obtain 53.8 g of N-methyltetrahydropyridine;

[0042] (2) 53.8 g of N-methyltetrahydropyridine obtained in step (1) was dissolved in 107.6 g of N,N-dimethylacetamide, 0.05 g of Pd(OAc)2, 0.1 g of tri(2-pyridyl)phosphine and 5.0 g of triethylamine were added, and the temperature was raised to 40°C after nitrogen replacement. 54.0 g of methyl chloroformate was added dropwise under nitrogen protection. After the addition was complete, the mixture was reacted at 90°C for 3 h, and the temperature was lowered to 20°C and filtered to obtain a filtrate;

[0043] (3) Add 52.5 g of methanesulfonic acid to the filtrate obtained in step (2), stir and react at 20°C for 2 h, cool to below 5°C, and filter to obtain 141.2 g of arecoline methanesulfonate;

[0044] (4) 141.2 g of arecoline methanesulfonate obtained in step (3) was added to 564.8 g of water, sodium hydroxide was added to adjust the pH to 10.0, and the mixture was extracted with dichloromethane. The obtained organic layer was concentrated to obtain crude arecoline, and negative pressure distillation was performed under vacuum at -0.098 MPa and 85-95°C to obtain 73.5 g of pure arecoline with an HPLC purity of 99.92% and a molar yield of 78.74% (based on 1,2,5,6-tetrahydropyridine). The H NMR spectrum of arecoline is shown in FIG. Figure 1 , NMR carbon spectrum see Figure 2 .

[0045] The preparation method of the oral bag base material comprises the following steps:

[0046] (A) 36.75 g of arecoline, 80.85 g of IRP64 hydrogen form cation exchange resin, and 73.5 g of glycerol were stirred and mixed, and then 220.5 g of ethanol and 55.15 g of HPMC were added and continued to stir and mix to obtain an arecoline spray slurry;

[0047] (B) 753.4 g of maltitol and 1286.25 g of microcrystalline cellulose pellet cores were mixed to obtain a mixture; the arecoline spray slurry was evenly sprayed into the mixture, and the mixture was dried and passed through a 60-mesh sieve to obtain a base material for an oral bag.

[0048] Example 2

[0049] The preparation method of arecoline comprises the following steps:

[0050] (1) Dissolve 50.0 g of 1,2,5,6-tetrahydropyridine and 57.5 g of formic acid in 250.0 g of water, heat to 70°C, add 175.0 g of a 40% formaldehyde aqueous solution dropwise, keep warm for 6 h after the addition is complete, adjust the pH to 10.7, extract with dichloromethane to obtain an organic layer, and spin-dry the organic layer to obtain 54.2 g of N-methyltetrahydropyridine;

[0051] (2) 54.2 g of N-methyltetrahydropyridine obtained in step (1) was dissolved in 271.0 g of N,N-dimethylacetamide, 0.15 g of PdCl2, 0.25 g of triphenylphosphine and 10.0 g of diazabicyclo were added, the temperature was raised to 50°C after nitrogen replacement, 57.5 g of methyl chloroformate was added dropwise under nitrogen protection, and after the addition was complete, the mixture was reacted at 105°C for 5 h, the temperature was lowered to 40°C and filtered to obtain a filtrate;

[0052] (3) Add 60.0 g of methanesulfonic acid to the filtrate obtained in step (2), stir and react at 40°C for 0.5 h, cool to below 5°C, and filter to obtain 142.4 g of arecoline methanesulfonate;

[0053] (4) 142.4 g of arecoline methanesulfonate obtained in step (3) was added into 427.2 g of water, sodium hydroxide was added to adjust the pH to 10.5, dichloromethane was used for extraction, and the obtained organic layer was concentrated to obtain crude arecoline. Under the conditions of a vacuum degree of -0.098 MPa and 85-95 °C, the arecoline was subjected to vacuum rectification to obtain 71.5 g of pure arecoline with a purity of 99.93% by HPLC and a molar yield of 76.60% (calculated based on 1,2,5,6-tetrahydropyridine).

[0054] A method for preparing a pouch base material, comprising the following steps:

[0055] (A) 71.5 g of arecoline, 214.5 g of IRP64 hydrogen type cation exchange resin, and 286.0 g of glycerol were stirred and mixed, and then 1072.5 g of ethanol and 178.8 g of H-HPC were added and stirred and mixed to obtain an arecoline spraying slurry;

[0056] (B) 1823.3 g of maltitol and 2717.0 g of microcrystalline cellulose were mixed to obtain a mixture, the arecoline spraying slurry was uniformly sprayed into the mixture, and the mixture was dried and passed through a 60-mesh sieve to obtain the pouch base material.

[0057] Example 3

[0058] A method for preparing arecoline, comprising the following steps:

[0059] (1) 50.0 g of 1,2,5,6-tetrahydropyridine and 54.3 g of formic acid were dissolved in 200.0 g of water, and then 163.0 g of a 37% mass concentration formaldehyde aqueous solution was added dropwise while the temperature was raised to 65 °C. After the dropwise addition was completed, the solution was kept at 65 °C for 4 h, the pH was adjusted to 11, dichloromethane was used for extraction, and the obtained organic layer was concentrated to obtain 54.6 g of N-methyltetrahydropyridine;

[0060] (2) 54.6 g of N-methyltetrahydropyridine obtained in step (1) was dissolved in 154.6 g of N,N-dimethylacetamide, 0.1 g of PdCl2, 0.14 g of triphenylphosphine, and 7.0 g of diisopropylamine were added, the system was replaced with nitrogen, the temperature was raised to 45 °C, and 55.8 g of methyl chloroformate was added dropwise under nitrogen protection. After the dropwise addition was completed, the system was kept at 100 °C for 4 h, the temperature was lowered to 30 °C, and the system was filtered to obtain a filtrate;

[0061] (3) 56.8 g of methanesulfonic acid was added to the filtrate obtained in step (2), the system was stirred at 30 °C for 1 h, the temperature was lowered to below 5 °C, and the system was filtered to obtain 142.8 g of arecoline methanesulfonate;

[0062] (4) 142.8 g of arecoline methanesulfonate obtained in step (3) was added to 500 g of water, and sodium hydroxide was added to adjust the pH to 10.3. The mixture was extracted with dichloromethane, and the obtained organic layer was concentrated to obtain crude arecoline. The crude arecoline was subjected to negative pressure distillation at a vacuum degree of -0.098 MPa and a temperature of 85-95°C to obtain 70.4 g of pure arecoline with an HPLC purity of 99.91% and a molar yield of 75.42% (based on 1,2,5,6-tetrahydropyridine).

[0063] The preparation method of the oral bag base material comprises the following steps:

[0064] (A) After stirring and mixing 70.4 g of arecoline, 188.6 g of IRP64 hydrogen-type cation exchange resin, and 240.8 g of glycerol, 817.0 g of ethanol and 160.7 g of PVP were added and continued to stir and mix to obtain an arecoline spray slurry;

[0065] (B) 1756.5 g of sorbitol and 2612.6 g of microcrystalline cellulose pellet cores were mixed to obtain a mixture; arecoline spray slurry was evenly sprayed into the mixture, and the mixture was dried and passed through a 70-mesh sieve to obtain an oral bag base material.

[0066] Comparative Example 1

[0067] Without adding tri(2-pyridyl)phosphine, the other steps were the same as in Example 1 to obtain 22.29 g of pure arecoline with an HPLC purity of 99.84% and a molar yield of 23.88% (based on 1,2,5,6-tetrahydropyridine).

[0068] Comparative Example 2

[0069] Without adding triethylamine, the other steps were the same as in Example 1 to obtain 39.62 g of pure arecoline with an HPLC purity of 99.86% and a molar yield of 42.45% (based on 1,2,5,6-tetrahydropyridine).

[0070] Comparative Example 3

[0071] No IRP64 hydrogen-type cation exchange resin was added, and the other steps were the same as in Example 1.

[0072] Sustained release experiment:

[0073] (1) Preparation of artificial saliva: The preparation method of artificial saliva is selected according to CDE-"Technical Guidelines for Research on Quality Attributes of Chewable Tablets (Chemical Drugs) (Trial)" (No. 7 of 2023). Specifically, 100 mg of anhydrous magnesium chloride, 220 mg of calcium chloride dihydrate, 1350 mg of disodium hydrogen phosphate heptahydrate, 680 mg of potassium dihydrogen phosphate, 750 mg of potassium chloride, 600 mg of urea and 600 mg of sodium chloride are taken, dissolved in purified water and diluted to 1000 ml, and the pH value is adjusted to 6.8 with sodium hydroxide.

[0074] (2) Preparation of reference solution: Weigh 1 mg of arecoline reference solution accurately, place it in a 1000 ml volumetric flask, add water to dissolve and dilute to the mark, shake well to obtain arecoline solution; accurately measure 5 ml of arecoline solution and place it in a 50 ml volumetric flask, add acetonitrile to dilute to the mark, shake well, and perform liquid chromatography detection, and record the peak area A 对 .

[0075] (3) Test sample: Take 500 mg of the oral bag base material prepared in Examples 1-3 and Comparative Example 3, seal it with non-woven fabric, place it in a circulation pool, add 200 ml of artificial saliva, keep the temperature at 37°C ± 0.5°C, and take samples at 5 min, 10 min, 15 min, 20 min, 25 min, 30 min, 35 min, and 40 min respectively; take 0.1 ml of precise sample each time, place it in a 10 ml volumetric flask, add acetonitrile to dilute to the scale, shake well, and perform liquid chromatography detection, and record the peak area A 样 .

[0076] (4) Liquid chromatography conditions: octadecylsilane bonded silica gel column, UV-visible detector, mobile phase of water-acetonitrile (55:45), column temperature 30 °C, flow rate 1.0 ml / min, detection wavelength 248 nm, injection volume 20 μl, detection time 20 min.

[0077] Dissolution (%) = (A 样 ×C 对 × V) / (A 对 ×G)×100%;

[0078] in,

[0079] A 样 : Peak area of ​​arecoline in the test sample;

[0080] A 对 : Peak area of ​​arecoline in reference substance;

[0081] G: theoretical content of arecoline in the base material of the oral bag, mg;

[0082] C 对 : Arecoline concentration of the reference solution, here taken as 0.1 mg / L;

[0083] V: dilution volume of the test sample, here the value is 20000ml.

[0084] The results of the sustained-release experiment are shown in Table 1.

[0085]

Claims

1. A method for preparing arecoline, characterized in that The steps include: (1) Dissolve 1,2,5,6-tetrahydropyridine and formic acid in water, add formaldehyde aqueous solution after heating, keep warm, adjust pH, extract to obtain organic layer, and spin-dry the organic layer to obtain N-methyltetrahydropyridine; (2) dissolving the N-methyltetrahydropyridine obtained in step (1) in N,N-dimethylacetamide, adding a palladium catalyst, a palladium catalyst ligand and an organic base catalyst, replacing the atmosphere with nitrogen, heating the mixture, adding methyl chloroformate under nitrogen protection to react, cooling the mixture and filtering the mixture to obtain a filtrate; (3) adding methanesulfonic acid to the filtrate obtained in step (2) to react, cooling and filtering to obtain arecoline methanesulfonate; (4) adding the arecoline methanesulfonate obtained in step (3) into water, adjusting the pH, extracting, concentrating the obtained organic layer to obtain crude arecoline, and performing vacuum distillation to obtain pure arecoline; In step (2), the palladium catalyst is one or both of Pd(OAc)2 and PdCl2, the palladium catalyst ligand is one or both of tri(2-pyridyl)phosphine and triphenylphosphine, and the organic base catalyst is one or more of triethylamine, diisopropylamine or diazabicycle.

2. the preparation method of arecoline according to claim 1, is characterized in that In step (1), the mass ratio of 1,2,5,6-tetrahydropyridine, formic acid, water and formaldehyde aqueous solution is 1:1.05-1.15:3-5:3-3.5, the mass concentration of formaldehyde aqueous solution is 35-40%, the temperature is raised to 60-70°C, the insulation time is 3-6h, the pH is adjusted to 10.5-11, and the extraction is carried out using dichloromethane.

3. The preparation method of arecoline according to claim 1, wherein In step (2), the mass ratio of N-methyltetrahydropyridine to N,N-dimethylacetamide is 1:2-5.

4. The preparation method of arecoline according to claim 1, wherein The mass ratio of the palladium catalyst in step (2) to the 1,2,5,6-tetrahydropyridine in step (1) is 0.001-0.003:1, the mass ratio of the palladium catalyst ligand to the 1,2,5,6-tetrahydropyridine in step (1) is 0.002-0.005:1, and the mass ratio of the organic base catalyst to the 1,2,5,6-tetrahydropyridine in step (1) is 0.1-0.2:

1.

5. The preparation method of arecoline according to claim 1, wherein The mass ratio of methyl chloroformate in step (2) to 1,2,5,6-tetrahydropyridine in step (1) is 1.08-1.15:1, the temperature is raised to 40-50°C, the reaction temperature is 90-105°C, the reaction time is 3-5h, and the temperature is lowered to 20-40°C.

6. The preparation method of arecoline according to claim 1, wherein The mass ratio of methanesulfonic acid in step (3) to 1,2,5,6-tetrahydropyridine in step (1) is 1.05-1.20:1, the reaction temperature is 20-40°C, the reaction time is 0.5-2h, and the temperature is lowered to below 5°C.

7. The preparation method of arecoline according to claim 1, wherein In step (4), the mass ratio of arecoline methanesulfonate to water is 1:3-4, the pH is adjusted to 10-10.5 by adding sodium hydroxide, and the extraction is performed using dichloromethane; the vacuum degree of the negative pressure distillation is ≤-0.097 MPa, and the temperature of the negative pressure distillation is 85-95°C.

8. A base material for oral bag, characterized in that The raw materials include arecoline prepared by the preparation method of arecoline according to any one of claims 1 to 7, cation exchange resin, glycerol, ethanol, a binder, a sweetener and microcrystalline cellulose pellet cores, and the cation exchange resin is IRP64 hydrogen-type cation exchange resin.

9. The oral bag base material according to claim 8, characterized in that The binder is one or more of hydroxypropyl methylcellulose, high-substituted hydroxypropyl cellulose or polyvinyl pyrrolidone, the sweetener is one or more of xylitol, maltitol or sorbitol, the mass ratio of arecoline, cation exchange resin, glycerol, ethanol and binder is 1:2.2-3.0:2.0-4.0:6.0-15.0:1.5-2.5, and the mass ratio of arecoline, sweetener and microcrystalline cellulose pellet core is 1:20.5-25.5:35.0-38.

0.

10. A method for preparing the oral bag base material according to claim 8, characterized in that The steps include: (A) stirring and mixing arecoline, a cation exchange resin, and glycerol, and then adding ethanol and a binder and continuing to stir and mix to obtain an arecoline spray slurry; (B) mixing a sweetener and microcrystalline cellulose pellet cores to obtain a mixture; spraying the arecoline spray slurry into the mixture, and drying and sieving the mixture to obtain an oral bag base material.

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