A process for the preparation of l-glufosinate-ammonium based on cyclic amides

Abstract

This invention discloses a method for preparing L-glufosinate or its salts. The method involves reacting an L-cycloamide with methylphosphonic dichloride in the presence of an acid-binding agent and a monoalkyl methylphosphonite ester to undergo phosphination and cyclization reactions, yielding an intermediate as shown in formula (4). This intermediate then undergoes Arbuzov rearrangement under the action of a rearrangement initiator to obtain an intermediate as shown in formula (5). Finally, the intermediate is reacted to obtain the L-glufosinate or its salts. The L-glufosinate preparation method provided by this invention uses a monoalkyl methylphosphonite ester, which is particularly suitable for dissolving chiral cycloamides, as a solvent and reaction intermediate. It has advantages such as high yield, simple synthesis steps, mild reaction conditions, and complete solvent reuse, making it suitable for industrial production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and specifically to a method for preparing L-glufosinate based on cyclic amides. Background Technology

[0002] Glufosinate, chemical formula C5H 15 N2O4P, with a molecular weight of 198.16, is a non-selective foliar organophosphorus herbicide. Its common English name is glufosinate ammonium, and its chemical name is 4-[hydroxy(methyl)phosphono]-DL-holylanine or 2-amino-4-[hydroxy(methyl)phosphono]butyrate ammonium. It has advantages such as low toxicity, high activity, and environmental friendliness. Because only the L-form (i.e., L-glufosinate, or glufosinate-ammonium) has herbicidal ability, its herbicidal activity is twice that of racemic mixtures. Since the D-form compound cannot produce herbicidal effects, the application rate of traditional D / L-glufosinate is also twice that of glufosinate-ammonium, which does not meet environmental protection requirements.

[0003] Currently, the main methods for preparing L-glufosinate reported both domestically and internationally are chemical and biological methods. Chemical methods utilize natural amino acids as chiral sources or construct chiral centers through asymmetric catalysis; however, most current routes involve complex synthetic steps, making industrial application difficult. Biological methods primarily involve substrate transformation via various enzyme catalysis to prepare L-glufosinate, but face challenges such as low optical purity and poor substrate tolerance.

[0004] Patent document CN111662326B discloses a method for preparing L-glufosinate or its salts, which involves reacting a cyclic amide with methylphosphine dichloride, followed by an Arbuzov rearrangement reaction, and then a hydrolysis reaction to prepare L-glufosinate. The reaction solvents in this patent, toluene, xylene, and trimethylbenzene, all have extremely poor solubility for LD- or LL-cyclic amides, making it difficult to support the dissolution and effective conversion of the cyclic amides, and thus difficult to obtain a considerable yield.

[0005] Patent documents CN115448950A and CN108484666A provide a method for preparing L-glufosinate based on cyclic amides. However, in this method, the cyclic amides need to be halogenated before phosphine rearrangement can be carried out. The reaction steps are numerous and complex, and the reaction yield still needs to be improved. Summary of the Invention

[0006] The technical problem to be solved by the present invention is to provide a method for preparing L-glufosinate based on cyclic amide with high yield.

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

[0008] The present invention provides a method for preparing L-glufosinate or its salt, wherein LL-cycloamide and methylphosphonic acid are subjected to phosphination and cyclization reaction in the presence of an acid-binding agent and with the participation of a monoalkyl methylphosphonate to obtain an intermediate shown in formula (4), and then the intermediate is rearranged by Arbuzov under the action of a rearrangement initiator to obtain an intermediate shown in formula (5), and finally reacted to obtain the L-glufosinate or its salt.

[0009] The structural formula of the LL-cycloamide is as follows:

[0010] The general structural formula of the monoalkyl methylphosphonite ester is: Wherein, R is a C1 to C8 saturated alkyl group;

[0011] The structural formula of the intermediate shown in equation (4) is:

[0012] The structural formula of the intermediate shown in equation (5) is:

[0013] According to some specific embodiments, using a monoalkyl methylphosphonite as a reactive solvent, LL-cycloamide is dissolved to obtain a homogeneous solution. An acid-binding agent is added to this solution, followed by the dropwise addition of the phosphinizing agent methylphosphonic dichloride. Phosphinization and cyclization reactions occur with the participation of the monoalkyl methylphosphonite. A rearrangement initiator is then added to complete the construction of the phosphorus-carbon bond. Finally, hydrolysis yields L-glufosinate. This method has few synthetic steps, is simple to operate, and has a high reaction yield.

[0014] In this application, saturated alkyl groups include straight-chain saturated alkyl groups and branched-chain saturated alkyl groups.

[0015] According to some specific embodiments, R is a C1-C5 saturated alkyl group.

[0016] According to some specific implementations, R is methyl, ethyl, or n-butyl.

[0017] According to some specific embodiments, the molar ratio of the LL-cycloamide and the monoalkyl methylphosphonate is 1:(0.5-10), for example 1:0.5, 1:1, 1:1.5, 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.

[0018] Further, the molar ratio of the LL-cyclic amide to the monoalkyl methylphosphonate is 1:(5-10). Even further, the molar ratio of the LL-cyclic amide to the monoalkyl methylphosphonate is 1:(6-10).

[0019] According to some specific embodiments, when the reactive solvent is monomethyl methyl methyl phosphonate, the molar ratio of the LL-cyclic amide to the monomethyl ...

[0020] According to some specific embodiments, the acid-binding agent is one or more organic bases.

[0021] According to some specific embodiments, the acid-binding agent is one or more of triethylamine, tributylamine, pyridine, ammonia, methylpyridine, and N,N-dimethylcyclohexylamine.

[0022] According to some specific embodiments, the rearrangement initiator is one or more of a haloalkane or a Lewis acid.

[0023] Furthermore, the haloalkane is one or more of iodomethane, iodoethane, 1-iodobutane, potassium iodide, and bromoethane, and the Lewis acid is one or more of elemental iodine, zinc chloride, anhydrous aluminum trichloride, trimethylchlorosilane, and trimethyliodosilane.

[0024] According to some specific embodiments, when the reactive solvent is monomethyl methylphosphonite, the rearrangement initiator is iodomethane; when the reactive solvent is monoethyl methylphosphonite, the rearrangement initiator is iodoethane; and when the reactive solvent is mono-n-butyl methylphosphonite, the rearrangement initiator is 1-iodobutane.

[0025] According to some specific embodiments, the molar ratio of the LL-cycloamide and the acid-binding agent is 1:(4-8), for example 1:4, 1:4.5, 1:5, 1:5.5, 1:6, 1:6.5, 1:7, 1:7.5, 1:8.

[0026] Further, the molar ratio of the LL-cyclic amide to the acid-binding agent is 1:(4-6). Even further, the molar ratio of the LL-cyclic amide to the acid-binding agent is 1:(4-5).

[0027] According to some specific embodiments, the molar ratio of the LL-cycloamide and the methylphosphine dichloride is 1:(2-5), for example 1:2, 1:2.5, 1:3, 1:3.5, 1:4, 1:4.5, 1:5.

[0028] Further, the molar ratio of the LL-cyclic amide to the methylphosphine dichloride is 1:(2-4). Even further, the molar ratio of the LL-cyclic amide to the methylphosphine dichloride is 1:(2-3).

[0029] According to some specific embodiments, the molar ratio of the LL-cyclic amide to the rearrangement initiator is 1:(0.01~0.1), for example 1:0.01, 1:0.02, 1:0.03, 1:0.04, 1:0.05, 1:0.06, 1:0.07, 1:0.08, 1:0.09, 1:0.1.

[0030] Further, the molar ratio of the LL-cyclic amide to the rearrangement initiator is 1:(0.03-0.07). Even further, the molar ratio of the LL-cyclic amide to the rearrangement initiator is 1:(0.04-0.06).

[0031] According to some specific embodiments, the temperature of the phosphating and cyclization reaction is -30 to 50°C, for example -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, 0°C, 5°C, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, and 50°C.

[0032] According to some specific embodiments, the temperature of the Arbuzov rearrangement reaction is 25 to 150°C, for example 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 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, 140°C, 145°C, and 150°C.

[0033] Furthermore, the Arbuzov rearrangement reaction is carried out at a temperature of 50–100°C, for example, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, or 100°C.

[0034] According to some specific embodiments, the preparation method includes the following steps:

[0035] (1) Dissolve the LL-cycloamide in the monoalkyl methylphosphonic acid ester;

[0036] (2) Add the acid-binding agent to the solution obtained in step (2), and then add the methyl dichloride dropwise; or, add the acid-binding agent to the solution obtained in step (2) while adding the methyl dichloride dropwise; carry out phosphination and cyclization reactions to obtain a reaction system containing the intermediate shown in formula (4);

[0037] (3) Add the rearrangement initiator to the reaction system of step (2) and react. After the reaction is complete, cool, filter and remove solvent to obtain the intermediate shown in formula (5).

[0038] (4) The intermediate shown in formula (5) is hydrolyzed to obtain the L-glufosinate; or, the intermediate shown in formula (5) is hydrolyzed and salted to obtain the salt of the L-glufosinate.

[0039] According to some specific embodiments, the methylphosphine dichloride is added at a temperature controlled between -30°C and 0°C. For example, the temperature at which the methylphosphine dichloride is added is -30°C, -25°C, -20°C, -15°C, -10°C, -5°C, or 0°C. Further, the methylphosphine dichloride is added at a temperature controlled between -20°C and -5°C.

[0040] According to some specific embodiments, after the methylphosphine dichloride is added, the temperature is raised to 10-50°C and maintained for reaction, for example, raised to 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, and 50°C. Further, the temperature is raised to 15-35°C and maintained for reaction.

[0041] According to some specific embodiments, after the methylphosphine dichloride is completely added, the reaction is kept at a certain temperature for 0.1 to 3 hours, for example, 0.1h, 0.2h, 0.3h, 0.4h, 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h, 2.5h, 2.6h, 2.7h, 2.8h, 2.9h, and 3h.

[0042] According to some specific embodiments, after the rearrangement initiator is added, the temperature is first raised to 25–75°C and held for 0.5–3 hours, then raised to 75–150°C and held for 3–10 hours. For example, after the rearrangement initiator is added, the temperature is first raised to 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, or 75°C and held for 0.5h, 0.6h, 0.7h, 0.8h, 0.9h, 1h, 1.1h, 1.2h, 1.3h, 1.4h, 1.5h, 1.6h, 1.7h, 1.8h, 1.9h, 2h, 2.1h, 2.2h, 2.3h, 2.4h, 2.5h, and 2.5h respectively. The reaction time is 2.6h, 2.7h, 2.8h, 2.9h or 3h, then the temperature is raised to 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, 120℃, 125℃, 130℃, 135℃, 140℃, 145℃ or 150℃ and kept at that temperature for 3h, 3.5h, 4h, 4.5h, 5h, 5.5h, 6h, 6.5h, 7h, 7.5h, 8h, 8.5h, 9h, 9.5h or 10h.

[0043] According to some other specific embodiments, after the rearrangement initiator is completely added, the temperature is raised to 75-150°C and the reaction is maintained for 5-12 hours. For example, after the rearrangement initiator is completely added, the temperature is raised to 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, 140°C, 145°C, or 150°C and the reaction is maintained for 5 hours, 5.5 hours, 6 hours, 6.5 hours, 7 hours, 7.5 hours, 8 hours, 8.5 hours, 9 hours, 9.5 hours, 10 hours, 10.5 hours, 11 hours, 11.5 hours, or 12 hours.

[0044] By adopting the above technical solution, the present invention has the following advantages compared with other processes:

[0045] This invention uses a monoalkyl methylphosphonite as a reactive solvent. It is both an excellent solvent for LL-cyclic amides, achieving efficient dissolution of chiral cyclic amides, and a reactant, participating in and promoting the phosphine cyclization reaction. From the perspectives of structure, mechanism, and solubility, monoalkyl methylphosphonite is significantly different from common solvents such as toluene, xylene, trimethylbenzene, chlorobenzene, dioxane, and 2-methyltetrahydrofuran, which are frequently used in this type of reaction. These solvents do not participate in the reaction and have extremely poor solubility for LL-cyclic amides, severely hindering the phosphine cyclization reaction and reducing yield. The L-glufosinate preparation method provided by this invention uses a monoalkyl methylphosphonite, which is particularly suitable for dissolving chiral cyclic amides, as a solvent and reaction intermediate. It has advantages such as high yield, simple synthesis steps, mild reaction conditions, and complete solvent reuse, making it suitable for industrial production. Detailed Implementation

[0046] To address the issue that the yield of L-glufosinate preparation in existing technologies still needs improvement, this application develops a new synthetic route and process for L-glufosinate based on the L-homoserine dimer LL-cyclic amide ((3S,6S)-3,6-bis(2-hydroxyethyl)piperazine-2,5-dione). Using a monoalkyl methyl phosphite as the reactive solvent solves the problem of extremely poor solubility of LL-cyclic amide in most common solvents, significantly improves the structural conversion rate of LL-cyclic amide, and has the advantage of high raw material utilization.

[0047] After trying several solvents that are inert to the phosphating reaction involved in this invention, it was found that the solubility of LL-cyclic amides was not ideal. Finally, it was found that monoalkyl methylphosphonite has excellent solubility for cyclic amides, but it reacts with methylphosphonic dichloride, which makes the phosphating reaction quite complicated. This means that in this reaction, monoalkyl methylphosphonite is not only a good solvent, but also a reactant, participating in and promoting the entire phosphating and cyclization reaction process.

[0048] The basic reaction process is shown in the following reaction equation:

[0049]

[0050] 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.

[0051] 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.

[0052] In this invention, operations without specific instructions are performed at room temperature. The raw materials used in this application are commercially available or can be prepared using conventional methods in the prior art. In this invention, unless otherwise specified, all contents are mass contents, and "%" represents a mass percentage.

[0053] The endpoints and any values ​​of the ranges disclosed herein are not limited to the precise ranges or values, and should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of the ranges, the endpoint values ​​of the ranges and individual point values, and individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed herein. The terms "optional" and "discretionary" mean that they may or may not be included (or may or may not be present).

[0054] Example 1

[0055] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 167.5 g (6 eq., 1.78 mol) of monomethyl methylphosphonite were added to a four-necked flask, purged with nitrogen, and cooled to an internal temperature of -10 °C. 135.1 g (4.5 eq., 1.34 mol) of triethylamine was added to the cooled solution in a single addition, followed by dropwise addition of 86.7 g (2.5 eq., 0.74 mol) of methylphosphonic acid, maintaining the internal temperature at -10 °C for 3 hours. After the addition was complete, the internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.1 g (0.05 eq., 14.8 mmol) of iodomethane, a rearrangement initiator, was added to the reaction system. After the addition was complete, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. After the reaction was complete, the system was cooled to 20°C, and triethylamine hydrochloride was precipitated by filtration. The resulting filtrate was desolventized under reduced pressure to remove low-boiling substances such as monomethyl ...

[0056] Example 2

[0057] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 224.5 g (7 eq., 2.08 mol) of monoethyl methylphosphonite were added to a four-necked flask, purged with nitrogen, and cooled to an internal temperature of -10 °C. 135.1 g (4.5 eq., 1.34 mol) of triethylamine was added to the cooled solution in a single addition, followed by dropwise addition of 86.7 g (2.5 eq., 0.74 mol) of methylphosphonic dichloride, maintaining the internal temperature at -10 °C for 3 hours. After the addition was complete, the internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.3 g (0.05 eq., 14.7 mmol) of iodoethane, a rearrangement initiator, was added to the reaction system. After the addition was complete, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. After the reaction was complete, the system was cooled to 20°C, and triethylamine hydrochloride was precipitated by filtration. The resulting filtrate was desolventized under reduced pressure to remove low-boiling substances such as monoethyl methylphosphonite and some chloromonoethyl methylphosphonite. The fraction could be used directly as a solvent for the next batch of reactions. After desolventizing, a light yellow solid was obtained and added to 162.3 g of 20% hydrochloric acid solution. The mixture was refluxed for 8 hours until hydrolysis was complete. After desolventizing, the solid was recrystallized from ethanol-water to obtain L-glufosinate with a yield of 86% and an ee value of 96%.

[0058] Example 3

[0059] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 323.1 g (8 eq., 2.37 mol) of methylphosphonite monobutyl ester were added to a four-necked flask. After purging with nitrogen, the flask was cooled to an internal temperature of -10 °C. 135.1 g (4.5 eq., 1.34 mol) of triethylamine was added to the cooled solution in a single addition, followed by dropwise addition of 86.7 g (2.5 eq., 0.74 mol) of methylphosphonic dichloride, maintaining the internal temperature at -10 °C for 3 hours. After the addition was complete, the internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.7 g (0.05 eq., 14.7 mmol) of 1-iodobutane, a rearrangement initiator, was added to the reaction system. After the addition was complete, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. After the reaction was complete, the system was cooled to 20°C, and triethylamine hydrochloride was precipitated by filtration. The resulting filtrate was desolventized under reduced pressure to remove low-boiling substances such as mono-n-butyl methylphosphonate and some chloro-n-butyl methylphosphonate. The fraction could be used directly as a solvent for the next batch of reactions. After desolventizing, a light yellow solid was obtained and added to 162.3 g of 20% hydrochloric acid solution. The mixture was refluxed for 8 h until hydrolysis was complete. After desolventizing, the solid was recrystallized from ethanol-water to obtain L-glufosinate with a yield of 87% and an ee value of 95%.

[0060] Example 4

[0061] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 224.5 g (7 eq., 2.08 mol) of monoethyl methylphosphonite were added to a four-necked flask, purged with nitrogen, and cooled to an internal temperature of -10 °C. 105.6 g (4.5 eq., 1.34 mol) of pyridine was added to the cooled solution in a single addition, followed by dropwise addition of 86.7 g (2.5 eq., 0.74 mol) of methylphosphonic dichloride, maintaining the internal temperature at -10 °C for 3 hours. After the addition was complete, the internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.3 g (0.05 eq., 14.7 mmol) of iodoethane, a rearrangement initiator, was added to the reaction system. After the addition was complete, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. After the reaction was complete, the system was cooled to 20°C, and pyridine hydrochloride was precipitated by filtration. The resulting filtrate was desolventized under reduced pressure to remove low-boiling substances such as monoethyl methylphosphonite and some chloromonoethyl methylphosphonite. The fraction could be used directly as a solvent for the next batch of reactions. After desolventizing, a light yellow solid was obtained and added to 162.3 g of 20% hydrochloric acid solution. The mixture was refluxed for 8 hours until hydrolysis was complete. After desolventizing, the solid was recrystallized from ethanol-water to obtain L-glufosinate with a yield of 84% and an ee value of 95%.

[0062] Example 5

[0063] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 224.5 g (7 eq., 2.08 mol) of monoethyl methylphosphonite were added to a four-necked flask, purged with nitrogen, and cooled to an internal temperature of -10 °C. 22.7 g (4.5 eq., 1.34 mol) of ammonia gas was introduced into the cooled solution over 3 hours. Simultaneously, 86.7 g (2.5 eq., 0.74 mol) of methylphosphonic acid was added dropwise over 3 hours, maintaining the internal temperature at -10 °C. After the ammonia introduction and methylphosphonic acid addition were complete, the internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.3 g (0.05 eq., 14.7 mmol) of iodoethane, a rearrangement initiator, was added to the reaction system. After the addition, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. After the reaction was complete, the system was cooled to 20°C, and ammonium chloride was precipitated by filtration. The resulting filtrate was desolventized under reduced pressure to remove low-boiling substances such as monoethyl methylphosphonite and some chloromonoethyl methylphosphonite. The fraction could be used directly as a solvent for the next batch of reactions. After desolventizing, a light yellow solid was obtained and added to 162.3 g of 20% hydrochloric acid solution. The mixture was refluxed for 8 hours until hydrolysis was complete. After further desolventizing, the solid was recrystallized from ethanol-water to obtain L-glufosinate with a yield of 87% and an ee value of 96%.

[0064] Example 6

[0065] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 224.5 g (7 eq., 2.08 mol) of monoethyl methylphosphonite were added to a four-necked flask, purged with nitrogen, and cooled to an internal temperature of -15 °C. 21.2 g (4.2 eq., 1.25 mol) of ammonia gas was then introduced into the cooled solution over 3 hours. Simultaneously, 76.3 g (2.2 eq., 0.65 mol) of methylphosphonic acid was added dropwise over 3 hours, maintaining the internal temperature at -15 °C. After the ammonia introduction and methylphosphonic acid addition were complete, the internal temperature was raised to 25 °C over 1.5 hours and maintained for 0.5 hours. 2.0 g (0.05 eq., 15 mmol) of anhydrous aluminum trichloride, a rearrangement initiator, was added to the reaction system. After the addition was complete, the internal temperature was raised to 90 °C and maintained for 8 hours. After the reaction was complete, the system was cooled to 20°C, and ammonium chloride was precipitated by filtration. The resulting filtrate was desolventized under reduced pressure to remove low-boiling substances such as monoethyl methylphosphonite and some chloromonoethyl methylphosphonite. The fraction could be used directly as a solvent for the next batch of reactions. After desolventizing, a light yellow solid was obtained and added to 162.3 g of 20% hydrochloric acid solution. The mixture was refluxed for 8 hours until hydrolysis was complete. After desolventizing, the solid was recrystallized from ethanol-water to obtain L-glufosinate with a yield of 88% and an ee value of 95%.

[0066] Example 7

[0067] Compared to Example 2, the solvent used was a mixture of chlorobenzene and monoethyl methylphosphonate. The specific steps of this example are as follows:

[0068] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide, 125 g of chlorobenzene, and 100 g of monoethyl methylphosphonite were added to a four-necked flask. After purging with nitrogen, the flask was cooled to an internal temperature of -10 °C, where the LL-cycloamide partially dissolved. 135.1 g (4.5 eq., 1.34 mol) of triethylamine was added to the cooled solution in a single addition, followed by dropwise addition of 86.7 g (2.5 eq., 0.74 mol) of methylphosphonic dichloride, maintaining the internal temperature at -10 °C for 3 hours. After the addition was complete, the internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.3 g (0.05 eq., 14.7 mmol) of iodoethane, a rearrangement initiator, was added to the reaction system. After the addition was complete, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. After the reaction was complete, the system was cooled to 20°C, and the precipitated triethylamine hydrochloride was filtered out. The resulting filtrate was subjected to desolvation under reduced pressure to remove low-boiling substances such as chlorobenzene, monoethyl methylphosphonite, and some chloroethyl methylphosphonite. A yellow solid was obtained after desolvation and added to 162.3 g of a 20% hydrochloric acid solution. The mixture was refluxed for 8 hours until hydrolysis was complete. After further desolvation, the solid was recrystallized from ethanol-water to obtain L-glufosinate with a yield of 70% and an ee value of 94%.

[0069] Comparative Example 1

[0070] Compared to Example 2, the solvent was changed to chlorobenzene. The specific steps of this example are as follows:

[0071] Under mechanical stirring, 60 g (1 eq., 0.30 mol) of LL-cycloamide and 225 g of chlorobenzene were added to a four-necked flask. After purging with nitrogen, the flask was cooled to an internal temperature of -10 °C. The LL-cycloamide remained largely insoluble, dispersed as a solid in the chlorobenzene. 135.1 g (4.5 eq., 1.34 mol) of triethylamine was added to the cooled solution in a single addition, followed by dropwise addition of 86.7 g (2.5 eq., 0.74 mol) of methylphosphine dichloride, maintaining the internal temperature at -10 °C for 3 hours. After the addition was complete, the LL-cycloamide showed virtually no reaction. The internal temperature was raised to 25 °C over 1.5 hours and held for 0.5 hours. 2.3 g (0.05 eq., 14.7 mmol) of iodoethane, a rearrangement initiator, was added to the reaction system. After the addition, the internal temperature was raised to 50 °C and held for 1 hour, then further raised to 90 °C and held for 6 hours. No effective reaction was observed in the control group. The system was cooled to 20°C, and triethylamine hydrochloride was precipitated by filtration, removing low-boiling substances such as chlorobenzene from the system. After solvent removal, a brown solid was obtained, which was added to 162.3 g of 20% hydrochloric acid solution and refluxed for 8 h. Hydrolysis was completed, but L-glufosinate was not obtained.

[0072] 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 L-glufosinate or a salt thereof, characterized by: LL-cycloamide and methylphosphonic acid are subjected to phosphineization and cyclization reactions in the presence of an acid-binding agent and with the participation of a monoalkyl methylphosphonate to obtain the intermediate shown in formula (4). Then, under the action of a rearrangement initiator, the intermediate is rearranged by Arbuzov to obtain the intermediate shown in formula (5). Finally, the intermediate is reacted to obtain the L-glufosinate or its salt. In the formula, the structure of the LL-cyclic amide is: The structural general formula of the methyl phosphinic monoalkyl ester is: In the formula, R is a saturated alkyl group with 1-8 carbon atoms. The structural formula of the intermediate shown in formula (4) is: The structural formula of the intermediate shown in formula (5) is:

2. The method of producing L-glufosinate-ammonium or a salt thereof according to claim 1, characterized by: R is methyl, ethyl, or n-butyl.

3. The method of preparing L-glufosinate-ammonium or a salt thereof according to claim 1, characterized by: The molar ratio of the LL-cycloamide to the monoalkyl methylphosphonate is 1:(0.5-10).

4. The method of producing L-glufosinate-ammonium or a salt thereof according to claim 4, characterized by: The molar ratio of the LL-cycloamide to the monoalkyl methylphosphonate is 1:(5-10).

5. The method of preparing L-glufosinate-ammonium or a salt thereof according to claim 1, characterized by: The acid-binding agent is one or more of triethylamine, tributylamine, pyridine, ammonia, methylpyridine, and N,N-dimethylcyclohexylamine; and / or, the rearrangement initiator is one or more of haloalkanes or Lewis acids.

6. The method of producing L-glufosinate-ammonium or a salt thereof according to claim 5, characterized by: The haloalkane is one or more of iodomethane, iodoethane, 1-iodobutane, potassium iodide, and bromoethane, and the Lewis acid is one or more of elemental iodine, zinc chloride, anhydrous aluminum trichloride, trimethylchlorosilane, and trimethyliodosilane.

7. The method for preparing L-glufosinate or its salt according to claim 1, characterized in that: The molar ratio of the LL-cyclic amide to the acid-binding agent is 1:(4-8); and / or, The molar ratio of the LL-cyclic amide to the methylphosphine dichloride is 1:(2-5); and / or, the molar ratio of the LL-cyclic amide to the rearrangement initiator is 1:(0.01-0.1).

8. The method for preparing L-glufosinate or its salt according to claim 1, characterized in that: The phosphating and cyclization reactions are performed at temperatures ranging from -30 to 50°C; and / or, The Arbuzov rearrangement reaction is carried out at temperatures ranging from 25 to 150°C.

9. The method for preparing L-glufosinate or its salt according to claim 1, characterized in that: The preparation method includes the following steps: (1) Dissolve the LL-cycloamide in the monoalkyl methylphosphonic acid ester; (2) Add the acid-binding agent to the solution obtained in step (2), and then add the methyl dichloride dropwise; or, add the acid-binding agent to the solution obtained in step (2) while adding the methyl dichloride dropwise; carry out phosphination and cyclization reactions to obtain a reaction system containing the intermediate shown in formula (4); (3) Add the rearrangement initiator to the reaction system of step (2) and react. After the reaction is complete, cool, filter and remove solvent to obtain the intermediate shown in formula (5). (4) The intermediate shown in formula (5) is hydrolyzed to obtain the L-glufosinate; or, the intermediate shown in formula (5) is hydrolyzed and salted to obtain the salt of the L-glufosinate.

10. The method for preparing L-glufosinate or its salt according to claim 1 or 9, characterized in that: The addition of the methylphosphine dichloride is controlled at -30 to 0°C; and / or, After the methylphosphine dichloride is completely added, the temperature is raised to 10–50°C and maintained for 0.1–3 hours; and / or, After the rearrangement initiator is added, the temperature is first raised to 25-75°C and kept at that temperature for 0.5-3 hours, then raised to 75-150°C and kept at that temperature for 3-10 hours; or, after the rearrangement initiator is added, the temperature is raised to 75-150°C and kept at that temperature for 5-12 hours.

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