A process for the preparation of aceclidine hydrochloride

Abstract

The application provides a preparation method of acetylcodeine hydrochloride, which comprises the following steps: dissolving 3-quinuclidinone hydrochloride in an organic solvent, adding an inorganic base, then adding a reducing agent to perform a reaction to obtain 3-quinuclidinol; dissolving the 3-quinuclidinol in an organic solvent, adding acetic anhydride to perform an esterification reaction, and then performing a reaction with concentrated hydrochloric acid to obtain the acetylcodeine hydrochloride. The preparation method of the acetylcodeine hydrochloride is simple, low in cost, and low in requirement for equipment, and uses 3-quinuclidinone hydrochloride as a starting material, and acetylcodeine hydrochloride is obtained through reduction and esterification.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for preparing acetylcholine hydrochloride. Background Technology

[0002] Accelidine is an acetylcholine receptor agonist. Compared to other miotics, it exhibits higher specificity in its action on the iris muscle, which controls pupil size. It primarily and selectively acts on the iris sphincter muscle without affecting the ciliary muscle. While constricting the pupil, it also relieves ciliary muscle contraction, reducing refractive changes in the lens. Studies have shown that aceelidine's mechanism of action is highly effective, producing both a miotic effect and improving myopic drift. Furthermore, aceelidine can almost immediately improve myopic acuity (within 30 to 60 minutes) while maintaining hyperopic acuity, and its effect is more lasting than other existing medications (approximately 10 hours). Therefore, aceelidine is a promising drug for the treatment of presbyopia.

[0003] Acetyldine hydrochloride is the form of acetyldine hydrochloride, which can be used to treat presbyopia. The chemical formula of acetyldine hydrochloride is C9H2O. 15 NO2·HCl, with a molecular weight of 205.68 and CAS number 6109-70-2, has the following structural formula: .

[0004] Chinese patent document CN120826399A discloses crystalline acetic acid HCl hemihydrate and its preparation method. The preparation method uses acetic acid HCl as a raw material for hydration to obtain crystalline acetic acid HCl hemihydrate. However, there are no reports on the preparation of acetic acid HCl in the prior art. Summary of the Invention

[0005] The technical problem to be solved by the present invention is to provide a method for preparing acetic acid ketidine.

[0006] The present invention solves the above-mentioned technical problems through the following technical means:

[0007] This invention provides a method for preparing acetylcholine hydrochloride, comprising the following steps: S1. Dissolve 3-quininecycloketone hydrochloride in an organic solvent, add an inorganic base, and then add a reducing agent to react and obtain 3-quininecyclool. S2. Dissolve 3-quininecyclool in an organic solvent, add acetic anhydride to carry out esterification reaction, and after the reaction is completed, react with concentrated hydrochloric acid to obtain acetic acid ...

[0008] Beneficial effects: This invention uses 3-quinine cycloketone hydrochloride as the starting material to obtain acetic acid ketidine hydrochloride through reduction and esterification reactions. The preparation method is simple to operate, low in cost, and has low equipment requirements.

[0009] Preferably, the specific operation of S1 is as follows: 3-quininecycloketone hydrochloride is added to an organic solvent at -5℃ to 5℃, an inorganic base is added and stirred, then a reducing agent is added, and the reaction is stirred for 2h to 6h to obtain 3-quininecyclool.

[0010] Preferably, 3-quininecyclool is purified. The specific purification procedure is as follows: concentrated hydrochloric acid is added to 3-quininecyclool until pH ≤ 6. The reaction solution is concentrated under reduced pressure until no fraction remains. The concentration temperature is maintained under reduced pressure. Water is added to dissolve the solution. Carbonate is added until saturated. Organic solvent is added for extraction 2-4 times. The extracted organic phases are combined. Then, a drying agent is added and the mixture is stirred to dry. The solution is filtered. The filtrate is concentrated under reduced pressure until no fraction remains. The concentration temperature is maintained. A crystallization solvent is added and stirred to dissolve the solution. The solution is cooled to 0-10°C to crystallize. The solution is filtered, and the filter cake is dried to obtain the purified 3-quininecyclool.

[0011] Preferably, the specific operation of S2 is as follows: 3-quinine alcohol is added to an organic solvent and stirred, then acetic anhydride is added and the temperature is raised to 40℃~50℃, and the reaction is maintained for 2h~8h to obtain acetic acid ketidine.

[0012] Preferably, aceklinidine is purified and then reacted with concentrated hydrochloric acid to obtain aceklinidine hydrochloride. The specific operation is as follows: the aceklinidine is cooled to 0-10℃, a carbonate solution is added to quench the reaction, the temperature is raised to 10℃-25℃ and stirred, and after standing and separation, the aqueous phase is extracted twice with ethyl acetate. The extracted organic phases are combined, a drying agent is added and stirred to dry, filtered, and the filtrate is concentrated under reduced pressure until no fraction remains. A crystallization solvent is added and stirred to dissolve the filtrate, filtered, and the filtrate is cooled to 0-10℃ and hydrochloric acid is added dropwise until the pH is ≤6. The temperature is maintained at 0-10℃, and the mixture is stirred to crystallize for 1-4 hours. The mixture is filtered, and the filter cake is dried to obtain purified aceklinidine hydrochloride.

[0013] Preferably, 3-quinine cyclic ketone hydrochloride is obtained by the following method: using ethyl N-ethyl acetate-4-piperidinecarboxylate as a raw material, a Dickmann condensation reaction is carried out under the conditions of an organic solvent and an organic base, and concentrated hydrochloric acid is added after the reaction to obtain 3-quinine cyclic ketone hydrochloride.

[0014] Preferably, the specific operation for obtaining 3-quinine cyclic ketone hydrochloride is as follows: an organic solvent is placed in a reaction vessel and a protective gas is introduced. An organic base is added and stirred to raise the temperature to 60°C to 100°C. Then, ethyl N-ethyl acetate-4-piperidinecarboxylate is added and the temperature is raised to 110°C and refluxed for 4 to 8 hours. After that, water is added to cool and quench the temperature to 0 to 10°C. Concentrated hydrochloric acid is added dropwise, stirred, allowed to stand, and separated. The aqueous phase is taken and stirred and refluxed for 10 to 25 hours to obtain 3-quinine cyclic ketone hydrochloride.

[0015] Preferably, 3-quinine cyclic ketone hydrochloride is purified. The specific purification procedure is as follows: the obtained 3-quinine cyclic ketone hydrochloride is heated to 60℃~80℃, activated carbon is added and stirred for decolorization, and the aqueous phase is obtained by filtration. The aqueous phase is cooled to 0~10℃, sodium hydroxide is added to adjust the pH to ≥8, organic solvent is added for extraction 2~4 times, the extracted organic phases are combined and backwashed once with sodium hydroxide aqueous solution, a drying agent is added and stirred for drying, and the solution is filtered. The filtrate is concentrated under reduced pressure until no fraction is distilled off, a crystallization solvent is added for dilution, and the solution is cooled to 0~10℃. Concentrated hydrochloric acid is added dropwise and stirred for crystallization, and the solution is filtered. The filter cake is dried to obtain the purified 3-quinine cyclic ketone hydrochloride.

[0016] Preferably, the organic solvent includes one or more of toluene, N,N-dimethylformamide, ethanol, ethyl acetate, dichloromethane, chloroform, n-heptane, acetone, butanone, or isopropanol.

[0017] Preferably, the organic base includes one or more of potassium tert-butoxide, sodium methoxide, and sodium ethoxide.

[0018] Preferably, the reducing agent is sodium borohydride or hydrogen gas.

[0019] Preferably, when the reducing agent is hydrogen, 3-quinine alcohol is dissolved in an organic solvent, an inorganic base is added and stirred, then hydrogen is introduced, and palladium and carbon are added to carry out a catalytic reaction. The reaction pressure is 0.05 MPa to 0.1 MPa, the reaction temperature is 40°C to 60°C, and the reaction time is 1 h to 3 h.

[0020] Preferably, the weight ratio of N-ethyl acetate-4-piperidinecarboxylate to organic base is 1:1.1 to 2.0.

[0021] Preferably, the weight ratio of 3-quinine cycloketone hydrochloride to inorganic base is 1:0.2 to 0.5.

[0022] Preferably, the inorganic base is sodium hydroxide or potassium hydroxide.

[0023] Preferably, the weight ratio of 3-quinine cycloketone hydrochloride to sodium borohydride is 1:0.06 to 0.2.

[0024] Preferably, the weight ratio of 3-quininecyclool to acetic anhydride is 1:1.2 to 1.6.

[0025] Preferably, the ratio of 3-quininecyclool to concentrated hydrochloric acid is 30g~31g:18ml~22.5ml.

[0026] Preferably, the desiccant includes one or more of anhydrous sodium sulfate, anhydrous magnesium sulfate, anhydrous calcium chloride, and molecular sieves.

[0027] Preferably, the crystallization solvent includes one or more of acetone, butanone, ethyl acetate, isopropanol, and n-hexane.

[0028] Preferably, the carbonate includes one or more of potassium carbonate, sodium carbonate, potassium bicarbonate, and sodium bicarbonate.

[0029] Beneficial effects: This invention provides a method for preparing acetic acid hydrochloride. Using ethyl N-ethyl acetate-4-piperidinecarboxylate as the starting material, acetic acid hydrochloride is obtained through Dickmann condensation, reduction and esterification reactions. The molar yield of acetic acid hydrochloride reaches more than 80% and the purity reaches 100%. The preparation method is simple to operate, low in cost and has low requirements for equipment. Attached Figure Description

[0030] Figure 1 This is the IR spectrum of acetylcholine hydrochloride prepared in Example 1 of the present invention; Figure 2 This is the HNMR spectrum of acetylchloride hydrochloride prepared in Example 1 of this invention; Figure 3 This is the CNMR spectrum of acetylcholine hydrochloride prepared in Example 1 of this invention; Figure 4 This is the TGA spectrum of acetylcholine hydrochloride prepared in Example 1 of this invention. Detailed Implementation

[0031] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only some embodiments of the present invention, 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.

[0032] Unless otherwise specified, all test materials and reagents used in the following examples are commercially available.

[0033] Unless otherwise specified in the embodiments, the techniques or conditions described in the literature in this field or in accordance with the product manual may be followed.

[0034] This embodiment provides a method for preparing acetic acid ketidine, including the following steps: Synthesis of S1,3-quinine cyclohexanone hydrochloride Ethyl N-ethyl 4-piperidinecarboxylate (99.98 g, 0.411 mol) was dissolved in 100 mL of toluene to obtain an ethyl N-ethyl 4-piperidinecarboxylate solution. 600 mL of toluene and 100 mL of N,N-dimethylformamide were added to a reaction vessel and nitrogen gas was introduced. Potassium tert-butoxide (141.03 g, 1.257 mol) was added, and the mixture was stirred and heated to 90 °C until dissolved. The ethyl N-ethyl 4-piperidinecarboxylate solution was then added dropwise, and the mixture was refluxed at 110 °C for 4–8 h (Dickmann condensation reaction). After the reaction was completed under controlled conditions, 100 mL of water was added, and the temperature was lowered to 0–10 °C. Concentrated hydrochloric acid (250 mL, 3 mol) was added dropwise with stirring, followed by 400 mL of water. The mixture was allowed to stand, and the aqueous phase was separated and refluxed for 10–25 h to obtain 3-quinine cycloketone hydrochloride.

[0035] The 3-quinine cyclic ketone hydrochloride was purified as follows: The obtained 3-quinine cyclic ketone hydrochloride was cooled to 60℃~80℃, activated carbon was added for decolorization by stirring, and the mixture was filtered. The aqueous phase was then cooled to 0~10℃, and sodium hydroxide was added to adjust the pH to ≥8. The mixture was extracted three times with dichloromethane (400 ml of dichloromethane each time). The organic phases from the three extractions were then combined, backwashed once with sodium hydroxide aqueous solution, and dried with anhydrous sodium sulfate for 0.5 h by stirring. The mixture was filtered, and the filtrate was concentrated under reduced pressure (65℃, -0.08~-0.1 MPa) until no fraction remained. Isopropanol was added to dilute the solution to 400 ml, and the mixture was cooled to 0~10℃. 40 ml of concentrated hydrochloric acid was added dropwise, and the mixture was stirred to crystallize and filtered. The filter cake was dried to obtain purified 3-quinine cyclic ketone hydrochloride (32.7 g, 0.202 mol), with a molar yield of 49.14%.

[0036] Synthesis of S2,3-quininecyclool 25.05 g (0.155 mol) of 3-quinine cyclohexane hydrochloride was added to 250 ml of ethanol at -5 °C to 5 °C. Sodium hydroxide (7.51 g, 0.188 mol) was added in batches and stirred for 0.5 h to 2 h. Sodium borohydride (4.13 g, 0.109 mol) was added in batches and stirred for 2 h to 6 h. The temperature was controlled at -5 to 5 °C throughout the process to obtain 3-quininecyclool.

[0037] 3-quininecyclool was purified using the following steps: After the reaction was completed under controlled conditions, concentrated hydrochloric acid (30 ml) was slowly added dropwise to the obtained 3-quininecyclool until the pH was approximately 4. The reaction solution was concentrated under reduced pressure (65℃, -0.08 to -0.1 MPa) until no fraction remained. The concentration temperature was maintained under reduced pressure, water (125 ml) was added and stirred until dissolved, potassium carbonate was added until saturated, and dichloromethane was added and stirred for extraction three times (150 ml of dichloromethane was used each time). The organic phases from the three extractions were combined, anhydrous sodium sulfate was added, stirred, and dried. The mixture was filtered, and the filtrate was concentrated under reduced pressure (65℃, -0.08 to -0.1 MPa) until no fraction remained. The concentration temperature was maintained, ethyl acetate was added and stirred until dissolved, and the mixture was cooled to 0–10℃ to crystallize. The crystals were filtered, and the filter cake was dried to obtain purified 3-quininecyclool (18.47 g, 0.105 mol), with a molar yield of 92.96%.

[0038] S3, Preparation of Acetylpyridinium Hydrochloride 3-quinol (30.08 g, 0.2365 mol) was added to ethyl acetate (300 ml) and stirred. Acetic anhydride (48.0 g, 0.47 mol) was then slowly added dropwise. The temperature was raised to 40℃~50℃ and the reaction was maintained for about 4 h to obtain acetic acid ketidine.

[0039] After purification, acetylcholine was reacted with concentrated hydrochloric acid. The specific steps are as follows: After the reaction was completed under central monitoring, the obtained acetylcholine hydrochloride was cooled to 0-10℃, and 300 ml of 40% potassium carbonate solution was slowly added dropwise to quench the reaction. The temperature was raised to 10℃-25℃ and stirred. After standing and separating the liquid, the aqueous phase was extracted twice with ethyl acetate (150 ml of ethyl acetate each time). The organic phases from the two extractions were combined, anhydrous sodium sulfate was added, stirred, and dried. The mixture was filtered, and the filtrate was concentrated under reduced pressure (65℃, -0.08 to -0.1 MPa) until no fraction was distilled off. 150 ml of acetone was added and stirred. The filtrate was cooled to 0-10℃, and 20 ml of concentrated hydrochloric acid was added dropwise while stirring. The temperature was maintained at 0-10℃, and the mixture was stirred to crystallize for 1-4 hours. The mixture was then filtered, and the filter cake was dried to obtain purified acetylcholine hydrochloride (42.72 g, 0.208 mol), with a molar yield of 88.51% and a purity of 100.0%.

[0040] The IR, HNMR, CNMR, and TGA spectra of acetate-krydidine hydrochloride prepared in this embodiment are shown below. Figures 1-4 As shown.

[0041] Figure 1 The infrared test results for acetic acid ketidine hydrochloride are shown in the figure; 3503 cm⁻¹ can be seen. -1 The characteristic stretching vibration peak of NH, 2781 cm⁻¹ -1 ~2571 cm -1 Multiple sawtooth peaks are ammonium salt N +-H characteristic stretching vibration peak, 2924 cm⁻¹ -1 1449 cm -1 1363 cm -1 The characteristic stretching vibration peak of CH, 1722 cm⁻¹ -1 The characteristic stretching vibration peak of C=O, 1236 cm⁻¹ -1 The characteristic stretching vibration peak of the C-C ratio, 1028 cm⁻¹ -1 The characteristic stretching vibration peak of CO.

[0042] Figure 2 The results of the 1H NMR spectrum of acetylcholine hydrochloride (dissolved in deuterated chloroform) show that 11.7 ppm corresponds to hydrogen in hydrochloride, 5.0 ppm corresponds to COOC-H hydrogen attached to the ester group, 3.6 ppm corresponds to methylene hydrogen attached to N and closest to the ester group, 3.2-3.0 ppm corresponds to -N-CH2 hydrogen attached to N in the ring structure, 2.3 ppm corresponds to CH in the ring structure at the para position of N, 2.0 ppm corresponds to α-ester methyl hydrogen -CH3, and 2.1-1.6 ppm corresponds to -CH2 hydrogen not attached to N in the ring structure.

[0043] Figure 3 The results of the carbon spectrum test of acetic acid ketidine (dissolved in deuterated chloroform) are shown in the figure. 170 ppm represents C=O carbon, 66 ppm represents CO carbon, 53 ppm, 46 ppm, and 45 ppm all represent CN carbon, and 24 ppm, 20 ppm, and 17 ppm all represent CH carbon.

[0044] Figure 4 The results of thermogravimetric analysis (TGA) of acetic acid ketrimidine hydrochloride (nitrogen atmosphere) show that the mass loss of acetic acid ketrimidine hydrochloride at 150℃ is due to the volatilization of water of crystallization, and the mass loss at 350℃ is due to the decomposition of the sample itself, with a final ash content of 1.4%.

[0045] Example 2 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, the difference in this embodiment is that in S1, the amount of potassium tert-butoxide is replaced by 199.96g instead of 141.03g. All other aspects are the same as in Example 1. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 87.32% and a purity of 100.0%.

[0046] Example 3 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, the difference in this embodiment is that in S1, the amount of potassium tert-butoxide is replaced by 109.98g instead of 141.03g. All other aspects are the same as in Example 1. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 84.6% and a purity of 100.0%.

[0047] Example 4 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, the difference in this embodiment is that in S2, the amount of sodium hydroxide is replaced by 5.01g instead of 7.51g. All other aspects are the same as in Example 1. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 82.2% and a purity of 100.0%.

[0048] Example 5 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, the difference in this embodiment is that in S2, the amount of sodium hydroxide is replaced by 12.53g instead of 7.51g. All other aspects are the same as in Example 1. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 83.1% and a purity of 100.0%.

[0049] Example 6 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, the difference in this embodiment is that in S2, the amount of sodium borohydride is replaced by 1.50g instead of 4.13g. All other aspects are the same as in Example 1. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 83.7% and a purity of 100.0%.

[0050] Example 7 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, the difference in this embodiment is that in S2, the amount of sodium borohydride is replaced by 5.00g instead of 4.13g. All other aspects are the same as in Example 1. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 87.1% and a purity of 100.0%.

[0051] Example 8 This embodiment provides a method for preparing acetic acid ...

[0052] Example 9 This embodiment provides a method for preparing acetic acid acetylcholine. Compared with Example 1, this embodiment differs in that step S1 is omitted, and the purchased 3-quinine cyclohexane hydrochloride is directly used in the reaction in S2 to obtain purified acetic acid acetylcholine hydrochloride with a molar yield of 85.3% and a purity of 100.0%.

[0053] Example 10 This embodiment provides a method for preparing acetic acid acetylcholine. The difference between this embodiment and Example 1 is that in step S2, 3-quinine alcohol (30.08 g, 0.235 mol) is dissolved in methanol, and sodium hydroxide (7.51 g, 0.188 mol) is added. The mixture is stirred for 0.5 h to 2 h, then hydrogen gas is introduced to initiate the reaction. Palladium and carbon are added for catalysis, wherein the mass of palladium accounts for 0.1% of the total mass of palladium on carbon. The reaction pressure is 0.08 MPa, the reaction temperature is 50 °C, and the reaction time is 2 h. Finally, purified acetic acid acetylcholine is obtained with a molar yield of 84.7% and a purity of 100.0%.

[0054] Comparative Example 1 This comparative example provides a method for preparing acetic acid ...

[0055] Comparative Example 2 This comparative example provides a method for preparing acetic acid acetic acid. The difference between this comparative example and Example 1 is that in S3, the mass fraction of potassium carbonate solution is replaced by 20% instead of 40%. All other aspects are the same as in Example 1. Finally, purified acetic acid acetic acid is obtained with a molar yield of 61.3% and a purity of 100.0%.

[0056] Comparative Example 3 This comparative example provides a method for preparing acetic acid hydrochloride. The difference between this comparative example and Example 1 is that in S3, the amount of concentrated hydrochloric acid is replaced by 25 ml instead of 20 ml. All other aspects are the same as in Example 1. Finally, purified acetic acid hydrochloride is obtained with a molar yield of 77.2% and a purity of 100.0%.

[0057] Comparative Example 4 This comparative example provides a method for preparing acetic acid ketoride. The difference between this comparative example and Example 1 is that in S2, the recrystallization and filtration of ethyl acetate was not performed. All other steps are the same as in Example 1. Finally, purified acetic acid ketoride was obtained with a molar yield of 79.3% and a purity of 96.7%.

[0058] Comparative Example 5 This comparative example provides a method for preparing acetic acid ...

[0059] The above embodiments are only used to illustrate the technical solutions of the present invention, and are not intended to limit it. Although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing acetylcholine hydrochloride, characterized in that, Includes the following steps: S1. Dissolve 3-quininecycloketone hydrochloride in an organic solvent, add an inorganic base, and then add a reducing agent to react and obtain 3-quininecyclool. S2. Dissolve 3-quininecyclool in an organic solvent, add acetic anhydride to carry out esterification reaction, and after the reaction is completed, react with concentrated hydrochloric acid to obtain acetic acid ...

2. The method for preparing acetylcholine hydrochloride according to claim 1, characterized in that, The specific operation of S1 is as follows: 3-quinine cyclohexane hydrochloride is added to an organic solvent at -5℃ to 5℃, an inorganic base is added and stirred, and then a reducing agent is added and stirred for 2h to 6h. The temperature is maintained at -5℃ to 5℃ throughout the process to obtain 3-quinine cyclohexane.

3. The method for preparing acetylcholine hydrochloride according to claim 2, characterized in that, Purification of 3-quininecyclool: Concentrated hydrochloric acid was added to 3-quininecyclool until pH ≤ 6. The reaction solution was concentrated under reduced pressure until no fraction remained. The concentration temperature was maintained under reduced pressure. Water was added to dissolve the solution. Carbonate was added until saturated. Organic solvent was added for extraction 2-4 times. The extracted organic phases were combined. A drying agent was added and the mixture was stirred to dry. The solution was filtered. The filtrate was concentrated under reduced pressure until no fraction remained. The concentration temperature was maintained. A crystallization solvent was added and stirred to dissolve the solution. The solution was cooled to 0-10℃ to crystallize. The crystals were filtered and the filter cake was dried to obtain purified 3-quininecyclool.

4. The method for preparing acetylcholine hydrochloride according to claim 1, characterized in that, The specific operation of S2 is as follows: 3-quinine alcohol is added to an organic solvent and stirred, then acetic anhydride is added and the temperature is raised to 40℃~50℃. The reaction is maintained at this temperature for 2h~8h to obtain acetic acid.

5. The method for preparing acetylcholine hydrochloride according to claim 4, characterized in that, After purification, aceclidin is reacted with concentrated hydrochloric acid to obtain aceclidin hydrochloride. The specific procedure is as follows: Acetyldine was cooled to 0–10°C, and a carbonate solution was added to quench the reaction. The temperature was then raised to 10–25°C and stirred. After standing and separation, the aqueous phase was extracted twice with an organic solvent. The extracted organic phases were combined, dried with a drying agent, filtered, and the filtrate was concentrated under reduced pressure until no fraction remained. A crystallization solvent was added and stirred to dissolve the filtrate. The filtrate was then cooled to 0–10°C, and concentrated hydrochloric acid was added dropwise. The temperature was maintained at 0–10°C, and the mixture was stirred to crystallize for 1–4 hours. The filtrate was then filtered, and the filter cake was dried to obtain purified acetyldine hydrochloride.

6. The method for preparing acetylcholine hydrochloride according to claim 1, characterized in that, 3-quinine cyclic ketone hydrochloride is obtained by the following method: using ethyl N-ethyl acetate-4-piperidinecarboxylate as a raw material, a Dickmann condensation reaction is carried out under the conditions of organic solvent and organic base. After the reaction is completed, concentrated hydrochloric acid is added to obtain 3-quinine cyclic ketone hydrochloride.

7. The method for preparing acetylcholine hydrochloride according to claim 6, characterized in that, The specific steps to obtain 3-quinine cyclic ketone hydrochloride are as follows: place the organic solvent in a reaction vessel and introduce a protective gas, add an organic base, stir and heat to 60℃~100℃, then add ethyl N-ethyl acetate-4-piperidinecarboxylate and heat to 110℃ and reflux for 4h~8h, then add water to cool and quench to 0~10℃, add concentrated hydrochloric acid dropwise, stir, let stand and separate the liquid, take the aqueous phase, stir and reflux for 10h~25h to obtain 3-quinine cyclic ketone hydrochloride.

8. The method for preparing acetylcholine hydrochloride according to claim 7, characterized in that, Purification of 3-quinine cyclic ketone hydrochloride was performed as follows: The obtained 3-quinine cyclic ketone hydrochloride was heated to 60℃~80℃, activated carbon was added and stirred for decolorization, and the aqueous phase was obtained by filtration. The aqueous phase was cooled to 0~10℃, sodium hydroxide was added to adjust the pH to ≥8, and organic solvent was added for extraction 2~4 times. The extracted organic phases were combined and backwashed once with sodium hydroxide aqueous solution. After drying with a drying agent, the solution was filtered, and the filtrate was concentrated under reduced pressure until no fraction was distilled off. After dilution with a crystallization solvent, the solution was cooled to 0~10℃, concentrated hydrochloric acid was added dropwise and stirred to induce crystallization, and the solution was filtered. The filter cake was dried to obtain the purified 3-quinine cyclic ketone hydrochloride.

9. The method for preparing acetylcholine hydrochloride according to claim 7, characterized in that, The organic base includes one or more of potassium tert-butoxide, sodium methoxide, and sodium ethoxide; the weight ratio of N-ethyl acetate-4-piperidinecarboxylate to the organic base is 1:1.1 to 2.

0.

10. The method for preparing acetylcholine hydrochloride according to claim 1, characterized in that, The weight ratio of 3-quininecyclool to acetic anhydride is 1:1.2 to 1.6; the reducing agent is sodium borohydride or hydrogen; the weight ratio of 3-quininecycloone hydrochloride to sodium borohydride is 1:0.06 to 0.2; the weight ratio of 3-quininecycloone hydrochloride to inorganic base is 1:0.2 to 0.5; the inorganic base is sodium hydroxide or potassium hydroxide.

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