A method for preparing a fine pendimethalin or a salt thereof

Abstract

The application provides a preparation method of glufosinate-ammonium or a salt thereof. The method comprises the following steps: step 1, reacting a first reaction raw material with a second reaction raw material in the presence of ammonia and / or an organic base to obtain an intermediate; step 2, hydrolyzing the intermediate by an acid to obtain glufosinate-ammonium acid salt; and step 3, preparing glufosinate-ammonium by using the glufosinate-ammonium acid salt as a raw material; wherein the first reaction raw material is L-2-amino-4-chlorobutyric acid ethyl ester and / or a salt thereof, the second reaction raw material is methyl phosphinic acid monoester, the structural formula of the methyl phosphinic acid monoester is the structural formula of the intermediate is the structural formula of the glufosinate-ammonium acid salt is R1 is selected from alkyl with 1-12 carbon atoms, A is selected from an acid, and the molar ratio of the ammonia and / or the organic base to the first reaction raw material is greater than 1. The preparation method is simple in steps, low in cost, can be produced on a large scale, and the prepared glufosinate-ammonium or the salt thereof is higher in quality.

Description

Technical Field

[0001] This invention belongs to the field of chemical engineering, and specifically relates to a method for preparing glufosinate or its salt. Background Technology

[0002] Glufosinate is a highly effective, broad-spectrum, low-toxicity, non-selective contact herbicide. Glufosinate includes L-glufosinate and racemic D-glufosinate, with the L-form being the main active molecule exhibiting herbicidal activity (i.e., glufosinate-ammonium, molecular formula: C5H). 12 NO4P (chemical name 4-[hydroxy(methyl)phosphono]-L-hoalanine ammonium salt), while D-glufosinate has almost no herbicidal activity. If commercially available racemic glufosinate products could be presented as the optically pure L-configuration isomer with higher atom economy, the application rate of glufosinate per acre could be reduced by about 50%, significantly reducing usage costs and alleviating environmental pressure, which is of great significance to the development of the herbicide industry.

[0003] Existing preparation processes for glufosinate mainly include biocatalysis and chemical synthesis. Biocatalysis primarily utilizes biocatalysis to convert D-glufosinate into a keto acid intermediate, followed by reductive amination to obtain L-glufosinate. However, this method involves high-cost, unstable, and environmentally sensitive enzymes, making large-scale production difficult. Chemical synthesis of glufosinate mainly includes chiral auxiliaries, racemic resolution, and asymmetric synthesis. These methods suffer from complex synthetic routes, low yields, expensive chiral resolution reagents, and the need for chiral racemization. The L-amino acid chiral introduction method is currently a more user-friendly chemical approach for preparing glufosinate. For example, patents such as US5443088, CN113248537, and CN106083922 disclose the synthesis of amino-protected or unprotected chlorohomoserine esters from L-homoserine or its lactones, followed by a Michaelis-Arbuzov reaction with methyl phosphite diester and hydrolysis to prepare glufosinate. The reaction routes are listed below.

[0004]

[0005] This method has advantages such as a short synthetic route and high operational continuity. However, the necessary reagent, methylphosphite, is expensive (e.g., diethyl methylphosphite, CAS: 15715-41-0, purity ≥98.0%, 10g, 3049 yuan, Beijing Bailingwei Technology Co., Ltd.), requires a large amount, has a low recovery rate, and the high temperature conditions required for the reaction will lead to a decrease in the product's ee value, making it difficult to guarantee product quality.

[0006] Therefore, there is an urgent need for a method for synthesizing glufosinate that is simple to operate, low in cost, inherently safe, and has industrial application value. Summary of the Invention

[0007] The technical problem to be solved by the present invention is to provide a method for preparing glufosinate or its salts. The preparation method is simple to operate, has higher atom economy, can be mass-produced, and produces glufosinate or its salts of high quality.

[0008] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0009] A method for preparing glufosinate-ammonium includes the following steps:

[0010] Step 1: React the first reactant with the second reactant in the presence of ammonia and / or an organic base to obtain an intermediate;

[0011] Step 2: The intermediate is acid-hydrolyzed to generate glufosinate;

[0012] Step 3: Prepare glufosinate using glufosinate as a raw material;

[0013] The first reactant is ethyl L-2-amino-4-chlorobutyrate and / or its salt, and the second reactant is methylphosphonic acid monoester, wherein the structural formula of the methylphosphonic acid monoester is [insert structural formula here]. The structural formula of the intermediate is as follows: The structural formula of the glufosinate is: R1 is selected from alkyl groups having 1 to 12 carbon atoms, and A is selected from acids.

[0014] The molar ratio of ammonia and / or organic base to the first reaction raw material is greater than 1.

[0015] Preferably, the molar ratio of the ammonia and / or organic base to the first reaction raw material is (1.01+n1) to (2.5+n1):1, where n1 is the molar percentage of the salt of L-2-amino-4-chlorobutyrate in the first reaction raw material.

[0016] More preferably, the molar ratio of the ammonia and / or organic base to the first reaction raw material is (1.5+n1)~(2.5+n1):1, where n1 is the molar percentage of the salt of L-2-amino-4-chlorobutyrate in the first reaction raw material.

[0017] More preferably, the molar ratio of the ammonia and / or organic base to the first reaction raw material is (1.7+n1)~(2.3+n1):1, where n1 is the molar percentage of the salt of L-2-amino-4-chlorobutyrate in the first reaction raw material.

[0018] In some embodiments, the first reactant is ethyl L-2-amino-4-chlorobutyrate, with the structural formula [insert structural formula here]. The molar ratio of ammonia and / or organic base to the first reaction raw material is preferably (1.5-2.5):1, and more preferably (1.8-2.2):1.

[0019] In some embodiments, the first reactant is a salt of ethyl L-2-amino-4-chlorobutyrate, with the structural formula shown below. The molar ratio of ammonia and / or organic base to the first reaction raw material is (2.01-3.5):1, more preferably (2.5-3.5):1, and even more preferably (2.8-3.2):1.

[0020] Preferably, the organic base is selected from one or more of triethylamine, diethylamine, dimethylamine, N,N-dimethylcyclohexylamine, tetrabutylammonium hydroxide, pyridine, and 4-dimethylaminopyridine.

[0021] Preferably, step 1 specifically includes:

[0022] Step 1.1: Under a nitrogen atmosphere, the second reaction raw material is mixed with ammonia and / or an organic base at a first temperature to prepare a mixture;

[0023] Step 1.2: Mix the first reaction raw material with an inert solvent, and selectively add ammonia and / or organic base;

[0024] Step 1.3: Control the temperature of the S2 mixture system to the second temperature. Under a nitrogen atmosphere, add the S1 mixture dropwise to the S2 mixture system. After the addition is complete, stir and then raise the system temperature to the third temperature for reaction.

[0025] Preferably, the first temperature is 10–80°C, more preferably 30–80°C, and even more preferably 30–50°C.

[0026] Preferably, the second temperature is -20 to 20°C, more preferably -10 to 10°C, and even more preferably -10 to 0°C.

[0027] Preferably, the third temperature is 70–120°C, and more preferably 80–100°C.

[0028] Preferably, the inert solvent is selected from one or more of toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, and 1,4-dioxane.

[0029] Preferably, the molar ratio of the first reactant to the second reactant is 1:(1 to 1.5), more preferably 1:(1 to 1.2), for example 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2.

[0030] Preferably, R1 is selected from alkyl groups having 1 to 10 carbon atoms.

[0031] More preferably, R1 is selected from alkyl groups having 1 to 5 carbon atoms, such as methyl, ethyl, propyl, or butyl.

[0032] More preferably, the second reactant is selected from one or more of monomethyl methylphosphonate, monoethyl methylphosphonate, monopropyl methylphosphonate, mono-n-butyl methylphosphonate, and monoisobutyl methylphosphonate.

[0033] Preferably, the preparation method further includes the steps of keeping the reaction system at 0-20°C after the reaction in step 1 is completed, filtering, and vacuum drying the filtrate until it becomes viscous to obtain the intermediate.

[0034] Preferably, in step 2, the acid is hydrochloric acid (i.e., A is HCl).

[0035] More preferably, step 2 specifically includes: mixing the intermediate with hydrochloric acid, heating under reflux while removing low-boiling-point substances, until the raw material is completely converted, and evaporating the reaction system to obtain glufosinate hydrochloride.

[0036] In some embodiments, in step 2, the molar ratio of the intermediate to the acid is 1:(5-15).

[0037] Preferably, step 3 specifically includes: dissolving glufosinate in water, adding ammonia to bring the pH to 2-3, keeping the mixture at 20-30°C with stirring until the inorganic salts are completely precipitated, filtering, concentrating the filtrate to dryness, adding an ethanol aqueous solution for reflux, cooling to crystallize, filtering, and drying to obtain glufosinate.

[0038] The present invention also provides a method for preparing glufosinate-ammonium salt, comprising reacting glufosinate-ammonium salt obtained by the preparation method described above with an alkali to generate glufosinate-ammonium salt.

[0039] Preferably, the glufosinate salt includes glufosinate sodium salt, glufosinate ammonium salt, or glufosinate potassium salt.

[0040] Preferably, the alkali is selected from ammonia, sodium hydroxide, or potassium hydroxide.

[0041] In some embodiments, the alkali is ammonia water, which is used to prepare glufosinate-phosphonium salt.

[0042] In some embodiments, the alkali is sodium hydroxide, prepared as sodium glufosinate.

[0043] In some embodiments, the alkali is potassium hydroxide, prepared as glufosinate potassium salt.

[0044] Preferably, the molar ratio of glufosinate to alkali is 1:(0.9-1.2), more preferably 1:(1-1.2), for example 1:1, 1:1.05, 1:1.1, 1:1.15, 1:1.2.

[0045] Due to the implementation of the above technical solutions, the present invention has the following advantages compared with the prior art:

[0046] The preparation method of the present invention has simple steps, higher atom economy, can be mass-produced, and the obtained glufosinate or its salt has higher quality. Attached Figure Description

[0047] Figure 1 The optical content detection spectrum of glufosinate in Example 1;

[0048] Figure 2 The chemical content detection spectrum of glufosinate in Example 1 is shown. Detailed Implementation

[0049] Existing technologies for preparing L-glufosinate typically require the use of excessive amounts of expensive, flammable, easily hydrolyzed and oxidized diethyl methyl phosphite. This invention creatively utilizes a more atom-economical monomethylphosphonic acid ester, which undergoes an esterification reaction with ethyl L-2-amino-4-chlorobutyrate and / or its salt in the presence of ammonia and / or an organic base. Following in-situ rearrangement at elevated temperature, a one-pot method is achieved to prepare the key intermediate 4-[alkoxy(methyl)phosphono]-L-hoalanine ethyl ester. By controlling the amount of ammonia and / or organic base added, which provides reducing and acid-binding properties, the entire reaction proceeds without significant side reactions, improving the overall yield of glufosinate and effectively suppressing its racemic tendency. Furthermore, the preparation method of this invention offers milder reaction conditions and has strong industrial application value. The following is a detailed discussion of this invention.

[0050] A method for preparing glufosinate-ammonium includes the following steps:

[0051] Step 1: React the first reactant with the second reactant in the presence of ammonia and / or an organic base to obtain an intermediate;

[0052] Step 2: The intermediate is acid-hydrolyzed to generate glufosinate;

[0053] Step 3: Prepare glufosinate using glufosinate as a raw material;

[0054] The first reactant is ethyl L-2-amino-4-chlorobutyrate and / or its salt, and the second reactant is methylphosphonic acid monoester, wherein the structural formula of the methylphosphonic acid monoester is [insert structural formula here]. The structural formula of the intermediate is as follows: The structural formula of the glufosinate is: R1 is selected from alkyl groups having 1 to 12 carbon atoms, and A is selected from acids.

[0055] The molar ratio of ammonia and / or organic base to the first reaction raw material is greater than 1.

[0056] According to the present invention, the preferred reaction route for the preparation of glufosinate is as follows:

[0057]

[0058] Among them, the compound shown in structural formula 2-1 is ethyl L-2-amino-4-chlorobutyrate, the compound shown in structural formula 2-2 is a salt of ethyl L-2-amino-4-chlorobutyrate, the compound shown in structural formula I is an intermediate, the compound shown in structural formula II is glufosinate hydrochloride, and the compound shown in structural formula III is glufosinate.

[0059] According to the present invention, chlorohomoserine ethyl ester or its hydrochloride is synthesized from L-homoserine lactone, and the specific reaction route is as follows:

[0060]

[0061] Among them, the compound shown in structural formula I is L-homoserine lactone.

[0062] Furthermore, chlorohomoserine ethyl ester or its hydrochloride can be synthesized according to the routes provided in patents WO2021098712A1 and CN115583967A.

[0063] The present invention will be further described in detail below with reference to specific embodiments. It should be understood that these embodiments are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited to the following embodiments. The implementation conditions used in the embodiments can be further adjusted according to specific requirements, and the implementation conditions not specified are generally the conditions in conventional experiments.

[0064] Unless otherwise specified, all raw materials and reagents used in the following examples are commercially available products.

[0065] Unless otherwise specified, the chlorohomoserine ethyl ester or its hydrochloride salt (compound 2-1, compound 2-2) in this invention can be synthesized according to the routes provided in patents WO2021098712A1 and CN115583967A, with ee values ​​of ≥98%, HPLC purity ≥95%, and yield of 90%. Specifically, the chlorohomoserine ethyl ester was prepared according to Example 1 of WO2021098712A1, and the chlorohomoserine ethyl ester hydrochloride was prepared according to Example 1 of WO2021098712A1.

[0066] To determine the optical purity of the prepared glufosinate, a chiral derivatization method was used, followed by high-performance liquid chromatography (HPLC). The specific method was as follows: Column: 250 mm × 4.6 mm (id) Inertsil ODS-SP stainless steel column, particle size 5 μm; Mobile phase: methanol: 0.05 mol / L ammonium acetate solution (pH = 5.7) = 8:92; Flow rate: 1.0 mL / min; Column temperature: 35 ℃; Detection wavelength: 230 nm; Injection volume: 5 μL; Retention time: L-glufosinate (refined glufosinate) 7.137 min, D-glufosinate 9.1 min.

[0067] The high-performance liquid chromatography (HPLC) conditions for determining the chemical content of glufosinate were as follows: Column: 250 mm × 4.6 mm (id) strong anion exchange stainless steel column packed with SAX and 5 μm packing material; Mobile phase preparation: 1.36 g potassium dihydrogen phosphate was weighed, dissolved in 970 mL of freshly distilled double-distilled water or ultrapure water, 30 mL of methanol was added, mixed well, filtered through a filter membrane, and degassed; Flow rate: 0.8 mL / min; Column temperature: 30 ℃; Detection wavelength: 195 nm; Injection volume: 20 μL; Retention time of glufosinate was 6.7 min.

[0068] Unless otherwise specified, the methyl phosphonate butyl ester, methyl phosphonate ethyl ester, and methyl phosphonate methyl ester used in the following examples are all self-made, and the synthesis methods are based on patent US5734072 and literature Angew Chemie Int Ed., 2018, 57, 5016-5019; the details are as follows.

[0069] Preparation method of methylphosphine butyl ester: At -10℃, n-butanol (100g, 1.35mol, 4eq) and triethylamine (35.35g, 0.35mol, 1.03eq) were added to a three-necked flask, followed by the slow dropwise addition of methylphosphine dichloride (39.75g, 0.34mol, 1eq) over approximately 2 hours. The mixture was then heated to 0℃ and reacted for 1 hour. The triethylamine hydrochloride was removed by filtration, and the butanol was removed by vacuum distillation. The final product was 41.6g of methylphosphine butyl ester, with a yield of 90%.

[0070] Preparation method of ethyl methylphosphinate: Ethanol (62.19 g, 1.35 mol, 4 eq) and triethylamine (35.35 g, 0.35 mol, 1.03 eq) were added to a three-necked flask at -10 °C. Then, methylphosphine dichloride (39.75 g, 0.34 mol, 1 eq) was slowly added dropwise over approximately 2 hours. The mixture was heated to 10 °C and reacted for 1 hour. The triethylamine hydrochloride was removed by filtration, and the ethanol was removed by vacuum distillation. The product was then purified by distillation to obtain 33.78 g of ethyl methylphosphinate, with a yield of 92%.

[0071] Preparation method of methyl methylphosphine: Methanol (43.2 g, 1.35 mol, 4 eq) and triethylamine (35.35 g, 0.35 mol, 1.03 eq) were added to a three-necked flask at -10 °C. Then, methylphosphine dichloride (39.75 g, 0.34 mol, 1 eq) was slowly added dropwise over approximately 2 hours. The mixture was heated to 10 °C and reacted for 1 hour. The triethylamine hydrochloride was removed by filtration, and the methanol was removed by vacuum distillation. The product was then purified by distillation to obtain 20.13 g of methyl methylphosphine, with a yield of 63%.

[0072] Examples 1-5

[0073] A method for preparing glufosinate-ammonium, the reaction route is as follows:

[0074]

[0075] Example 1

[0076] Under a nitrogen atmosphere, methylphosphinate butyl ester (CAS: 6172-80-1, self-made; 19.3 g, 0.142 mol) and triethylamine (27.3 g, 0.27 mol) were mixed in a reaction flask and heated to 50 °C for 1 hour with stirring. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and trimethylbenzene (60 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface, and the system was allowed to fully release nitrogen. After the reaction was completed, the temperature was lowered to 0°C. The pre-prepared mixture of methylphosphinate and triethylamine was then added dropwise to the reaction system at a constant temperature of 50°C. After the addition was completed in about 40 minutes, the reaction system was stirred at 0°C for 10 minutes. A large amount of solid began to precipitate. The reaction system was then heated to 90°C. The system changed from pale yellow to brown. After the reaction of the raw materials was completed under GC control, the system was lowered to 10°C and kept at that temperature for 30 minutes. The by-product triethylamine hydrochloride was removed by vacuum filtration. The filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-1.

[0077] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 105℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 31.72g of crude glufosinate hydrochloride (compound II), with a content of about 89% and a yield of 96.1% (calculated as compound 2-1).

[0078] Crude glufosinate hydrochloride was dissolved in 50g of water, and the pH was adjusted to 2.5 with ammonia. The mixture was kept at room temperature with stirring, and insoluble matter was removed by filtration. The filtrate was further concentrated to dryness, and 90g of 95% ethanol aqueous solution was added. The mixture was then refluxed, cooled to crystallize, filtered, and dried to obtain 22.75g of white solid glufosinate (compound III), with a purity of 98.9% and a yield of 92% (calculated based on compound 2-1). The L-body percentage was 98.5% (ee value 97%). Optical and chemical content detection spectra of glufosinate are shown below. Figure 1 and Figure 2 .

[0079] Example 2

[0080] Under a nitrogen atmosphere, methylphosphinate butyl ester (2.89 kg, 21.3 mol) and triethylamine (4.1 kg, 40.5 mol) were mixed in a reaction flask and heated to 50°C for 1 hour with stirring. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 3.53 kg, 20.25 mol) and trimethylbenzene (9 kg) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface. After the nitrogen gas had fully overflowed, the mixture was cooled to 0°C. The pre-prepared mixture of methylphosphinate and triethylamine was added dropwise to the reaction system at a constant temperature of 50°C. After the addition was completed in about 1.5 hours, the reaction system was stirred at 0°C for 30 minutes, and a large amount of solid began to precipitate. The reaction system was then heated to 90°C, and the system changed from pale yellow to brown. After the reactants were completely reacted in GC, the system was cooled to 10°C and kept at that temperature for 1 hour. The byproduct triethylamine hydrochloride was removed by vacuum filtration, and the filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-1.

[0081] Without purification (calculated as 100%), 36% hydrochloric acid (12.3 kg) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 105°C, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 4.73 kg of crude glufosinate hydrochloride with a content of about 89.3% and a yield of 95.9% (calculated based on compound 2-1).

[0082] The crude glufosinate hydrochloride was dissolved in 7.5 kg of water, the pH was adjusted to 2.5 with ammonia, and the mixture was kept at room temperature with stirring. The insoluble matter in the system was removed by suction filtration, and the filtrate was further concentrated to dryness. 14.2 kg of 95% ethanol aqueous solution was added, and the mixture was refluxed, cooled to crystallize, filtered, and dried to obtain 3.42 kg of white solid glufosinate with a purity of 99% and a yield of 92.4% (calculated based on compound 2-1). The L-body content was 98.9% (ee value 97.8%).

[0083] Example 3

[0084] Under a nitrogen atmosphere, methyl phosphinic acid butyl ester (19.3 g, 0.142 mol) and triethylamine (27.3 g, 0.27 mol) were mixed in a reaction flask and stirred at 10°C for 3 hours. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and trimethylbenzene (60 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface. After the nitrogen gas had fully overflowed, the mixture was cooled to 0°C, and the pre-prepared methyl phosphinic acid butyl ester was added. The mixture of triethylamine and ethylamine was added dropwise to the reaction system at a constant rate at 10°C. After the addition was completed in about 40 minutes, the reaction system was kept at 0°C and stirred for 10 minutes. Solids began to precipitate. The reaction system was then heated to 90°C, and the system changed from pale yellow to brown. The reaction was maintained at this temperature for 10 hours. The peak area of ​​the raw material in the GC test was finally reduced to 9%. The peak area no longer changed after the reaction was continued. The system was then cooled to 10°C and kept at this temperature for 30 minutes. The byproduct triethylamine hydrochloride was removed by vacuum filtration. The filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-1.

[0085] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 101℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 30.89g of crude glufosinate hydrochloride with a content of about 81% and a yield of 85.2% (calculated based on compound 2-1).

[0086] The crude glufosinate hydrochloride was dissolved in 50g of water, the pH was adjusted to 2.5 with ammonia, and the mixture was kept at room temperature with stirring. The insoluble matter in the system was removed by suction filtration, and the filtrate was further concentrated to dryness. 90g of 95% ethanol aqueous solution was added, and the mixture was refluxed, cooled to crystallize, filtered, and dried to obtain 21.18g of gray solid glufosinate with a purity of 92% and a yield of 79.7% (calculated based on compound 2-1). The L-body content was 98.1% (ee value 96.2%).

[0087] Example 4

[0088] Under a nitrogen atmosphere, methylphosphinate butyl ester (19.3 g, 0.142 mol) and triethylamine (27.3 g, 0.27 mol) were mixed in a reaction flask and heated to 50 °C for 1 hour with stirring. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and trimethylbenzene (60 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface. After the nitrogen gas had fully overflowed, the mixture was cooled to 0 °C. The pre-prepared mixture of butyl methylphosphonate and triethylamine was added dropwise to the reaction system at a constant temperature of 50°C. After the addition was completed in about 40 minutes, the reaction system was stirred at 0°C for 10 minutes, and a large amount of solid began to precipitate. The reaction system was then heated to 110°C, and the system changed from light yellow to dark brown. After the reactants were completely reacted in GC, the system was cooled to 10°C and kept at that temperature for 30 minutes. The byproduct triethylamine hydrochloride was removed by vacuum filtration, and the filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-1.

[0089] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 105℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 31.33g of crude glufosinate hydrochloride with a content of about 82.5% and a yield of 88% (calculated based on compound 2-1).

[0090] Crude glufosinate hydrochloride was dissolved in 50g of water, and the pH was adjusted to 2.5 with ammonia. The mixture was kept at room temperature and stirred. The insoluble matter in the system was removed by suction filtration. The filtrate was further concentrated to dryness, and 90g of 95% ethanol aqueous solution was added. The mixture was refluxed, cooled to crystallize, filtered, and dried to obtain 21.5g of white solid glufosinate with a purity of 94.5% and a yield of 83.1% (calculated based on compound 2-1). The L-body content was 98.4% (ee value 96.8%).

[0091] Example 5

[0092] In a three-necked flask, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol), thiol (60 g), and triethylamine (27.3 g, 0.27 mol) were added sequentially. The nitrogen gas line was inserted below the liquid surface. After the nitrogen gas had fully overflowed, the temperature was lowered to 0°C. Then, methylphosphinate butyl ester (19.3 g, 0.142 mol) was added dropwise to the reaction system at 50°C at a uniform rate. After approximately 40 minutes of addition, the reaction mixture... The mixture was kept at 0°C and stirred for 10 minutes. A large amount of solid began to precipitate. The reaction system was then heated to 90°C, and the system changed from pale yellow to brown. After 10 hours of heating, the peak area of ​​the raw material in the GC test was finally 6.8%. The reaction was continued for 14 hours, and the peak area of ​​the raw material in the GC test dropped to 2.4% and then remained unchanged. The system was then cooled to 10°C and kept at that temperature for 30 minutes. The byproduct triethylamine hydrochloride was removed by vacuum filtration. The filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-1.

[0093] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 103℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 31.63g of crude glufosinate hydrochloride with a content of about 84.5% and a yield of 91% (calculated based on compound 2-1).

[0094] Crude glufosinate hydrochloride was dissolved in 50g of water, and the pH was adjusted to 2.5 with ammonia. The mixture was kept at room temperature and stirred. The insoluble matter in the system was removed by suction filtration. The filtrate was further concentrated to dryness. 90g of 95% ethanol aqueous solution was added and the mixture was refluxed, cooled to crystallize, filtered, and dried to obtain 22.45g of white solid glufosinate with a purity of 93.9% and a yield of 86.2% (calculated based on compound 2-1). The L-body content was 98.5% (ee value 97%).

[0095] Example 6

[0096] A method for preparing glufosinate-ammonium, the reaction route is as follows:

[0097]

[0098] Under a nitrogen atmosphere, ethyl methylphosphinic acid (CAS: 16391-07-4, self-made, 15.35 g, 0.142 mol) and triethylamine (27.3 g, 0.27 mol) were mixed in a reaction flask and heated to 40 °C for 1 hour with stirring. The mixture was then set aside. Subsequently, 95% pure ethyl chlorohomoserine (compound 2-1, 23.54 g, 0.135 mol) and toluene (55 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface, and the system was allowed to fully release nitrogen. After extraction, the temperature was lowered to 0°C, and the pre-prepared mixture of ethyl methylphosphonate and triethylamine was added dropwise to the reaction system at a constant temperature of 40°C. After the addition was completed in about 50 minutes, the reaction system was kept at 0°C and stirred for 10 minutes. A large amount of solid began to precipitate. The reaction system was then heated to 85°C, and the system changed from pale yellow to yellow. After the reactants were completely reacted in the GC, the system was lowered to 10°C and kept at that temperature for 30 minutes. The byproduct triethylamine hydrochloride was removed by vacuum filtration, and the filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-2.

[0099] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 103℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 30.93g of crude glufosinate hydrochloride (compound II), with a content of about 91% and a yield of 95.8% (calculated as compound 2-1).

[0100] The crude glufosinate hydrochloride was dissolved in 50g of water, the pH was adjusted to 2.5 with ammonia, stirred at room temperature, and the system was filtered to remove insoluble matter. The filtrate was further concentrated to dryness, and 90g of 95% ethanol aqueous solution was added for reflux, cooling and crystallization, filtration, and drying to obtain 22.79g of white solid glufosinate (compound III), with a purity of 98.8% and a yield of 92.1% (calculated based on compound 2-1), and an L-body content of 98.7% (ee value 97.4%).

[0101] Example 7

[0102] A method for preparing glufosinate-ammonium, the reaction route is as follows:

[0103]

[0104] Under a nitrogen atmosphere, ethyl methylphosphinic acid (15.35 g, 0.142 mol) and triethylamine (27.3 g, 0.27 mol) were mixed in a reaction flask and heated to 40 °C for 1 hour with stirring. The mixture was then set aside. Subsequently, 97% pure chlorohomoserine ethyl ester hydrochloride (compound 2-2, 28.12 g, 0.135 mol), triethylamine (13.66 g, 0.135 mol), and chlorobenzene (60 g) were added sequentially to a three-necked flask. After stirring thoroughly for about 0.5 hours, the nitrogen gas line was inserted below the liquid surface. After the nitrogen gas in the system has fully escaped, the temperature is lowered to -10℃. The pre-prepared mixture of ethyl methylphosphonate and triethylamine is added dropwise to the reaction system at a constant temperature of 40℃. After the addition is completed in about 50 minutes, the reaction system is kept at -10℃ and stirred for 10 minutes. The temperature is then slowly raised to 0℃, and a large amount of solid begins to precipitate. The reaction system is then raised to 85℃ and the reaction is continued. After the raw materials have reacted completely under GC control, the system is lowered to 10℃ and kept at that temperature for 30 minutes. The by-product triethylamine hydrochloride is removed by vacuum filtration. The filtrate is dried under high vacuum until it becomes viscous to obtain a brown oily compound I-2.

[0105] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 103℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 31.47g of crude glufosinate hydrochloride (compound II), with a content of about 87% and a yield of 93.2% (calculated as compound 2-2).

[0106] The crude glufosinate hydrochloride was dissolved in 50g of water, the pH was adjusted to 2.5 with ammonia, stirred at room temperature, and the system was filtered to remove insoluble matter. The filtrate was further concentrated to dryness, and 90g of 95% ethanol aqueous solution was added for reflux, cooling and crystallization, filtration, and drying to obtain 22.07g of white solid glufosinate (compound III), with a purity of 97.5% and a yield of 88% (calculated based on compound 2-2), and an L-body content of 98.1% (ee value 96.2%).

[0107] Example 8

[0108] A method for preparing glufosinate-ammonium, the reaction route is as follows:

[0109]

[0110] Under a nitrogen atmosphere, methyl methylphosphinic acid (CAS: 16391-06-3, self-made; 13.36 g, 0.142 mol) and pyridine (21.36 g, 0.27 mol) were mixed in a reaction flask and heated to 30 °C for 30 minutes with stirring. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and toluene (55 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface, and the system was allowed to fill with nitrogen. After the mixture overflows, it is cooled to -10℃. The pre-prepared mixture of methyl methylphosphonate and pyridine is added dropwise to the reaction system at a constant temperature of 30℃. After the addition is completed in about 70 minutes, the reaction system is kept at -10℃ and stirred for 10 minutes. The temperature is then slowly raised to 0℃, and a large amount of solid begins to precipitate. The reaction system is then heated to 80℃ and the reaction is continued. After the raw materials have reacted completely in the GC, the system is cooled to 10℃ and kept at that temperature for 30 minutes. The by-product pyridine hydrochloride is removed by vacuum filtration. The filtrate is dried under high vacuum until it becomes viscous to obtain a yellow oily compound I-3.

[0111] Without purification (calculated as 100%), 30% hydrochloric acid (98.4 g) was directly added to the system of compound I-3, and the temperature was raised to reflux while continuously collecting low-boiling substances. The internal temperature was raised to 101 °C, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 31.05 g of crude glufosinate hydrochloride (compound II), with a content of about 89.4% and a yield of 94.5% (calculated as compound 2-1).

[0112] The crude glufosinate hydrochloride was dissolved in 50g of water, the pH was adjusted to 2.5 with ammonia, stirred at room temperature, and the system was filtered to remove insoluble matter. The filtrate was further concentrated to dryness, and 90g of 95% ethanol aqueous solution was added for reflux, cooling and crystallization, filtration, and drying to obtain 22.71g of white solid glufosinate (compound III), with a purity of 98.1% and a yield of 91.1% (calculated based on compound 2-1), and an L-body content of 98.9% (ee value 97.8%).

[0113] Example 9

[0114] A method for preparing glufosinate-ammonium, the reaction route is as follows:

[0115]

[0116] Under a nitrogen atmosphere, methyl methylphosphinic acid (13.36 g, 0.142 mol) and diethylamine (19.75 g, 0.27 mol) were mixed in a reaction flask and heated to 30 °C for 1.5 h with stirring. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and toluene (55 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface, and the nitrogen gas was allowed to fully overflow from the system. Then, the temperature was lowered to 0℃, and the pre-prepared mixture of methyl methylphosphonate and diethylamine was added dropwise to the reaction system at a constant temperature of 30℃. After the addition was completed in about 75 minutes, the reaction system was kept at 0℃ and stirred for 10 minutes. Solids began to precipitate from the system. The reaction system was then heated to 80℃ and the reaction was continued. After the raw materials were completely reacted in the GC, the system was lowered to 0℃ and kept at that temperature for 30 minutes. The by-product diethylamine hydrochloride was removed by vacuum filtration, and the filtrate was dried under high vacuum until it became viscous to obtain a yellow oily compound I-3.

[0117] Without purification (calculated as 100%), 30% hydrochloric acid (98.4 g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 101 °C, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 31 g of crude glufosinate hydrochloride with a content of about 88.9% and a yield of 93.8% (calculated based on compound 2-1).

[0118] The crude glufosinate hydrochloride was dissolved in 50g of water, the pH was adjusted to 2.5 with ammonia, stirred at room temperature, and the system was filtered to remove insoluble matter. The filtrate was further concentrated to dryness, and 90g of 95% ethanol aqueous solution was added for reflux, followed by cooling and crystallization, filtration, and drying to obtain 22.32g of white solid glufosinate, with a purity of 97.5% and a yield of 89% (calculated based on compound 2-1). The L-body content was 97.9% (ee value 95.8%).

[0119] Example 10

[0120] A method for preparing glufosinate-ammonium salt, the reaction route is as follows:

[0121]

[0122] 12g of glufosinate prepared in Example 2 was dissolved in 30g of water. Ammonia was added to the system until pH=8. The solvent was removed, methanol was added to the system, the mixture was heated to reflux, cooled to crystallize, filtered, and dried to obtain 12.85g of white solid glufosinate ammonium salt with a content of 99.1%, a yield of 97%, and an L- content of 99% (ee value of 98%).

[0123] Example 11

[0124] A method for preparing sodium glufosinate, the reaction route is as follows:

[0125]

[0126] 12g of glufosinate prepared in Example 2 was added to 53g of 5% NaOH aqueous solution and stirred at room temperature for 2 hours. The system was concentrated to a solute concentration of about 50%, cooled to crystallize, filtered, and dried to obtain 11.81g of grayish-white solid glufosinate sodium salt with a content of 98%, a yield of 86%, and an L- content of 96.1% (ee value of 92.2%).

[0127] Example 12

[0128] A method for preparing glufosinate potassium salt, the reaction route is as follows:

[0129]

[0130] 12g of glufosinate prepared in Example 2 was added to 37g of 10% KOH aqueous solution and stirred at room temperature for 2 hours. The system was concentrated to a solute concentration of about 50%, cooled to crystallize, filtered, and dried to obtain white solid glufosinate potassium salt with a yield of 79% and an L- content of 92.2%.

[0131] Comparative Example 1

[0132] The specific steps of this comparative example are similar to those of Example 1, except that triethylamine is not added to the reaction. The specific steps are as follows:

[0133] Add 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and 60 g of trimethylbenzene to a three-necked flask. Insert the nitrogen line below the liquid surface and wait for the nitrogen to fully overflow. Then, cool the system to 0°C. Add methylphosphinate butyl ester (19.3 g, 0.142 mol) dropwise to the reaction system at a constant temperature of 50°C. After the addition is completed in about 40 minutes, keep the reaction system at 0°C and stir for 10 minutes. No solid precipitates in the system. The raw materials were not converted in the GC test, and the corresponding compound I-1 could not be synthesized.

[0134] Comparative Example 2

[0135] Under a nitrogen atmosphere, methylphosphinate butyl ester (19.3 g, 0.142 mol) and triethylamine (14.4 g, 0.142 mol) were mixed in a reaction flask and heated to 50 °C for 1 hour with stirring. The mixture was then set aside. Subsequently, 95% pure chlorohomoserine ethyl ester (compound 2-1, 23.54 g, 0.135 mol) and thiol (60 g) were added sequentially to a three-necked flask. The nitrogen gas line was inserted below the liquid surface. After the nitrogen gas had fully overflowed from the system, the temperature was lowered to 0 °C, and the pre-prepared methylphosphinate butyl ester was added. A mixture of butyl phosphonate and triethylamine was added dropwise to the reaction system at a constant temperature of 50°C. After the addition was completed in about 40 minutes, the reaction system was stirred at 0°C for 10 minutes, and only a small amount of solid precipitated. The reaction system was then heated to 90°C, and the system changed from pale yellow to brown. The peak area of ​​the raw material in the GC test was finally 54% remaining. The peak area no longer changed after the reaction was continued. The system was then cooled to 10°C and kept at that temperature for 30 minutes. The byproduct triethylamine hydrochloride was removed by vacuum filtration, and the filtrate was dried under high vacuum until it became viscous, yielding a brown oily compound I-1.

[0136] Without purification (calculated as 100%), 36% hydrochloric acid (82g) was directly added to the system, the temperature was raised to reflux, and low-boiling substances were continuously collected. The internal temperature was raised to 101℃, and the process was controlled by MS until the raw material was completely converted. The acid water was evaporated under negative pressure to obtain 21.9g of glufosinate hydrochloride (compound II) viscous substance with a content of about 55% and a yield of 41% (calculated as compound 2-1).

[0137] The viscous glufosinate hydrochloride was dissolved in 50g of water, and the pH was adjusted to 2.5 with ammonia. The mixture was kept at room temperature and stirred. The insoluble matter in the system was removed by filtration. The filtrate was further concentrated to dryness. 90g of 95% ethanol aqueous solution was added and the mixture was refluxed and cooled to crystallize. Only a small amount of solid precipitated. 6.69g of dark gray solid was obtained by filtration, with a content of 72% and a yield of 19.7% (calculated based on compound 2-1). The L-body content was 98.1% (ee value 96.2%).

[0138] By comparing Example 1 and Comparative Example 2, it was found that if the amount of triethylamine added was too low, it would affect the product yield and quality. The inventors speculated that in addition to acting as an acid-binding agent, triethylamine plays a key role in the intermediate transposition of methylphosphinate butyl ester and chlorohomoserine ethyl ester, and additional triethylamine is required to promote the complete reaction.

[0139] The above embodiments are merely for illustrating the technical concept and features of the present invention. Their purpose is to enable those skilled in the art to understand the content of the present invention and implement it accordingly. They should not be used to limit the scope of protection of the present invention. All equivalent changes or modifications made in accordance with the spirit and essence of the present invention should be covered within the scope of protection of the present invention.

Claims

1. A method for preparing glufosinate-ammonium, characterized in that, The preparation method includes the following steps: Step 1: React the first reactant with the second reactant in the presence of ammonia and / or an organic base to obtain an intermediate; Step 2: The intermediate is acid-hydrolyzed to generate glufosinate; Step 3: Prepare glufosinate using glufosinate as a raw material; The first reactant is ethyl L-2-amino-4-chlorobutyrate and / or its salt, and the second reactant is methylphosphonic acid monoester, wherein the structural formula of the methylphosphonic acid monoester is [insert structural formula here]. The structural formula of the intermediate is as follows: The structural formula of the glufosinate is as follows: R1 is selected from alkyl groups having 1 to 12 carbon atoms, and A is selected from acids. The molar ratio of ammonia and / or organic base to the first reaction raw material is greater than 1.

2. The preparation method according to claim 1, characterized in that, The molar ratio of ammonia and / or organic base to the first reaction raw material is (1.01+n1)~(2.5+n1):1, where n1 is the molar percentage of the salt of L-2-amino-4-chlorobutyrate in the first reaction raw material.

3. The preparation method according to claim 1 or 2, characterized in that, The organic base is selected from one or more of triethylamine, diethylamine, dimethylamine, N,N-dimethylcyclohexylamine, tetrabutylammonium hydroxide, pyridine, and 4-dimethylaminopyridine.

4. The preparation method according to claim 1, characterized in that, Step 1 specifically includes: Step 1.1: Under a nitrogen atmosphere, the second reaction raw material is mixed with ammonia and / or an organic base at a first temperature to prepare a mixture; Step 1.2: Mix the first reaction raw material with an inert solvent, and selectively add ammonia and / or organic base; Step 1.3: Control the temperature of the S2 mixture system to the second temperature. Under a nitrogen atmosphere, add the S1 mixture dropwise to the S2 mixture system. After the addition is complete, stir and then raise the system temperature to the third temperature for reaction.

5. The preparation method according to claim 4, characterized in that, The first temperature is 10~80℃, the second temperature is -20~20℃, the third temperature is 70~120℃, and the inert solvent is selected from one or more of toluene, xylene, mesitylene, chlorobenzene, dichlorobenzene, and 1,4-dioxane.

6. The preparation method according to claim 1, characterized in that, The molar ratio of the first reactant to the second reactant is 1:(1~1.5). The second reaction raw material is selected from one or more of monomethyl methylphosphonate, monoethyl methylphosphonate, monopropyl methylphosphonate, mono-n-butyl methylphosphonate, and monoisobutyl methylphosphonate.

7. The preparation method according to claim 1, characterized in that, The preparation method further includes the steps of keeping the reaction system at 0~20℃ after the reaction in step 1 is completed, filtering, and vacuum drying the filtrate to a viscous state to obtain the intermediate.

8. The preparation method according to claim 1, characterized in that, In step 2, the acid is hydrochloric acid. Step 2 specifically includes: mixing the intermediate with hydrochloric acid, heating under reflux while removing low-boiling substances, until the raw material is completely converted, and then evaporating the reaction system to obtain glufosinate hydrochloride.

9. The preparation method according to claim 1, characterized in that, Step 3 specifically includes: dissolving glufosinate in water, adding ammonia to bring the pH to 2-3, keeping the temperature at 20-30°C and stirring until the inorganic salts are completely precipitated, filtering, concentrating the filtrate to dryness, adding an ethanol aqueous solution for reflux, cooling and crystallizing, filtering, and drying to obtain glufosinate.

10. A method for preparing glufosinate-ammonium salt, characterized in that, The preparation method according to any one of claims 1 to 9 further includes the following steps: The prepared glufosinate was reacted with an alkali to form glufosinate salt.

11. The preparation method according to claim 10, characterized in that, The glufosinate includes glufosinate sodium salt, glufosinate ammonium salt, or glufosinate potassium salt.

12. The preparation method according to claim 10, characterized in that, The alkali is selected from ammonia, sodium hydroxide, or potassium hydroxide. The molar ratio of glufosinate to alkali is 1:(0.9~1.2).

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