Synthesis method of methoxyamine hydrochloride

Abstract

The invention discloses a method for synthesizing methoxyamine hydrochloride, which comprises the following steps of: adding sodium nitrite into acetylacetone under an acidic condition to synthesize 2, 3, 4-pentanetrione oxime; adjusting the reaction liquid to be alkaline, and adding a phase transfer catalyst and a methylation reagent to synthesize 3-(O-methyl oxime)-2, 3, 4-pentanetrione; and adjusting the reaction liquid to be strongly acidic, hydrolyzing, and rectifying to recover pentane-2, 3, 4-triketone, thereby obtaining the methoxyamine hydrochloride. According to the method, acetylacetone is adopted as a synthesis raw material, only an organic solvent is used for extracting an intermediate product before rectification, inorganic salt in reaction liquid is separated, the problem of recovery of difficult-to-recover substances such as ethyl alcohol and acetic acid is solved, the synthesis route is simple, operation is easy and convenient, aftertreatment is convenient, few hazardous waste is generated, investment cost is low, and labor cost and energy consumption are reduced; meanwhile, side reactions in the hydrolysis process can be reduced, and the yield of the product is improved.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical manufacturing intermediates technology, and more specifically, to a method for synthesizing methoxyamine hydrochloride. Background Technology

[0002] Methoxyamine hydrochloride is an organic compound with the chemical formula CH6ONCl, and is a white or slightly yellow crystalline solid. It is an important chemical raw material used in the production of antibiotics such as cefuroxime axetil and phenoxyamine bactericides. Methoxyamine hydrochloride is also a pharmaceutical product commonly used in surgery to maintain or restore arterial pressure, particularly effective for reducing blood pressure caused by spinal anesthesia.

[0003] Currently, the main methods used to synthesize methoxyamine hydrochloride are: Ji Yongxin (Chemistry and Adhesion, 2001, 5, 200-202) introduced a synthetic route: sodium hydroxylamine sulfite is first synthesized by reacting sodium bisulfite and sulfur dioxide with sodium nitrite, followed by methylation, hydrolysis, and neutralization to form the product. This process requires the use of liquid sulfur dioxide and sodium nitrite, which are highly toxic and cause serious pollution. Furthermore, producing one ton of product generates more than ten tons of wastewater containing large amounts of sodium sulfate, as well as large quantities of nitrogen oxides and other waste gases, thus posing certain safety and environmental problems.

[0004] Han Shidong et al. (Zhejiang Chemical Industry, 2005, 36(9), 14-16) and Pan Zhongwen et al. (Fine Chemical Intermediates, 2007, 37(6), 17-18, 21) introduced a process for synthesizing alkoxyamines by hydrolysis of acetone oxime ether and O-alkyl phthalimide. The hydrolysis of acetone oxime ether requires continuous distillation of acetone in a distillation column to promote the reaction. Azeotropic dehydrating agents such as toluene and hexane are also added to help dehydration. Furthermore, it is not easy to control the side reactions generated during the hydrolysis process, which leads to a decrease in yield and an increase in cost.

[0005] Li Wenxiao et al. (Fine Chemical Raw Materials and Intermediates, 2007, 22-23, 29) introduced a process for preparing ethoxyamine by protecting N-ethylamine through oxime reaction of ethyl acetate and hydroxylamine, followed by ethylation with diethyl sulfate to generate ether, and then hydrolysis. In this process, after ethylation, impurities such as N-ethyl-O-ethylamine are removed by vacuum distillation. The product ethoxyamine is obtained by acid hydrolysis, neutralization, and distillation, with a yield of 85% and a product molar fraction of 98%. However, the process has problems such as difficulty in achieving the desired effect in removing impurities by distillation and difficulty in controlling the process conditions such as ethylation.

[0006] The invention patent application document CN101357895A, entitled "Method for Synthesizing Methoxyamine Hydrochloride", is basically the same as the method described by Li Wenxiao et al. above. Both of them have the problems of large investment and high recovery costs for ethanol and acetic acid, as well as long synthesis routes and complicated post-processing.

[0007] In view of the above, this application is hereby submitted. Summary of the Invention

[0008] To address the aforementioned technical problems in the existing technology, this invention provides a method for synthesizing methoxyamine hydrochloride, using acetylacetone as the raw material. It only requires the extraction of intermediate products with an organic solvent before distillation to separate inorganic salts from the reaction solution, thus avoiding the recovery problems of difficult-to-recover substances such as ethanol and acetic acid. At the same time, it can reduce side reactions in the hydrolysis process and improve the product yield.

[0009] This invention is achieved through the following technical solution: A method for synthesizing methoxyamine hydrochloride includes the following steps: 2,3,4-pentanetrione oxime was synthesized by adding sodium nitrite to acetylacetone under acidic conditions; After adjusting the reaction solution to alkaline, a phase transfer catalyst and a methylation reagent were added to synthesize 3-(O-methyloxime)-2,3,4-pentanetrione; The reaction solution was adjusted to a strongly acidic state for hydrolysis, and after pentane-2,3,4-trione was recovered by distillation, methoxyamine hydrochloride was obtained.

[0010] In one specific embodiment, the reaction route of methoxyamine hydrochloride is shown below: .

[0011] In a specific embodiment, the specific synthesis steps of methoxyamine hydrochloride are as follows: S1, add acetylacetone, water, and sodium nitrite to the reaction vessel; S2, lower the temperature to 0~25℃, and slowly add inorganic acid over a period of 0.5~3 hours; After adding S3, keep the reaction at 5~30℃ for 3~6 hours. S4, after the reaction is complete, add an inorganic base to adjust the reaction solution to alkaline, and then add a phase transfer catalyst; S5, lower the temperature to 0~15℃, and slowly add the methylating agent over a period of 0.5~3 hours; S6, after the reaction is complete, add an organic solvent to extract 3-(O-methyloxime)-2,3,4-pentanetrione; S7, hydrochloric acid is used to adjust the organic solvent to a strong acid; S8. The mixed solution obtained in step S7 is distilled. The temperature of the lower half of the distillation column is controlled at 40~65℃. The organic solvent is recovered from the top of the column and the distillation continues until no more organic solvent is distilled from the top of the column. The temperature of the lower half of the distillation column is controlled at 80~95℃. The pentane-2,3,4-trione is recovered from the bottom of the column. The bottom of the column is an aqueous solution of methoxyamine hydrochloride. The aqueous solution of methoxyamine hydrochloride at the bottom of the column is heated and evaporated to obtain its hydrochloride concentrate, or it is vacuum dried to obtain its hydrochloride solid product.

[0012] In one specific embodiment, in step S1, the amount of water used is 3 to 10 times the weight of acetylacetone; the molar ratio of sodium nitrite to acetylacetone is 1.2 to 2.5:1. Preferably, the amount of water used is 5 to 10 times the weight of acetylacetone to avoid insufficient water affecting stirring efficiency and slowing down the reaction rate due to continuous addition of materials in the "one-pot method".

[0013] In one specific embodiment, in step S2, the molar ratio of inorganic acid to acetylacetone is 1.2~2.5:1.

[0014] In one specific embodiment, in step S2, the inorganic acid is one or more of hydrochloric acid, nitric acid, and sulfuric acid.

[0015] In a specific embodiment, in step S3, the reaction temperature is preferably 5~10℃, the reaction time is preferably 4~6h, and the acetylacetone content is controlled to be ≤5%.

[0016] In a specific embodiment, in step S4, the molar ratio of inorganic base to acetylacetone is 2.5~3.5:1; the amount of phase transfer catalyst is 0.01~0.05 times the weight of acetylacetone; the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; the phase transfer catalyst is one or more of tetrabutylammonium bromide, trimethyldodecylammonium chloride, and triethylamine.

[0017] In a specific embodiment, in step S5, the molar ratio of the methylating agent to acetylacetone is 1.1 to 1.5:1; the methylating agent is dimethyl sulfate, bromomethane, or chloromethane.

[0018] In one specific embodiment, in step S6, the organic solvent is dichloromethane, petroleum ether, dichloroethane, or ethyl acetate.

[0019] In one specific embodiment, in step S7, the molar ratio of hydrochloric acid to acetylacetone is 1.6~2.5:1.

[0020] Compared with the prior art, the present invention has the following advantages and beneficial effects: 1. The method for synthesizing methoxyamine hydrochloride provided in this embodiment of the invention has a simple synthesis route and simple operation. It only requires the extraction of intermediate products with organic solvents before distillation and the separation of inorganic salts in the reaction solution. The post-processing is convenient, the generation of hazardous waste is small, the investment cost is low, and the labor cost and energy consumption are reduced. 2. The method for synthesizing methoxyamine hydrochloride provided in this embodiment of the invention avoids the problem of recovering difficult-to-recover substances such as ethanol and acetic acid compared with the original ethyl acetate oxime process. The process is simple and reduces investment costs. 3. The method for synthesizing methoxyamine hydrochloride provided in this embodiment of the invention uses acetylacetone as a raw material, which can reduce side reactions in the hydrolysis process and improve the synthesis yield of methoxyamine hydrochloride. Detailed Implementation

[0021] To make the objectives, technical solutions, and advantages of this invention clearer, the invention will be further described in detail below with reference to the embodiments. The illustrative embodiments and descriptions of this invention are only used to explain this invention and are not intended to limit this invention.

[0022] In the following description, numerous specific details are set forth in order to provide a thorough understanding of the invention. However, it will be apparent to those skilled in the art that these specific details are not necessary to practice the invention. In other embodiments, well-known materials or methods have not been specifically described in order to avoid obscuring the invention.

[0023] Throughout this specification, references to “an embodiment,” “an example,” or “an example” mean that a particular feature, structure, or characteristic described in connection with that embodiment or example is included in at least one embodiment of the invention. Therefore, the phrases “an embodiment,” “an example,” “an example,” or “an example” appearing in various places throughout the specification do not necessarily refer to the same embodiment or example. Furthermore, specific features, structures, or characteristics can be combined in one or more embodiments or examples in any suitable combination and / or sub-combination. The term “and / or” as used herein includes any and all combinations of one or more of the associated listed items.

[0024] The "range" disclosed in this application is defined by a lower limit and an upper limit. A given range is defined by selecting a lower limit and an upper limit, which define the boundaries of a particular range. Ranges defined in this way can include or exclude endpoints and can be arbitrarily combined; that is, any lower limit can be combined with any upper limit to form a range. For example, if ranges of 60–120 and 80–110 are listed for a specific parameter, it is understood that ranges of 60–110 and 80–120 are also expected. Furthermore, if minimum range values ​​of 1 and 2 are listed, and if maximum range values ​​of 3, 4, and 5 are listed, then the following ranges are all expected: 1–3, 1–4, 1–5, 2–3, 2–4, and 2–5. In this application, unless otherwise stated, the numerical range "a–b" represents a shortened representation of any combination of real numbers between a and b, where a and b are real numbers. For example, the numerical range "0-5" indicates that all real numbers between "0" and "5" have been listed in this document; "0-5" is merely a shortened representation of these numerical combinations. Furthermore, when a parameter is described as an integer ≥2, it is equivalent to disclosing that the parameter is, for example, an integer 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, etc. Unless otherwise specified, all steps in this application can be performed sequentially or randomly, preferably sequentially. For example, the method includes steps (a) and (b), indicating that the method may include steps (a) and (b) performed sequentially, or it may include steps (b) and (a) performed sequentially. For example, the method may also include step (c), indicating that step (c) can be added to the method in any order; for example, the method may include steps (a), (b), and (c), or it may include steps (a), (c), and (b), or it may include steps (c), (a), and (b), etc.

[0025] Current methods for synthesizing methoxyamine hydrochloride suffer from problems such as high investment and high recovery costs for ethanol and acetic acid, as well as long synthesis routes and cumbersome post-processing.

[0026] To address the aforementioned technical problems in the existing technology, the present invention provides a method for synthesizing methoxyamine hydrochloride, comprising the following steps: 2,3,4-pentanetrione oxime was synthesized by adding sodium nitrite to acetylacetone under acidic conditions; After adjusting the reaction solution to alkaline, a phase transfer catalyst and a methylation reagent were added to synthesize 3-(O-methyloxime)-2,3,4-pentanetrione; The reaction solution was adjusted to a strongly acidic state for hydrolysis, and after pentane-2,3,4-trione was recovered by distillation, methoxyamine hydrochloride was obtained.

[0027] In one specific embodiment, the reaction route of methoxyamine hydrochloride is shown below: .

[0028] In a specific embodiment, the specific synthesis steps of methoxyamine hydrochloride are as follows: S1, add acetylacetone, water, and sodium nitrite to the reaction vessel; S2, lower the temperature to 0~25℃, and slowly add inorganic acid over a period of 0.5~3 hours; After adding S3, keep the reaction at 5~30℃ for 3~6 hours. S4, after the reaction is complete, add an inorganic base to adjust the reaction solution to alkaline, and then add a phase transfer catalyst; S5, lower the temperature to 0~15℃, and slowly add the methylating agent over a period of 0.5~3 hours; S6, after the reaction is complete, add an organic solvent to extract 3-(O-methyloxime)-2,3,4-pentanetrione; S7, hydrochloric acid is used to adjust the organic solvent to a strong acid; S8. The mixed solution obtained in step S7 is distilled. The temperature of the lower half of the distillation column is controlled at 40~65℃. The organic solvent is recovered from the top of the column and the distillation continues until no more organic solvent is distilled from the top of the column. The temperature of the lower half of the distillation column is controlled at 80~95℃. The pentane-2,3,4-trione is recovered from the bottom of the column. The bottom of the column is an aqueous solution of methoxyamine hydrochloride. The aqueous solution of methoxyamine hydrochloride at the bottom of the column is heated and evaporated to obtain its hydrochloride concentrate, or it is vacuum dried to obtain its hydrochloride solid product.

[0029] In one specific embodiment, in step S1, the amount of water used is 3 to 10 times the weight of acetylacetone; the molar ratio of sodium nitrite to acetylacetone is 1.2 to 2.5:1. Preferably, the amount of water used is 5 to 10 times the weight of acetylacetone to avoid insufficient water affecting stirring efficiency and slowing down the reaction rate due to continuous addition of materials in the "one-pot method".

[0030] In one specific embodiment, in step S2, the molar ratio of inorganic acid to acetylacetone is 1.2~2.5:1.

[0031] In one specific embodiment, in step S2, the inorganic acid is one or more of hydrochloric acid, nitric acid, and sulfuric acid.

[0032] In a specific embodiment, in step S3, the reaction temperature is preferably 5~10℃, the reaction time is preferably 4~6h, and the acetylacetone content is controlled to be ≤5%.

[0033] In a specific embodiment, in step S4, the molar ratio of inorganic base to acetylacetone is 2.5~3.5:1; the amount of phase transfer catalyst is 0.01~0.05 times the weight of acetylacetone; the inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; the phase transfer catalyst is one or more of tetrabutylammonium bromide, trimethyldodecylammonium chloride, and triethylamine.

[0034] In a specific embodiment, in step S5, the molar ratio of the methylating agent to acetylacetone is 1.1 to 1.5:1; the methylating agent is dimethyl sulfate, bromomethane, or chloromethane.

[0035] In one specific embodiment, in step S6, the organic solvent is dichloromethane, petroleum ether, dichloroethane, or ethyl acetate.

[0036] In one specific embodiment, in step S7, the molar ratio of hydrochloric acid to acetylacetone is 1.6~2.5:1.

[0037] Example 1 This invention provides a method for synthesizing methoxyamine hydrochloride, comprising the following steps: (1) In a 1000 mL three-necked flask equipped with an electric stirrer, thermometer, and condenser, 100 g of acetylacetone, 87.6 g of anhydrous sodium nitrite, and 650 ml of drinking water were added. The stirrer was turned on, and 211.5 g of 50% sulfuric acid was added dropwise at 10-20℃. The reaction was maintained at 10-15℃ for 3 h. The acetylacetone concentration was measured to be 2.14%. 206 g of sodium carbonate and 2.0 g of TBAB were added. 181 g of dimethyl sulfate was added dropwise at 0-10℃. The reaction was maintained at 10-15℃ for 3 h. 130 ml of dichloromethane was added for extraction twice. (2) Add 305 g of 20% hydrochloric acid aqueous solution to dichloromethane phase and stir for 0.5 h. Prepare a glass distillation column with an inner diameter of 20 mm and a height of 1000 mm and filled with spring glass packing. Connect a 500 mL distillation flask to the lower end of the distillation column and a preheating device below it. (3) Preheat the distillation flask and the lower half of the distillation column to 45°C, collect the top fraction of the column until no more dichloromethane is distilled out, and the distillate contains 301 g; (4) Continue to preheat the lower half to 95°C for distillation, collect the top fraction until no more fractions are distilled off, and recover 107.1g; (5) The residual liquid in the bottle is 198 g. The residual liquid is distilled under reduced pressure at 50℃ until there is no distillate. The product is dried under vacuum at 50℃ to obtain 73.58 g of product, with a yield of 88.1% and a molar fraction of 99.5%. It is a white crystal with a melting point of 149.2-151.5℃ and a content of 99.4% (GC). 1HNMR(DMSO-d6)δ(ppm):3.79(t,3H-CH3),11.03 (s,3H,-NH3 + ).

[0038] Example 2 This invention provides a method for synthesizing methoxyamine hydrochloride, comprising the following steps: (1) In a 500 mL three-necked flask equipped with an electric stirrer, thermometer, and condenser, 50 g of acetylacetone, 48 g of anhydrous sodium nitrite, and 250 ml of drinking water were added. The stirrer was turned on, and 107.14 g of 50% sulfuric acid was added dropwise at 10-20℃. The reaction was maintained at 10-15℃ for 3 h. The acetylacetone concentration was measured to be 2.01%. 110 g of potassium carbonate and 0.95 g of TBAB were added. 94 g of dimethyl sulfate was added dropwise at 0-10℃. The reaction was maintained at 10-15℃ for 3 h. 70 ml of dichloroethane was added for extraction twice. (2) Add 160 g of 20% hydrochloric acid aqueous solution to dichloroethane phase and stir for 0.5 h. Prepare a glass distillation column with an inner diameter of 20 mm and a height of 1000 mm and filled with spring glass packing. Connect a 250 mL distillation flask to the lower end of the distillation column and a preheating device below it. (3) Preheat the distillation flask and the lower half of the distillation column to 45°C, collect the top fraction of the column until no more dichloroethane is distilled off, and the distillate contains 129 g. (4) Continue to preheat the lower half to 95°C for distillation, collect the top fraction until no more fractions are distilled off, and recover 50 g; (5) The residual liquid in the bottle is 91.39 g. The residual liquid is distilled under reduced pressure at 50℃ until there is no distillate. The product is dried under vacuum at 50℃ to obtain 35.58 g of product, with a yield of 85.2% and a molar fraction of 99.7%. It is a white crystal with a melting point of 149.2-151.5℃ and a content of 99.2% (GC). 1 HNMR(DMSO-d6)δ(ppm):3.79(t,3H-CH3),11.03 (s,3H,-NH3 + ).

[0039] Example 3 This invention provides a method for synthesizing methoxyamine hydrochloride, comprising the following steps: (1) In a 500 mL three-necked flask equipped with an electric stirrer, thermometer, and condenser, add 50 g of acetylacetone, 50 g of anhydrous sodium nitrite, and 300 ml of drinking water. Turn on the stirrer and add 45 g of 50% hydrochloric acid dropwise at 10-20℃. Keep the reaction temperature at 10-15℃ for 3 h. The acetylacetone concentration is 2.01%. Add 39 g of sodium hydroxide and 1 g of TBAB. Keep the temperature at 0-10℃ and add 100 g of dimethyl sulfate dropwise. Keep the reaction temperature at 10-15℃ for 3 h. Add 100 ml of dichloromethane and extract twice. (2) Add 150 g of 20% hydrochloric acid aqueous solution to dichloromethane phase and stir for 0.5 h. Prepare a glass distillation column with an inner diameter of 20 mm and a height of 1000 mm and filled with spring glass packing. Connect a 250 mL distillation flask to the lower end of the distillation column and a preheating device below it. (3) Preheat the distillation flask and the lower half of the distillation column to 45°C, collect the top fraction of the column until no more dichloroethane is distilled off, and the distillate contains 144 g. (4) Continue to preheat the lower half to 95°C for distillation, collect the top fraction until no more fractions are distilled off, and recover 67 g; (5) The residual liquid in the bottle is 95.87 g. The residual liquid is distilled under reduced pressure at 50℃ until there is no distillate. The product is dried under vacuum at 50℃ to obtain 35.93 g of product, with a yield of 86.05% and a molar fraction of 99.3%. It is a white crystal with a melting point of 149.2-151.5℃ and a content of 99% (GC). 1 HNMR(DMSO-d6)δ(ppm):3.79(t,3H-CH3),11.03 (s,3H,-NH3 + ).

[0040] Example 4 This invention provides a method for synthesizing methoxyamine hydrochloride, comprising the following steps: (1) In a 500 mL three-necked flask equipped with an electric stirrer, thermometer, and condenser, 50 g of acetylacetone, 49.52 g of anhydrous sodium nitrite, and 300 ml of drinking water were added. The stirrer was turned on, and 97.15 g of 50% nitric acid was added dropwise at 10-20℃. The reaction was maintained at 10-15℃ for 3 h. The acetylacetone concentration was measured to be 2.11%. 42 g of potassium hydroxide and 1 g of TBAB were added. 96 g of dimethyl sulfate was added dropwise at 0-10℃. The reaction was maintained at 10-15℃ for 3 h. 100 ml of dichloromethane was added for extraction twice. (2) Add 150 g of 20% hydrochloric acid aqueous solution to dichloromethane phase and stir for 0.5 h. Prepare a glass distillation column with an inner diameter of 20 mm and a height of 1000 mm and filled with spring glass packing. Connect a 250 mL distillation flask to the lower end of the distillation column and a preheating device below it. (3) Preheat the distillation flask and the lower half of the distillation column to 45°C, collect the top fraction of the column until no more dichloroethane is distilled off, and the distillate contains 147g. (4) Continue to preheat the lower half to 95°C for distillation, collect the top fraction until no more fractions are distilled off, and recover 70 g; (5) The residual liquid in the bottle is 94.28 g. The residual liquid is distilled under reduced pressure at 50℃ until there is no distillate. The product is dried under vacuum at 50℃ to obtain 34.68 g of product, with a yield of 83.05% and a molar fraction of 99.4%. It is a white crystal with a melting point of 149.2-151.5℃ and a content of 99.5% (GC). 1 HNMR(DMSO-d6)δ(ppm):3.79(t,3H-CH3),11.03 (s,3H,-NH3 + ).

[0041] Comparative Example 1 Add 90g of water and 10g of sodium hydroxide to a 150ml flask equipped with an electric stirrer, thermometer, and condenser. After dissolving by stirring at room temperature, add 8.7g of butanone oxime and 0.3g of PEG500. Cool to 5°C and begin adding 16.4g of dimethyl sulfate. Separate the upper organic layer to obtain 3.8g. Distill the aqueous layer by heating, collecting the distillate. Stop distilling when the vapor temperature of the distillate reaches 95°C, yielding 12.3g. Combine the organic layer and distillate, add 22.6g of 30% hydrochloric acid, and mix thoroughly.

[0042] Prepare a glass-packed distillation column with an inner diameter of 20 mm and a height of 1600 mm. The column consists of two parts: a feed device in the middle and a condenser at the top. A 100 mL distillation flask is connected to the lower end of the column, and a preheating device is located below. Preheat the distillation flask and the lower half of the column to 85°C. Then, slowly add a hydrochloric acid solution of methyl ethyl ketone (MEK) oxime ether from the middle, maintaining the temperature of the lower half of the column and the distillation flask at 85-87°C. Collect the top fraction and perform GC analysis until no MEK distillates. The distillate contains 18.4 g, and the residue in the distillation flask contains 14.2 g. Distill the residue under reduced pressure at 50°C until no fraction remains. Add a small amount of ethanol for recrystallization, and dry under vacuum at 50°C to obtain 4.84 g of product, with a yield of 57.96% and a gas phase purity of 98.55%.

[0043] The results above show that the methoxyamine hydrochloride obtained by the preparation methods of Examples 1-4 of the present invention has significantly higher purity and yield than the methoxyamine hydrochloride obtained by the existing process in Comparative Example 1.

[0044] The specific embodiments described above further illustrate the purpose, technical solution, and beneficial effects of the present invention. It should be understood that the above description is only a specific embodiment of the present invention and is not intended to limit the scope of protection of the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing methoxyamine hydrochloride, characterized in that, Includes the following steps: 2,3,4-pentanetrione oxime was synthesized by adding sodium nitrite to acetylacetone under acidic conditions; After adjusting the reaction solution to alkaline, a phase transfer catalyst and a methylation reagent were added to synthesize 3-(O-methyloxime)-2,3,4-pentanetrione; The reaction solution was adjusted to a strongly acidic state for hydrolysis, and after pentane-2,3,4-trione was recovered by distillation, methoxyamine hydrochloride was obtained.

2. The method for synthesizing methoxyamine hydrochloride according to claim 1, characterized in that, The reaction route is shown below: 。 3. The method for synthesizing methoxyamine hydrochloride according to claim 1, characterized in that, The specific synthesis steps are as follows: S1, add acetylacetone, water, and sodium nitrite to the reaction vessel; S2, lower the temperature to 0~25℃, and slowly add inorganic acid over a period of 0.5~3 hours; After adding S3, keep the reaction at 5~30℃ for 3~6 hours. S4, after the reaction is complete, add an inorganic base to adjust the reaction solution to alkaline, and then add a phase transfer catalyst; S5. Lower the temperature to 0~15℃ and slowly add the methylating agent over 0.5~3 hours. S6, after the reaction is complete, add an organic solvent to extract 3-(O-methyloxime)-2,3,4-pentanetrione; S7, hydrochloric acid is used to adjust the organic solvent to a strong acid; S8. The mixed solution obtained in step S7 is distilled to recover pentane-2,3,4-trione. The aqueous solution of methoxyamine hydrochloride at the bottom of the column is heated and evaporated to obtain methoxyamine hydrochloride.

4. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S1, the amount of water used is 3 to 10 times the weight of acetylacetone; the molar ratio of sodium nitrite to acetylacetone is 1.2 to 2.5:

1.

5. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S2, the molar ratio of inorganic acid to acetylacetone is 1.2 to 2.5:1, and the inorganic acid is one or more of hydrochloric acid, nitric acid, and sulfuric acid.

6. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S3, the reaction temperature is 5~10℃, the reaction time is 4~6h, and the acetylacetone content is controlled to be ≤5%.

7. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S4, the molar ratio of inorganic base to acetylacetone is 2.5~3.5:1, and the amount of phase transfer catalyst used is 0.01~0.05 times the weight of acetylacetone. The inorganic base is one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate, and potassium bicarbonate; the phase transfer catalyst is one or more of tetrabutylammonium bromide, trimethyldodecylammonium chloride, and triethylamine.

8. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S5, the molar ratio of the methylating agent to acetylacetone is 1.1~1.5:1; The methylating agent is dimethyl sulfate, bromomethane, or chloromethane.

9. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S6, the organic solvent used is dichloromethane, petroleum ether, dichloroethane, or ethyl acetate.

10. The method for synthesizing methoxyamine hydrochloride according to claim 3, characterized in that, In step S7, the molar ratio of hydrochloric acid to acetylacetone is 1.6~2.5:1.

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