阅读说明：本技术 一种羟吡酮乙胺盐的合成方法 (Synthesis method of pirenone ethylamine salt ) 是由 王利民 谈平忠 邓倩 郑守军 于 2021-08-06 设计创作，主要内容包括：本发明公开了羟吡酮乙胺盐的合成方法,包括如下步骤：S1向容器中加入异壬酰氯、路易斯酸、3,3-二甲基丙烯酸甲酯进行傅克酰化反应,得中间体M1；S2向溶剂中加入中间体M1、盐酸羟胺,0-140℃下进行关环、羟胺化反应,得中间体M2；S3中间体M2与乙醇胺成盐反应得到羟吡酮乙胺盐。本发明仅仅在一个反应体系下就可以实现关环、羟胺化反应得到羟吡酮,相较于现行的采用先关环得到内酯、再羟胺化得到羟吡酮的两个反应体系,简化了羟吡酮乙胺盐的合成方法流程。且反应体系温度低,对工艺及设备要求降低、反应条件安全,操作简便,适合工业化大生产；且不需要使用浓硫酸、醋酸、碱、催化剂,安全环保、降低成本。(The invention discloses a method for synthesizing an ethylpyraponamine salt, which comprises the following steps: s1 adding isononanoyl chloride, Lewis acid and 3, 3-dimethyl methyl acrylate into a container to carry out Friedel-crafts acylation reaction to obtain an intermediate M1; s2, adding the intermediate M1 and hydroxylamine hydrochloride into a solvent, and performing ring closing and hydroxylamine amination reaction at 0-140 ℃ to obtain an intermediate M2; s3 intermediate M2 reacts with ethanolamine to obtain the acetamidine hydrochloride. The invention can realize ring closing and hydroxylamination reactions to obtain the hydroxypyrazine only in one reaction system, and simplifies the synthesis process of the ethylpyrazine salt compared with the prior two reaction systems which firstly obtain lactone by ring closing and then obtain the hydroxypyrazine by hydroxylamination. The reaction system has low temperature, low requirements on the process and equipment, safe reaction conditions and simple and convenient operation, and is suitable for industrial mass production; and does not need to use concentrated sulfuric acid, acetic acid, alkali and catalyst, thereby being safe and environment-friendly and reducing the cost.)

1. A method for synthesizing an ethylpyraponamine salt is characterized by comprising the following steps:

s1: adding isononanoyl chloride, Lewis acid and 3, 3-dimethyl methyl acrylate into a container to carry out Friedel-crafts acylation reaction to obtain an intermediate M1;

s2: adding the intermediate M1 and hydroxylamine hydrochloride into a solvent, and performing ring closing and hydroxylamine amination reaction at 0-140 ℃ to obtain an intermediate M2;

s3: and salifying the intermediate M2 and ethanolamine to obtain the ethylpyraponate.

2. The method of synthesizing etilamine of hydroxypyrrolidone according to claim 1, wherein the temperature of the ring closing reaction is 40-120 ℃.

3. The method of synthesizing etilamine hydroxypyrazine according to claim 1, wherein the time of the ring closure reaction is 0.5-50 h.

4. The method for synthesizing an acetamiprid salt of hydroxypyrrolidone according to claim 1, wherein the solvent in step S2 is selected from one or more of water, C1-C6 haloalkane solvents, C1-C4 nitrile solvents, C1-C6 ketone solvents, C1-C6 amide solvents, C1-C6 maple solvents, C1-C6 alcohol solvents, C1-C6 ethers, and benzene solvents.

5. The method for synthesizing etilamine of claim 1, wherein the solvent in step S2 is one or more of C1-C6 ether solvents.

6. The method of synthesizing etilamine of hydroxypyrrolidone according to claim 1, wherein the molar ratio of methyl 3, 3-dimethacrylate to isononanoyl chloride is 1: 1.0-1: 1.5.

7. the method of synthesizing etilamine hydroxypyrazine according to claim 1, wherein the molar ratio of methyl 3, 3-dimethacrylate to lewis acid is 1: 1.0-1: 5.0.

8. the method of synthesizing etilamine of claim 8, wherein the Lewis acid is selected from one of zinc dichloride, aluminum trichloride, ferric trichloride, titanium tetrachloride and tin tetrachloride.

9. The method of synthesizing etilamine hydroxypyrazole according to claim 1, wherein the molar ratio of intermediate M1 to hydroxylamine hydrochloride is 1: 0.8-1: 1.5.

Technical Field

The invention relates to the technical field of synthesis of an etilamine hydroxypyrazole, and particularly relates to a synthesis method of an etilamine hydroxypyrazole.

Background

The ethylpyraponamine salt has excellent itching relieving effect, unique effect on eliminating skin itch, capability of effectively killing fungi living on the skin, special body odor eliminating effect, good compounding property, safety, no toxicity and no irritation, is an ideal high-efficiency bactericide, and is mainly used for hair washing, hair care, bath foam, cosmetics, skin care products and washing products.

At present, the currently reported process basically adopts Friedel-crafts reaction of methyl acrylate and isononyl chloride to obtain 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester, the methyl ester is subjected to ring closure reaction to obtain 4-methyl- (2,4, 4-trimethyl amyl) -2H-pyran-2-one, the pyrone is hydrolyzed by hydroxylamine to obtain the hydroxypyrone, and then the hydroxypyrone and ethanolamine are subjected to salt forming reaction to obtain the hydroxypyrone ethylamine salt. The preparation method is characterized in that the preparation method is prepared by taking methyl acrylate and isononanoyl chloride as raw materials through four steps of Friedel-crafts reaction, cyclization reaction, hydroxylamine decomposition and salt forming reaction, and the specific reaction process is as follows:

patent CN110372654A reports a synthesis process method of an important intermediate 4-methyl- (2,4, 4-trimethylpentyl) -2H-pyran-2-one of hydroxypyrrolidone ethylamine salt, wherein isononanoyl chloride and 3, 3-dimethyl methyl acrylate are used as raw materials, and acylation reaction is carried out under the action of a catalyst to synthesize 3,7,9, 9-tetramethyl-2-decene-5-methyl keto-acid; then carrying out cyclization reaction under the catalytic action of concentrated sulfuric acid and glacial acetic acid to obtain 4-methyl- (2,4, 4-trimethyl amyl) -2H-pyran-2-ketone. However, the method for preparing the hydroxypyrone ethylamine salt needs to firstly cyclize 3,7,9, 9-tetramethyl-2-decene-5-methyl keto acid ester into 4-methyl- (2,4, 4-trimethyl amyl) -2H-pyran-2-one and then carry out hydroxylamine decomposition reaction to prepare the hydroxypyrone ethylamine salt, and the route is long. In addition, in the method, concentrated sulfuric acid and glacial acetic acid are used as solvents for the ring closing reaction of the 3,7,9, 9-tetramethyl-2-decene-5-methyl keto acid, so that more waste water and liquid are generated, the environmental pollution is large, the corrosion to equipment is large, and the requirement on the equipment is high.

Therefore, the prior process has the problems of long process route, low yield, difficult guarantee of product purity and great environmental pollution. The demand of the current market for the eperisone is large, and a synthesis method which is short in synthesis route, low in raw material cost, safe, mild in reaction condition and free of pollution needs to be researched urgently.

Disclosure of Invention

The invention aims to solve the technical problems of long process route, low yield, difficult guarantee of product purity and great environmental pollution of the existing method for preparing the pirenone ethylamine, and aims to provide a method for synthesizing the pirenone ethylamine, which solves the problems of long process route, low yield, difficult guarantee of product purity and great environmental pollution of the existing method for preparing the pirenone ethylamine.

The invention is realized by the following technical scheme:

a method for synthesizing an ethylpyraponamine salt comprises the following steps:

s1: adding isononanoyl chloride, Lewis acid and 3, 3-dimethyl methyl acrylate into a container to carry out Friedel-crafts acylation reaction to obtain an intermediate M1;

s2: adding the intermediate M1 and hydroxylamine hydrochloride into a solvent, and performing ring closing and hydroxylamine amination reaction at 0-140 ℃ to obtain an intermediate M2;

s3: and salifying the intermediate M2 and ethanolamine to obtain the ethylpyraponate.

In step S1, isononanoyl chloride is dissolved in an organic solvent such as halogenated hydrocarbon, and after stirring and dissolving, methyl 3, 3-dimethacrylate is added to carry out reflux reaction at the internal temperature of 35-80 ℃. The progress of the reaction was judged by detecting 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester by HPLC. After the reaction is finished, pouring the reaction system into ice water or a mixed solution of ice water and acid liquor to quench the reaction liquid system, then carrying out layering, washing and drying, and concentrating the organic phase to obtain an intermediate M1, namely 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester.

In step S2, the 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester obtained in step S1 is dissolved in water or an organic solvent, such as a haloalkane solvent, an ether solvent, an alcohol solvent, a ketone solvent, or an amide solvent, with stirring, and added to hydroxylamine hydrochloride, and the reaction system is subjected to ring closing and hydroamination at 0 to 140 ℃. Or firstly suspending hydroxylamine hydrochloride in the above various organic solvents, then adding 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester, and carrying out ring closing reaction at 0-140 ℃.

And stopping the reaction when the consumption of the compound 3,7,9, 9-tetramethyl-2-decene-5-methyl keto-acid is completely detected by TLC thin layer chromatography. After the reaction is finished, cooling, concentrating, extracting, washing, drying and concentrating to obtain the crude product of the hydroxypyrazine.

In step S3, the crude product of hydroxypyrrolidone obtained in step S2 is dissolved in a solvent such as ethyl acetate, acetonitrile, isopropyl acetate, methyl tert-butyl ether and the like, the temperature is raised to dissolve and clarify the crude product of hydroxypyrrolidone, ethanolamine is added, and when a solid is precipitated, the product is cooled, crystallized, filtered and dried to obtain the final product, namely, an ethylamine salt of hydroxypyrrolidone.

Preferably, the temperature of the ring closure reaction is 40-120 ℃.

Preferably, the time for the ring closure reaction is from 0.5 to 50h, more preferably from 26 to 28 h.

Preferably, the solvent in the step S2 is selected from one or more of water, C1-C6 haloalkane hydrocarbon solvents, C1-C4 nitrile solvents, C1-C6 ketone solvents, C1-C6 amide solvents, C1-C6 maple solvents, C1-C6 alcohol solvents, C1-C6 ethers, benzene solvents, more preferably C1-C6 ethers solvents, and more preferably 1, 4-dioxane.

Preferably, the molar ratio of the methyl 3, 3-dimethacrylate to the isononanoyl chloride is 1: 1.0-1: 1.5, more preferably 1: 1.2.

Preferably, the molar ratio of the methyl 3, 3-dimethacrylate to the lewis acid is 1: 1.0-1: 5.0, more preferably 1: 2.1.

Preferably, the lewis acid is selected from one of zinc dichloride, aluminum trichloride, ferric trichloride, titanium tetrachloride and stannic tetrachloride, and is more preferably aluminum trichloride.

Preferably, the molar ratio of the intermediate M1 to hydroxylamine hydrochloride is 1: 0.8-1: 1.5, more preferably 1: 1.0.

The reaction process for preparing the ethylpyraponamine salt of the invention is as follows:

compared with the prior art, the invention has the following advantages and beneficial effects:

(1) according to the synthesis method of the epyrone ethylamine salt, provided by the embodiment of the invention, after an intermediate M13,7,9, 9-tetramethyl-2-decene-5-methyl keto acid is obtained, a suitable solvent is selected, and the ring closing and the hydroxylamination reaction of the 3,7,9, 9-tetramethyl-2-decene-5-methyl keto acid can be realized under 0-140 ℃ only in one reaction system to obtain the epyrone.

The reaction system for preparing the hydroxypyrazone can be realized at low temperature, the requirements on the process and equipment are reduced, the reaction conditions are safe and environment-friendly, the operation is simple and convenient, and the method is suitable for industrial mass production; concentrated sulfuric acid and acetic acid which are needed in the ring closing reaction in the prior art do not need to be used, more corresponding waste water and waste liquid are not generated, the pollution to the environment and the high requirement on equipment are reduced, meanwhile, the corresponding waste water and waste liquid generated by using the concentrated sulfuric acid and the acetic acid are also saved, and the production cost is reduced.

In the prior art, sulfuric acid and acetic acid solution are required to be used, 2-aminopyridine or DMAP (4-dimethylaminopyridine) is also required to be used as a catalyst, ring closure is carried out at a high temperature of 200 ℃ under an alkaline condition to obtain the hydroxypyralone lactone (4-methyl- (2,4, 4-trimethylpentyl) -2H-pyran-2-one), then the hydroxypyralone lactone is aminolyzed under the action of hydroxylamine hydrochloride to obtain the hydroxypyralone, and the 2-aminopyridine or DMAP used in the process is expensive. The synthesis method of the pirenone ethylamine salt provided by the invention does not need to use a catalyst or alkali in the process of ring closing hydroxylamination, thereby further reducing the production cost.

Meanwhile, according to the synthesis method of the pirfenidone ethylamine provided by the embodiment of the invention, after a crude product of the pirfenidone is obtained, the subsequent salt forming reaction can be carried out without refining, and impurities in the crude product of the pirfenidone can be removed in the process of the salt forming reaction, so that the process flow can be simplified, and the yield and the purity can be improved.

(2) According to the synthesis method of the eperisone ethylamine salt, provided by the embodiment of the invention, the proper proportion of the 3, 3-methyl dimethacrylate, the Lewis acid and the isononanoyl chloride is selected, the yield of the obtained intermediate M1 reaches 95.47% -104%, and compared with the yield of the 3,7,9, 9-tetramethyl-2-decene-5-methyl keto acid in the prior art, the yield is improved, and a good basis is provided for the high yield of the final product.

Drawings

In order to more clearly illustrate the technical solutions of the exemplary embodiments of the present invention, the drawings that are required to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and that for those skilled in the art, other related drawings can be obtained from these drawings without inventive effort. In the drawings:

FIG. 1 is a nuclear magnetic resonance spectrogram of an etidronate prepared by the method for synthesizing an etidronate provided by the embodiment of the present invention.

FIG. 2 is a diagram showing the results of elemental analysis of an etilamine hydroxypyrazole prepared by a method for synthesizing an etilamine provided by an embodiment of the present invention.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is further described in detail below with reference to examples, and the exemplary embodiments and descriptions thereof are only used for explaining the present invention and are not used as limitations of the present invention.

Throughout the specification, reference to "one embodiment," "an embodiment," "one example," or "an example" means: the particular features, characteristics, or characteristics described in connection with the embodiment or example are included in at least one embodiment of the present invention. Thus, the appearances of the phrases "one embodiment," "an embodiment," "one example" or "an example" in various places throughout this specification are not necessarily all referring to the same embodiment or example. Furthermore, the particular features, characteristics may be combined in any suitable combinations and/or sub-combinations in one or more embodiments or examples. As used herein, the term "and/or" includes any and all combinations of one or more of the associated listed items.

Example 1:

s1: preparation of methyl 3,7,9, 9-tetramethyl-2-decene-5-keto acid (intermediate M1):

dichloroethane (25ml), isononanoyl chloride (9.23g, 52.6mmol, 1.2eq) and ferric trichloride (8.53g, 52.6mmol, 1.2eq) were sequentially added to a three-necked flask, and after stirring at room temperature for 30min, methyl 3, 3-dimethacrylate (5.0g, 43.8mmol, 1.0eq) was added, and after the addition, the system was refluxed at an external temperature of 40 ℃ and an internal temperature of 37 ℃ to complete the reaction as detected by HPLC. The reaction system was poured into a mixed solution of ice water (40ml) and hydrochloric acid (2.0ml), stirred to separate layers, and the organic phase was washed with water, saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and concentrated to give 10.0g of intermediate M1 as a reddish brown oil in 89.77% yield and 96.7% HPLC purity.

S2: crude hydroxypyrazone (intermediate M2) preparation:

hydroxylamine hydrochloride (4.10g, 59mmol, 1.5eq) was suspended in 100ml, 10ml/g acetonitrile solution, 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester (10.0g, 39.3mmol, 1.0eq) was added, the temperature was raised to 86 ℃ in an external bath, the internal temperature was 82 ℃, the reaction was stirred and refluxed for 28 hours, TLC detected that the compound 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester was completely consumed, and the reaction was stopped. After the reaction is finished, cooling to room temperature of 20-30 ℃, distilling under reduced pressure at 40 ℃ to recover acetonitrile solution to obtain concentrated mother liquor, adding 50ml of ethyl acetate and 30ml of purified water into the concentrated mother liquor, stirring for 30min, layering, extracting a water layer by using 10ml of ethyl acetate, combining organic layers, adding anhydrous sodium sulfate to dry the organic layers, and concentrating to obtain 9.09g of crude hydroxypyrone of a brownish red solid, wherein the yield is 97.43%, and the HPLC purity is 85.7%.

S3: preparation of ethylpyraponamine salt:

9g of the crude product of the hydroxypyrazone in S2 is taken to be dissolved in 45ml of acetonitrile, heated and dissolved, then 3.47g of ethanolamine is added, when solid is separated out, heating is stopped, natural cooling is carried out to the room temperature, stirring is carried out for crystallization, the filtration is carried out at the room temperature, and a filter cake is dried to obtain 6.48g of off-white solid, the yield is 57.3 percent, and the purity is 99.1 percent.

Results of the epyrone ethylamine salt test:

1HNMR(DMSO-d6)：0.80-0.85ppm(m，12H)，1.03-1.05ppm(m，1H)，1.07-1.08ppm(m，1H)，1.99-2.08ppm(m，4H)，2.28-2.33ppm(m，1H)，2.57-2.66ppm(m，3H)，3.41-3.44ppm(t，2H)，5.23ppm(br，4H)，5.89ppm(d，1H)，6.10ppm(d，1H)。

elemental analysis: 64.6 percent of C, 10.35 percent of H and 9.4 percent of N.

Example 2:

s1: preparation of methyl 3,7,9, 9-tetramethyl-2-decene-5-keto acid (intermediate M1):

1, 2-dichloroethane (25ml), isononanoyl chloride (9.23g, 52.6mmol, 1.2eq), and anhydrous tin tetrachloride (11.41g, 43.8mmol, 1.0eq) were sequentially added to a three-necked flask, and after stirring at room temperature for 30min, methyl 3, 3-dimethacrylate (5.0g, 43.8mmol, 1.0eq) was added, and after completion of the addition, the reaction was refluxed at an external temperature of 84 ℃ and an internal temperature of 80 ℃ to complete the HPLC detection reaction. The reaction system was poured into a mixed solution of ice water (40ml) and hydrochloric acid (2.0ml), stirred to separate layers, and the organic phase was washed with water, then washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, collected and concentrated to give 9.26g of intermediate M1 as a reddish brown oil in 83.11% yield and 97.5% purity.

S2: preparation of crude product of hydroxypyrrolidone:

hydroxylamine hydrochloride (4.10g, 59mmol, 1.5eq) is suspended in 100ml, 10ml/g ethylene glycol diethyl ether solution, then 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester (10.0g, 39.3mmol, 1.0eq) is added, after the addition is finished, the temperature is raised to 110 ℃ in an external bath and 108 ℃ in an internal temperature, the stirring reflux reaction is carried out for 26h, the consumption of the compound 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester is detected by TLC, and the reaction is stopped. After the reaction is finished, cooling to room temperature of 20-30 ℃, adding 100ml of ethyl acetate and 100ml of water into the reaction solution, stirring and layering, extracting the water layer once by using 20ml of ethyl acetate, combining the organic layers, washing the organic phase once by using 50ml of water, washing the organic phase once by using salt solution, layering, combining the organic layers, adding anhydrous sodium sulfate, drying, stirring, filtering and concentrating to obtain about 9.02g of crude product of the red brown solid, wherein the yield is 96.57%, and the HPLC purity is 90.7%.

S3: preparation of ethylpyraponamine salt:

9g of the crude product of the hydroxypyrazone in S2 is taken to be dissolved in 45ml of isopropyl acetate solution, heated and dissolved, then 3.47g of ethanolamine is added, when solid is separated out, heating is stopped, natural cooling is carried out to the room temperature, stirring is carried out for crystallization, filtering is carried out at the room temperature, and filter cakes are dried to obtain 6.80 g of off-white solid, the yield is 60.1%, and the HPLC purity is 99.2%.

Example 3:

s1: preparation of methyl 3,7,9, 9-tetramethyl-2-decene-5-keto acid (intermediate M1):

dichloromethane (125ml) and isononanoyl chloride (46.15g, 0.26mol, 1.2eq) are sequentially added into a three-neck flask, the temperature is reduced to minus 9 ℃, then aluminum trichloride (73.00g, 0.55mol, 2.5eq) is added at one time at the temperature, after stirring for 30min at room temperature, methyl 3, 3-dimethacrylate (25.0g, 0.22mol, 1.0eq) is added, after the addition is finished, the system is refluxed at the external temperature of 40 ℃ and the internal temperature of 37 ℃, the reaction progress is detected by HPLC, after the reaction is finished, the reaction system is poured into ice water (200ml), stirred and layered, an organic phase is washed by 1mol/L hydrochloric acid solution, then washed by purified water once, dried by anhydrous sodium sulfate, and concentrated to obtain 52.60g of an intermediate M1 of a dark green oily substance, the yield is 94.42%, and the HPLC purity is 97.2%.

S2: crude hydroxypyrazone (intermediate M2) preparation:

adding 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester (50.86g,0.2mol and 1.0eq) in S1 into a reaction kettle containing 250g of 1, 4-dioxane solution, starting stirring and dissolving, then adding hydroxylamine hydrochloride (13.90g,0.2mol and 1.0eq) into the reaction kettle, stirring, carrying out oil bath heating until the external temperature is raised to 105 +/-5 ℃, and carrying out reflux reaction for 26 hours. After the reaction is finished, stopping heating, filtering, collecting filtrate, and distilling the filtrate under reduced pressure at 50 ℃ to recover the 1, 4-dioxane solution to obtain concentrated mother liquor. And then adding 115g of ethyl acetate and 50g of purified water into the concentrated mother liquor, stirring for 30min, demixing, adding 25g of anhydrous sodium sulfate into an organic layer, stirring for 30min, and filtering. Evaporating to dryness to obtain 55g of crude product of the hydroxypyrazine, wherein the yield is over 100 percent, and the HPLC purity is 85.4 percent.

S3: preparation of an ethanolamine salt of hydroxypyrrolidone:

dissolving the crude product of the hydroxypyrrolidone (55g, 0.23mol, 1.0eq) in the S2 in 250ml of ethyl acetate, heating for dissolving, then adding ethanolamine (21.2g, 0.35mol, 1.5eq), stopping heating when a solid is separated out, naturally cooling to room temperature, stirring for crystallization, filtering at room temperature, and drying a filter cake in a vacuum drying oven to obtain 40.68 g of a white-like solid, wherein the yield is 58.87% and the HPLC purity is 99.3%. Namely the ethylpyraponamine salt.

Example 4:

s1: preparation of methyl 3,7,9, 9-tetramethyl-2-decene-5-keto acid (intermediate M1):

1, 2-dichloroethane (25ml), isononanoyl chloride (9.23g, 52.6mmol, 1.2eq) and anhydrous titanium tetrachloride (8.3g, 43.8mmol, 1.0eq) were sequentially added to a three-necked flask, and after stirring at room temperature for 30min, methyl 3, 3-dimethacrylate (5.0g, 43.8mmol, 1.0eq) was added, and after the addition, the reaction was refluxed at an external temperature of 84 ℃ and an internal temperature of 80 ℃ to complete the HPLC detection reaction. The reaction system was poured into a mixed solution of ice water (40ml) and hydrochloric acid (2.0ml), stirred to separate layers, washed with water by an organic camera, then washed with a saturated aqueous solution of sodium bicarbonate, dried over anhydrous sodium sulfate, and the organic phase was concentrated to give 8.75g of intermediate M1 as a black oil in 78.55% yield and 96.2% purity by HPLC.

S2: preparation of crude product of hydroxypyrrolidone:

hydroxylamine hydrochloride (4.10g, 59mmol, 1.5eq) was suspended in 100ml, 10ml/g anisole solution, 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester (10.0g, 39.3mmol, 1.0eq) was added, the temperature was raised to 105 ℃ in the external bath, the internal temperature was 100 ℃, the reaction was stirred for 26 hours, TLC detected that the compound 3,7,9, 9-tetramethyl-2-decene-5-keto acid methyl ester was completely consumed, and the reaction was stopped. After the reaction is finished, cooling to room temperature of 20-30 ℃, adding 100ml of ethyl acetate and 100ml of water into the reaction solution, stirring and layering, extracting the water layer once by using 20ml of ethyl acetate, combining the organic layers, washing the organic layer once by using 50ml of water, washing the organic layer once by using salt solution, layering, combining the organic layers, adding anhydrous sodium sulfate to dry the organic layer, stirring, filtering and concentrating to obtain 9.05g of crude product of the red brown solid, wherein the yield is 96.9%, and the HPLC purity is 89.2%.

S3: preparation of ethylpyraponamine salt:

9g of crude hydroxypyrazone in S2 is dissolved in 45ml of methyl tert-butyl ether, heated and dissolved, then 3.47g of ethanolamine is added, heating is stopped when solid is separated out, natural cooling is carried out to room temperature, stirring is carried out for crystallization, filtering is carried out at room temperature, and filter cakes are dried to obtain 6.67 g of white-like solid, the yield is 59.1%, and the HPLC purity is 99.5%.

The above-mentioned embodiments are intended to illustrate the objects, technical solutions and advantages of the present invention in further detail, and it should be understood that the above-mentioned embodiments are merely exemplary embodiments of the present invention, and are not intended to limit the scope of the present invention, and any modifications, equivalent substitutions, improvements and the like made within the spirit and principle of the present invention should be included in the scope of the present invention.