Preparation method of optical pure amino acid herbicide

Abstract

The invention discloses a preparation method of an optical pure amino acid herbicide. The preparation method comprises a preparation method of a refined glufosinate-ammonium intermediate. The method comprises the following steps: carrying out cyclization reaction on a compound as shown in a formula (III) and a compound as shown in a formula (IV) in the presence of a solvent and organic alkali to obtain a compound as shown in a formula (V), and then carrying out intramolecular Arbuzov rearrangement reaction under the action of a halogenation catalyst to obtain the refined glufosinate-ammonium intermediate. The preparation method is simple in process, the synthesis route is reduced, complex and tedious separation and purification processes are avoided in the synthesis steps, particularly, waste salt, waste acid and toxic waste gas are not generated in the aspect of three-waste control, and the product quality is high. In addition, the reaction conditions are mild, the operation is simple, the continuity among the working sections is strong, the raw material cost and the industrial investment are effectively reduced, and the trend of green chemical industry is met.

Description

A method for preparing an optically pure amino acid herbicide Technical Field

[0001] This invention belongs to the field of fine chemical process synthesis, specifically relating to a method for preparing an optically pure amino acid herbicide. Background Technology

[0002] Chiral pesticides are agricultural chemicals whose molecules possess a chiral center. Chiral pesticides composed of a single enantiomer are called optically pure chiral pesticides. After entering the organism, the enantiomers can exhibit significant differences in bioabsorption, translocation, transformation, and protein interaction, thus causing chiral pesticides to show enantioselectivity in target biological activity, non-target biological toxicity, and environmental adaptability. Therefore, optically pure pesticides often possess superior biological activity and bioavailability.

[0003] Glufosinate (L-configuration) is the active ingredient with major herbicidal activity in a racemic mixture of glufosinate (containing both L- and D-configurations). As a novel optically pure amino acid herbicide, the market launch and application of glutfosinate can greatly reduce the waste of resources caused by the ineffective component (D-glufosinate) entering the environment. It is of great significance for improving pesticide utilization and reducing environmental pressure.

[0004] Existing preparation processes for glufosinate mainly include biocatalysis and chemical synthesis. Chemical synthesis uses optically pure chiral amino acids as raw materials or employs asymmetric synthesis to prepare glufosinate. Patents such as US5442088, WO2021143712, WO2021143713, and CN106083922 disclose the synthesis of amino-protected or unprotected chlorohomoserine esters from L-homoserine or its lactones, followed by Arbuzov reaction with methyl phosphite diester and hydrolysis to prepare glufosinate (reaction routes are listed below). This method involves a large amount of methyl phosphite diester, is easily hydrolyzed and oxidized, has a low recovery rate, and requires high-temperature conditions (130–150°C), which leads to a decrease in the enantiomeric excess value of the product, high raw material costs, difficulty in guaranteeing product quality and reaction yield, and significant challenges in industrialization.

[0005]

[0006] Patents CN113490671 and CN116041387 disclose a method for preparing phosphonium amide intermediates by reacting chlorohomoserine esters with in-situ synthesized methyl chlorophosphonate alkyl esters or methyl chlorophosphonate alkylamides, followed by intramolecular Arbuzov reaction to further synthesize pentavalent phosphonamide intermediates, and finally hydrolysis to prepare glufosinate. This method significantly improves the utilization rate and reaction conversion rate of trivalent phosphine reagents, and reduces raw material costs and process safety risks. However, the methyl chlorophosphonate alkyl ester process inevitably generates equivalent amounts of potent carcinogens, chloroalkanes, and irreversible ethylation impurities; the methyl chlorophosphonate alkylamide process uses excessive amounts of nucleophilic secondary amine organic bases, generating secondary amine substitution impurities that affect the reaction yield, and the secondary amine recovery process is complex and prone to cost waste.

[0007]

[0008] Furthermore, all of the above processes use chlorohomoserine ester intermediates, which have poor thermal stability and are prone to polymerization. Many preparation methods require the use of strong acids and highly corrosive chlorinating agents such as HCl and thionyl chloride. The esterification reaction requires a large excess of alcohol reagents, necessitating a large number of complex and cumbersome separation and purification processes. This results in serious waste problems, poor atom economy, high equipment investment, and high energy consumption for solvent purification and recovery, which is not conducive to industrial production.

[0009] With the significant increase in market demand for glufosinate, there is an urgent need for a synthesis method of glufosinate that is simple to operate, has high atom economy, allows for controllable waste, is low in cost, and has industrial application value. Summary of the Invention

[0010] The technical problem to be solved by the present invention is to provide a method for preparing optically pure amino acid herbicides via different reaction routes.

[0011] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0012] 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) undergo a cyclization reaction in the presence of a solvent and an organic base to obtain the compound shown in formula (V), and then an intramolecular Arbuzov rearrangement reaction occurs under the action of a halogenated catalyst to obtain the glufosinate intermediate;

[0013] The structural formula of the compound shown in formula (III) is as follows:

[0014] The structural formula of the compound shown in formula (IV) is Among them, X 1 It is a halogen;

[0015] The structural formula of the compound shown in formula (V) is

[0016] The structural formula of the glufosinate intermediate is as follows:

[0017] According to some specific embodiments, the halogen is fluorine, chlorine, or bromine. Further, X 1 It is chlorine.

[0018] According to some specific embodiments, the solvent is an inert solvent. Further, the solvent is selected from one or more of toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and 1,4-dioxane.

[0019] According to some specific embodiments, the organic base is selected from one or more of triethylamine, diethylamine, dimethylamine, diisopropylamine, N,N-dimethylcyclohexylamine, pyridine, 1,3,5-trimethylpyridine, and 4-dimethylaminopyridine.

[0020] According to some specific embodiments, the molar ratio of the compound shown in formula (III) to the compound shown in formula (IV) is 1:(1-2), for example, 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:(1-1.1).

[0021] According to some specific embodiments, the molar ratio of the compound shown in formula (III) to the organic base is 1:(2-5), for example 1:2, 1:2.1, 1:2.2, 1:2.3, 1:2.4, 1:2.5, 1:2.6, 1:2.7, 1:2.8, 1:2.9, 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5. Further, the molar ratio of the compound shown in formula (III) to the organic base is 1:(2-2.5).

[0022] According to some specific embodiments, the halogenated catalyst is one or more of C1-C12 halogenated alkanes, metal halides, and halogenated silanes. Further, the halogenated catalyst is one or more of iodoethane, iodopropane, bromoethane, bromopropane, trimethylchlorosilane, sodium iodide, potassium iodide, sodium bromide, potassium bromide, boron trifluoride, and aluminum trichloride.

[0023] According to some specific embodiments, the molar ratio of the halogenated catalyst 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. Further, the molar ratio of the halogenated catalyst to the compound shown in formula (III) is (0.02–0.1):1.

[0024] According to some specific embodiments, the weight ratio of the compound shown in formula (III) to the solvent is 1:(1-10), for example 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. Further, the weight ratio of the compound shown in formula (III) to the solvent is 1:(2-5). Wherein, the solvent is the total mass of the solvent in the cyclization reaction system.

[0025] Furthermore, the solvent is added to the reaction system in two parts: one part is mixed with the compound shown in formula (III), and the other part is mixed with the compound shown in formula (IV) to form a mixture which is then added to the reaction system.

[0026] According to some specific embodiments, the reaction temperature of the cyclization reaction is from -10°C to 50°C, for example, -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. Further, the reaction temperature of the cyclization reaction is from -5°C to 30°C.

[0027] According to some specific implementation methods, the cyclization reaction time is 0.5h to 24h, 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, 20h, 20.5h, 21h, 21.5h, 22h, 22.5h, 23h, 23.5h, and 24h. Furthermore, the cyclization reaction takes place over a period of 1 to 6 hours.

[0028] According to some specific embodiments, the reaction temperature of the intramolecular Arbuzov rearrangement reaction is 50℃ to 120℃, for example, 50℃, 55℃, 60℃, 65℃, 70℃, 75℃, 80℃, 85℃, 90℃, 95℃, 100℃, 105℃, 110℃, 115℃, and 120℃. Further, the reaction temperature of the intramolecular Arbuzov rearrangement reaction is 60℃ to 90℃.

[0029] According to some specific embodiments, the intramolecular Arbuzov rearrangement reaction time is 2h to 16h, for example 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, and 16h. Further, the intramolecular Arbuzov rearrangement reaction time is 4h to 12h.

[0030] According to some specific embodiments, the reaction is carried out under the protection of an inert gas. Further, the inert gas is nitrogen or argon.

[0031] According to some specific embodiments, the preparation method of the glufosinate intermediate includes the following steps:

[0032] Under an inert atmosphere, the compound shown in formula (III) and part of the solvent were added to a reaction vessel, and the temperature was lowered to -10°C to 0°C. The organic base was added to the reaction vessel, and after mixing, a mixture of the compound shown in formula (IV) and the remaining part of the solvent was added dropwise to the reaction vessel. After the dropwise addition was completed, the temperature was slowly raised to the reaction temperature for a heat preservation reaction within 1 hour. After the reaction was completed, the halogenated catalyst was added to the reaction vessel, and after mixing, the temperature was raised to the reaction temperature to obtain the glufosinate intermediate.

[0033] Further, after the reaction is completed, the reaction system is filtered, and the filtrate is dried under vacuum until it becomes viscous to obtain the glufosinate intermediate.

[0034] According to some specific embodiments, the compound shown in formula (III) is obtained by cyclization of the amino and carboxyl groups in the L-homoserine molecule.

[0035] 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.

[0036] A second aspect of this invention provides a method for preparing glufosinate-ammonium, comprising the following steps:

[0037] (1) Prepare glufosinate intermediate according to the above preparation method;

[0038] (2) After removing the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1), water is added to the system to carry out the hydrolysis reaction of cyclophosphamide. After the reaction is completed, a solid acid catalyst is added to carry out the hydrolysis reaction of the intracyclic acid anhydride to obtain the cyclophosphamide.

[0039] According to some specific implementation methods, the temperature for carrying out the hydrolysis reaction of cyclophosphamide is 0℃~50℃, for example 0℃, 5℃, 10℃, 15℃, 20℃, 25℃, 30℃, 35℃, 40℃, 45℃, 50℃.

[0040] According to some specific implementation methods, the hydrolysis reaction of cyclophosphamide takes 1 to 3 hours.

[0041] According to some specific embodiments, the mass of water added during the hydrolysis reaction of cyclophosphamide is 2.5 to 6 times the mass of the compound shown in formula (III).

[0042] According to some specific implementation methods, the water added during the hydrolysis reaction of cyclophosphamide is an ice-water mixture.

[0043] According to some specific implementation methods, solid acid catalysts are used for the hydrolysis reaction of intracyclic acid anhydrides. The solid acid catalysts can be recovered through filtration and directly reused in the next batch of reaction, thereby reducing raw material costs. The use of solid acid catalysts not only avoids equipment corrosion but also effectively shortens reaction time, controls product racemization, reduces impurity generation, and is of great significance for improving the purity of the final product.

[0044] According to some specific embodiments, the solid acid catalyst is a macroporous resin solid acid catalyst, a solid superacid catalyst, or a perfluorosulfonic acid resin solid acid catalyst, including but not limited to Amberlyst-15 solid acid catalyst, Amberlyst-35 solid acid catalyst, HND-580 solid acid catalyst, HND-34 solid acid catalyst, and HNF-5W solid acid catalyst.

[0045] 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), for example, 0.1 times, 0.2 times, 0.3 times, 0.4 times, 0.5 times, 0.6 times, 0.7 times, 0.8 times, 0.9 times, or 1 times, preferably 0.2 to 0.6 times, and more preferably 0.2 to 0.5 times.

[0046] According to some specific implementation methods, the temperature for hydrolysis of intracyclic anhydrides is 80℃~105℃.

[0047] According to some specific implementation methods, the hydrolysis reaction of intracyclic acid anhydrides is carried out under negative pressure conditions.

[0048] Furthermore, the negative pressure condition is controlled between 0 MPa and -0.05 MPa, preferably between 0 MPa and -0.04 MPa, more preferably between 0 MPa and -0.03 MPa, and even more preferably between -0.01 MPa and -0.02 MPa.

[0049] According to some specific implementation methods, the reaction time for the hydrolysis reaction of intracyclic anhydrides is 4h to 20h.

[0050] According to some specific implementation methods, after the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1) are removed, water is directly added to carry out hydrolysis reaction without purification treatment.

[0051] 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 filtered and concentrated, and without purification, an ice-water mixture is directly added to the reaction system to carry out the hydrolysis reaction of cyclophosphamide; after the reaction is completed, a solid acid catalyst is added to the reaction system, condensed at -20℃ to 0℃, and then the hydrolysis reaction of the 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, and the mixture is pulped at room temperature, filtered, and dried to obtain the refined glufosinate.

[0052] A third aspect of the present invention provides a method for preparing glufosinate hydrochloride, comprising the following steps:

[0053] (1) Prepare glufosinate intermediate according to the above preparation method;

[0054] (2) After removing the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1), water is added to the system to carry out the hydrolysis reaction of cyclophosphamide. After the reaction is completed, the system is concentrated until no distillate is distilled off. After cooling to room temperature, hydrochloric acid is added to carry out the reaction to obtain the glufosinate hydrochloride.

[0055] The hydrolysis conditions of cyclophosphamide in step (2) of preparing glufosinate hydrochloride are the same as those of the hydrolysis conditions of cyclophosphamide in step (2) of preparing glufosinate as described above, and will not be repeated here.

[0056] According to some specific embodiments, the mass concentration of the hydrochloric acid is 25-35%.

[0057] 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.

[0058] According to some specific implementation methods, hydrochloric acid is added to react until the reaction is completed, the reaction solution is concentrated under negative pressure, then ethanol is added for reflux, and the solution is cooled to crystallize, filtered, and dried to obtain the glufosinate hydrochloride.

[0059] A fourth aspect of this invention provides a method for preparing glufosinate-ammonium salt, comprising the following steps:

[0060] (1) Prepare glufosinate intermediate according to the above preparation method;

[0061] (2) After removing the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1), water is added to the system to carry out the hydrolysis reaction of cyclophosphamide. After the reaction is completed, a solid acid catalyst or hydrochloric acid is added to carry out the reaction to obtain the cyclophosphamide or its hydrochloride salt.

[0062] (3) The glufosinate or its hydrochloride obtained in step (2) is reacted with ammonia to obtain the glufosinate ammonium salt.

[0063] According to some specific implementation methods, glufosinate ammonium salt is prepared by reacting glufosinate ammonium with ammonia water. 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.

[0064] 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).

[0065] By adopting the above technical solution, the present invention has the following advantages compared with other processes:

[0066] This invention uses L-homoserine intracyclic anhydride as a raw material to directly synthesize glufosinate or its salts via intramolecular cyclization, Arbuzov rearrangement, and hydrolysis. This preparation method is simple, reduces the synthetic route, and avoids complex and cumbersome separation and purification processes. Particularly noteworthy is its effectiveness in controlling waste, as it generates no waste salts, waste acids, or toxic gases, and produces high-quality products. Furthermore, the reaction conditions are mild, the operation is simple, and the processes are highly interconnected, effectively reducing raw material costs and industrialization investment, aligning with the trend of green chemistry. Attached Figure Description

[0067] Figure 1 shows the LC-MS control spectrum of the hydrolysis reaction in Example 1;

[0068] Figure 2 shows the MS (ESI, [M+1]+) spectrum of the hydrolysis reaction product in Example 1;

[0069] Figure 3 shows the optical content detection spectrum of glufosinate in Example 1. Detailed Implementation

[0070] To address the problems of complex operation, low atom economy, large amount of waste, and high cost in existing technological processes, the applicant has developed a new route for the preparation of glufosinate and its salts, as shown below:

[0071]

[0072] Research has revealed that, compared to existing technologies, the present invention offers at least the following advantages:

[0073] This invention utilizes L-homoserine intracyclic anhydride prepared by L-homoserine cyclization as a raw material, and prepares a six-membered ring intracyclic phosphorous amide intermediate using intramolecular amphiphilic sites. Further rearrangement yields an intracyclic phosphonamide intermediate, which is then hydrolyzed to obtain the target product. This process innovates in its route design, avoiding the preparation of chlorohomoserine and its esters under strong acid and corrosive conditions as in existing technologies. Furthermore, the intramolecular Arbuzov reaction under trace halide catalysis avoids the generation of equivalent amounts of toxic haloalkanes and the use of high-cost methyl phosphite diesters, reducing raw material costs and potential environmental and safety risks. In addition, the stepwise hydrolysis reaction avoids strong exothermic reactions; the use of a solid acid catalyst improves the hydrolysis efficiency of the intracyclic anhydride, and its recycling reduces costs, minimizes equipment corrosion, maintains product chirality, and reduces impurity formation. The preparation of glufosinate-ammonium salt produces no large amounts of waste salt, making it simpler, more environmentally friendly, and reducing equipment and engineering investment.

[0074] 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.

[0075] 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.

[0076] 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.

[0077] To determine the optical purity of the prepared glufosinate, a chiral column method was used, and high-performance liquid chromatography (HPLC) was employed. The specific method was as follows: Column: 50 mm × 4.6 mm (id) Dassell column, packed with CHIRALPAK MA(+) at a 3 μm depth; Mobile phase preparation: 0.16 g CuSO4 was accurately weighed and dissolved in 1000 mL of ultrapure water, then 3.0 mL of acetonitrile was accurately transferred, mixed thoroughly, filtered through a 0.22 μm filter membrane, and degassed; Flow rate: 0.4 mL / min; Column temperature: 30℃; Detection wavelength: 230 nm; Injection volume: 5 μL; Retention time of glufosinate (L-form glufosinate) was 10.5 min, and retention time of D-form glufosinate was 8.8 min. The methods for determining the optical purity of glufosinate hydrochloride and glufosinate ammonium salt were the same as those for glufosinate.

[0078] 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.

[0079] 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 a solid product of L-homoserine intracyclic anhydride (compound shown in Formula III), 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).

[0080] Example 1

[0081] A method for preparing glufosinate-ammonium, the reaction route is as follows:

[0082]

[0083] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5 °C, and triethylamine (63.75 g, 0.63 mol) was added. After thorough mixing, a mixture of methyl phosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system. The addition was completed in about 1.5 hours. The temperature was slowly raised to 20 °C over 1 hour, during which triethylamine hydrochloride continuously precipitated. The reaction was maintained at this temperature for 2 hours to ensure complete reaction. Iodoethane (0.93 g, 0.006 mol) was then added to the system. After mixing, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. The system gradually changed from light yellow to a yellow suspension. After the reaction was completed, the temperature was lowered to 10 °C and maintained for 2 hours. The reaction solution was filtered to remove insoluble triethylamine hydrochloride. The filtrate was dried under high vacuum until it was molten, yielding a yellow oily compound VI.

[0084] The crude product VI, without purification, was added to a system with 250g of an ice-water mixture. A small amount of heat was released. After the system stabilized, the temperature was raised to 30°C and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst (CAS: 39389-20-3, purchased from Bide Pharmaceuticals) was added. The system was then refluxed at -10°C under a slight negative pressure of -0.015 MPa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased as controlled by LC-MS. The solid acid catalyst was filtered while hot, and after rinsing, the filtrate was concentrated to dryness. 150g of [unspecified ingredient] was added... The mixture was slurried in 95% ethanol at room temperature, filtered, and dried to obtain 49.86 g of off-white solid glufosinate (compound I). The L / D mixture content was 99%, the L-isomer content was 99.1% (enantiomer excess was 98.2%), and the absolute yield of glufosinate was 90.1% (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 in Figures 1, 2, and 3, respectively.

[0085] Example 2

[0086] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5 °C, and triethylamine (63.75 g, 0.63 mol) was added. After thorough mixing, a mixture of methyl phosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system. The addition was completed in about 1.5 hours. The temperature was slowly raised to 20 °C over 1 hour, during which triethylamine hydrochloride continuously precipitated. The reaction was maintained at this temperature for 2 hours to ensure complete reaction. Bromoethane (1.63 g, 0.015 mol) was then added to the system. After mixing, the temperature was raised to 90 °C and the reaction was carried out for 8 hours. The system gradually changed from light yellow to a yellow suspension. After the reaction was completed, the temperature was lowered to 10 °C and maintained at this temperature for 2 hours. The reaction solution was filtered to remove insoluble triethylamine hydrochloride. The filtrate was dried under high vacuum until it was molten, yielding a yellow oily compound VI.

[0087] Without purification, 250g of an ice-water mixture was added to the crude product VI. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added. The system was then refluxed at -10℃ under a slight negative pressure of -0.015 MPa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 50.47g of off-white solid glufosinate (compound I) was obtained. The L / D mixture content was 97.9%, the L-isomer percentage was 98.8% (enantiomer excess was 97.6%), and the absolute yield of glufosinate was 89.9% (based on compound III).

[0088] Example 3

[0089] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 140 g of mesitylene in a reaction flask. The solution was cooled to 0 °C, and triethylamine (63.75 g, 0.63 mol) was added. After thorough mixing, a mixture of methylphosphoric acid (39 g, 0.33 mol, 99% purity) and 39 g of mesitylene was added dropwise to the reaction system over approximately 2 hours. The temperature was then slowly increased to 20 °C over 1 hour, during which triethylamine hydrochloride continuously precipitated. The reaction was maintained at this temperature for 2 hours to ensure complete reaction. Sodium bromide (3.09 g, 0.03 mol) was then added to the system, and the mixture was heated to 90 °C. The reaction was allowed to proceed for 12 hours, during which the system gradually changed from a light yellow to a brown suspension. After the reaction was complete, the temperature was lowered to 5 °C and maintained for 2 hours. The reaction solution was then filtered, and the filtrate was dried under high vacuum until it reached a molten state, yielding a brown oily compound VI.

[0090] Without purification, 250g of an ice-water mixture was added to the crude product VI. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added. The system was then refluxed at -10℃ under a slight negative pressure of -0.015 MPa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 49.15g of off-white solid glufosinate (compound I) was obtained. The L / D mixture content was 97.7%, the L-isomer percentage was 98.5% (enantiomer excess was 97.0%), and the absolute yield of glufosinate was 87.1% (based on compound III).

[0091] Example 4

[0092] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5 °C, and triethylamine (63.75 g, 0.63 mol) was added. After thorough mixing, a mixture of methyl phosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system. The addition was completed in about 1.5 hours. The temperature was slowly raised to 20 °C over 1 hour, during which triethylamine hydrochloride continuously precipitated. The reaction was maintained at this temperature for 2 hours to ensure complete reaction. Iodoethane (0.93 g, 0.006 mol) was then added to the system. After mixing, the temperature was raised to 70 °C and the reaction was carried out for 6 hours. The system gradually changed from light yellow to a yellow suspension. After the reaction was completed, the temperature was lowered to 10 °C and maintained for 2 hours. The reaction solution was filtered to remove insoluble triethylamine hydrochloride. The filtrate was dried under high vacuum until it was molten, yielding a yellow oily compound VI.

[0093] Without purification, 250g of an ice-water mixture was added to the system. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 13g of HND-580 solid acid catalyst (purchased from Jiangsu Nanda Synthetic) was added to the system. The system was then refluxed at -15℃ under a slight negative pressure of -0.02Mpa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 50.3g of off-white solid glufosinate (compound I) was obtained. The L / D mixture content was 99.1%, the L-isomer percentage was 98.6% (enantiomer excess value was 97.2%), and the absolute yield of glufosinate was 90.5% (based on compound III).

[0094] Based on Examples 1 and 4 above, the effects of different types of solid acid catalysts and different reaction conditions on the reaction yield and the corresponding isomer excess value in the hydrolysis reaction are summarized and listed in Table 1 below.

[0095] Table 1

[0096]

[0097] Hydrolysis of intracyclic anhydrides using solid acids as catalysts was employed. By adjusting the catalyst type, reaction temperature, and vacuum level, suitable reaction conditions were identified for the preparation of glufosinate. This hydrolysis scheme achieves high yields, allows for catalyst recovery and reuse, maintains product chirality, and reduces the difficulty of post-processing purification, making it suitable for industrial production.

[0098] Example 5

[0099] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5°C, and diethylamine (46.08 g, 0.63 mol) was added. After thorough mixing, a mixture of methyl phosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system over approximately 2 hours. The temperature was then slowly increased to 25°C over 1 hour, during which diethylamine hydrochloride continuously precipitated. The reaction was maintained at this temperature for 2 hours to ensure complete reaction. Iodoethane (1.4 g, 0.009 mol) was then added to the system, and the mixture was heated to 70°C. The reaction was continued for 4 hours, during which the system gradually changed from a pale yellow to a yellow suspension. After the reaction was complete, the temperature was lowered to 5°C and maintained for 2 hours. The reaction solution was filtered to remove insoluble diethylamine hydrochloride. The filtrate was dried under high vacuum until it reached a molten state, yielding a yellow oily compound VI.

[0100] Without purification, 250g of an ice-water mixture was added to the crude product VI. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added. The system was then refluxed at -10℃ under a slight negative pressure of -0.015 MPa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 50.64g of white solid glufosinate (compound I) was obtained. The L / D mixture content was 99%, the L-isomer percentage was 99.1% (enantiomer excess was 98.2%), and the absolute yield of glufosinate was 91.5% (based on compound III).

[0101] Example 6

[0102] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5 °C, and pyridine (49.83 g, 0.63 mol) was added. After thorough mixing, a mixture of methylphosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system over approximately 2 hours. The temperature was slowly increased to 25 °C over 1 hour, during which pyridine hydrochloride continuously precipitated. The reaction was maintained at this temperature for 3 hours to ensure complete reaction. Iodoethane (1.4 g, 0.009 mol) was then added to the system, mixed, and the temperature was increased to 70 °C. The reaction was carried out for 5 hours, during which the system gradually changed from a light yellow to a dark yellow suspension. After the reaction was complete, the temperature was lowered to 0 °C and maintained for 2 hours. The reaction solution was filtered to remove insoluble pyridine hydrochloride. The filtrate was dried under high vacuum until it reached a molten state, yielding a yellow oily compound VI.

[0103] Without purification, 250g of an ice-water mixture was added to the crude product VI. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added. The system was then refluxed at -10℃ under a slight negative pressure of -0.015 MPa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 49.6g of grayish-white solid glufosinate (compound I) was obtained. The L / D mixture content was 98%, the L-isomer percentage was 98.2% (enantiomer excess was 96.4%), and the absolute yield of glufosinate was 87.9% (based on compound III).

[0104] Example 7

[0105] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5°C, and triethylamine (45.5 g, 0.45 mol) was added. After thorough mixing, a mixture of methylphosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system over approximately 1.5 hours. The temperature was slowly increased to 20°C over 1 hour, during which triethylamine hydrochloride continuously precipitated. After maintaining the temperature for 2 hours, iodoethane (0.93 g, 0.006 mol) was added to the system. After mixing, the temperature was increased to 70°C, and after reacting for 16 hours, the temperature was lowered to 10°C and maintained for 2 hours. The reaction solution was filtered to remove insoluble triethylamine hydrochloride. The filtrate was dried under high vacuum until it reached a molten state, yielding a yellow oily intermediate.

[0106] Without purification, 250g of an ice-water mixture was added to the system. The system was exothermic. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added to the system. The system was then refluxed at -10℃ under a slight negative pressure of -0.015 MPa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 46.05g of brown glufosinate crude product was obtained. The L / D mixture content was 81.2%, the L-isomer ratio was 98.3% (enantiomer excess value was 96.6%), and the absolute yield of glufosinate was 67.7% (based on compound III).

[0107] Example 8

[0108] Under nitrogen-free conditions, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5°C, and triethylamine (63.75 g, 0.63 mol) was added. After thorough mixing, a mixture of methyl phosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system over approximately 1.5 hours. The temperature was slowly increased to 20°C over 1 hour, during which triethylamine hydrochloride continuously precipitated. After maintaining the temperature for 2 hours, iodoethane (0.93 g, 0.006 mol) was added to the system. After mixing, the temperature was increased to 70°C, and after reacting for 8 hours, the temperature was lowered to 10°C and maintained for 2 hours. The reaction solution was filtered to remove insoluble triethylamine hydrochloride. The filtrate was dried under high vacuum until it reached a molten state, yielding a yellow oily intermediate.

[0109] Without purification, 250g of an ice-water mixture was added to the system. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30℃ and held for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added to the system. The system was then refluxed at -10℃ under a slight negative pressure of -0.015Mpa. The reaction was stopped when the mass spectrum peak area of ​​the product no longer increased in LC-MS. The solid acid catalyst was filtered while hot, and the filtrate was concentrated to dryness after rinsing. 150g of 95% ethanol was added and the mixture was stirred at room temperature. After filtration and drying, 46.17g of grayish-white glufosinate crude product was obtained. The L / D mixture content was 87%, the L-isomer ratio was 98.4% (enantiomer excess value was 96.8%), and the absolute yield of glufosinate was 72.8% (based on compound III).

[0110] Example 9

[0111] A method for preparing glufosinate hydrochloride, the reaction route is as follows:

[0112]

[0113] Crude intermediate VI was prepared according to the method in Example 1. Without purification, 250g of an ice-water mixture was added to the system. The system released a small amount of heat. After the system stabilized, the temperature was raised to 30°C and held for 1 hour. The system was concentrated until no fraction was distilled off. After cooling to room temperature, 145g of 30% hydrochloric acid was added, and the system was heated to reflux. After the mass spectrum peak area of ​​the product no longer increased in LC-MS, the reaction was stopped. The acid water was concentrated under negative pressure, and 120g of anhydrous ethanol was added and refluxed. The mixture was cooled to crystallize, filtered, and dried to obtain 60.04g of off-white solid, namely glufosinate hydrochloride (compound II). The L / D mixture content was 99.1%, the L-isomer percentage was 98.7% (enantiomer excess value was 97.4%), and the absolute yield of glufosinate hydrochloride was 90% (based on compound III).

[0114] Example 10

[0115] A method for preparing glufosinate-ammonium salt, the reaction route is as follows:

[0116]

[0117] 20g of glufosinate prepared in Example 1 was dissolved in 50g 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 21.19g of white solid glufosinate ammonium salt. The L / D mixture content was 99.2%, the L-isomer percentage was 99.3% (enantiomer excess value was 98.6%), and the absolute yield of glufosinate ammonium salt was 97.2%.

[0118] Comparative Example 1

[0119] Under a nitrogen atmosphere, L-homoserine intracyclic anhydride (43.5 g, 0.3 mol) was suspended in 90 g of chlorobenzene in a reaction flask. The solution was cooled to -5°C, and triethylamine (63.75 g, 0.63 mol) was added. After thorough mixing, a mixture of methyl phosphorus dichloride (39 g, 0.33 mol, 99% purity) and 39 g of chlorobenzene was added dropwise to the reaction system over approximately 1.5 hours. The temperature was slowly increased to 20°C over 1 hour, during which triethylamine hydrochloride continuously precipitated. After maintaining the temperature for 2 hours, the mixture was mixed and the temperature was increased to 90°C. After reacting for 20 hours, the temperature was lowered to 10°C and maintained for 2 hours. The reaction solution was filtered to remove insoluble triethylamine hydrochloride. The filtrate was dried under high vacuum until it reached a molten state, yielding a yellow oily intermediate.

[0120] Without purification, 250g of an ice-water mixture was added to the crude product. The system exhibited vigorous exothermic reaction. After the system stabilized, it was kept at 30°C for 1 hour. Then, 22g of Amberlyst-15 solid acid catalyst was added to the system. The mixture was then refluxed at -10°C under a slight negative pressure of -0.015 MPa. LC-MS analysis showed no product peak in the reaction solution, and the main peak was ESI-10 2.01 m / z [M+1]. + .

[0121] Comparative analysis of Example 1 and Comparative Example 1 revealed that without the addition of a halogenated catalyst, the intramolecular rearrangement reaction could not occur, and the product glufosinate could not be prepared. Comparative analysis of Examples 1, 7, and 8 showed that insufficient triethylamine addition led to incomplete formation of hydrogen chloride bound acid during the intramolecular phosphination process, resulting in low raw material conversion. Furthermore, the hydrogen chloride further caused acid decomposition and ring opening in the intermediate. The lack of nitrogen protection during the reaction caused the trivalent phosphine in intermediate V to undergo oxidation under exothermic conditions, affecting subsequent rearrangement reactions, all of which impacted product yield and quality.

[0122] 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) and the compound shown in formula (IV) undergo a cyclization reaction in the presence of a solvent and an organic base to obtain the compound shown in formula (V). Then, an intramolecular Arbuzov rearrangement reaction occurs under the action of a halogenated catalyst to obtain the glufosinate intermediate. The compound shown in formula (III) has the following structural formula: The structural formula of the compound shown in formula (IV) is Among them, X 1 It is a halogen; the structural formula of the compound shown in formula (V) is The structural formula of the glufosinate intermediate is as follows:

2. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: The solvent is an inert solvent; or the organic base is selected from one or more of triethylamine, diethylamine, dimethylamine, diisopropylamine, N,N-dimethylcyclohexylamine, pyridine, 1,3,5-trimethylpyridine, and 4-dimethylaminopyridine; or the molar ratio of the compound shown in formula (III) to the compound shown in formula (IV) is 1:(1-2). Alternatively, the molar ratio of the compound shown in formula (III) to the organic base is 1:(2-5); or, the halogenated catalyst is one or more of C1-C12 halogenated alkanes, metal halides, and halogenated silanes; or, the molar ratio of the halogenated catalyst to the compound shown in formula (III) is (0.01-0.5):1; or X 1 It is chlorine; or, the weight ratio of the compound shown in formula (III) to the solvent is 1:(1 to 10).

3. The method for preparing the glufosinate intermediate according to claim 2, characterized in that: The solvent is selected from one or more of toluene, xylene, trimethylbenzene, chlorobenzene, dichlorobenzene, and 1,4-dioxane; or, the molar ratio of the compound shown in formula (III) to the compound shown in formula (IV) is 1:(1-1.1); or, the molar ratio of the compound shown in formula (III) to the organic base is 1:(2-2.5); or, the halogenated catalyst is one or more of iodoethane, iodopropane, bromoethane, bromopropane, trimethylchlorosilane, sodium iodide, potassium iodide, sodium bromide, potassium bromide, boron trifluoride, and aluminum trichloride; or, the molar ratio of the halogenated catalyst to the compound shown in formula (III) is (0.02-0.1):1; or, the weight ratio of the compound shown in formula (III) to the solvent is 1:(2-5).

4. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: The cyclization reaction is carried out at a temperature of -10°C to 50°C; or, the cyclization reaction takes 0.5 h to 24 h; or, the intramolecular Arbuzov rearrangement reaction takes 50°C to 120°C; or, the intramolecular Arbuzov rearrangement reaction takes 2 h to 16 h.

5. The method for preparing the glufosinate intermediate according to claim 4, characterized in that: The cyclization reaction is carried out at a temperature of -5℃ to 30℃; or, the cyclization reaction takes 1h to 6h; or, the intramolecular Arbuzov rearrangement reaction takes 60℃ to 90℃; or, the intramolecular Arbuzov rearrangement reaction takes 4h to 12h.

6. The method for preparing the glufosinate intermediate according to claim 1, characterized in that: The reaction is carried out under the protection of an inert gas, which is either nitrogen or argon.

7. The method for preparing the glufosinate intermediate according to any one of claims 1 to 6, characterized in that: The process includes the following steps: under an inert atmosphere, the compound shown in formula (III) and a portion of the solvent are added to a reaction vessel, the temperature is lowered to -10℃ to 0℃, the organic base is added to the reaction vessel, and after mixing, a mixture of the compound shown in formula (IV) and the remaining portion of the solvent is added dropwise to the reaction vessel. After the dropwise addition is complete, the temperature is slowly raised to the reaction temperature for a heat preservation reaction within 1 hour. After the reaction is completed, the halogenated catalyst is added to the reaction vessel, mixed, and then the temperature is raised to the reaction temperature to obtain the glufosinate intermediate.

8. A method for preparing glufosinate-ammonium, characterized in that: The process includes the following steps: (1) preparing glufosinate intermediate according to any one of claims 1 to 7; (2) removing the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1), adding water to the system to carry out the hydrolysis reaction of cyclophosphamide, and after the reaction is completed, adding a solid acid catalyst to carry out the hydrolysis reaction of intracyclic acid anhydride to obtain glufosinate.

9. The method for preparing glufosinate according to claim 8, characterized in that: The hydrolysis reaction of cyclophosphamide is carried out at a temperature of 0℃ to 50℃; or, the hydrolysis reaction of intracyclic anhydride is carried out at a temperature of 80℃ to 105℃; or, the hydrolysis reaction of intracyclic anhydride is carried out under negative pressure.

10. A method for preparing a salt of glufosinate, characterized in that: The salt of glufosinate includes glufosinate hydrochloride or glufosinate ammonium salt, wherein the preparation method of glufosinate hydrochloride includes the following steps: (1) preparing glufosinate intermediate according to any one of claims 1 to 7; (2) removing the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1), adding water to the system to carry out the hydrolysis reaction of cyclophosphamide, and after the reaction is completed, concentrating the system until no fraction is distilled off, cooling to room temperature, adding hydrochloric acid to carry out the reaction, and obtaining glufosinate hydrochloride; or The preparation method of the glufosinate-ammonium salt described herein includes the following steps: (1) preparing glufosinate-ammonium intermediate according to any one of claims 1 to 7; (2) removing the salt, low-boiling substances and solvent generated in the reaction system obtained in step (1), adding water to the system to carry out the hydrolysis reaction of cyclophosphamide, and after the reaction is completed, adding a solid acid catalyst or hydrochloric acid to carry out the reaction to obtain the glufosinate-ammonium or its hydrochloride salt; (3) reacting the glufosinate-ammonium or its hydrochloride salt prepared in step (2) with ammonia water to obtain the glufosinate-ammonium salt.

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