Preparation method of intermediate N, N-dimethyl carbamic acid m-dimethylamino phenyl ester

Abstract

The invention discloses a preparation method of an intermediate N, N-dimethyl carbamic acid m-dimethyl amino phenyl ester, which comprises the following preparation steps: S1, mixing m-nitrophenol, an organic solvent and an acid-binding agent, dropwise adding dimethyl carbamoyl chloride, reacting to obtain an intermediate N, N-dimethyl carbamic acid m-nitrophenyl ester solution, and recording as an intermediate A; s2, adding the intermediate A, a catalyst and a reducing agent into a hydrogenation reduction kettle, and reacting to obtain an intermediate N, N-dimethyl carbamic acid m-amino phenyl ester solution which is marked as an intermediate B; and S3, adding the intermediate B into a reaction bottle, dropwise adding a methylation reagent, and reacting to obtain the intermediate N, N-dimethyl carbamic acid m-dimethylamino phenyl ester. According to the invention, m-nitrophenol is taken as a starting material, the reaction functional group is single, the reaction selectivity is good, side reactions are few, and the product purity is high.

Description

Technical Field

[0001] The invention belongs to the technical field of pharmaceutical raw material preparation, and specifically relates to a method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate. Background Art

[0002] Neostigmine bromide and neostigmine methylsulfate are both cholinesterase inhibitors, which are used to antagonize the residual muscle relaxant effect of non-depolarizing muscle relaxants at the end of surgery. They can also be used for myasthenia gravis, functional intestinal flatulence and urinary retention after various surgeries, movement disorders after brain trauma, tuberculous meningitis, paralysis in the recovery period of poliomyelitis and encephalitis, optic atrophy and neuritis, as well as various bradyparalysis, muscle and neurosis in other internal medicine, gynecology and ENT departments.

[0003] The existing mature production process mainly involves the reaction of m-aminophenol and dimethyl sulfate to generate m-dimethylaminophenol, which is then reacted with dimethylaminoformyl chloride to generate the key intermediate N,N-dimethylaminoformic acid m-dimethylaminophenyl ester of neostigmine methylsulfate. Finally, the intermediate is reacted with monobromomethane to generate neostigmine bromide, and the intermediate is reacted with dimethyl sulfate to generate neostigmine methylsulfate.

[0004] Although the technical route for preparing the intermediate N,N-dimethylaminophenyl dimethylcarbamate is relatively mature and has been adopted by many companies, the reaction selectivity of the process is very poor, there are many impurities, a large amount of asphalt tar will be produced, and many impurities are also genotoxic, and each step of the reaction requires complex refining operations. The yield of the finished product is extremely low, and the quality of the product is difficult to meet the requirements of the pharmacopoeia. In view of this, it is necessary to study a preparation method for the intermediate N,N-dimethylaminophenyl dimethylcarbamate. Summary of the invention

[0005] To overcome the deficiencies in the prior art, the present invention provides a method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate, which uses m-nitrophenol as a starting material, has a single reaction functional group, good reaction selectivity, few side reactions, and high product purity.

[0006] In order to achieve the above object, the present invention adopts the following technical solution:

[0007] A method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate comprises the following preparation steps:

[0008] S1, after m-nitrophenol, an organic solvent and an acid-binding agent are mixed, dimethylcarbamoyl chloride is added dropwise, and after reaction, a solution of an intermediate N,N-dimethylcarbamic acid m-nitrophenyl ester is obtained, which is recorded as intermediate A;

[0009] S2, adding intermediate A, a catalyst and a reducing agent into a hydrogenation reduction kettle, and obtaining a solution of intermediate N,N-dimethylaminophenylcarbamate after reaction, which is recorded as intermediate B;

[0010] S3, adding intermediate B into a reaction bottle, adding a methylating agent dropwise, and obtaining the intermediate N,N-dimethylaminophenyl dimethylcarbamate after reaction;

[0011] The reaction process route is as follows:

[0012]

[0013] Preferably, in the aforementioned step S1, the acid binding agent is a combination of one or more of triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, N-methylmorpholine, N-methylpiperidine, N,N-dimethylaminopyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and sodium acetate; the organic solvent is a combination of one or more of toluene, chlorobenzene, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, and acetonitrile; and the molar ratio of the m-nitrophenol, the acid binding agent, and the dimethylaminoformyl chloride is 1:1.1-2:1.1-2.

[0014] Preferably, in the aforementioned step S2, the catalyst is a combination of one or more of palladium carbon, metallic palladium black, palladium calcium carbonate, Raney nickel, and loaded nickel; the reducing agent is a combination of one or more of hydrogen and zinc powder, iron powder, magnesium powder, hydrosulfite, sodium sulfide, or a reduction electrode in an electrochemical reduction method; the mass ratio of N,N-dimethylaminoacetic acid m-nitrophenyl ester to the catalyst is 1:0.01-0.1; the reaction pressure is 0.1-1 MPa, and the reaction temperature is room temperature to 100°C.

[0015] Preferably, in the aforementioned step S3, the reaction solvent is toluene, the methylating agent is dimethyl sulfate, and the molar ratio of N,N-dimethylaminophenyl carbamate to dimethyl sulfate is 1:2-4.

[0016] The intermediate N,N-dimethylcarbamic acid m-dimethylaminophenyl ester is used in the preparation of neostigmine bromide. The preparation method of neostigmine bromide is as follows: a solvent is added to the intermediate N,N-dimethylcarbamic acid m-dimethylaminophenyl ester, and the mixture is stirred and dissolved, and then transferred to an autoclave, monobromomethane is introduced, and neostigmine bromide is obtained after reaction.

[0017] Preferably, the aforementioned solvent is acetone, the molar ratio of N,N-dimethylaminophenyl dimethylcarbamate to methyl bromide is 1:1-2, and the reaction temperature is room temperature to 80°C.

[0018] The intermediate N,N-dimethylaminophenyl dimethylcarbamate is used in the preparation of neostigmine methylsulfate. The preparation method of neostigmine methylsulfate is as follows: a solvent and dimethyl sulfate are added to the intermediate N,N-dimethylaminophenyl dimethylcarbamate to obtain neostigmine methylsulfate after reaction.

[0019] Preferably, the molar ratio of the aforementioned solvents ethyl acetate, N,N-dimethylaminophenyl dimethylcarbamate and dimethyl sulfate is 1:1-2.

[0020] The present invention is beneficial in that:

[0021] (1) The present invention uses m-nitrophenol as a starting material, has a single reaction functional group, good reaction selectivity, few side reactions, and high product purity, which meets the quality requirements of the pharmacopoeia;

[0022] (2) The process of the present invention is simple to operate, has a single solvent, and multiple-step reactions are directly connected without purification, which is simple and efficient, avoiding the complex operations of concentration, distillation, recrystallization, filtration, drying, etc. that must be performed in multiple-step reactions in the original process, thereby improving production efficiency;

[0023] (3) The process conditions of the present invention are mild, the operation is simple and efficient, the product yield is high, the quality is good, and it is suitable for large-scale commercial production. BRIEF DESCRIPTION OF THE DRAWINGS

[0024] Figure 1 This is the process route for synthesizing the intermediate N,N-dimethylaminophenyl dimethylcarbamate of the present invention;

[0025] Figure 2 is the mass spectrum of the intermediate N,N-dimethylaminoformic acid m-nitrophenyl ester in Example 1;

[0026] Figure 3 is the mass spectrum of the intermediate N,N-dimethylaminophenyl carbamate in Example 1;

[0027] Figure 4 is the mass spectrum of the intermediate product N,N-dimethylcarbamic acid m-methylaminophenyl ester in Example 1;

[0028] Figure 5 is the mass spectrum of the intermediate N,N-dimethylaminophenyl dimethylcarbamate in Example 1;

[0029] Figure 6 is the mass spectrum of the finished product of neostigmine bromide in Example 1;

[0030] Figure 7 It is the liquid phase detection spectrum of the finished product of neostigmine bromide in Example 1;

[0031] Figure 8is the mass spectrum of the intermediate N,N-dimethylaminoformic acid m-nitrophenyl ester in Example 3;

[0032] Fig. 9 is the mass spectrum of the intermediate N,N-dimethylcarbamic acid m-aminophenyl ester in Example 3;

[0033] Fig.10 is the mass spectrum of the intermediate product N,N-dimethylaminoformic acid m-methylaminophenyl ester in Example 3;

[0034] Fig.11 is the mass spectrum of the intermediate N,N-dimethylaminophenyl dimethylcarbamate in Example 3;

[0035] Fig.12 is the mass spectrum of the finished product of neostigmine methylsulfate in Example 3;

[0036] Fig.13 It is the liquid phase detection spectrum of the finished product of neostigmine methylsulfate in Example 3. DETAILED DESCRIPTION

[0037] The present invention is described in detail below with reference to the accompanying drawings and specific embodiments.

[0038] Embodiment 1, the preparation step of neostigmine bromide is as follows:

[0039] S1. Add 500mL toluene, 100.0g m-nitrophenol, and 100.0g triethylamine to a 1L reaction bottle, start stirring, and begin to drop 100.0g dimethylaminoformyl chloride at room temperature. After the drop is completed, heat to 80℃ and keep warm to react until the remaining amount of m-nitrophenol is less than 1%. After the reaction is completed, cool to 0℃ and filter. Wash the filter cake with 50mL toluene, combine the washing filtrate, add 100.0g ice water, stir for 15 minutes, and drop 10% sodium carbonate solution until the pH of the aqueous phase is 7.5-8.0. Let stand for stratification, add 100.0g water to the organic phase, stir for 15 minutes, separate the water layer, and add 30g anhydrous sodium sulfate to the organic phase for drying. Filter to obtain a toluene solution of N,N-dimethylaminoformic acid m-nitrophenyl ester, an intermediate of neostigmine bromide, which can be directly reacted in the next step without purification.

[0040] S2, the toluene solution of N,N-dimethylaminophenyl ester of bromide neostigmine intermediate obtained in step S1 is added to a 1L hydrogenation reduction kettle, 5g of Raney nickel is added, and after nitrogen replacement three times, hydrogen is passed to a pressure of 0.5MPa at room temperature, and the reaction is stirred until no hydrogen is absorbed. The catalyst is filtered and recovered to obtain a toluene solution of N,N-dimethylaminophenyl ester of bromide neostigmine intermediate, which can be directly subjected to the next step reaction without purification.

[0041] S3, add the toluene solution of N,N-dimethylaminophenyl bromide obtained in step S2 to a 1L reaction bottle, add 272g of dimethyl sulfate dropwise under room temperature stirring, and heat to 70°C, keep warm until the sum of the content of N,N-dimethylaminophenyl bromide intermediate and intermediate product N,N-dimethylaminophenyl bromide in the lower layer sample of the reaction solution is less than 2%. After the reaction conversion is qualified, cool to 10°C, add an appropriate amount of powdered sodium carbonate, and adjust the pH of the reaction solution to 7.5-8.0. Filter, decompress the filtrate to recover the solvent, and recover the solvent. The key intermediate of neostigmine bromide, N,N-dimethylaminophenyl dimethylamine, is obtained, and the next step of reaction can be directly carried out without purification.

[0042] S4, add 800mL of acetone to the N,N-dimethylaminophenyl bromide intermediate obtained in step S3, transfer to an autoclave after stirring and dissolving, and introduce monobromomethane to a pressure of 0.3MPa after nitrogen replacement. Stir, heat to 55°C, and keep warm to react until the N,N-dimethylaminophenyl bromide intermediate is completely reacted. Cool to 0°C, keep warm and stir for 3 hours, filter, dissolve the filter cake with 1.0 times the weight of the filter cake in anhydrous ethanol, add 8g of activated carbon for decolorization, filter, add 4 times the weight of the filter cake in acetone to the filtrate, stir evenly, cool to 0°C, add an appropriate amount of seed crystals, stir to precipitate crystals, continue to slowly cool to -10°C, and keep warm and stir for 4 hours. After filtration, the filter cake was vacuum dried at a vacuum degree of -0.08 to -0.095 MPa and a temperature of 50° C. for 6 to 8 hours to obtain 175 g of a finished product of neostigmine bromide.

[0043] The reaction process route is as follows:

[0044]

[0045] Embodiment 2, the preparation step of neostigmine bromide is as follows:

[0046] S1. Add 500mL toluene, 100.0g m-nitrophenol, and 77.0g pyridine to a 1L reaction bottle, start stirring, and begin to drop 100.0g dimethylaminoformyl chloride at room temperature. After the drop is completed, heat to 80℃ and keep warm to react until the remaining amount of m-nitrophenol is less than 1%. After the reaction is completed, cool to 0℃ and filter. Wash the filter cake with 50mL toluene, combine the washing filtrate, add 100.0g ice water, stir for 15 minutes, and drop 10% sodium carbonate solution until the pH of the aqueous phase is 7.5-8.0. Let stand for stratification, add 100.0g water to the organic phase, stir for 15 minutes, separate the water layer, and add 30g anhydrous sodium sulfate to the organic phase for drying. Filter to obtain a toluene solution of N,N-dimethylaminoformic acid m-nitrophenyl ester, an intermediate of neostigmine bromide, which can be directly used for the next step of reaction.

[0047] S2, add the toluene solution of N,N-dimethylaminophenyl bromide obtained in step S1 into a 1L hydrogenation reduction kettle, add 4g of palladium carbon with a palladium content of 10%, replace it with nitrogen three times, pass hydrogen to a pressure of 0.5MPa at room temperature, and stir to react until no hydrogen is absorbed. Filter and recover the catalyst to obtain a toluene solution of N,N-dimethylaminophenyl bromide, an intermediate of neostigmine, which can be directly used for the next step without purification.

[0048] S3, add the toluene solution of N,N-dimethylaminophenyl bromide obtained in step S2 to a 1L reaction bottle, add 272g of dimethyl sulfate dropwise under room temperature stirring, and heat to 70°C, keep warm until the sum of the content of N,N-dimethylaminophenyl bromide intermediate and intermediate product N,N-dimethylaminophenyl bromide in the lower layer sample of the reaction solution is less than 2%. After the reaction conversion is qualified, cool to 10°C, add an appropriate amount of powdered sodium carbonate, and adjust the pH of the reaction solution to 7.5-8.0. Filter, decompress the filtrate to recover the solvent, and recover the solvent. The key intermediate of neostigmine bromide, N,N-dimethylaminophenyl dimethylamine, is obtained, and the next step of reaction can be directly carried out without purification.

[0049] S4, add 800ml of acetone to the N,N-dimethylaminophenyl bromide intermediate obtained in step S3, stir and dissolve, transfer to an autoclave, and after nitrogen replacement, introduce bromomethane to a pressure of 0.3MPa. Stir, heat to 55°C, and keep warm to react until the N,N-dimethylaminophenyl bromide intermediate is completely reacted. Cool to 0°C, keep warm and stir for 3 hours, filter, dissolve the filter cake with 1.0 times the weight of the filter cake in anhydrous ethanol, add 8g of activated carbon for decolorization, filter, add 4 times the weight of the filter cake in acetone to the filtrate, stir evenly, cool to 0°C, add an appropriate amount of seed crystals, stir to precipitate crystals, continue to slowly cool to -10°C, and keep warm and stir for 4 hours. After filtration, the filter cake was vacuum dried at a vacuum degree of -0.08 to -0.095 MPa and a temperature of 50° C. for 6 to 8 hours to obtain 177 g of a finished product of neostigmine bromide.

[0050] Embodiment 3, the preparation steps of neostigmine bromide are as follows:

[0051] S1. Add 500mL toluene, 100.0g m-nitrophenol, and 100.0g triethylamine to a 1L reaction bottle, start stirring, and begin to drop 100.0g dimethylaminoformyl chloride at room temperature. After the drop is completed, heat to 80℃ and keep warm to react until the remaining amount of m-nitrophenol is less than 1%. After the reaction is completed, cool to 0℃ and filter. Wash the filter cake with 50mL toluene, combine the washing filtrate, add 100.0g ice water, stir for 15 minutes, and drop 10% sodium carbonate solution until the pH of the aqueous phase is 7.5-8.0. Let stand for stratification, add 100.0g water to the organic phase, stir for 15 minutes, separate the water layer, and add 30g anhydrous sodium sulfate to the organic phase for drying. Filter to obtain a toluene solution of N,N-dimethylaminoformic acid m-nitrophenyl ester, an intermediate of neostigmine methylsulfate, which can be directly used for the next step of reaction.

[0052] S2, the toluene solution of N, N-dimethylaminophenyl methylsulfate intermediate of neostigmine obtained in step S1 is added to a 1L hydrogenation reduction kettle, 5g of Raney nickel is added, and after nitrogen replacement three times, hydrogen is passed to a pressure of 0.5MPa at room temperature, and the reaction is stirred until no hydrogen is absorbed. The catalyst is filtered and recovered to obtain a toluene solution of N, N-dimethylaminophenyl methylsulfate intermediate of neostigmine, which can be directly subjected to the next step of reaction without purification.

[0053] S3, add the toluene solution of the intermediate N,N-dimethylaminophenyl carbamate of neostigmine methylsulfate obtained in step S2 to a 1L reaction bottle, add 272g of dimethyl sulfate dropwise under stirring at room temperature, raise the temperature to 70°C, and keep the reaction warm until the sum of the intermediate N,N-dimethylaminophenyl carbamate of neostigmine methylsulfate and the intermediate product N,N-dimethylaminophenyl carbamate in the lower layer sample of the reaction solution is less than 2%. After the reaction conversion is qualified, the solvent is recovered under reduced pressure and the recovery is completed. The key intermediate N,N-dimethylaminophenyl carbamate of neostigmine methylsulfate is obtained, and the next step reaction can be directly carried out without purification.

[0054] S4, add 800mL ethyl acetate and 136g dimethyl sulfate to the intermediate N,N-dimethylaminophenyl dimethylcarbamate of neostigmine methylsulfate obtained in step S3. Stir, heat to 55°C, and keep warm to react until the intermediate N,N-dimethylaminophenyl dimethylcarbamate of neostigmine methylsulfate reacts completely, and a large amount of white crystals are precipitated. Cool to 0°C, keep warm and stir for 3 hours, and filter. The filter cake is dissolved in anhydrous ethanol 1.5 times the weight of the filter cake, 8g activated carbon is added for decolorization, filtered, 4.0 times the weight of the filter cake acetone is added to the filtrate, stirred evenly, cooled to 0°C, added with an appropriate amount of seed crystals, stirred to precipitate crystals, and then slowly cooled to -10°C, kept warm and stirred for 4 hours. Filter, the filter cake is vacuum dried for 6 to 10 hours under the conditions of vacuum degree of -0.08 to -0.095Mpa and temperature of 55°C to obtain 206g of finished product of neostigmine methylsulfate.

[0055] The reaction process route is as follows:

[0056]

[0057] Embodiment 4, the preparation steps of neostigmine bromide are as follows:

[0058] S1. Add 500mL toluene, 100.0g m-nitrophenol, and 77.0g pyridine to a 1L reaction bottle, start stirring, and begin to drop 100.0g dimethylaminoformyl chloride at room temperature. After the drop is completed, heat to 80℃ and keep warm to react until the remaining amount of m-nitrophenol is less than 1%. After the reaction is completed, cool to 0℃ and filter. Wash the filter cake with 50mL toluene, combine the washing filtrate, add 100.0g ice water, stir for 15 minutes, and drop 10% sodium carbonate solution until the pH of the aqueous phase is 7.5-8.0. Let stand for stratification, add 100.0g water to the organic phase, stir for 15 minutes, separate the water layer, and add 30g anhydrous sodium sulfate to the organic phase for drying. Filter to obtain a toluene solution of N,N-dimethylaminoformic acid m-nitrophenyl ester, an intermediate of neostigmine methylsulfate, which can be directly used for the next step of reaction.

[0059] S2, the toluene solution of the neostigmine methylsulfate intermediate N,N-dimethylaminophenyl carbamate obtained in step S1 is added to a 1L hydrogenation reduction kettle, 4g of palladium carbon with a palladium content of 10% is added, and after nitrogen replacement three times, hydrogen is passed to a pressure of 0.5MPa at room temperature, and the reaction is stirred until no hydrogen is absorbed. The catalyst is filtered and recovered to obtain a toluene solution of the neostigmine methylsulfate intermediate N,N-dimethylaminophenyl carbamate, which can be directly used for the next step reaction without purification.

[0060] S3, add the toluene solution of the intermediate N,N-dimethylaminophenyl carbamate of neostigmine methylsulfate obtained in step S2 to a 1L reaction bottle, add 272g of dimethyl sulfate dropwise under stirring at room temperature, raise the temperature to 70°C, and keep the reaction warm until the sum of the intermediate N,N-dimethylaminophenyl carbamate of neostigmine methylsulfate and the intermediate product N,N-dimethylaminophenyl carbamate in the lower layer sample of the reaction solution is less than 2%. After the reaction conversion is qualified, the solvent is recovered under reduced pressure and the recovery is completed. The key intermediate N,N-dimethylaminophenyl carbamate of neostigmine methylsulfate is obtained, and the next step reaction can be directly carried out without purification.

[0061] S4, add 800mL ethyl acetate and 136g dimethyl sulfate to the intermediate N,N-dimethylaminophenyl dimethylcarbamate of neostigmine methylsulfate obtained in step S3. Stir, heat to 55°C, and keep warm to react until the intermediate N,N-dimethylaminophenyl dimethylcarbamate of neostigmine methylsulfate reacts completely, and a large amount of white crystals are precipitated. Cool to 0°C, keep warm and stir for 3 hours, and filter. The filter cake is dissolved with 1.5 times the weight of the filter cake in anhydrous ethanol, 8g of activated carbon is added for decolorization, filtered, 4.0 times the weight of the filter cake is added to the filtrate, acetone is added dropwise, stirred evenly, cooled to 0°C, an appropriate amount of seed crystals is added, and after stirring and precipitating crystals, the temperature is slowly cooled to -10°C, and the temperature is kept warm and stirred for 4 hours. Filter, the filter cake is vacuum dried for 6 to 10 hours under the conditions of vacuum degree of -0.08 to -0.095Mpa and temperature of 55°C to obtain 208g of finished product of neostigmine methylsulfate.

[0062] The intermediates and products obtained in Examples 1 to 4 were subjected to high performance liquid chromatography (HPLC) analysis experiments to obtain HPLC purity and calculate the yield. The specific results are shown in Table 1.

[0063] Table 1 HPLC purity and yield of each intermediate and product

[0064]

[0065]

[0066] The above shows and describes the basic principles, main features and advantages of the present invention. Those skilled in the art should understand that the above embodiments do not limit the present invention in any form, and any technical solution obtained by equivalent replacement or equivalent transformation falls within the protection scope of the present invention.

Claims

1. A method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate, characterized in that: The method comprises the following preparation steps: S1, after m-nitrophenol, an organic solvent and an acid-binding agent are mixed, dimethylcarbamoyl chloride is added dropwise, and after reaction, a solution of an intermediate N,N-dimethylcarbamic acid m-nitrophenyl ester is obtained, which is recorded as intermediate A; S2, adding intermediate A, a catalyst and a reducing agent into a hydrogenation reduction kettle, and obtaining a solution of intermediate N,N-dimethylaminophenylcarbamate after reaction, which is recorded as intermediate B; S3, adding intermediate B into a reaction bottle, adding a methylating agent dropwise, and obtaining the intermediate N,N-dimethylaminophenyl dimethylcarbamate after reaction; The reaction process route is as follows:

2. The method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate according to claim 1, characterized in that: In the step S1, the acid binding agent is a combination of one or more of triethylamine, diisopropylethylamine, N,N-dimethylaniline, pyridine, N-methylmorpholine, N-methylpiperidine, N,N-dimethylaminopyridine, sodium bicarbonate, sodium carbonate, potassium carbonate, calcium carbonate, potassium bicarbonate, and sodium acetate; the organic solvent is a combination of one or more of toluene, chlorobenzene, ethyl acetate, dichloromethane, chloroform, tetrahydrofuran, and acetonitrile; and the molar ratio of the m-nitrophenol, the acid binding agent, and the dimethylaminoformyl chloride is 1:1.1-2:1.1-2.

3. The method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate according to claim 1, characterized in that: In the step S2, the catalyst is a combination of one or more of palladium carbon, metal palladium black, palladium calcium carbonate, Raney nickel, and supported nickel; the reducing agent is a combination of one or more of hydrogen and zinc powder, iron powder, magnesium powder, hydrosulfite, sodium sulfide, or a reduction electrode in an electrochemical reduction method; The mass ratio of N,N-dimethylaminoacetic acid m-nitrophenyl ester to the catalyst is 1:0.01-0.1; the reaction pressure is 0.1-1MPa, and the reaction temperature is room temperature-100°C.

4. The method for preparing an intermediate N,N-dimethylaminophenyl dimethylcarbamate according to claim 1, characterized in that: In the step S3, the reaction solvent is toluene, the methylating agent is dimethyl sulfate, and the molar ratio of N,N-dimethylaminophenyl carbamate to dimethyl sulfate is 1:2-4.

5. The use of an intermediate N,N-dimethylaminophenyl dimethylcarbamate in the preparation of neostigmine bromide according to claim 1, characterized in that: The preparation method of neostigmine bromide is as follows: a solvent is added to the intermediate N,N-dimethylaminophenyl dimethylcarbamate, the mixture is stirred and dissolved, and then the mixture is transferred into an autoclave, monobromomethane is introduced, and neostigmine bromide is obtained after reaction.

6. The use according to claim 5, characterized in that: The solvent is acetone, the molar ratio of N,N-dimethylaminophenyl dimethylcarbamate to methyl bromide is 1:1-2, and the reaction temperature is room temperature-80°C.

7. Use of an intermediate N,N-dimethylaminophenyl dimethylcarbamate according to claim 1 in the preparation of neostigmine methylsulfate, characterized in that: The preparation method of neostigmine methylsulfate is as follows: a solvent and dimethyl sulfate are added to an intermediate N,N-dimethylaminophenyl dimethylcarbamate, and neostigmine methylsulfate is obtained after reaction.

8. The use according to claim 7, characterized in that: The molar ratio of the solvent ethyl acetate, N,N-dimethylaminophenyl dimethylcarbamate and dimethyl sulfate is 1:1-2.

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