A total synthesis of clethodim

Abstract

The application discloses a full synthesis method of clethodim, and the method is characterized by reasonable selection / design of a process route, simplified process flow, reduced separation and purification operation, effectively reduced production cost and improved production efficiency, further improved yield of a key intermediate through research and screening of process conditions of the key step, reduced generation of impurities, and improved product quality and yield of the target product.

Description

Technical Field

[0001] This application belongs to the field of herbicide preparation technology, specifically relating to a method for the total synthesis of clethodim. Background Technology

[0002] Clthodim, also known as celecoxib, is scientifically named 2-{1-[(3-chloro-2-allyl)oxy]iminopropyl}-5-[2-(ethylthio)propyl]-3-hydroxy-2-cyclohexen-1-one, with the structural formula […]. It is a systemic herbicide applied as a foliar spray, which has a strong killing effect on grass weeds and excellent selectivity. It has little or no activity against sedges and dicotyledonous plants.

[0003] In recent years, the domestic and international markets for clethodim have shown a rapid growth trend, replacing some herbicides with high residues and severe phytotoxicity. Furthermore, with the continuous expansion of its applications, the clethodim market is also constantly expanding. Therefore, research on the synthesis and processing of clethodim is of great significance for industrial production.

[0004] Through in-depth research, this invention analyzes, selects, and improves the process conditions of existing clethodim preparation methods, exploring a total synthesis route suitable for industrial production. This simplifies the process flow, reduces production costs, increases the total yield of clethodim, and reduces the impurity content in the product. Summary of the Invention

[0005] The purpose of this invention is to provide a total synthetic route for clethodim suitable for industrial production. By rationally selecting / designing the process route, the process flow can be simplified and production costs reduced. Furthermore, by studying and screening process conditions, the product yield and product quality can be improved.

[0006] According to the present invention, a method for the total synthesis of clethodim is provided, and the process route is as follows:

[0007]

[0008] Step 1 is carried out at 40-50℃. The specific operation is as follows: 96% caustic soda flakes (the impurity is sodium chloride) and methanol are mixed at room temperature and reacted at 40℃~50℃. After the reaction is complete, the mixture is subjected to sedimentation treatment, and the supernatant is distilled to obtain a 30% sodium methoxide-methanol solution, which can be directly used in step 5 without further treatment.

[0009] Step 2 is carried out in the presence of triethylamine. The specific operation is as follows: Crotonaldehyde and triethylamine are added to the synthesis reactor and stirred. Ethyl mercaptan is added dropwise at room temperature for 2-3 hours, and the temperature is controlled at 55℃-65℃. After the addition is completed, the temperature is kept at 60℃-68℃ for 3.5 hours to obtain β-ethylthiobutyraldehyde, which is then cooled for later use.

[0010] Step 3 is operated as follows: Methyl acetoacetate and water are added to the synthesis reactor and stirred. 32% liquid alkali is added dropwise at room temperature for 4-5 hours, and the temperature is controlled at 35℃-40℃. After the addition is completed, the temperature is kept at 35℃-40℃ for 3 hours to obtain sodium acetoacetate solution for later use.

[0011] Step 4 is performed as follows: The sodium acetoacetate solution prepared in step 3 is transferred into the synthesis vessel, toluene and piperidine are added, and the mixture is stirred. Acetic acid is added dropwise at room temperature for 2 hours until the pH reaches 7.3, and the temperature is controlled at 35℃~40℃. After the addition is complete, β-ethylthiobutyraldehyde prepared in step 2 is transferred in, and 75% acetic acid is added dropwise for 7 hours, maintaining the pH at 6.8~6.9 and controlling the temperature at 35℃~40℃. After toluene extraction, layering, washing with water, and drying, a toluene solution of 6-ethylthio-3-hepten-2-one is obtained.

[0012] Step 5 is performed as follows: 30% sodium methoxide-methanol solution prepared in step 1 is added to the reactor and stirred. Toluene is added and the temperature is raised to 110°C to concentrate and remove methanol. The temperature is lowered to 30-40°C, and toluene is added again. Dimethyl malonate is added dropwise at 30-40°C for 1.5-2 hours. The temperature is maintained at 30-40°C for 1 hour. 6-Ethio-3-hepten-2-one prepared in step 4 is added dropwise for 1.5-2 hours. The temperature is maintained for 0.5 hours, and the temperature is raised to 110°C to react. Part of the toluene and the methanol produced in the reaction are distilled off. The temperature is lowered to obtain a toluene solution of heptenone cyclization product 1.

[0013] Steps 6-7 are performed as follows: Heptenone cyclization product 1 is transferred into the reactor, propionyl chloride is added dropwise at room temperature for 1-1.5 hours, and the temperature is controlled at 50℃-60℃. After the addition is complete, the temperature is raised to 90℃ and kept at that temperature for 2 hours. The temperature is then lowered by 40℃ to obtain acylated product 2 solution. Triethylamine is added directly to adjust the pH value, and then 4-dimethylaminopyridine (DMAP) / toluene solution is added. The temperature is then raised to 90℃ and kept at that temperature for 6 hours. The temperature is then lowered by 40℃ to obtain rearrangement product 3 solution.

[0014] Step 8 is performed as follows: Transfer rearrangement product 3 into the reactor, add 31% hydrochloric acid and fresh water at room temperature, acid wash, neutralize the alkali and DMAP, stir for 0.5 h, let stand for 0.5 h, separate the organic phase, continue to add fresh water at room temperature, add 32% liquid alkali dropwise for 1 to 1.5 h, control the temperature at 20℃ to 40℃, after the addition is complete, raise the temperature to 70℃, keep it at 4 h, lower the temperature to 40℃, extract and separate the phases, let stand for 0.5 h, take the aqueous layer, and obtain hydrolysis product 4.

[0015] Step 9 is operated as follows: Hydrolysis product 4 is transferred into the reactor, the temperature is lowered to below 40°C, 31% hydrochloric acid is added dropwise for 2.5 to 3 hours, the temperature is controlled to be less than 20°C to 40°C, after the addition is completed, the mixture is stirred for 2 hours to obtain propionyltrione 5. After extraction, the solvent is removed by distillation, and the purified propionyltrione 5 is obtained by fractional distillation.

[0016] In the total synthesis route of this application, no intermediate product separation and purification operations are performed in the process from step 5 to step 9 to obtain purine propionyltrione 5, which effectively improves production efficiency.

[0017] In step 5, by adding toluene for distillation before the reaction to remove methanol as much as possible, the forward reaction is facilitated, and the reaction exhibits significantly higher reactivity under the cyclization reaction conditions of the present invention, effectively improving the yield of the cyclization product.

[0018] In steps 6-7, existing methods often require adding water to wash away excess propionyl chloride after the dropwise addition of propionyl chloride, followed by adding alkali to adjust the pH. This method significantly increases the processing time, and the acylation product is easily decomposed in water, especially in alkaline aqueous solutions. In contrast, this application directly adds triethylamine to the obtained acylation product solution to adjust the pH value, and then adds DMAP to carry out the rearrangement reaction, avoiding the decomposition of the acylation product, reducing the generation of impurities, and improving the yield of the target product.

[0019] Step 10 is operated as follows: Hydroxylamine hydrochloride and pure water are prepared into 40% hydroxylamine hydrochloride in a preparation vessel. The prepared 40% hydroxylamine hydrochloride and methyl acetate are added to the vessel, stirred, cooled to 20°C, and 32% liquid alkali is added dropwise. The temperature is controlled at 20°C to 25°C. The dropwise addition is completed in 9 hours. The temperature is kept warm for 1 hour to obtain acetamide sodium hydroxyl solution.

[0020] Step 11 is operated as follows: Add tetrabutylammonium iodide to the sodium acetamide solution obtained in step 10, continue to add dichloropropene dropwise for 1 hour while controlling the temperature, raise the temperature to 50-60℃ and keep it at that temperature for 9 hours, lower the temperature by 30-40℃, and the reaction will generate etherified product 6 solution. Continue to add 31% hydrochloric acid dropwise for 2 hours to acidify the etherified product into salt, raise the temperature to 70-80℃ and keep it at that temperature for 2 hours, add fresh water, add 32% liquid alkali dropwise to neutralize and adjust the pH to the appropriate level, add dichloromethane for extraction, and obtain an aqueous phase containing etherified product hydrochloride.

[0021] Step 12 is performed as follows: Add 32% liquid alkali to the hydrochloride solution of the etherified product obtained in step 11, and add it dropwise at 30-40°C for about 2 hours until it becomes alkaline. Add dichloromethane for extraction, separate the organic layer and remove the solvent to obtain 3-chloroallyloxyamine.

[0022] Step 13 is operated as follows: Add the glycerol propionate prepared in step 9 and the 3-chloroallyloxyamine prepared in step 12 into the reactor, stir, heat to 45-50℃, keep warm for 5 hours, add 31% hydrochloric acid, petroleum ether or cyclohexane solvent, acid wash, mix and stir, let stand, separate the organic phase, wash with water, separate the organic layer, remove solvent and cool down to obtain clethodim.

[0023] In steps 10 to 12 of this application, the process of obtaining 3-chloroallyloxyamine does not involve the separation and purification of intermediate products, effectively improving production efficiency. Using methyl acetate as a raw material, the intermediate is obtained in the form of acetamide sodium hydroxyl solution by controlling process conditions. By adding the catalyst tetrabutylammonium iodide and strictly controlling the feeding method and reaction conditions of dichloropropene, the formation of dichloropropene dietherification products is reduced, further improving the yield of 3-chloroallyloxyamine. Tetrabutylammonium iodide not only possesses phase transfer catalysis, but the iodide ions in the system also exhibit excellent promoting effects on this substitution reaction.

[0024] Compared with existing technologies, the process of this invention has the following advantages: This invention discloses a total synthesis process of clethodim, which simplifies the process flow, reduces separation and purification operations, effectively reduces production costs and improves production efficiency through the rational selection / design of the process route; through the research and screening of process conditions for key steps, the yield of key intermediates is further improved, the generation of impurities is reduced, and the product quality and the yield of the target product are improved. Detailed Implementation

[0025] The present invention will be further described in detail below with reference to specific embodiments. Unless otherwise specified, the methods used herein are conventional methods in the art, and the reagents used are all obtained through conventional commercial channels.

[0026] Example 1: Synthesis of sodium methoxide-methanol solution

[0027] CH3OH + NaOH → CH3ONa

[0028] 96% caustic soda flakes (with sodium chloride as an impurity) were mixed with methanol at room temperature and dissolved by circulating the solution at 40℃~50℃. Methanol was continuously added and pumped into the spray system to dissolve the caustic soda until the solution met the required standard. The solution was then transferred to a settling tank for settling. The supernatant was continuously pumped into a distillation column for distillation at 60℃~100℃. Wastewater was collected from the bottom of the first column, and a qualified sodium methoxide solution was collected from the bottom of the second column. The conversion rate of sodium hydroxide (to sodium methoxide) was 100%.

[0029] The molar yield of sodium methoxide was 96.1%.

[0030] Example 2: Synthesis of β-ethylthiobutyraldehyde

[0031]

[0032] Put crotonaldehyde (247 mL, 3 mol) and a catalytic amount of triethylamine (5 mL) into the synthesis kettle, stir, and start dropping ethanethiol (222 mL, 3 mol) at room temperature. The dropping time is 2 - 3 h, and the temperature is controlled at 55°C - 65°C. After the dropping is completed, keep the temperature at 60°C - 68°C for 3.5 h, take a sample, and after it is qualified, cool down to obtain a yellow liquid for standby. The conversion rate of crotonaldehyde (to form β-ethylthio butyraldehyde) is 98.5%, and the molar yield of β-ethylthio butyraldehyde is 98.5%.

[0033] Example 3 Synthesis of Sodium Acetoacetate

[0034]

[0035] Put methyl acetoacetate (324 mL, 3 mol) and water (200 mL) into the synthesis kettle, stir, and start slowly dropping 32% liquid alkali (750 mL, 6 mol) at room temperature. The dropping time is 4 - 5 h, and the temperature is controlled at 35°C - 40°C. After the dropping is completed, keep the temperature at 35°C - 40°C for 3 h to obtain a sodium acetoacetate solution, and concentrate it for standby. The conversion rate of methyl acetoacetate (to form sodium salt) is 100%, and the molar yield of the sodium salt is 100%.

[0036] Example 4 Synthesis of 6-Ethylthio-3-hepten-2-one

[0037]

[0038] Transfer the sodium acetoacetate solution (3 mol) prepared in Example 3 into the synthesis kettle, add toluene (500 mL) and piperidine (10 mL), stir, and start dropping acetic acid for 2 h until pH = 7.3 at room temperature. The temperature is controlled at 35°C - 40°C. After the dropping is completed, drop the β-ethylthio butyraldehyde prepared in Example 2 (about 3 mol), and at the same time drop 75% acetic acid. The dropping time is 7 h, keep pH = 6.8 - 6.9, control the temperature at 35°C - 40°C. After the sample is qualified, let it stand for 0.5 h. The organic layer is washed with water, and vacuum reflux dehydration is carried out until there is no obvious water temperature in the system, and then cool down to 40°C to obtain a toluene solution of 6-ethylthio-3-hepten-2-one. The conversion rate of β-ethylthio butyraldehyde (to form 6-ethylthio-3-hepten-2-one) is 92.6%, the conversion rate of side reaction (to form crotonaldehyde) is 2.0%, and the conversion rate of side reaction (to form bis-ethylthio heptenone) is 2.0%. The molar yield of 6-ethylthio-3-hepten-2-one is 92.6%.

[0039] Example 5 Synthesis of Heptenone Cyclization Product 1

[0040]

[0041] A 30% sodium methoxide-methanol solution (from Example 1) (180 g, 1 mol) was added to a reactor and stirred. Toluene (500 mL) was added, and the mixture was heated to 110 °C to concentrate and remove methanol. The temperature was then lowered to 30–40 °C, and toluene (500 mL) was added again. Dimethyl malonate (1.2 mol) was added dropwise at 30–40 °C over 1.5–2 h. The mixture was kept at 30–40 °C for 1 h. A toluene solution of 6-ethylthio-3-hepten-2-one (1 mol) was added dropwise over 1.5–2 h. The mixture was kept at 30–40 °C for 0.5 h, and the temperature was raised to 110 °C for 15 h. Subsequently, some of the toluene was distilled off, and the alcohol generated in the reaction was removed. The mixture was then cooled to obtain a toluene solution of heptenone cyclization product 1. The conversion rate of 6-ethylthio-3-hepten-2-one (to generate heptenone cyclization product 1) was 100%, and the molar yield of heptenone cyclization product 1 was 100%.

[0042] Example 6 Acylation and Rearrangement

[0043]

[0044] A toluene solution of heptenone cyclization product 1 prepared in Example 5 was transferred into the reactor, and propionyl chloride (1.1 mol) was added dropwise at room temperature for 1 to 1.5 h while maintaining the temperature at 50 to 60 °C. After the addition was complete, the temperature was raised to 90 °C and held for 2 h, then lowered by 40 °C to obtain a solution of acylated product 2.

[0045] Triethylamine was added to the acylation product 2 solution to adjust the pH to 7.2, and then a toluene solution of 4-dimethylaminopyridine (DMAP) (10 g) was added. The temperature was raised to 90 °C and held for 6 h, and then cooled to 40 °C to obtain a toluene solution of rearrangement product 3.

[0046] The conversion rate of heptenone cyclization product 1 (to generate acylated product 2) was 97%; the conversion rate of acylated product 2 (to generate rearranged product 3) was 95%; the molar yield of acylated product 2 was 97%; and the molar yield of rearranged product 3 was 95%.

[0047] Example 7 Synthesis of Hydrolysis Product 4

[0048]

[0049] The rearrangement product 3 was transferred into the reactor, and 31% hydrochloric acid and fresh water were added at room temperature. The mixture was acid-washed to neutralize the alkali and DMAP in the system. The mixture was stirred for 0.5 h, allowed to stand for 0.5 h, and the organic phase was separated. Fresh water (100 mL) was added at room temperature, followed by dropwise addition of 32% liquid alkali (125 mL) over 1–1.5 h at a controlled temperature of 20–40 °C. After the addition was complete, the temperature was raised to 70 °C and maintained for 4 h. The temperature was then lowered to 40 °C, and the layers were extracted and separated. The layers were allowed to stand for 0.5 h, and the aqueous layer was collected to obtain hydrolysis product 4. The conversion rate of rearrangement product 3 (resulting in hydrolysis product 4) was 96%, and the molar yield of hydrolysis product 4 was 96%.

[0050] Example 8 Synthesis of Propionyltrione 5

[0051]

[0052] The hydrolysis product prepared in Example 7 was transferred into the reactor, cooled to below 40°C, and 31% hydrochloric acid (120 mL) was added dropwise over 2.5–3 hours, with the temperature controlled below 20°C–40°C. After the addition was complete, the mixture was stirred for 2 hours to obtain the decarboxylation product. This product was extracted with toluene (300 mL), washed with alkali, and then with water. A vacuum of approximately -0.09 MPa was applied, and the temperature was raised to 135°C to remove the solvent toluene, yielding crude propionyl trione 5. The crude trione was continuously pumped into a scraped evaporator, with the flow rate controlled, the vacuum below 500 Pa, and the temperature at 220°C, continuously yielding 95% purified propionyl trione 5. The conversion rate of hydrolysis product 4 (producing propionyl trione 5) was 95%, and the conversion rate of the side reaction (producing undecarboxylated trione) was 3%. The molar yield of propionyl trione 5 was 93.6%.

[0053] Example 9: Synthesis of sodium acetamide

[0054]

[0055] Hydroxylamine hydrochloride (208.5 g, 3 mol) and pure water were mixed in a reaction vessel to prepare 40% hydroxylamine hydrochloride. The prepared 40% hydroxylamine hydrochloride and methyl acetate (240 g, 3 mol) were added to the vessel, stirred, and cooled to 20°C. 32% liquid alkali (750 g, 6 mol) was added dropwise, maintaining the temperature between 20°C and 25°C, for a total of 9 hours. The mixture was then kept at this temperature for 1 hour to obtain sodium acetamide. The conversion rate of hydroxylamine hydrochloride (to sodium acetamide) was 100%, and the molar yield of sodium acetamide was 99.7%.

[0056] Example 10 Synthesis of the etherified product hydrochloride

[0057]

[0058] Add 55.5 g (0.15 mol) of tetrabutylammonium iodide catalyst to the sodium acetamide solution obtained in Example 9, and continue to add dichloropropylene (333 g (3 mol)) dropwise over 1 hour. The temperature is raised to 50–60 °C and maintained for 9 hours, then lowered by 30–40 °C. Ether 6 is generated. 31% hydrochloric acid is added dropwise for 2 hours to acidify the etherified product into a salt. The temperature is raised to 70–80 °C and maintained for 2 hours. Fresh water is added, and 32% liquid alkali is added dropwise to neutralize and adjust the pH to the appropriate level. Vacuum distillation at -0.080 MPa is initiated to remove volatile impurities and some water. Dichloromethane is added for extraction to obtain an aqueous phase containing the etherified product hydrochloride. The conversion rate of sodium acetamide (to etherified product) is 92.5%, the conversion rate of the side reaction (to dietherified product) is 6.1%, and the conversion rate of the etherified product (to ammonium chloride hydrochloride) is 100%. The molar yield of the ether was 91.3%; the molar yield of the ammonium chloride hydrochloride was 100%.

[0059] Example 11 Synthesis of 3-chloroallyloxyamine

[0060]

[0061] The aqueous phase containing the etherified product hydrochloride prepared in Example 10 was added to the reactor. After about 2 hours, 32% liquid alkali was added dropwise at 30-40°C until alkaline. Dichloromethane was added for extraction, and the organic layer was separated. Dichloromethane was removed by distillation at 70°C under vacuum of -0.08 MPa to obtain 3-chloroallyloxyamine with a purity of 97%. The conversion rate of the etherified product hydrochloride (to generate 3-chloroallyloxyamine) was 100%, and the molar yield of 3-chloroallyloxyamine was 100%.

[0062] Example 12 Synthesis of Clethodim

[0063]

[0064] 284.5 g (1 mol) of 95% glyceryl propionate prepared in Example 8 and 500 mL of ethanol were added to the reactor. The temperature was controlled below 20 °C. 133 g (1.2 mol) of 97% 3-chloroallyloxyamine prepared in Example 11 was added dropwise. The mixture was stirred, heated to 45–50 °C, and kept at this temperature for 5 hours. 31% hydrochloric acid and petroleum ether or cyclohexane were added for acid washing. The mixture was stirred and allowed to stand. The organic layer was washed with fresh water, stirred and allowed to stand to separate into layers, resulting in an organic material layer. The solution was removed at 70 °C under a vacuum of -0.09 MPa to obtain clethodim. The conversion rate of glyceryl propionate (to clethodim) was 96%, the conversion rate of the side reaction (to generate isomer impurities) was 2.4%, the molar yield of clethodim was 95.8%, and the clethodim content was 95.6%.

[0065] Comparative Example 1

[0066] Methanol was distilled off at 65°C without the addition of toluene, and diethyl malonate (1.2 mol) was added dropwise. The remaining operations were the same as in Example 5. The conversion rate of 6-ethylthio-3-hepten-2-one (generating heptenone cyclization product) was 85%, and the molar yield of heptenone cyclization product was 81.5%.

[0067] Comparative Example 2

[0068] Without the addition of the catalyst tetrabutylammonium iodide, the remaining operations were the same as in Example 10. The conversion rate of sodium acetamide (to form an ether) was 62.5%, and the conversion rate of the side reaction (to form a diether) was 30.1%. The conversion rate of the ether (to form ammonium chloride hydrochloride) was 100%, and the molar yield of the ether was 61.3%. The molar yield of ammonium chloride hydrochloride was 100%.

[0069] Comparative Example 3

[0070] Tetrabutylammonium bromide was substituted for tetrabutylammonium iodide, and the remaining operations were the same as in Example 10. The conversion rate of acetamide sodium (to generate ether) was 73.2%, and the conversion rate of the side reaction (to generate diether) was 24.1%. The conversion rate of the ether (to generate ammonium chloride hydrochloride) was 100%, and the molar yield of the ether was 71.5%. The molar yield of ammonium chloride hydrochloride was 100%.

Claims

1. A method for the total synthesis of clethodim, characterized in that, The process route is as follows: ； Step 2 is as follows: Crotonaldehyde and triethylamine are added to the synthesis reactor and stirred. Ethyl mercaptan is added dropwise at room temperature for 2-3 hours, while controlling the temperature at 55℃-65℃. After the addition is complete, the temperature is maintained at 60℃-68℃ for 3.5 hours to obtain β-ethylthiobutyraldehyde. The mixture is then cooled for later use. Step 5 is as follows: Add the 30% sodium methoxide-methanol solution prepared in step 1 to the reactor, stir, add toluene, heat to 110℃ to concentrate and remove methanol, cool to 30-40℃, continue to add toluene, add dimethyl malonate dropwise at 30-40℃ for 1.5-2 hours, keep warm at 30-40℃ for 1 hour, add 6-ethylthio-3-hepten-2-one prepared in step 4 dropwise for 1.5-2 hours, keep warm for 0.5 hours, continue to heat to 110℃ to react, distill off some toluene and the methanol generated in the reaction, cool to obtain a toluene solution of heptenone cyclization product 1; Steps 6-7 are as follows: Heptenone cyclization product 1 is transferred into the reactor, propionyl chloride is added dropwise at room temperature for 1-1.5 hours, and the temperature is controlled at 50℃-60℃. After the addition is complete, the temperature is raised to 90℃ and kept at that temperature for 2 hours. The temperature is then lowered by 40℃ to obtain acylated product 2 solution. Triethylamine is added directly to adjust the pH value, and then 4-dimethylaminopyridine (DMAP) / toluene solution is added. The temperature is raised to 90℃ and kept at that temperature for 6 hours. The temperature is then lowered by 40℃ to obtain rearrangement product 3 solution. Step 8 is performed as follows: Transfer the rearrangement product 3 solution into the reactor, add 31% hydrochloric acid and fresh water at room temperature, acid wash, neutralize the alkali and DMAP, stir for 0.5 h, let stand for 0.5 h, separate the organic phase, continue to add fresh water at room temperature, add 32% liquid alkali dropwise for 1 to 1.5 h, control the temperature at 20℃ to 40℃, after the addition is complete, raise the temperature to 70℃, keep it at 4 h, lower the temperature to 40℃, extract and separate the phases, let stand for 0.5 h, take the aqueous layer, and obtain hydrolysis product 4; Step 9 is as follows: Hydrolysis product 4 is transferred into the reactor, the temperature is lowered to below 40°C, 31% hydrochloric acid is added dropwise for 2.5 to 3 hours, the temperature is controlled to be below 20°C to 40°C, after the addition is completed, the mixture is stirred for 2 hours to obtain propionyl trione 5. After extraction, the solvent is removed by distillation, and propionyl trione 5 is obtained by fractional distillation. Step 10 is as follows: Hydroxylamine hydrochloride and pure water are mixed in a mixing tank to prepare 40% hydroxylamine hydrochloride. The prepared 40% hydroxylamine hydrochloride and methyl acetate are added to the tank, stirred, cooled to 20°C, and 32% liquid alkali is added dropwise. The temperature is controlled at 20°C to 25°C. The dropwise addition is completed in 9 hours. The temperature is maintained for 1 hour to obtain acetamide sodium hydroxyl solution. Step 11 is performed as follows: Add tetrabutylammonium iodide to the sodium acetamide solution obtained in step 10, continue to add dichloropropene dropwise for 1 hour while controlling the temperature, raise the temperature to 50-60℃ and keep it at that temperature for 9 hours, lower the temperature by 30-40℃, and the reaction will generate etherified product 6 solution. Continue to add 31% hydrochloric acid dropwise for 2 hours to acidify the etherified product into salt, raise the temperature to 70-80℃ and keep it at that temperature for 2 hours, add fresh water, add 32% liquid alkali dropwise to neutralize and adjust the pH to the appropriate level, add dichloromethane for extraction, and obtain an aqueous phase containing etherified product hydrochloride. Step 12 is performed as follows: Add 32% liquid alkali to the hydrochloride solution of the etherified product obtained in step 11, and add it dropwise at 30-40°C for about 2 hours until it becomes alkaline. Add dichloromethane for extraction, separate the organic layer and remove the solvent to obtain 3-chloroallyloxyamine. Step 13 is performed as follows: Add the glycerol propionyl trione prepared in step 9 and the 3-chloroallyloxyamine prepared in step 12 into the reactor, stir, heat to 45-50℃, keep warm for 5 hours, add 31% hydrochloric acid, petroleum ether or cyclohexane solvent, acid wash, mix and stir, let stand, separate the organic phase, wash with water, separate the organic layer, remove solvent and cool to obtain clethodim.

2. The method for total synthesis of clethodim according to claim 1, characterized in that, Step 1 is performed as follows: 96% sodium methoxide flakes and methanol are mixed at room temperature and reacted at 40℃~50℃. After the reaction is complete, the mixture is subjected to sedimentation treatment, and the supernatant is distilled to obtain a 30% sodium methoxide-methanol solution, which can be directly used in step 5 without further treatment. The impurity of the 96% sodium methoxide flakes is sodium chloride.

3. The method for total synthesis of clethodim according to claim 1, characterized in that, Step 3 is as follows: Add methyl acetoacetate and water to the synthesis reactor, stir, and start adding 32% liquid alkali dropwise at room temperature for 4-5 hours, controlling the temperature at 35℃-40℃. After the addition is complete, keep the temperature at 35℃-40℃ for 3 hours to obtain a sodium acetoacetate solution for later use.

4. The method for total synthesis of clethodim according to claim 1, characterized in that, Step 4 is performed as follows: The sodium acetoacetate solution prepared in step 3 is transferred into the synthesis vessel, toluene and piperidine are added, and the mixture is stirred. Acetic acid is added dropwise at room temperature for 2 hours until the pH reaches 7.3, and the temperature is controlled at 35℃~40℃. After the addition is complete, β-ethylthiobutyraldehyde prepared in step 2 is transferred in, and 75% acetic acid is added dropwise for 7 hours, maintaining the pH at 6.8~6.9 and controlling the temperature at 35℃~40℃. After toluene extraction, layering, washing with water, and drying, a toluene solution of 6-ethylthio-3-hepten-2-one is obtained.

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