Preparation method of 4-[hydroxyl (methyl) phosphonyl]-L-homoalanine and salt thereof

Abstract

The invention discloses a preparation method of 4-[hydroxyl (methyl) phosphonyl]-L-homoalanine and salt thereof, which comprises the following steps: carrying out nucleophilic substitution reaction on a compound shown in a formula (III) and a compound shown in a formula (IV) or a compound shown in a formula (V) in the presence of a solvent, and then carrying out rearrangement conversion reaction under the action of a halogenation catalyst to obtain the refined glufosinate-ammonium intermediate. Wherein the structural formula of the compound shown in the formula (III) is shown in the formula (IV), the structural formula of the compound shown in the formula (V) is shown in the formula (V), and the structural formula of the refined glufosinate-ammonium intermediate is shown in the specification.

Description

Technical Field

[0001] This invention belongs to the field of fine chemical process synthesis, specifically relating to a method for preparing 4-[hydroxy(methyl)phosphono]-L-hoalanine and its salts. Background Technology

[0002] 4-[hydroxy(methyl)phosphono]-homoalanine (Chinese name: glufosinate) is a highly effective, low-toxicity, broad-spectrum, and environmentally friendly non-selective herbicide developed in the 1980s. Its weeding mechanism involves inhibiting glutamine synthase in weeds, interfering with the synthesis and metabolism of growth substances, inhibiting weed growth and development, and ultimately leading to weed death. Chemically, this molecule is a DL-racemic mixture and is currently the most widely sold product. Literature indicates that the herbicidal activity of the pure optical isomer 4-[hydroxy(methyl)phosphono]-L-homoalanine (Chinese name: glufosinate) is twice that of its racemic mixture.

[0003] Chiral source synthesis is currently the mainstream route in the chemical synthesis of glufosinate. It involves using L-configured amino acids, such as L-methionine, L-homoserine, and L-allyline, as starting materials and modifying them with functional groups to synthesize glufosinate. Among these methods, the preparation of glufosinate starting from L-homoserine or its dehydration product (S)-3-aminodihydrofuran-2(3H)-one is the most widely reported in the literature.

[0004] Patents US5442088, CN111662324, and CN112574119 disclose various processes for preparing glufosinate, specifically: (S)-3-aminodihydrofuran-2(3H)-one is subjected to amino protection, ring-opening chlorination, and esterification to prepare a chlorinated intermediate containing a double-protected group; or a chlorinated intermediate is formed by cyclizing the amino and carboxyl groups of homoserine followed by chlorination, then reacted with methylphosphonite in an intermolecular Abzov rearrangement reaction, and finally hydrolyzed and purified to obtain the product. Patents CN113248537, WO2021143712A, and WO2021143713A report a novel preparation process of the amino-unprotected chlorinated intermediate (S)-2-amino-4-chlorobutyric acid and diethyl methylphosphonite under catalysis, improving the synthesis efficiency and atom economy of glufosinate. Furthermore, patents such as CN113490671, CN114650997, and CN116041387 have improved the key Abuzov reaction, disclosing an intramolecular Abuzov reaction that uses an amino-free protected chlorinated intermediate (S)-2-amino-4-chlorobutyric acid (or its ester) as a raw material to react with an in-situ synthesized methyl chlorophosphonic acid alkyl ester (or amide), effectively controlling the consumption of phosphine reagents, thereby reducing raw material costs and the occurrence of side reactions.

[0005] The above analysis reveals that the main process route for synthesizing chiral sources of glufosinate in existing technologies involves L-homoserine or the equivalent intermediate (S)-3-aminodihydrofuran-2(3H)-one, followed by halogenation, esterification (cyclization), Abuzov rearrangement, and hydrolysis to obtain the product. Because the key reactions—the preparation of the halogenated intermediate and the corresponding Abuzov rearrangement—involve the gain or loss of halogen atoms, strong acids and highly corrosive chlorinating agents are required for chlorination and rearrangement reactions, and the reactions generate toxic byproducts, such as alkyl halides. Furthermore, the phosphineation reaction requires a high-temperature, weakly alkaline environment, which is detrimental to maintaining the product's chirality. This results in low overall atom utilization, high separation and purification costs, and significant waste issues, hindering large-scale production. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing 4-[hydroxy(methyl)phosphono]-L-hoalanine and its salts by different reaction routes. This preparation method does not involve the gain or loss of halogen atoms and has high atom utilization.

[0007] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0008] The first aspect of the present invention provides a method for preparing a glufosinate intermediate, wherein the compound shown in formula (III) and the compound shown in formula (IV) or the compound shown in formula (V) undergo a nucleophilic substitution reaction in the presence of a solvent, and then a rearrangement transformation reaction is carried out in the presence of a halogenated catalyst to obtain the glufosinate intermediate;

[0009] The structural formula of the compound shown in formula (III) is as follows:

[0010] The structural formula of the compound shown in formula (IV) is

[0011] The structural formula of the compound shown in formula (V) is

[0012] The structural formula of the glufosinate intermediate is as follows:

[0013] Among them, R 1 It is a straight-chain or branched C1-C12 alkyl group.

[0014] According to some specific implementation methods, R 1 It can be methyl, ethyl, isopropyl, n-propyl, or n-butyl.

[0015] According to some specific embodiments, the nucleophilic substitution reaction and the rearrangement transformation reaction are carried out under the protection of an inert gas.

[0016] Furthermore, the inert gas is nitrogen or argon.

[0017] According to some specific embodiments, the molar ratio of the compound shown in formula (III) to the compound shown in formula (IV) is 1:(0.95 to 2), for example 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2. Further, the molar ratio of the compound shown in formula (III) to the compound shown in formula (IV) is 1:(0.95 to 1.2).

[0018] According to some specific embodiments, the molar ratio of the compound shown in formula (III) to the compound shown in formula (V) is 1:(0.95~2), for example 1:0.95, 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9, 1:2. Further, the molar ratio of the compound shown in formula (III) to the compound shown in formula (V) is 1:(0.95~1.2).

[0019] According to some specific embodiments, the solvent is one or more of 1,2-dichloroethane, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, toluene, mesitylene, chlorobenzene, and 1,4-dioxane.

[0020] According to some specific embodiments, in the initial stage of the nucleophilic substitution reaction, the mass ratio of the compound shown in formula (III) to the solvent is 1:(2-10), for example 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8, 1:8.5, 1:9, 1:9.5, 1:10. Further, in the initial stage of the nucleophilic substitution reaction, the mass ratio of the compound shown in formula (III) to the solvent is 1:(2-5).

[0021] According to some specific embodiments, the reaction temperature of the nucleophilic substitution reaction is -20℃ to 20℃, for example -20℃, -15℃, -10℃, -5℃, 0℃, 5℃, 10℃, 15℃, and 20℃. Further, the reaction temperature of the nucleophilic substitution reaction is -20℃ to 10℃. Still further, the reaction temperature of the nucleophilic substitution reaction is -15℃ to 0℃.

[0022] According to some specific embodiments, the reaction temperature of the rearrangement transformation reaction is 40℃ to 120℃, for example, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, and 120℃. Further, the reaction temperature of the rearrangement transformation reaction is 40℃ to 100℃. Further, the reaction temperature of the rearrangement transformation reaction is 50℃ to 100℃.

[0023] According to some specific embodiments, the reaction time of the nucleophilic substitution reaction is 0.5h to 10h, for example 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, and 10h. Further, the reaction time of the nucleophilic substitution reaction is 0.5h to 5h.

[0024] According to some specific embodiments, the reaction time of the rearrangement transformation reaction is 0.5h to 20h, for example, 0.5h, 1h, 1.5h, 2h, 2.5h, 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h, 10h, 10.5h, 11h, 11.5h, 12h, 12.5h, 13h, 13.5h, 14h, 14.5h, 15h, 15.5h, 16h, 16.5h, 17h, 17.5h, 18h, 18.5h, 19h, 19.5h, and 20h. Further, the reaction time of the rearrangement transformation reaction is 0.5h to 10h. Even further, the reaction time of the rearrangement transformation reaction is 1h to 10h.

[0025] According to some specific embodiments, the halogenated catalyst is a metal halide or hydrogen halide.

[0026] Furthermore, the metal halide is one or more of sodium iodide, potassium iodide, sodium bromide, potassium bromide, zinc chloride, zinc bromide, and aluminum trichloride.

[0027] Further, the molar ratio of the metal halide to the compound shown in formula (III) is (0.01–0.5):1, for example, 0.01:1, 0.05:1, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, or 0.5:1. Even further, the molar ratio of the metal halide to the compound shown in formula (III) is (0.1–0.3):1.

[0028] Furthermore, the hydrogen halide is one or more of hydrogen chloride, hydrogen bromide, and hydrogen iodide.

[0029] Further, the molar ratio of the hydrogen halide to the compound shown in formula (III) is (0.1 to 1):1, for example, 0.1:1, 0.15:1, 0.2:1, 0.25:1, 0.3:1, 0.35:1, 0.4:1, 0.45:1, 0.5:1, 0.55:1, 0.6:1, 0.65:1, 0.7:1, 0.75:1, 0.8:1, 0.85:1, 0.9:1, 0.95:1, or 1:1. Even further, the molar ratio of the hydrogen halide to the compound shown in formula (III) is (0.3 to 1):1.

[0030] According to some specific embodiments, after the compound shown in formula (III) undergoes the nucleophilic substitution reaction with the compound shown in formula (IV), the reaction system is sealed, and the rearrangement transformation reaction occurs under the catalysis of the hydrogen chloride generated by the nucleophilic substitution reaction or the added halogenated catalyst.

[0031] Furthermore, the hydrogen chloride generated by the nucleophilic substitution reaction is used to carry out the rearrangement conversion reaction by sealing the reaction system, thereby reducing excessive volatilization of hydrogen chloride, improving the conversion rate of the rearrangement conversion reaction, improving the yield and quality of the product, and eliminating the need for additional halogenated catalysts, thus further reducing raw material costs.

[0032] Furthermore, the reaction vessel for preparing the glufosinate intermediate can be any container capable of sealing the reaction system and withstanding a certain internal pressure, including but not limited to sealed containers, pressure-resistant reaction flasks, pressure-resistant reactors, etc.

[0033] Furthermore, the gauge pressure range of the rearrangement conversion reaction is 0 MPa to 0.05 MPa.

[0034] According to some specific embodiments, after the compound shown in formula (III) undergoes the nucleophilic substitution reaction with the compound shown in formula (V), the system is concentrated, the low-boiling secondary amine is removed, and then a solvent and a halogenated catalyst are added to carry out the rearrangement conversion reaction.

[0035] Further, the system is concentrated at temperatures ranging from 60°C to 140°C, for example, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, and 140°C. Further, the system is concentrated at temperatures ranging from 60°C to 90°C.

[0036] Furthermore, after removing the low-boiling secondary ammonia, the mass of the added solvent is 6 to 7 times the mass of the compound shown in formula (III) fed into the reactor.

[0037] Furthermore, when the added halogenated catalyst is in the gaseous state, the rearrangement conversion reaction is carried out in a closed system.

[0038] Furthermore, the gauge pressure range of the closed system is 0 MPa to 0.05 MPa.

[0039] According to some more specific embodiments, the method for preparing the glufosinate intermediate includes method a or method b.

[0040] The specific steps of method a are as follows: under an inert atmosphere, the compound shown in formula (III) and the solvent are added to a reaction vessel, the temperature is lowered to -15℃ to 0℃, and a mixture of the compound shown in formula (IV) and the solvent is added dropwise to the reaction vessel. After the addition is completed, the reaction is kept at the temperature for 0.5h to 5h. Then the reaction vessel is sealed, the temperature is raised to 40℃ to 100℃, and the reaction is kept at the temperature for 2h to 10h to obtain the glufosinate intermediate.

[0041] The specific steps of method b are as follows: Under an inert atmosphere, the compound shown in formula (III) and the solvent are added to the reaction vessel, the temperature is lowered to -15℃ to 0℃, and a mixture of the compound shown in formula (V) and the solvent is added dropwise to the reaction vessel. After the addition is completed, the reaction is kept at the temperature for 0.5h to 5h. The reaction system is concentrated under negative pressure at 40℃ to 100℃ to remove low-boiling secondary amines. Then, the solvent and halogenated catalyst are added to the reaction vessel, the temperature is raised to 40 to 120℃, and the reaction is kept at the temperature for 2h to 10h to obtain the glufosinate intermediate.

[0042] According to some specific embodiments, the compound shown in formula (III) is obtained by cyclization of the amino and carboxyl groups in an L-homoserine molecule.

[0043] Furthermore, the compound shown in formula (III) is prepared by dispersing L-homoserine in an organic solvent and adding phosgene, triphosgene or phosgene derivatives for cyclization reaction.

[0044] A second aspect of the present invention provides a method for preparing 4-[hydroxy(methyl)phosphono]-L-homoalanine, comprising the following steps:

[0045] (1) Prepare glufosinate intermediate according to the above preparation method;

[0046] (2) The glufosinate intermediate prepared in step (1) is concentrated and the solvent is removed. Water is added to carry out the hydrolysis reaction of phosphoramide. Then, a solid acid catalyst is added to carry out the hydrolysis reaction of intracyclic acid anhydride to obtain the 4-[hydroxy(methyl)phosphono]-L-hoalanine.

[0047] According to some specific embodiments, the temperature for carrying out the hydrolysis reaction of phosphoramide is 0℃ to 70℃, for example, 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃, 55℃, 60℃, 65℃, and 70℃. Further, the temperature for carrying out the hydrolysis reaction of phosphoramide is 0℃ to 50℃.

[0048] According to some specific implementation methods, the hydrolysis reaction of phosphoramide takes 1 to 3 hours.

[0049] According to some specific embodiments, the mass of water added during the hydrolysis reaction of phosphoramide is 2.5 to 3.5 times the mass of the compound shown in formula (III).

[0050] According to some specific implementation methods, the water added during the hydrolysis reaction of phosphoramide is an ice-water mixture.

[0051] According to some specific implementation methods, after the hydrolysis reaction of phosphoramide is completed, the low-boiling secondary ammonia is concentrated and removed under negative pressure, and then the solid acid catalyst or hydrochloric acid is added to the reaction system.

[0052] According to some specific implementation methods, a solid acid catalyst is used for the hydrolysis reaction of intracyclic acid anhydrides. The solid acid catalyst can be recovered by filtration and can be directly reused in the next batch of reaction, thereby reducing the cost of raw materials.

[0053] According to some specific embodiments, the solid acid catalyst is a macroporous resin solid acid catalyst, including but not limited to Amberlyst-15 solid acid catalyst and Amberlyst-35 solid acid catalyst.

[0054] According to some specific embodiments, the mass of the solid acid catalyst is 0.1 to 1 times the mass of the compound shown in formula (III), preferably 0.2 to 0.5 times.

[0055] According to some specific implementation methods, water is also added to the reaction system during the hydrolysis reaction of intracyclic anhydrides.

[0056] Furthermore, the mass of water added is 2.5 to 3 times the mass of the compound shown in formula (III) added.

[0057] According to some specific implementation methods, the temperature for hydrolysis of intracyclic anhydrides is 90℃~105℃.

[0058] According to some specific implementation methods, the hydrolysis reaction of intracyclic acid anhydrides is carried out under negative pressure conditions.

[0059] Furthermore, the negative pressure condition is controlled between 0 MPa and -0.04 MPa, preferably between 0 MPa and -0.03 MPa, and more preferably between -0.01 MPa and -0.02 MPa.

[0060] According to some specific implementation methods, the reaction time for the hydrolysis reaction of intracyclic anhydrides is 4h to 6h.

[0061] According to some specific embodiments, the specific steps of step (2) are as follows: the reaction solution obtained after the reaction in step (1) is concentrated, and without purification, an ice-water mixture is directly added to the reaction system to carry out the hydrolysis reaction of phosphoramide; after the reaction is completed, the low-boiling-point secondary ammonia is removed by negative pressure concentration; water and solid acid catalyst are added to the reaction system, and the system is condensed at -20℃ to 0℃, and then the hydrolysis reaction of intracyclic acid anhydride is carried out under negative pressure; after the reaction is completed, the solid acid catalyst is filtered while hot, the filtrate is concentrated, ethanol is added, the mixture is pulped at room temperature, filtered, and dried to obtain the refined glufosinate.

[0062] A third aspect of this invention provides a method for preparing 4-[hydroxy(methyl)phosphono]-L-hoalanine hydrochloride, comprising the following steps:

[0063] (1) Prepare glufosinate intermediate according to the above preparation method;

[0064] (2) The glufosinate intermediate prepared in step (1) is concentrated and the solvent is removed. Water is added to carry out the hydrolysis reaction of phosphoramide, and then hydrochloric acid is added to carry out the hydrolysis reaction of intracyclic anhydride to obtain the 4-[hydroxy(methyl)phosphono]-L-hoalanine hydrochloride.

[0065] The conditions for the hydrolysis reaction of phosphoramide in step (2) of preparing 4-[hydroxy(methyl)phosphono]-L-homoalanine hydrochloride are the same as those for the hydrolysis reaction of phosphoramide in step (2) of preparing 4-[hydroxy(methyl)phosphono]-L-homoalanine as described above, and will not be repeated here.

[0066] According to some specific embodiments, the mass concentration of the hydrochloric acid is 25-35%.

[0067] According to some specific embodiments, the mass of hydrogen chloride in the hydrochloric acid is 0.9 to 1.2 times the mass of the compound shown in formula (III) fed into the feed.

[0068] According to some specific embodiments, after the hydrolysis reaction of the phosphoramide is completed, the reaction solution is concentrated, and then hydrochloric acid is added to the reaction system. The system is heated to reflux until the reaction is complete, and then post-processed to obtain glufosinate hydrochloride.

[0069] Furthermore, the post-processing method involves concentrating the reaction solution under negative pressure, then adding ethanol for reflux, cooling and crystallizing, filtering, and drying to obtain the glufosinate hydrochloride.

[0070] A fourth aspect of this invention provides a method for preparing 4-[hydroxy(methyl)phosphono]-L-hoalanine ammonium salt, comprising the following steps:

[0071] (1) Prepare glufosinate intermediate according to the above preparation method;

[0072] (2) The glufosinate intermediate prepared in step (1) is concentrated and the solvent is removed. Water is added to carry out the hydrolysis reaction of phosphoramide. Then, a solid acid catalyst or hydrochloric acid is added to carry out the hydrolysis reaction of intracyclic acid anhydride to obtain 4-[hydroxy(methyl)phosphono]-L-hoalanine or its hydrochloride salt.

[0073] (3) The 4-[hydroxy(methyl)phosphono]-L-homoalanine or its hydrochloride obtained in step (2) is reacted with ammonia to obtain the 4-[hydroxy(methyl)phosphono]-L-homoalanine ammonium salt.

[0074] According to some specific implementation methods, phosphonium salt is prepared by reacting 4-[hydroxy(methyl)phosphono]-L-hoalanine (phosphonium phosphate) with ammonia. No large amount of waste salt is generated during the preparation process, which has significant advantages in terms of waste control and purification compared with existing technologies.

[0075] According to some specific embodiments, the molar ratio of glufosinate to ammonia in ammonia water is 1:(0.9-1.2), and more preferably 1:(1-1.2).

[0076] By adopting the above technical solution, the present invention has the following advantages compared with other processes:

[0077] This invention uses the compound of formula (III), which is protected by the cyclization of the amino and carboxyl groups in L-homoserine molecules, as a raw material. It undergoes a nucleophilic reaction with chloromethylphosphine monoamide of formula (IV) or methylphosphine diamide of formula (V). The rearrangement reaction is carried out using hydrogen chloride generated in situ or an additional halogenated catalyst. Finally, glufosinate or its salt is prepared by a one-pot hydrolysis reaction. This process has a short synthetic route, mild reaction conditions, simple post-processing and purification, no complicated purification operations, and low raw material and equipment input costs. At the same time, the secondary amine base, solvent and solid acid catalyst involved in the process can be recycled in a closed loop, without generating a large amount of waste. It is an environmentally friendly process and is suitable for industrial production. Attached Figure Description

[0078] Figure 1 This is the LC-MS controlled spectrum of the hydrolysis reaction in Example 1;

[0079] Figure 2 The MS (ESI, [M+H]+ and [MH]+) spectra of the hydrolysis reaction products in Example 1 are shown below.

[0080] Figure 3 This is the optical content detection spectrum of glufosinate in Example 1. Detailed Implementation

[0081] To address the problems of halogen atom gain and loss, low atom utilization, high separation and purification costs, and large amounts of waste in existing technological processes, the applicant has developed a new route for preparing glufosinate and its salts, which is shown as route a or route b below.

[0082] Route a:

[0083]

[0084] Route b:

[0085]

[0086] Research has revealed that, compared to existing technologies, the present invention offers at least the following advantages:

[0087] ① The nucleophilic and rearrangement reactions of L-homoserine intracyclic anhydride with chloromethylphosphine monoamide or methylphosphine diamide are carried out in a weakly acidic or neutral environment and do not involve high temperature conditions. Therefore, the rearrangement intermediate will not be excessively racemic, which improves the product quality of subsequent glufosinate.

[0088] ② This process does not require the introduction of additional chlorine atoms through hydroxyl chlorination. It creatively utilizes by-product hydrogen chloride or additional halogenated catalysts to carry out nucleophilic reactions and in-situ skeletal rearrangement to construct CP bonds, achieving high atom utilization. At the same time, it avoids the generation of equivalent amounts of toxic haloalkanes and causes no environmental pollution.

[0089] ③ By utilizing stepwise hydrolysis catalyzed by pure water and solid acid, secondary amines and solid acid catalysts are effectively recovered, avoiding the introduction of impurities and product racemization in the final product. All materials are recycled in a closed loop, with no significant generation of waste, reducing equipment and engineering investment.

[0090] All features disclosed in this invention, or steps in all methods or processes disclosed, may be combined in any way, except for mutually exclusive features or steps.

[0091] The technical solutions of the present invention will be further described below with reference to specific embodiments. However, the present invention should not be limited to these embodiments. Unless specifically stated otherwise, all features can be replaced by other equivalent or similar alternative features. Unless specifically stated otherwise, each feature is only one example of a series of equivalent or similar features. The terminology used in the present invention, unless otherwise stated, generally has the meaning commonly understood by those skilled in the art. The implementation conditions adopted in the embodiments can be further adjusted according to different requirements of specific use. Implementation conditions not specified are conventional conditions in the industry. The technical features involved in the various embodiments of the present invention can be combined with each other as long as they do not conflict with each other.

[0092] In this invention, operations without specific instructions are performed at room temperature. The raw materials used in this application can be commercially available or prepared using conventional methods in the prior art. In this invention, unless otherwise specified, all contents are mass contents, and "%" represents a mass percentage.

[0093] To determine the optical purity of the prepared glufosinate, a chiral derivatization method was employed, 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, 5 μm particle size; 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 (glufosinate) 6.76 min, D-glufosinate 8.47 min. The methods for determining the optical purity of glufosinate hydrochloride and glufosinate ammonium salt were the same as those for glufosinate.

[0094] The raw material L-homoserine intracyclic anhydride used in the following examples can be self-made. For example, the synthesis method can be found in patent CN 117586494; the details are as follows.

[0095] L-homoserine (119 g, 1 mol) and 500 mL of tetrahydrofuran were added to a 1 L reaction flask, and triphosgene (118.7 g, 0.4 mol) was added in portions. The reaction was carried out at 50 °C for 24 h. After the reaction was completed, the solvent and low-boiling substances were removed by concentration to obtain a bright yellow oily crude product. This crude product was purified by crystallization in toluene to obtain the solid product of L-homoserine intracyclic anhydride, with a yield of 90.7% and an HPLC purity of 98%. NMR data were also obtained. 1 H NMR (D2O, 400Hz) δ: 8.01 (s, 1H, NH), 4.47-4.55 (m, 2H, CH2), 3.70-3,78 (m, 2H, CH2).

[0096] The raw materials chloromethylphosphine monoamide and methylphosphine diamide used in the following examples can be self-made. For example, the synthesis methods can be found in patents CN116041387 and CN115873033. The solvents used can be the same as the aprotic reaction solvents in the examples, and are not limited to the solvents in the following examples.

[0097] Preparation of N,N-diethyl-chloromethylphosphine monoamide: Diethylamine (29.26 g, 0.4 mol) was dissolved in 82 g of chlorobenzene, and the mixture was cooled to -15 °C under nitrogen protection. Methylphosphine dichloride (23.62 g, 0.2 mol, 99% purity) was slowly added dropwise to the reaction system, and the mixture was kept at -10 °C for 1 hour. The diethylamine hydrochloride was removed by pressure filtration under nitrogen to obtain a 27% concentration of compound IV-1 chlorobenzene mixture, which was directly used for subsequent reactions.

[0098] Preparation of N,N-diisopropyl-chloromethylphosphine monoamide: Diisopropylamine (40.48 g, 0.4 mol) was dissolved in 92 g of chlorobenzene, and the mixture was cooled to -10 °C under nitrogen protection. Methylphosphine dichloride (23.62 g, 0.2 mol, 99% purity) was slowly added dropwise to the reaction system, and the mixture was kept at -10 °C for 1 hour. The diisopropylamine hydrochloride was removed by pressure filtration under nitrogen to obtain a 28% concentration of compound IV-2 chlorobenzene mixture, which was directly used for subsequent reactions.

[0099] Preparation of N,N,N,N-Tetraethyl-Methylphosphine diamide: Diethylamine (58.52 g, 0.8 mol) was dissolved in 120 g of chlorobenzene, and the mixture was cooled to -15 °C under nitrogen protection. Methylphosphine dichloride (23.62 g, 0.2 mol, 99% purity) was slowly added dropwise to the reaction system, and the mixture was kept at -10 °C for 3 hours. The diethylamine hydrochloride was removed by pressure filtration under nitrogen to obtain a 24% concentration of compound V-1 chlorobenzene mixture, which was directly used for subsequent reactions.

[0100] Preparation of N,N,N,N-tetraisopropyl-methylphosphine biamide: Diisopropylamine (80.96 g, 0.8 mol) was dissolved in 140 g of chlorobenzene, and the mixture was cooled to -10 °C under nitrogen protection. Methylphosphine dichloride (23.62 g, 0.2 mol, 99% purity) was slowly added dropwise to the reaction system, and the mixture was kept at -10 °C for 5 hours. The diisopropylamine hydrochloride was removed by pressure filtration under nitrogen to obtain a 26% concentration of compound V-2 chlorobenzene mixture, which was directly used for subsequent reactions.

[0101] Example 1

[0102]

[0103] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g of chlorobenzene were placed in a 500 mL pressure-resistant reaction flask. The temperature was lowered to -15 °C, and a 27% concentration of compound IV-1 chlorobenzene mixture (136 g, 0.2 mol) was added dropwise to the system over approximately 3 hours. During the addition process, the temperature rise was kept below 2 °C. After the reaction was maintained at this temperature for 1 hour, the system was sealed, the temperature was raised to 70 °C, and maintained for 3 hours. The maximum pressure was 0.04 MPa. The color of the reaction system gradually changed from yellow to brown. After the reaction was completed, the reaction solution was concentrated under high vacuum to obtain the crude compound VII-1. Without purification, 80g of an ice-water mixture was added to the system, the temperature was raised to 30℃, and the mixture was kept at this temperature for 1 hour. The diethylamine was then concentrated under negative pressure to remove it (it can be recovered after purification). Next, 80g of water and 14.5g of Amberlyst-15 solid acid catalyst (CAS: 39389-20-3, purchased from Bide Pharmaceuticals) were added to the material. The mixture was then refluxed at -10℃ under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100g of [unspecified substance] was added. The mixture was homogenized with 95% ethanol at room temperature, filtered, and dried to obtain 32.35 g of off-white solid glufosinate (compound I). The total content of the L / D mixture was 98.9%, the L-body content was 99% (ee value 98%), and the absolute yield of glufosinate was 87.5% (based on compound III). The LC-MS control spectrum of the hydrolysis reaction, the MS spectrum of the product, and the optical content detection spectrum of glufosinate are shown below. Figure 1 , Figure 2 and Figure 3 .

[0104] Example 2

[0105]

[0106] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g of chlorobenzene were placed in a 500 mL pressure-resistant reaction flask. The temperature was lowered to -15 °C, and a 28% concentration of compound IV-2 chlorobenzene mixture (136.3 g, 0.21 mol) was added dropwise to the system over approximately 3 hours. During the addition process, the temperature rise was kept below 2 °C. After the reaction was maintained at this temperature for 1 hour, the system was sealed, the temperature was raised to 80 °C, and maintained for 3 hours. The maximum pressure was 0.05 MPa. The color of the reaction system gradually changed from yellow to brown. After the reaction was completed, the reaction solution was concentrated under high vacuum to obtain the crude compound VII-2. Without purification, 80g of an ice-water mixture was added to the system, heated to 50℃, and kept at that temperature for 2 hours. The diisopropylamine was then concentrated under negative pressure to remove it (it can be recovered after purification). Next, 80g of water and 14.5g of Amberlyst-15 solid acid catalyst were added to the material. The mixture was then condensed at -10℃ and heated to reflux under a slight negative pressure of -0.015 MPa. The reaction was stopped after 5 hours. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 31.89g of off-white solid glufosinate (compound I) was obtained. The total content of the L / D mixture was 98.5%, the L content was 99% (ee value 98%), and the absolute yield of glufosinate was 85.9% (based on compound III).

[0107] Example 3

[0108] The specific steps of Example 3 are similar to those of Example 1, except that the rearrangement reaction is carried out in a non-closed system, and the specific reaction is as follows:

[0109] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g chlorobenzene were placed in a 500 mL glass reaction flask. The temperature was lowered to -15 °C, and a 27% concentration of compound IV-1 chlorobenzene mixture (136 g, 0.2 mol) was added dropwise to the system. The addition was completed in about 3 hours, and the temperature rise during the addition was kept within 2 °C. After the reaction was kept at this temperature for 1 hour, the temperature was raised to 70 °C and kept at this temperature for 8 hours. After the reaction was completed, the reaction solution was concentrated under high vacuum to obtain a concentrated solution containing compound VII-1. Without purification, 100g of an ice-water mixture was added to the system, heated to 30℃, and kept at that temperature for 1 hour. Diethylamine was removed by negative pressure concentration (it can be recovered after purification). 80g of water and 14.5g of Amberlyst-15 solid acid catalyst were then added to the material. The mixture was condensed at -10℃, and under a slight negative pressure of -0.015 MPa, the system was heated to reflux. The reaction was stopped after 5 hours. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness. 100g of 95% ethanol was added, and the mixture was stirred at room temperature. After filtration and drying, 30.52g of yellow solid glufosinate crude product was obtained. The total L / D mixture content was 71.5%, the L content was 98.2% (ee value 96.4%), and the absolute yield of glufosinate was 59.2% (based on compound III).

[0110] Comparing Examples 1 and 3, it was found that the rearrangement reaction was carried out in a non-closed system, which would affect the product yield and quality. The main reason is that the hydrogen chloride, which plays a catalytic role, overflows from the reaction liquid under heating, which cannot meet the concentration requirements of the subsequent rearrangement reaction, resulting in a decrease in the conversion rate of the rearrangement reaction.

[0111] Example 4

[0112] The specific steps of Example 4 are similar to those of Example 1, except that the nucleophilic rearrangement reaction is carried out in a non-nitrogen environment. The specific reaction is as follows:

[0113] In an open glass reaction flask, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g chlorobenzene were added. The temperature was lowered to -15°C, and a 27% concentration of compound IV-1 chlorobenzene mixture (136 g, 0.2 mol) was added dropwise over approximately 3 hours, with the temperature rise maintained below 2°C during the addition. After reacting for 1 hour, the system was sealed, the temperature was raised to 70°C, and maintained for 8 hours. The color of the reaction system gradually changed from yellow to dark brown. After the reaction was complete, the reaction solution was concentrated under high vacuum to obtain a concentrated solution containing compound VII-1. Without purification, 100 g of an ice-water mixture was added to the system, the temperature was raised to 30°C, and maintained for 1 hour. Diethylamine was removed by negative pressure concentration (it can be recovered after purification). 80 g of water and 14.5 g of... were then added to the material. After using Amberlyst-15 solid acid catalyst, the system was refluxed at -10℃ under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was then stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100 g of 95% ethanol was added and stirred at room temperature. The mixture was then filtered and dried to obtain 30.94 g of brown solid glufosinate crude product. The total content of the L / D mixture was 89.9%, the L content was 98% (ee value 96%), and the absolute yield of glufosinate was 75.3% (based on compound III).

[0114] Comparing Examples 1 and 4, it was found that the yield and product quality were affected when the nucleophilic rearrangement reaction was carried out in a non-nitrogen environment. The main reason is that the trivalent phosphine intermediate is easily oxidized to pentavalent phosphine by oxygen in the air, and thus the rearrangement reaction cannot occur.

[0115] Example 5

[0116]

[0117] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g chlorobenzene were placed in a 500 mL glass reaction flask. The temperature was lowered to 0 °C, and a 24% concentration of compound V-1 chlorobenzene mixture (166.5 g, 0.21 mol) was added dropwise over approximately 1 hour. After maintaining the reaction temperature for 2 hours, the system was concentrated under negative pressure at 60 °C to remove diethylamine (which can be reused after purification). The mixture was then further concentrated. Add 200g of chlorobenzene and sodium iodide (3g, 0.02mol), heat to 80℃, and maintain this temperature for 6 hours. The color of the reaction system gradually changes from yellow to dark brown. After the reaction is complete, concentrate the reaction solution under high vacuum to obtain crude compound VII-1. Without purification, add 100g of an ice-water mixture to the system, heat to 30℃, and maintain this temperature for 1 hour. Concentrate under negative pressure to remove diethylamine (which can be recovered after purification). Continue to add 80g of water and 14.5g of sodium iodide to the material. After using Amberlyst-15 solid acid catalyst, the system was refluxed at -10℃ under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was then stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100 g of 95% ethanol was added and stirred at room temperature. The mixture was then filtered and dried to obtain 31.90 g of off-white solid glufosinate. The total content of the L / D mixture was 97.8%, the L content was 98.5% (ee value 97%), and the absolute yield of glufosinate was 84.9% (based on compound III).

[0118] Example 6

[0119]

[0120] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g chlorobenzene were placed in a 500 mL glass reaction flask. The temperature was lowered to 0 °C, and a 24% concentration of compound V-1 chlorobenzene mixture (166.5 g, 0.21 mol) was added dropwise over approximately 1 hour. After maintaining the reaction temperature for 2 hours, the system was concentrated under negative pressure at 60 °C to remove diethylamine (which can be reused after purification). Then, 2 g of chlorobenzene was added to the system. 0.00 g of chlorobenzene and 8.18 g of zinc chloride (0.06 mol) were heated to 100 °C and held for 10 hours. The color of the reaction system gradually changed from yellow to dark brown. After the reaction was complete, the reaction solution was concentrated under high vacuum to obtain crude compound VII-1. Without purification, 100 g of ice-water mixture was added to the system, the temperature was raised to 30 °C and held for 1 hour, and the diethylamine was removed by negative pressure concentration (it can be recovered after purification). Then, 80 g of water and 14.5 g of... After using Amberlyst-15 solid acid catalyst, the system was refluxed at -10℃ under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was then stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100 g of 95% ethanol was added and stirred at room temperature. The mixture was then filtered and dried to obtain 31.77 g of off-white solid glufosinate. The total content of the L / D mixture was 97.2%, the L content was 98.6% (ee value 97.2%), and the absolute yield of glufosinate was 84.1% (based on compound III).

[0121] Example 7

[0122]

[0123] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g chlorobenzene were placed in a 500 mL glass reaction flask. The temperature was lowered to 0 °C, and a 26% concentration of compound V-2 chlorobenzene mixture (208.5 g, 0.22 mol) was added dropwise over approximately 1.5 hours. After maintaining the reaction temperature for 5 hours, the system was concentrated under negative pressure at 80 °C to remove diisopropylamine (which can be reused after purification). The mixture was then further concentrated. Add 200g of chlorobenzene and sodium iodide (4.5g, 0.03mol), heat to 80℃, and maintain the temperature for 6 hours. The color of the reaction system gradually changes from yellow to dark brown. After the reaction is complete, concentrate the reaction solution under high vacuum to obtain crude compound VII-2. Without purification, add 100g of ice-water mixture to the system, heat to 30℃, and maintain the temperature for 1 hour. Concentrate under negative pressure to remove diisopropylamine (which can be recovered after purification). Continue to add 80g of water and 14.5g of sodium iodide to the material. After using Amberlyst-15 solid acid catalyst, the system was refluxed at -10℃ under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was then stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100 g of 95% ethanol was added and stirred at room temperature. The mixture was then filtered and dried to obtain 30.66 g of grayish-white solid glufosinate. The total content of the L / D mixture was 97.5%, the L content was 98.1% (ee value 96.2%), and the absolute yield of glufosinate was 81% (based on compound III).

[0124] Example 8

[0125] The specific steps of Example 8 are similar to those of Example 7, except that the secondary amine byproduct was not removed after the nucleophilic reaction. The specific reaction is as follows:

[0126] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g chlorobenzene were placed in a 500 mL glass reaction flask. The temperature was lowered to 0 °C, and a 26% concentration of compound V-2 chlorobenzene mixture (208.5 g, 0.22 mol) was added dropwise over approximately 1.5 hours. After maintaining the reaction temperature for 5 hours, sodium iodide (4.5 g, 0.03 mol) was added directly to the system, and the temperature was raised to 80 °C and maintained for 8 hours. The color of the reaction system gradually changed from yellow to dark brown. After the reaction was complete, the reaction solution was concentrated under high vacuum to obtain the crude compound VII-2. Without purification, 100 g of an ice-water mixture was added to the system, and the temperature was raised to 30 °C. The mixture was heated to -10℃ and kept at that temperature for 1 hour. Diisopropylamine was then concentrated under negative pressure to remove it (it can be recovered after purification). 80g of water and 14.5g of Amberlyst-15 solid acid catalyst were added to the material. The mixture was then refluxed at -10℃ under a slight negative pressure of -0.015Mpa. The reaction was stopped after 5 hours. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness. 100g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 31.11g of grayish-white solid glufosinate was obtained. The total content of the L / D mixture was 97.3%, the L content was 92.8% (ee value 85.6%), and the absolute yield of glufosinate was 77.6% (based on compound III).

[0127] Comparing Examples 7 and 8, it was found that failure to remove the secondary amine byproduct after the nucleophilic reaction would lead to a higher racemization rate of the intermediate and product, affecting product quality. The main reason is that the secondary amine byproduct is basic, and under heating conditions, it accelerates the racemization of the substrate.

[0128] Example 9

[0129]

[0130] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g of chlorobenzene were placed in a 500 mL pressure-resistant reaction flask. The temperature was lowered to 0 °C, and a 24% concentration of compound V-1 chlorobenzene mixture (166.5 g, 0.21 mol) was added dropwise over approximately 1 hour. After reacting at this temperature for 2 hours, the system was concentrated under negative pressure at 60 °C to remove diethylamine (which can be reused after purification). 200 g of chlorobenzene was then added to the system, and a drying agent was passed through it. Hydrogen chloride gas (7.33 g, 0.2 mol) was introduced into a sealed system, which was then heated to 80°C and held for 5 hours at a maximum pressure of 0.05 MPa. The reaction mixture gradually changed from yellow to brown. After the reaction was complete, the reaction solution was concentrated under high vacuum to obtain crude compound VII-1. Without purification, 100 g of an ice-water mixture was added to the system, and the temperature was raised to 30°C and held for 1 hour. Diethylamine was then concentrated under negative pressure to remove it (this diethylamine can be recovered after purification). Finally, 80 g of water and 14.5 g of... After using Amberlyst-15 solid acid catalyst, the system was refluxed at -10℃ under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was then stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100 g of 95% ethanol was added and stirred at room temperature. The mixture was then filtered and dried to obtain 31.22 g of off-white solid glufosinate. The total content of the L / D mixture was 96.8%, the L content was 98.8% (ee value 97.6%), and the absolute yield of glufosinate was 82.5% (based on compound III).

[0131] Example 10

[0132]

[0133] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (29.02 g, 0.2 mol) and 60 g of 1,2-dichloroethane were placed in a 250 mL pressure-resistant reaction flask. The temperature was lowered to 0 °C, and a 24% concentration of a 1,2-dichloroethane mixture of compound V-1 (166.5 g, 0.21 mol) was added dropwise over approximately 1 hour. After reacting at this temperature for 3 hours, the system was concentrated under negative pressure at 60 °C to remove diethylamine (which can be reused after purification). Then, 180 g of [unspecified substance] was added to the system. 1,2-Dichloroethane was reacted with dry hydrogen bromide gas (4.85 g, 0.06 mol). The system was sealed and heated to 60°C, held for 1 hour, with a maximum pressure of 0.01 MPa. The color of the reaction system gradually changed from yellow to brownish-yellow. After the reaction was complete, the reaction solution was concentrated under high vacuum to obtain crude compound VII-1. Without purification, 100 g of an ice-water mixture was added to the system, the temperature was raised to 30°C, and held for 1 hour. Diethylamine was removed by negative pressure concentration (it can be recovered after purification). 80 g of water and 14.5 g of Amberlyst-15 solid acid catalyst were added to the material. The system was refluxed at -10°C under a slight negative pressure of -0.015 MPa for 5 hours. The reaction was stopped, and the solid acid catalyst was filtered while hot. The filtrate was concentrated to dryness, and 100 g of... The mixture was pulped in 95% ethanol at room temperature, filtered, and dried to obtain 32.33 g of off-white solid glufosinate. The total content of the L / D mixture was 97.6%, the L-body content was 98.9% (ee value 97.8%), and the absolute yield of glufosinate was 86.2% (based on compound III).

[0134] Example 11

[0135] A method for preparing glufosinate hydrochloride, the reaction route is as follows:

[0136]

[0137] The crude intermediate VII-1 was prepared according to the method in Example 1. Without purification, 100g of an ice-water mixture was added to the system, the temperature was raised to 30°C, and the temperature was maintained for 1 hour. The system was concentrated until no fraction was distilled off. After cooling to room temperature, 100g of 30% hydrochloric acid was added, and the system was heated to reflux. After about 10 hours, the reaction was stopped. The acid solution was concentrated under negative pressure, 90g of anhydrous ethanol was added, and the mixture was refluxed. After cooling and crystallization, the product was filtered and dried to obtain 38.79g of off-white solid, namely glufosinate hydrochloride (compound II). The L / D mixture content was 97.5%, the L body percentage was 98.8% (ee value 97.6%), and the absolute yield of glufosinate hydrochloride was 85.9% (based on compound III).

[0138] Example 12

[0139] A method for preparing glufosinate-ammonium salt, the reaction route is as follows:

[0140]

[0141] 10g of glufosinate prepared in Example 1 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 10.56g of white solid glufosinate ammonium salt. The L / D mixture content was 99.1%, the L content was 99.2% (ee value was 98.4%), and the yield was 95%.

[0142] The present invention has been described in detail above, with the aim of enabling those skilled in the art to understand and implement the invention. However, this description should not be construed as limiting the scope of protection of the invention. All equivalent changes or modifications made in accordance with the spirit and essence of the invention should be included within the scope of protection of the invention.

Claims

1. A method for preparing a glufosinate intermediate, characterized in that: The compound shown in formula (III) is subjected to a nucleophilic substitution reaction with the compound shown in formula (IV) or the compound shown in formula (V) in the presence of a solvent, followed by a rearrangement transformation reaction under the action of a halogenated catalyst to obtain the glufosinate intermediate. The structural formula of the compound shown in formula (III) is as follows: The structural formula of the compound shown in formula (IV) is The structural formula of the compound shown in formula (V) is The structural formula of the glufosinate intermediate is as follows: Among them, R 1 It is a straight-chain or branched C1-C12 alkyl group.

2. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: R 1 It is methyl, ethyl, isopropyl, n-propyl, or n-butyl; or, The solvent is one or more selected from 1,2-dichloroethane, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, toluene, mesitylene, chlorobenzene, and 1,4-dioxane; or... The halogenated catalyst is a metal halide or a hydrogen halide; or... The molar ratio of the compound shown in formula (III) to the compound shown in formula (IV) is 1:(0.95–2); or, The molar ratio of the compound shown in formula (III) to the compound shown in formula (V) is 1:(0.95–2); or, The nucleophilic substitution reaction is carried out at a temperature of -20°C to 20°C; or... The reaction temperature for the rearrangement transformation reaction is 40℃~120℃; or... The nucleophilic substitution reaction takes 0.5 h to 10 h; or, The reaction time for the rearrangement transformation reaction is 0.5 h to 20 h.

3. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: The nucleophilic substitution reaction and the rearrangement transformation reaction are carried out under the protection of an inert gas, namely nitrogen or argon.

4. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: After the compound shown in formula (III) undergoes the nucleophilic substitution reaction with the compound shown in formula (IV), the reaction system is sealed, and the rearrangement transformation reaction occurs under the catalysis of the hydrogen chloride generated by the nucleophilic substitution reaction or the added halogenated catalyst.

5. The method for preparing the glufosinate intermediate according to claim 4, characterized in that: The gauge pressure range for the rearrangement conversion reaction is 0 MPa to 0.05 MPa.

6. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: After the compound shown in formula (III) undergoes the nucleophilic substitution reaction with the compound shown in formula (V), the system is concentrated, the low-boiling secondary amine is removed, and then a solvent and a halogenated catalyst are added to carry out the rearrangement transformation reaction.

7. The method for preparing the glufosinate intermediate according to any one of claims 1 to 6, characterized in that: The method for preparing the glufosinate intermediate includes method a or method b; wherein, The specific steps of method a are as follows: under an inert atmosphere, the compound shown in formula (III) and the solvent are added to the reaction vessel, the temperature is lowered to -15℃~0℃, and a mixture of the compound shown in formula (IV) and the solvent is added dropwise to the reaction vessel. After the addition is completed, the reaction is kept at the temperature for 0.5h~5h. Then the reaction vessel is sealed, the temperature is raised to 40℃~100℃, and the reaction is kept at the temperature for 2h~10h to obtain the glufosinate intermediate. The specific steps of method b are as follows: Under an inert atmosphere, the compound shown in formula (III) and the solvent are added to the reaction vessel, the temperature is lowered to -15℃ to 0℃, and a mixture of the compound shown in formula (V) and the solvent is added dropwise to the reaction vessel. After the addition is completed, the reaction is kept at the temperature for 0.5h to 5h. The reaction system is concentrated under negative pressure at 40℃ to 100℃ to remove low-boiling secondary amines. Then, the solvent and halogenated catalyst are added to the reaction vessel, the temperature is raised to 40 to 120℃, and the reaction is kept at the temperature for 2h to 10h to obtain the glufosinate intermediate.

8. A method for preparing 4-[hydroxy(methyl)phosphono]-L-homoalanine, characterized in that: Includes the following steps: (1) Prepare the glufosinate intermediate according to any one of claims 1 to 7; (2) The glufosinate intermediate prepared in step (1) is concentrated and the solvent is removed. Water is added to carry out the hydrolysis reaction of phosphoramide. Then, a solid acid catalyst is added to carry out the hydrolysis reaction of intracyclic acid anhydride to obtain the 4-[hydroxy(methyl)phosphono]-L-hoalanine.

9. The method for preparing 4-[hydroxy(methyl)phosphono]-L-homoalanine according to claim 8, characterized in that: The hydrolysis temperature for phosphoramide is 0℃~70℃; or the hydrolysis temperature for intracyclic anhydride is 90℃~105℃; or the hydrolysis of intracyclic anhydride is carried out under negative pressure.

10. A method for preparing 4-[hydroxy(methyl)phosphono]-L-hoalanine salt, characterized in that: The 4-[hydroxy(methyl)phosphono]-L-homalanine salt includes 4-[hydroxy(methyl)phosphono]-L-homalanine hydrochloride or 4-[hydroxy(methyl)phosphono]-L-homalanine ammonium salt, wherein, The preparation method of the 4-[hydroxy(methyl)phosphono]-L-homoalanine hydrochloride includes the following steps: (1) Prepare the glufosinate intermediate according to any one of claims 1 to 7; (2) The glufosinate intermediate prepared in step (1) is concentrated and the solvent is removed without separation. Water is added to carry out the hydrolysis reaction of the phosphoramide, and then hydrochloric acid is added to carry out the hydrolysis reaction of the intracyclic anhydride to obtain the 4-[hydroxy(methyl)phosphono]-L-hoalanine hydrochloride; or The preparation method of the 4-[hydroxy(methyl)phosphono]-L-homoalanine ammonium salt includes the following steps: (1) Prepare the glufosinate intermediate according to any one of claims 1 to 7; (2) The glufosinate intermediate prepared in step (1) is concentrated and the solvent is removed. Water is added to carry out the hydrolysis reaction of phosphoramide. Then, a solid acid catalyst or hydrochloric acid is added to carry out the hydrolysis reaction of intracyclic acid anhydride to obtain 4-[hydroxy(methyl)phosphono]-L-hoalanine or its hydrochloride salt. (3) The 4-[hydroxy(methyl)phosphono]-L-homoalanine or its hydrochloride obtained in step (2) is reacted with ammonia to obtain the 4-[hydroxy(methyl)phosphono]-L-homoalanine ammonium salt.

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