A process for the synthesis of guanfacine hydrochloride

Abstract

The application discloses a synthesis process of guanfacine hydrochloride, and the guanfacine hydrochloride raw medicine is obtained through three chemical reactions of urea methylation, amide condensation and amination reaction and one step of salification and recrystallization by taking 2,6-dichlorobenzoic acid and urea as starting materials. The starting material of the application is urea with lower selection cost, and the advantages are that a genotoxic impurity is easy to detect and the workshop detection cost is reduced; the intermediate is O-methyl isourea p-toluenesulfonate, and the advantages are that the intermediate has high stability and the quality is easy to control; and the amination reaction is performed by using ammonium chloride instead of ammonia water, so that the reaction cost is reduced and the workshop operation is more convenient.

Description

Technical Field

[0001] This invention belongs to the field of pharmaceutical technology, specifically relating to a synthesis process for guanethidine hydrochloride. Background Technology

[0002] Guanifacin hydrochloride is an antihypertensive drug, chemically named N-amidinyl-2-(2,6-dichlorophenyl)acetamide monohydrochloride, with the molecular formula C9H9Cl2N3O·HCl and a molecular weight of 282.55. Guanifacin hydrochloride is a selective α2-adrenergic receptor agonist, selectively activating central α2-adrenergic receptors and inhibiting sympathetic nerve activity, thereby reducing peripheral vascular resistance and heart rate, achieving an antihypertensive effect. In September 2009, guanifacin hydrochloride extended-release tablets were approved by the U.S. Food and Drug Administration (FDA) for marketing in the United States for the treatment of attention deficit hyperactivity disorder (ADHD) in children and adolescents aged 6-17 years. This is because guanifacin hydrochloride can directly bind to α2A-adrenergic receptors in the prefrontal cortex of the brain, reducing excessive dopamine release and achieving effects such as improving behavioral inhibition, attention, and impulse control, thus being used to treat ADHD. Its chemical structure is as follows:

[0003]

[0004] Patent CN106831496A discloses a synthesis process for guanifacine hydrochloride, using O-methylisothiourea hydrochloride as the starting material. The process involves first treating the hydrochloric acid molecules with a strong base, then condensing it with 2,6-dichlorophenylacetic acid, and finally amination in ammonia water to obtain the free guanifacine base, which is then reacted with hydrochloric acid to form guanifacine hydrochloride. However, the synthesis of the starting material O-methylisothiourea hydrochloride in this process often involves the use of dimethyl sulfate in the methylation step. Since dimethyl sulfate and its impurities such as diethyl sulfate are difficult to detect, this poses a significant challenge to guanifacine hydrochloride API projects. Furthermore, the use of a strong base to treat O-methylisothiourea hydrochloride may cause unstable O-methylisothiourea to hydrolyze again into urea, further increasing the difficulty of the process. In addition, the use of ammonia water in the amination reaction results in a strong odor, high irritation, and high cost. The synthesis process is as follows:

[0005]

[0006] Patent CN115028554B discloses guanifacine hydrochloride and its preparation method. Using 2,6-dichlorophenylacetic acid and Boc-guanidine as starting materials, the mixture undergoes an acylation reaction after treatment with thionyl chloride to obtain Boc-protected guanifacine. Finally, the Boc protecting group is hydrolyzed with hydrochloric acid to obtain guanifacine hydrochloride. This preparation process has high Boc-guanidine costs, and the Boc fragment cannot be effectively utilized (it is ultimately removed), resulting in low atom utilization. Furthermore, there is no national standard for Boc-guanidine, making quality control difficult, and impurity research is relatively more challenging than with urea. The synthesis process is as follows:

[0007]

[0008] The article "Solid-phase synthesis of N,N′-substituted acylguanidines" (authors: Dharmpal S. Dodd and Yufen Zhao et al.) reports a solid-phase synthesis method for guanethidine. This method uses (7-azabenzotriazol-1-oxo)tripyrrolephosphonium hexafluorophosphate as a coupling agent to immobilize the resin on methoxyisothiourea, followed by acylation with 2,6-dichlorophenylacetic acid. However, this method is currently in the pilot-scale development stage and does not yet have the potential for large-scale application. The synthesis process is as follows:

[0009]

[0010] The article doi.org / 10.1002 / chin.197602155 reports a method for synthesizing guanifacine hydrochloride using 2,6-dichlorophenylacetonitrile as the starting material. However, the raw materials used in this synthesis process are relatively expensive, offering no cost advantage. The synthesis process is as follows:

[0011] Summary of the Invention

[0012] In view of the above-mentioned deficiencies of the prior art, the present invention provides a synthesis process for guanidine hydrochloride. The synthesis process for preparing guanidine hydrochloride not only facilitates the stable progress of the reaction, but also reduces the cost. The guanidine hydrochloride prepared has a high yield and a purity of over 99%.

[0013] To achieve the above objectives, the present invention provides a synthetic process for guanifacine hydrochloride, the synthetic process comprising: methylating urea with a methylating agent to obtain intermediate 1; then reacting intermediate 1 with 2,6-dichlorophenylacetic acid to obtain intermediate 2; reacting intermediate 2 with an aqueous solution of an amination reagent to obtain intermediate 3; reacting intermediate 3 with a salting agent to obtain a crude product; and recrystallizing the crude product in a recrystallization solvent to obtain the finished guanifacine hydrochloride.

[0014] Preferably, intermediate 1 is p-toluenesulfonate of O-methylisothiourea, with the following structural formula:

[0015]

[0016] Preferably, the intermediate 3 is a free guanidine fumarate with the following structural formula:

[0017]

[0018] During the acyl chloride reaction between intermediate 1 and 2,6-dichlorophenylacetic acid, a supported DMAP catalyst was also added. The supported DMAP catalyst was prepared by supporting DMAP with MCM-41 mesoporous silica or functionalized sepiolite.

[0019] Preferably, the synthesis process of the guanidine hydrochloride specifically includes the following steps, in parts by weight:

[0020] (1) Synthesis of intermediate 1: 185-187 parts of methylating agent were added to the reaction flask, and then 48-52 parts of urea were added. The temperature was raised to 118-122℃ and the reaction was sealed for 2.5-3.5h. After the reaction was completed, the temperature was lowered to 35-50℃, 195-205 parts of dichloromethane were added, and the mixture was stirred for 1h. The temperature was lowered to 15-20℃, filtered, and dried to obtain white solid intermediate 1.

[0021] (2) Synthesis of intermediate 2: 141-142 parts of 2,6-dichlorophenylacetic acid were added to a reaction flask, 1480-1520 parts of dichloromethane were added, 98-99 parts of thionyl chloride were added at room temperature, and then the temperature was raised to 38-52℃ and kept at the temperature for 1.5-2.5h. After the reaction was completed, intermediate 1 prepared in step (1) above was added, 209-210 parts of triethylamine were added, and the reaction was carried out for 25-35min. After the reaction was completed, 1480-1520 parts of water were added, the liquid phase was separated, the aqueous phase was washed, and the mixture was concentrated to obtain a pale yellow solid intermediate 2.

[0022] Alternatively, the synthesis of intermediate 2: 141-142 parts of 2,6-dichlorophenylacetic acid were added to a reaction flask, followed by 1480-1520 parts of dichloromethane. 98-99 parts of thionyl chloride were added at room temperature, and the temperature was raised to 38-52℃ and maintained for 1.5-2.5 h. After the reaction was complete, 0.25-0.3 parts of the supported DMAP catalyst and intermediate 1 prepared in step (1) above were added, followed by 209-210 parts of triethylamine. The reaction was carried out for 25-35 min. After the reaction was complete, 1480-1520 parts of water were added, the mixture was separated, the aqueous phase was washed, and the mixture was concentrated to obtain a pale yellow solid intermediate 2.

[0023] (3) Synthesis of intermediate 3: The intermediate 2 prepared in step (2) above is added to a reaction flask, and 780-800 parts of anhydrous ethanol are added. The mixture is stirred and completely dissolved to obtain mixed solution 1. 97-97.2 parts of the amination reagent are added to 95-105 parts of water and completely dissolved to obtain an aqueous solution of the amination reagent. The aqueous solution of the amination reagent is added to the above mixed solution 1, and the mixture is heated to 78-82℃ and refluxed for 2-3 hours. After the reaction is completed, 680-700 parts of water are added, and a pale yellow solid is precipitated. The solid is slurried with water 2-3 times and dried to obtain a pale yellow solid intermediate 3.

[0024] (4) Synthesis of crude product: The intermediate 3 prepared in step (3) above is added to a reaction flask, 370-375 parts of anhydrous ethanol is added and stirred, 50-52 parts of salt-forming reagent is added, the temperature is raised to 40-50℃, and the reaction is stirred for 1.5-2.5h; after the reaction is completed, the temperature is lowered to 0-5℃, filtered, dried, and crude guanidine hydrochloride is obtained.

[0025] (5) Synthesis of guanifacine hydrochloride: Add the crude guanifacine hydrochloride obtained in step (4) above into a reaction flask, add 5.8-5.9 parts of activated carbon, add 340-350 parts of recrystallization solvent, heat to 78-82℃ and reflux for 25-35 min, filter while hot, cool to crystallize, filter by suction, dry to obtain guanifacine hydrochloride.

[0026] Preferably, the method for preparing the supported DMAP catalyst includes the following steps, in parts by weight:

[0027] S1. Mix 0.8-1.2 parts of support, 1.8-2.2 parts of 3-chloropropyltrimethoxysilane and 48-50 parts of o-xylene, and reflux the mixture under nitrogen atmosphere at 145-150°C for 14-20 h with stirring. After the reaction is complete, centrifuge, collect the solid, wash with anhydrous ethanol, and dry under vacuum at 45-55°C to obtain the modified support.

[0028] S2. Mix 1.8-2.2 parts of modified support, 0.28-0.32 parts of 4-dimethylaminopyridine, 0.9-0.95 parts of potassium iodide, 0.75-0.8 parts of potassium carbonate and 45-55 parts of o-xylene, and stir the mixture under a nitrogen atmosphere at 125-135°C for 10-15 h. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene, then wash with anhydrous ethanol and water, and vacuum dry at 45-55°C to obtain the supported DMAP catalyst.

[0029] More preferably, the carrier is selected from MCM-41 mesoporous silica and functionalized sepiolite.

[0030] Further explanation of the present invention: 4-Dimethylaminopyridine (DMAP) is a commonly used small organic molecule catalyst. Its nitrogen atom possesses a lone pair of electrons, enabling it to form a stable intermediate with the carbonyl carbon atom in the acyl chloride, thereby lowering the activation energy and accelerating the reaction rate. During the reaction, DMAP stabilizes the transition state, promoting the condensation reaction between the acyl chloride and intermediate 1, and improving reaction efficiency. However, when DMAP is used in its free state, it suffers from drawbacks such as difficulty in separating it from the reaction system, impacting product quality, and inability to be recycled or reused, or for continuous operation. Therefore, the present invention prepares a supported DMAP catalyst by introducing a support to load DMAP, which not only avoids the problem of difficult separation and recovery but also exhibits high catalytic activity.

[0031] In further detail, during the preparation of the supported DMAP catalyst, MCM-41 mesoporous silica or functionalized sepiolite is selected as the support and undergoes a coupling reaction with 3-chloropropyltrimethoxysilane to form silicon-oxygen bonds. 3-chloropropyltrimethoxysilane is then grafted onto the support to obtain a modified support. The modified support is then reacted with potassium iodide, where the chloropropyl group in the modified support undergoes a halogen exchange reaction with potassium iodide to generate an iodopropyl intermediate. The generated iodopropyl intermediate undergoes an N-alkylation reaction with 4-dimethylaminopyridine, fixing 4-dimethylaminopyridine onto the support surface to obtain the supported DMAP catalyst.

[0032] More preferably, the preparation method of the functionalized sepiolite includes the following steps, in parts by weight:

[0033] Add 18-22 parts of sepiolite to 180-220 parts of 1-2 mol / L hydrochloric acid aqueous solution and mix evenly. After ultrasonic treatment for 20-30 min, stir at 75-85℃ for 7-10 h. After filtration, wash with water until neutral and dry at 90-110℃ for 1-3 h to obtain acid-activated sepiolite. Add 13-15 parts of acid-activated sepiolite and 6.5-7.5 parts of modifier to 120-135 parts of ethylene glycol, ultrasonically disperse for 30-40 min, and then mix and stir at 80-85℃ for 6-8 h. Centrifuge, collect the precipitate, wash with ethanol 2-3 times, and vacuum dry at 40-45℃ for 20-25 h to obtain functionalized sepiolite.

[0034] More preferably, the modifier is selected from one of tannic acid, urushiol, and cashew nut phenol.

[0035] Further explanation of the present invention: In the preparation process of the above-mentioned functionalized sepiolite, after acid treatment, surface impurities of sepiolite are removed, exposing more hydroxyl and silanol groups. Tannic acid, urushiol, and cashew nut shell powder are selected as modifiers and mixed with the acidified sepiolite for reaction. The phenolic hydroxyl groups in the modifier structure form hydrogen bonds with the exposed hydroxyl and silanol groups on the surface of the acidified sepiolite, grafting them onto the sepiolite to obtain functionalized sepiolite. The present invention has found that the functionalized sepiolite has better dispersibility, avoiding the aggregation phenomenon of sepiolite, and adjusting the hydrophilicity and hydrophobicity of the sepiolite surface, which helps to improve the catalyst loading efficiency and the adsorption capacity of the reactants.

[0036] Preferably, the methylating agent is methyl p-toluenesulfonate.

[0037] Preferably, the amination reagent is ammonium chloride.

[0038] Preferably, the salt-forming reagent is concentrated hydrochloric acid.

[0039] Preferably, the recrystallization solvent is anhydrous ethanol.

[0040] Regarding further explanation of the present invention, in step (1), this application selects methyl p-toluenesulfonate, which can be directly detected by liquid phase method, for this methylation reaction, avoiding the problem that most other methylation reagents can only be detected by Ms., and the methyl p-toluenesulfonate after the reaction can be removed by washing with dichloromethane. At the same time, intermediate 1 prepared in step (1) is produced in the form of p-toluenesulfonate of O-methylisothiourea, which is not only convenient for purification by organic solvent slurrying, but also can be washed away with water in the subsequent step (2) as the reaction is completed, as p-toluenesulfonic acid forms a salt with the base.

[0041] In step (2), the condensation reaction is carried out directly in the form of O-methylisourea p-toluenesulfonate prepared in step (1). The reaction is rapid and can be completed within 10 minutes. This application found that compared with the reaction of free O-methylisourea without p-toluenesulfonate, the reaction time of O-methylisourea p-toluenesulfonate is not significantly affected, but its stability as an intermediate is much higher than that of free O-methylisourea.

[0042] In step (3), this application selects ammonium chloride as the amination reagent, which not only reduces the cost but also reduces the difficulty of the process operation compared to the traditional ammonia water.

[0043] In step (4), this application uses hydrochloric acid to form salt, thereby removing the organic solvent of hydrochloric acid and avoiding the generation pathway of genotoxic impurities.

[0044] The beneficial effects of this invention are:

[0045] 1. Compared with the prior art, this application selects urea, which has a lower cost, as the starting material. Compared with the traditional synthesis of guanidine hydrochloride facsimile, which selects guanidine hydrochloride, O-methylisourea sulfate, or O-methylisourea hydrochloride as the starting material, this application has the advantages of easy detection of genotoxic impurities and reduced workshop testing costs.

[0046] 2. Compared with existing technologies, this application uses the more stable intermediate O-methylisourea p-toluenesulfonate to react with 2,6-dichlorophenylacetic acid, instead of free O-methylisourea, which has the advantages of high stability and easy quality control. Using ammonium chloride instead of ammonia for the amination reaction reduces reaction costs and makes workshop operations more convenient. Furthermore, this application introduces a supported DMAP catalyst in the preparation step of intermediate 2, effectively improving the reaction efficiency of intermediate 2 and increasing its yield. Attached Figure Description

[0047] Figure 1 A synthetic route diagram of guanidine hydrochloride provided for this invention;

[0048] Figure 2 This is the HPLC spectrum of intermediate 1 in Example 1 of the present invention;

[0049] Figure 3 This is the HPLC spectrum of intermediate 2 in Example 1 of the present invention;

[0050] Figure 4 This is the HPLC spectrum of intermediate 3 in Example 1 of the present invention;

[0051] Figure 5 This is the HPLC chromatogram of the crude product in Example 1 of the present invention;

[0052] Figure 6 This is the HPLC chromatogram of the finished product guanidine hydrochloride in Example 1 of the present invention. Detailed Implementation

[0053] The parameters and sources of the specific chemical substances used.

[0054] MCM-41 mesoporous silica, particle size: 5nm, product number: Q-0012580, sourced from Xi'an Qiyue Biotechnology Co., Ltd.

[0055] Coarse-pore microsphere silica gel, mesh size: 100 mesh, brand: Chenrong;

[0056] Sepiolite: Specific surface area is 300 m² 2 / g;

[0057] Cashew phenol, model: NX-2021, brand: Cardlä Company;

[0058] Urushiol: CAS No.: 35237-02-6.

[0059] In the various embodiments of this application, the high-performance liquid chromatography (HPLC) used for the detection of methyl toluenesulfonate is performed under the following conditions:

[0060]

[0061] This application uses the above chromatographic conditions for liquid chromatography detection of methyl p-toluenesulfonate, and we use methyl methanesulfonate as the reference standard. System suitability requirements:

[0062] (1) In the reference solution chromatogram, methyl benzenesulfonate and methyl p-toluenesulfonate eluted in sequence, and the resolution between methyl benzenesulfonate and methyl p-toluenesulfonate should be no less than 3.0.

[0063] (2) The control solution was injected 6 times consecutively. The RSD of the ratio of the peak height of methyl benzenesulfonate to that of the internal standard should not be greater than 2.0%, and the methyl benzenesulfonate content was calculated using the average value.

[0064] (3) After the test solution is injected, inject the control solution once. If the test solution is injected continuously for more than 6 hours, inject the control solution once every 6 hours. All control solution injections are used as surrounding standard injections. The RSD of the ratio of the peak height of methyl benzenesulfonate to the internal standard should not be greater than 2.0%.

[0065] The quality standard for guanidine hydrochloride specifies a limit of 10 ppm for methyl toluenesulfonate. This limit is based on the fact that the limits for this substance in similar products are generally around 10 ppm, such as atracurium benzenesulfonate.

[0066] In the various embodiments of this application, the purity of intermediates 1-3, crude guanidine hydrochloride, and guanidine hydrochloride is calculated using the area normalization method based on the peak area of ​​the obtained HPLC chromatogram. Example 1

[0067] A synthetic process for guanidine hydrochloride includes the following steps:

[0068] (1) Synthesis of intermediate 1: 186.00 g of methyl p-toluenesulfonate was added to a reaction flask, followed by 50.00 g of urea. The mixture was heated to 120 °C and reacted under closed conditions for 3 h. After the reaction was completed, the mixture was cooled to 40 °C, 200 mL of dichloromethane was added, and the mixture was stirred for another 1 h. The mixture was then cooled to 18 °C, filtered, and dried to obtain 170.17 g of white solid intermediate 1. The purity was 97.82% (purity is expressed as the sum of the peaks of p-toluenesulfonic acid and O-methylisourea), and the yield was 83.0%.

[0069] (2) Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40°C and the reaction was maintained for 2 h. After the reaction was complete, 170.0 g of intermediate 1 prepared in step (1) was added, followed by 209.47 g of triethylamine. The addition temperature was controlled to be less than 40°C. After the addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. The dichloromethane was concentrated under reduced pressure by rotary evaporation to obtain 158.04 g of pale yellow solid intermediate 2. The purity was 94.09% and the yield was 87.6%.

[0070] (3) Synthesis of intermediate 3: 158.00g of intermediate 2 prepared in step (2) above was added to a reaction flask, 790mL of anhydrous ethanol was added, and the mixture was stirred until completely dissolved to obtain mixed solution 1; 97.12g of ammonium chloride solid was added to 100mL of water and completely dissolved to obtain ammonium chloride aqueous solution. The ammonium chloride aqueous solution was added dropwise to the above mixed solution 1 at a rate of 2 drops / s, and the mixture was heated to 80℃ and refluxed for 2.5h; after the reaction was completed, 690mL of water was added, and a pale yellow solid precipitated. The solid was slurried twice with 790mL of water and dried to obtain 124.94g of pale yellow solid intermediate 3; purity 93.57%, yield 83.9%;

[0071] (4) Synthesis of crude product: 124.00g of intermediate 3 prepared in step (3) above was added to a reaction flask, 372mL of anhydrous ethanol was added and stirred, and 51.09g of concentrated hydrochloric acid (36wt%) was added dropwise at a rate of 1 drop / s. The temperature was raised to 45℃ and the reaction was stirred for 2h. After the reaction was completed, the temperature was lowered to 3℃, filtered, and dried to obtain 116.32g of crude guanidine hydrochloride; purity 90.13%, yield 81.7%;

[0072] (5) Synthesis of guanidine hydrochloride: 116.00g of crude guanidine hydrochloride prepared in step (4) above was added to a reaction flask, 5.82g of activated carbon was added, 348mL of anhydrous ethanol was added, the temperature was raised to 80℃ and refluxed for 30min, filtered while hot, cooled to crystallize, filtered by suction, and dried to obtain 97.79g of guanidine hydrochloride; purity 99.78%, yield 84.3%.

[0073] The final product (guanifacine hydrochloride) prepared in this invention was tested using nuclear magnetic resonance (NMR) spectrometry. The test methods and conditions are as follows:

[0074] Nuclear Magnetic Resonance Spectrometer: Take 5 mg of sample and put it into a 5 mm NMR tube. Add 550 μL of deuterated dimethyl sulfoxide to dissolve the sample, cover with the NMR cap, and send for testing.

[0075] The proton NMR spectrum obtained by nuclear magnetic resonance (NMR) spectra shows the following characteristic peaks:

[0076] 1 H NMR (DMSO, 500 MHz) 1H NMR (DMSO, 500 MHz) δ 12.28 (s, 1H), 8.36 (m, 2H), 8.28 (m, 2H), 7.51 (d, 2H, J=9.7 Hz), 7.38 (t, 1H, J=9.2 Hz), 4.13(s, 2H).

[0077] 13 C NMR (125 MHz, DMSO) δ 171.51, 156.32, 137.52, 132.74, 131.98,129.36, 41.04.

[0078] Exact Mass: 245.01.

[0079] found (M+H) + : 246.02.

[0080] The control reagent (98%) of guanifacine hydrochloride was purchased from Beijing Bailingwei Technology Co., Ltd.

[0081] Based on NMR, mass spectrometry, and the purchased guanidine hydrochloride reference reagent, it can be determined that the final product obtained by the preparation method of this invention is guanidine hydrochloride.

[0082] The measured values ​​of the final product, guanidine hydrochloride, are as follows:

[0083]

[0084] Example 2

[0085] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0086] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of supported DMAP catalyst and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, and the dropwise temperature was controlled to be less than 40 °C. After the dropwise addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0087] The preparation method of the supported DMAP catalyst includes the following steps:

[0088] S1. Mix 1g of MCM-41 mesoporous silica, 2mL of 3-chloropropyltrimethoxysilane and 50mL of o-xylene, stir under nitrogen atmosphere and reflux at 148°C for 16h; after the reaction is complete, centrifuge, collect the solid, wash 3 times with anhydrous ethanol, and dry under vacuum at 50°C to obtain modified MCM-41 mesoporous silica.

[0089] S2. 2g of modified MCM-41 mesoporous silica, 0.3g of 4-dimethylaminopyridine, 0.92g of potassium iodide, 0.77g of potassium carbonate and 50mL of o-xylene were mixed and stirred at 130°C for 12h under a nitrogen atmosphere. After the reaction was completed, the mixture was centrifuged, separated, and the solid was collected. The solid was washed with o-xylene until no 4-dimethylaminopyridine residue was detected in the o-xylene solution after washing. Then it was washed three times with anhydrous ethanol and water and dried under vacuum at 50°C to obtain the supported DMAP catalyst.

[0090] Example 3

[0091] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0092] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of supported DMAP catalyst and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, and the dropwise temperature was controlled to be less than 40 °C. After the dropwise addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0093] The preparation method of the supported DMAP catalyst includes the following steps:

[0094] S1. Mix 1g of functionalized sepiolite, 2mL of 3-chloropropyltrimethoxysilane and 50mL of o-xylene, stir and reflux at 148°C for 16h under a nitrogen atmosphere; after the reaction is complete, centrifuge, collect the solid, wash three times with anhydrous ethanol, and dry under vacuum at 50°C to obtain modified sepiolite.

[0095] S2. Mix 2g of modified sepiolite, 0.3g of 4-dimethylaminopyridine, 0.92g of potassium iodide, 0.77g of potassium carbonate and 50mL of o-xylene, and stir at 130°C for 12h under a nitrogen atmosphere. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene until no 4-dimethylaminopyridine residue is detected in the o-xylene solution after washing, and then wash three times with anhydrous ethanol and water. Dry under vacuum at 50°C to obtain the supported DMAP catalyst.

[0096] The preparation method of the functionalized sepiolite includes the following steps:

[0097] 20g of sepiolite was added to 200g of 2mol / L hydrochloric acid aqueous solution and mixed evenly. After ultrasonic treatment for 30min, it was stirred at 80℃ for 8h. After filtration, it was washed with distilled water until neutral and dried at 100℃ for 2h to obtain acid-activated sepiolite. 14g of acid-activated sepiolite and 7g of cashew phenol were added to 130g of ethylene glycol and ultrasonically dispersed for 35min. Then, it was mixed and stirred at 82℃ for 7h. After centrifugation, the precipitate was collected, washed three times with ethanol, and vacuum dried at 42℃ for 24h to obtain functionalized sepiolite.

[0098] Example 4

[0099] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0100] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of supported DMAP catalyst and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, and the dropwise temperature was controlled to be less than 40 °C. After the dropwise addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0101] The preparation method of the supported DMAP catalyst includes the following steps:

[0102] S1. Mix 1g of functionalized sepiolite, 2mL of 3-chloropropyltrimethoxysilane and 50mL of o-xylene, stir and reflux at 148°C for 16h under a nitrogen atmosphere; after the reaction is complete, centrifuge, collect the solid, wash three times with anhydrous ethanol, and dry under vacuum at 50°C to obtain modified sepiolite.

[0103] S2. Mix 2g of modified sepiolite, 0.3g of 4-dimethylaminopyridine, 0.92g of potassium iodide, 0.77g of potassium carbonate and 50mL of o-xylene, and stir at 130°C for 12h under a nitrogen atmosphere. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene until no 4-dimethylaminopyridine residue is detected in the o-xylene solution after washing, and then wash three times with anhydrous ethanol and water. Dry under vacuum at 50°C to obtain the supported DMAP catalyst.

[0104] The preparation method of the functionalized sepiolite includes the following steps:

[0105] 20g of sepiolite was added to 200g of 2mol / L hydrochloric acid aqueous solution and mixed evenly. After ultrasonic treatment for 30min, it was stirred at 80℃ for 8h, filtered, washed with distilled water until neutral, and dried at 100℃ for 2h to obtain acid-activated sepiolite. 14g of acid-activated sepiolite and 7g of urushiol were added to 130g of ethylene glycol and ultrasonically dispersed for 35min. Then, they were mixed and stirred at 82℃ for 7h. After centrifugation, the precipitate was collected, washed three times with ethanol, and vacuum dried at 42℃ for 24h to obtain functionalized sepiolite.

[0106] Example 5

[0107] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0108] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of supported DMAP catalyst and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, and the dropwise temperature was controlled to be less than 40 °C. After the dropwise addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0109] The preparation method of the supported DMAP catalyst includes the following steps:

[0110] S1. Mix 1g of functionalized sepiolite, 2mL of 3-chloropropyltrimethoxysilane and 50mL of o-xylene, stir and reflux at 148°C for 16h under a nitrogen atmosphere; after the reaction is complete, centrifuge, collect the solid, wash three times with anhydrous ethanol, and dry under vacuum at 50°C to obtain modified sepiolite.

[0111] S2. Mix 2g of modified sepiolite, 0.3g of 4-dimethylaminopyridine, 0.92g of potassium iodide, 0.77g of potassium carbonate and 50mL of o-xylene, and stir at 130°C for 12h under a nitrogen atmosphere. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene until no 4-dimethylaminopyridine residue is detected in the o-xylene solution after washing, and then wash three times with anhydrous ethanol and water. Dry under vacuum at 50°C to obtain the supported DMAP catalyst.

[0112] The preparation method of the functionalized sepiolite includes the following steps:

[0113] 20g of sepiolite was added to 200g of 2mol / L hydrochloric acid aqueous solution and mixed evenly. After ultrasonic treatment for 30min, it was stirred at 80℃ for 8h, filtered, washed with distilled water until neutral, and dried at 100℃ for 2h to obtain acid-activated sepiolite. 14g of acid-activated sepiolite and 7g of tannic acid were added to 130g of ethylene glycol, ultrasonically dispersed for 35min, and then mixed and stirred at 82℃ for 7h. After centrifugation, the precipitate was collected, washed three times with ethanol, and vacuum dried at 42℃ for 24h to obtain functionalized sepiolite.

[0114] Comparative Example 1

[0115] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0116] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of supported DMAP catalyst and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, and the dropwise temperature was controlled to be less than 40 °C. After the dropwise addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0117] The preparation method of the supported DMAP catalyst includes the following steps:

[0118] S1. Mix 1g of acid-activated sepiolite, 2mL of 3-chloropropyltrimethoxysilane and 50mL of o-xylene, stir and reflux at 148°C for 16h under a nitrogen atmosphere; after the reaction is complete, centrifuge, collect the solid, wash 3 times with anhydrous ethanol, and dry under vacuum at 50°C to obtain modified sepiolite.

[0119] S2. Mix 2g of modified sepiolite, 0.3g of 4-dimethylaminopyridine, 0.92g of potassium iodide, 0.77g of potassium carbonate and 50mL of o-xylene, and stir at 130°C for 12h under a nitrogen atmosphere. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene until no 4-dimethylaminopyridine residue is detected in the o-xylene solution after washing, and then wash three times with anhydrous ethanol and water. Dry under vacuum at 50°C to obtain the supported DMAP catalyst.

[0120] The preparation method of the acid-activated sepiolite includes the following steps:

[0121] 20g of sepiolite was added to 200g of 2mol / L hydrochloric acid aqueous solution and mixed evenly. After ultrasonic treatment for 30min, it was stirred at 80℃ for 8h. After filtration, it was washed with distilled water until neutral and dried at 100℃ for 2h to obtain acid-activated sepiolite.

[0122] Comparative Example 2

[0123] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0124] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of supported DMAP catalyst and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, and the dropwise temperature was controlled to be less than 40 °C. After the dropwise addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0125] The preparation method of the supported DMAP catalyst includes the following steps:

[0126] S1. Dry the coarse-porous silica microspheres at 105°C for 15 min to obtain dry coarse-porous silica microspheres. Then, mix 1 g of dry coarse-porous silica microspheres, 2 mL of 3-chloropropyltrimethoxysilane and 50 mL of o-xylene. Under a nitrogen atmosphere, mix and stir and reflux at 148°C for 16 h. After the reaction is complete, centrifuge, collect the solid, wash with anhydrous ethanol, and dry under vacuum at 50°C to obtain γ-chloropropylated silica.

[0127] S2. Mix 2g of γ-chloropropylated silica gel, 0.3g of 4-dimethylaminopyridine, 0.92g of potassium iodide, 0.77g of potassium carbonate and 50mL of o-xylene, and stir at 130°C for 12h under a nitrogen atmosphere. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene until no 4-dimethylaminopyridine residue is detected in the o-xylene solution after washing, and then wash three times with anhydrous ethanol and water. Dry under vacuum at 50°C to obtain the supported DMAP catalyst.

[0128] Comparative Example 3

[0129] A synthetic process for guanidine hydrochloride differs from that in Example 1 in that step (2) is as follows:

[0130] Synthesis of intermediate 2: 141.48 g of 2,6-dichlorophenylacetic acid was added to a reaction flask, followed by 1500 mL of dichloromethane. 98.51 g of thionyl chloride was added dropwise at a rate of 20 drops / min at room temperature. After the addition was complete, the temperature was raised to 40 °C and the reaction was maintained for 2 h. After the reaction was complete, 0.28 g of 4-dimethylaminopyridine (DMAP) and 170.0 g of intermediate 1 prepared in step (1) above were added. 209.47 g of triethylamine was added dropwise, with the addition temperature controlled below 40 °C. After the addition was complete, the reaction was continued for 30 min. After the reaction was complete, 1500 mL of water was added, the mixture was separated, and the aqueous phase was washed with 750 mL of dichloromethane. Excess dichloromethane was removed by rotary evaporation under reduced pressure to obtain a pale yellow solid intermediate 2.

[0131] Test Example 1

[0132] Intermediate 2 yield test

[0133] The intermediates 2 prepared in Examples 1-5 and Comparative Examples 1-3 were statistically analyzed, and the theoretical yield was calculated based on the molar mass of the reactants and the chemical equations of the reactions; the test results are shown in Table 1.

[0134] Table 1

[0135]

[0136] As shown in Table 1, comparing Examples 1-5 and Comparative Examples 1-3, the yields of Examples 2-5 and Comparative Examples 1-3 were higher than that of Example 1. This indicates that the introduction of a catalyst is beneficial to promoting the reaction and increasing the yield of intermediate 2. The reason for this may be that the introduction of the catalyst DMAP helps to lower the activation energy, improve the selectivity and stability of the reaction, and accelerate the condensation reaction rate of 2,6-dichlorophenylacetic acid with intermediate 1. Without a catalyst, the reaction rate is slower and there are more side reactions, resulting in a lower yield of intermediate 2.

[0137] Comparing Examples 2-5 and Comparative Examples 1-3, the yields of Examples 2-5 and Comparative Examples 1-2 were higher than those of Comparative Example 3. This indicates that compared to Comparative Example 3, which introduced a DMAP catalyst, the introduction of a supported DMAP catalyst is more conducive to promoting the reaction and thus achieving a higher yield. The reason for this may be that the supported catalyst can uniformly disperse DMAP on the surface of the support, preventing DMAP from agglomerating or being lost during the reaction, thereby improving the utilization rate of the catalyst. At the same time, the support has good thermal and chemical stability, which can protect the DMAP catalyst during the reaction and prevent it from being deactivated or falling off. This is conducive to increasing the contact area between the reactants and the catalyst, thereby improving the reaction rate and yield.

[0138] Comparing Examples 2-5 and Comparative Examples 1-2, it was found that the yields of Examples 3-5 and Comparative Example 1 were higher than those of Examples 2 and Comparative Example 2. This indicates that compared to introducing MCM-41 mesoporous silica or coarse-porous microsphere silica to support DMAP catalysts, introducing sepiolite to support DMAP catalysts is more beneficial for improving the yield, and the modified sepiolite has a better effect on improving the yield. The reason for this may be that, compared to MCM-41 mesoporous silica and coarse-porous microsphere silica, sepiolite is a natural fibrous silicate mineral with a higher specific surface area and abundant pore structure. This structural characteristic allows sepiolite to provide more active sites for DMAP loading, thereby increasing the number of active sites on the catalyst and improving catalytic efficiency. At the same time, the surface of sepiolite is rich in hydroxyl and silanol groups. After acid activation and functionalization, these hydroxyl groups can form stronger chemical bonds with 3-chloropropyltrimethoxysilane. This bonding not only increases the DMAP loading but also enhances the stability of DMAP on the catalyst surface, thereby improving catalytic efficiency.

[0139] Comparing Examples 3-5 with Comparative Example 1, the yields of Examples 3-5 were higher than those of Comparative Example 1, with Example 5 showing the highest yield. This indicates that compared to introducing acid-activated sepiolite-supported DMAP catalysts, introducing tannic acid, cashew phenol, and urushiol-modified sepiolite-supported DMAP catalysts is more beneficial for improving the yield, and the tannic acid-modified sepiolite-supported DMAP catalyst shows the best effect. The reason for this may be that, compared to acid-activated sepiolite, the sepiolite further modified with tannic acid, cashew phenol, and urushiol not only increases the number of active sites on its surface, but also may have a more optimized pore structure, which can better accommodate reactant molecules and prolong the residence time of reactants on the catalyst surface, thereby improving the reaction efficiency. The yield of Example 5 was higher than that of Examples 3-4. The reason for this may be that, compared to urushiol and cashew phenol, tannic acid contains multiple hydroxyl groups in its structure. When grafted onto the surface of sepiolite, multiple hydroxyl groups are introduced. By introducing tannic acid-modified sepiolite as a support in the preparation of the DMAP catalyst, it can better undergo coupling reaction with 3-chloropropyltrimethoxysilane, forming more silicon-oxygen bonds. This allows more 3-chloropropyltrimethoxysilane to be grafted onto the support, which is beneficial for subsequent halogen exchange and N-alkylation reactions. Ultimately, this increases the loading rate of DMAP, thereby achieving better catalytic effect and further improving the reaction yield.

[0140] Test Example 2

[0141] Determination of DMAP (4-dimethylaminopyridine) loading in DMAP-supported catalysts

[0142] The DMAP loading of the supported DMAP catalysts prepared in Examples 2-5 and Comparative Examples 1-2 of this invention was calculated by the difference between the concentration of DMAP in the system after the addition of the precursor 4-dimethylaminopyridine (DMAP) and the residual DMAP concentration in the system after the reaction was terminated. The concentration of DMAP in the reaction was determined by TLC. The specific steps are as follows:

[0143] (1) Prepare the developing solvent: chloroform: distilled water: methanol: concentrated ammonia = 13:0.8:5:0.5 (volume ratio). Accurately transfer the solvent into the developing tank, shake it thoroughly, and place it in a fume hood for 1 hour to allow it to become homogeneous before use.

[0144] (2) Capillary spotting: Spotting with treated silica gel plates. Care should be taken and accurate during the process to reduce human error.

[0145] (3) Plate running: Place the silica gel plate with the sampled sample in the developing tank and run it. When the liquid level rises to the designated position, remove it and ventilate it.

[0146] (4) Color development: When the silica gel plate is irradiated with ultraviolet light, DMAP absorption occurs at 254nm. The black spots on the plate are the locations where DMAP is present.

[0147] (5) Use CamScanner to scan the silicone plate after color development to obtain the corresponding scanned image;

[0148] (6) Data processing: Use software such as Photoshop and Gel-Pro analyzer to process the scanned images, convert the spots into corresponding grayscale data, and then use the grayscale data to calculate the amount of DMAP.

[0149] The test results are shown in Table 2.

[0150] Table 2

[0151]

[0152] Table 2 shows that, comparing Examples 2-5 and Comparative Examples 1-2, the loading rates of Examples 3-5 and Comparative Example 1 were higher than those of Examples 2 and Comparative Example 2, with Comparative Example 2 having the lowest loading rate at only 0.86 mmol / g. This indicates that compared to introducing MCM-41 mesoporous silica and coarse-porous microsphere silica gel to support DMAP catalysts, introducing sepiolite as a support is more beneficial for improving the DMAP loading rate, and the modified sepiolite has a better DMAP loading effect. Comparing Examples 3-5 and Comparative Example 1, the DMAP loading rate of Examples 3-5 was higher than that of Comparative Example 1, and Example 5 had the highest DMAP loading rate, reaching 3.26 mmol / g. This indicates that compared to using acid-activated sepiolite to prepare supported DMAP catalysts, further modifying acid-activated sepiolite with tannic acid, cashew phenol, and urushiol to prepare supported DMAP catalysts is more beneficial for improving the DMAP loading rate, and the DMAP loading rate of the supported DMAP catalyst prepared by selecting tannic acid-modified sepiolite is the highest.

Claims

1. A process for synthesizing guanidine hydrochloride, characterized in that, The process includes the following steps: methylating urea with a methylating agent to obtain intermediate 1; then reacting intermediate 1 with 2,6-dichlorophenylacetic acid to obtain intermediate 2; reacting intermediate 2 with an aqueous solution of an amination agent to obtain intermediate 3; reacting intermediate 3 with a salting agent to obtain a crude product; and recrystallizing the crude product in a recrystallization solvent to obtain the final product, guanidine hydrochloride; wherein the methylating agent is methyl p-toluenesulfonate. Intermediate 1 is p-toluenesulfonate of O-methylisourea, and its structural formula is as follows: The intermediate 3 is a free guanidine fumarate, and its structural formula is as follows: During the reaction of intermediate 1 with 2,6-dichlorophenylacetic acid, a supported DMAP catalyst was also added. The supported DMAP catalyst was prepared by using functionalized sepiolite, which was prepared by modifying MCM-41 mesoporous silica or acid-activated sepiolite with cashew phenol, urushiol and tannic acid as modifiers, as a support for DMAP. The preparation method of the supported DMAP catalyst includes the following steps, in parts by weight: S1. Mix 0.8-1.2 parts of support, 1.8-2.2 parts of 3-chloropropyltrimethoxysilane and 48-50 parts of o-xylene, and reflux the mixture under nitrogen atmosphere at 145-150°C for 14-20 h with stirring. After the reaction is complete, centrifuge, collect the solid, wash with anhydrous ethanol, and dry under vacuum at 45-55°C to obtain the modified support. S2. Mix 1.8-2.2 parts of modified support, 2.8-3.2 parts of 4-dimethylaminopyridine, 0.9-0.95 parts of potassium iodide, 0.75-0.8 parts of potassium carbonate, and 45-55 parts of o-xylene. Stir and react under nitrogen atmosphere at 125-135°C for 10-15 h. After the reaction is complete, centrifuge, separate, collect the solid, wash with o-xylene, then wash with anhydrous ethanol and water, and vacuum dry at 45-55°C to obtain the supported DMAP catalyst. The preparation method of the functionalized sepiolite includes the following steps, in parts by weight: 18-22 parts of sepiolite were added to 180-220 parts of 1-2 mol / L hydrochloric acid aqueous solution and mixed evenly. After ultrasonic treatment for 20-30 min, the mixture was stirred at 75-85℃ for 7-10 h. After filtration, the mixture was washed with water until neutral and dried at 90-110℃ for 1-3 h to obtain acid-activated sepiolite. 13-15 parts of acid-activated sepiolite and 6.5-7.5 parts of modifier were added to 120-135 parts of ethylene glycol and ultrasonically dispersed for 30-40 min. Then, the mixture was stirred at 80-85℃ for 6-8 h. After centrifugation, the precipitate was collected, washed 2-3 times with ethanol, and vacuum dried at 40-45℃ for 20-25 h to obtain functionalized sepiolite. The modifier is selected from one of tannic acid, urushiol, and cashew nut phenol.

2. The synthesis process of guanidine hydrochloride as described in claim 1, characterized in that, The synthesis process specifically includes the following steps, in parts by weight: (1) Synthesis of intermediate 1: 48-52 parts of urea were added to 185-187 parts of methylating agent, the temperature was raised to 118-122℃, and the reaction was carried out in a closed container for 2.5-3.5h; after the reaction was completed, the temperature was lowered to 35-50℃, 195-205 parts of dichloromethane were added, the mixture was stirred for 1h, the temperature was lowered to 15-20℃, the mixture was filtered and dried to obtain white solid intermediate 1; (2) Synthesis of intermediate 2: 141-142 parts of 2,6-dichlorophenylacetic acid were added to a reaction flask, 1480-1520 parts of dichloromethane were added, 98-99 parts of thionyl chloride were added at room temperature, and then the temperature was raised to 38-52℃ and kept at the temperature for 1.5-2.5h. After the reaction was completed, 0.25-0.3 parts of supported DMAP catalyst and intermediate 1 prepared in step (1) above were added, 209-210 parts of triethylamine were added, and the reaction was carried out for 25-35min. After the reaction was completed, 1480-1520 parts of water were added, the liquid phase was separated, the aqueous phase was washed, and the liquid phase was concentrated to obtain a pale yellow solid intermediate 2. (3) Synthesis of intermediate 3: The intermediate 2 prepared in step (2) above is added to a reaction flask, and 780-800 parts of anhydrous ethanol are added. The mixture is stirred and completely dissolved to obtain mixed solution 1. 97-97.2 parts of the amination reagent are added to 95-105 parts of water and completely dissolved to obtain an aqueous solution of the amination reagent. The aqueous solution of the amination reagent is added to the above mixed solution 1, and the mixture is heated to 78-82℃ and refluxed for 2-3 hours. After the reaction is completed, 680-700 parts of water are added, and a pale yellow solid is precipitated. The solid is slurried with water 2-3 times and dried to obtain a pale yellow solid intermediate 3. (4) Synthesis of crude product: The intermediate 3 prepared in step (3) above is added to a reaction flask, 370-375 parts of anhydrous ethanol is added and stirred, 50-52 parts of salt-forming reagent is added, the temperature is raised to 40-50℃, and the reaction is stirred for 1.5-2.5h; after the reaction is completed, the temperature is lowered to 0-5℃, filtered, dried, and crude guanidine hydrochloride is obtained. (5) Synthesis of guanifacine hydrochloride: Add the crude guanifacine hydrochloride obtained in step (4) above into a reaction flask, add 5.8-5.9 parts of activated carbon, add 340-350 parts of recrystallization solvent, heat to 78-82℃ and reflux for 25-35 min, filter while hot, cool to crystallize, filter by suction, dry to obtain guanifacine hydrochloride.

3. The synthesis process of guanidine hydrochloride as described in claim 1 or 2, characterized in that: The amination reagent is ammonium chloride.

4. The synthesis process of guanidine hydrochloride as described in claim 1 or 2, characterized in that: The salt-forming reagent is concentrated hydrochloric acid.

5. The synthesis process of guanidine hydrochloride as described in claim 1 or 2, characterized in that: The recrystallization solvent is anhydrous ethanol.

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