A method for preparing glufosinate

Abstract

The present application relates to a method for preparing glufosinate. Specifically, it relates to a method for preparing glufosinate or its salt, enantiomer or a mixture of enantiomers in any proportion represented by formula (I), which comprises the following steps: reacting a compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in any proportion with an alcohol compound or a phenolic compound, and hydrolyzing the reaction product after separating by-products to obtain the compound of formula (I). The by-products can be separated through a simple separation process, and a recovery rate of more than 90% can be achieved. The obtained by-products can be sold externally or recycled after further purification, greatly reducing the raw material cost and reducing the discharge of three wastes. In addition, since the by-products can be separated and recovered before hydrolysis, the difficulty of separation and purification of the final product is greatly reduced, the product yield is significantly improved, and at the same time, the content is slightly increased and the ee value is maintained.

Description

Technical Field

[0001] The present application relates to the field of pesticide herbicides, and specifically, to a preparation method of glufosinate-ammonium. Background Art

[0002] Glufosinate-ammonium was developed and produced by Hoechst AG in Germany. Its chemical name is 4-[hydroxy(methyl)phosphinyl]-DL-homoalanine, and it is a glutamine synthetase inhibitor and a non-selective contact herbicide. Its mechanism of action is to inhibit the activity of glutamine synthetase in plants, resulting in blocked glutamine synthesis, disrupted nitrogen metabolism, and accumulation of ammonium ions, thereby interfering with the metabolism of plants and causing plant death.

[0003] Glufosinate-ammonium has the characteristics of a broad herbicide spectrum, low toxicity, high activity, good environmental compatibility, and low drift. It can control and quickly kill more than 100 annual and perennial broad-leaved weeds and gramineous weeds such as Digitaria sanguinalis and Lolium perenne. The speed at which it exerts its active effect is slower than paraquat but better than glyphosate, and it is a non-selective herbicide that coexists with glyphosate and paraquat.

[0004] The glufosinate-ammonium molecule contains a chiral carbon and has two different configurations, namely L-glufosinate-ammonium and D-glufosinate-ammonium. Only the L-isomer has herbicidal activity, and it is more easily decomposed in the soil, less toxic to humans and animals, and can greatly reduce environmental pressure. Therefore, its activity and the control effect against resistant weeds are also better than those of ordinary glufosinate-ammonium.

[0005] In recent years, with the ban on paraquat and the prominent problem of glyphosate resistance, and at the same time, the global glufosinate-ammonium resistance gene has been further introduced into dozens of crops such as rice, wheat, corn, sugar beet, tobacco, soybean, cotton, potato, tomato, rapeseed, and sugarcane, which has accelerated the substitution process of glufosinate-ammonium for the other two. Although most of the glufosinate-ammonium products sold on the market are still its racemate at present, with the innovation and progress of technology, the entry of L-glufosinate-ammonium into the mainstream market is irresistible.

[0006] The existing methods for preparing chiral pure L-glufosinate-ammonium mainly include chemical methods and biological methods. Among them, chemical methods include chemical resolution methods and chemical synthesis methods.

[0007] The preparation of L-glufosinate-ammonium by chemical synthesis can be further subdivided into: using asymmetric synthesis methods and total synthesis methods with natural or fermented L-amino acids as raw materials. The latter has a more convenient synthesis route and good ee value retention characteristics because its raw materials already have a high-purity amino acid chiral center, and this method has been increasingly valued by domestic and foreign enterprises and research institutions.

[0008] The patent specification with the publication number US5442088A discloses a method for obtaining L-glufosinate hydrochloride, which uses an amino-protected L-homoserine lactone as a raw material and undergoes ring-opening chlorination, esterification, Michaelis-Arbuzov reaction with dimethyl phosphite, and finally hydrolysis and purification.

[0009]

[0010] The unit operations of this multi-step reaction process are convenient, but the activity of the chlorinated substrate, which is the raw material for the Michaelis-Arbuzov reaction, is relatively low, and usually requires a relatively high temperature to proceed. At the same time, due to the side reaction between the chlorinated alkane by-product and dimethyl phosphite at high temperature, its unit consumption increases significantly. In addition, at this temperature, the reaction causes a decrease in the L-enantiomeric excess value due to the racemization of some raw materials or products.

[0011] The patent specification with the publication number CN113490671B discloses that using a halogenated homoserine ester with or without amino protection as a raw material, condensing it with monochloro methylphosphonate, and undergoing an intramolecular Michaelis-Arbuzov reaction to form a ring to obtain an intermediate, and then hydrolyzing it to obtain L-glufosinate.

[0012]

[0013] In this synthetic route, the Michaelis-Arbuzov reaction inevitably produces halogenated alkanes. Small molecule halogenated hydrocarbons are class 3 carcinogens and have a destructive effect on the ozone in the atmosphere. In addition, the in-situ preparation of monochloro methylphosphonate still requires the use of diethyl methylphosphite.

[0014] The patent with the application number CN202310033931.0 provides a synthetic route for preparing glufosinate using halogenated homoserine and its derivatives as raw materials, through condensation, cyclization, hydrolysis, and purification with methylphosphonodiamide and its analogues. Due to the different reaction mechanisms, this route can avoid the halogenated hydrocarbon by-products in the Michaelis-Arbuzov reaction. At the same time, the increase in the activity of the reaction substrate also reduces the reaction temperature, thereby increasing the content of the L-configuration in the product. However, this method will introduce by-products such as ammonium salts during the hydrolysis process, which is not conducive to product purification and yield improvement.

[0015] In recent years, with the ban on paraquat and the problem of glyphosate resistance, the demand for glufosinate has been increasing year by year. Therefore, developing a glufosinate synthesis method with mild reaction conditions, higher yield, lower cost, and simple operation is of great significance for reducing the use of herbicides and increasing efficiency. Summary of the Invention

[0016] For the sake of simplicity, the "compound of formula (N) (such as the compound of formula (II))" described hereinafter may also cover any optical isomer, geometric isomer, tautomer or isomer mixture of the compound of formula (N), or an agriculturally acceptable salt.

[0017] The term "optical isomer" means that when a compound has one or more chiral centers, each chiral center can exist in the R configuration or the S configuration, and the various isomers thus formed are optical isomers. Optical isomers include all diastereomers, enantiomers, meso forms, racemates or mixtures thereof. For example, optical isomers can be separated by a chiral chromatographic column or by chiral synthesis.

[0018] The term "geometric isomer" means that when there is a double bond in a compound, the compound can exist as a cis isomer, a trans isomer, an E isomer and a Z isomer. Geometric isomers include cis isomers, trans isomers, E isomers, Z isomers or mixtures thereof.

[0019] The term "tautomer" refers to isomers resulting from the rapid movement of an atom in a molecule between two positions. Those skilled in the art can understand that tautomers can interconvert with each other and may reach an equilibrium state and coexist in a certain state.

[0020] Unless otherwise specified, when referring to the "compound of formula (N) (such as the compound of formula (II))" herein, it also covers isotopically labeled compounds in which any atom in the compound is replaced by its isotopic atom. That is, the present invention includes all agriculturally acceptable isotopically labeled compounds of the compound of formula (N), wherein one or more atoms are replaced by atoms having the same atomic number but different atomic mass or mass number as the atoms usually found in nature.

[0021] Examples of isotopes suitable for inclusion in the compounds of the present invention include isotopes of hydrogen, such as 2 H (D) and 3 H (T), isotopes of carbon, such as 11 C, 13 C and 14 C, isotopes of chlorine, such as 37 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O, 17 O and 18 O, and isotopes of sulfur, such as 35 S.

[0022] Isotopically labeled compounds of formula (N) can generally be prepared by conventional techniques known to those skilled in the art or by using appropriate isotopically labeled reagents in place of the previously used unlabeled reagents in a manner similar to the methods described in the examples and preparations attached herein.

[0023] Compounds of formula (N) can exist in the form of agriculturally acceptable salts, for example, acid addition salts and / or base addition salts of the compounds of formula (N). Unless otherwise specified, "agriculturally acceptable salts" as used herein include acid addition salts or base addition salts that can occur within the compounds of formula (N).

[0024] Agriculturally acceptable salts of the compounds of formula (N) include their acid addition salts and base addition salts. Suitable acid addition salts are formed from acids that form non-toxic salts. Examples thereof include, but are not limited to: acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, bisulfates / sulfates, borates, camphorsulfonates, citrates, cyclohexanesulfonates, ethanedisulfonates, formates, fumarates, glucoheptonates, gluconates, glucuronates, hexafluorophosphates, 2-(4-hydroxybenzyl)benzoates, hydrochlorides / chlorides, hydrobromides / bromides, hydroiodides / iodides, 2-hydroxyethanesulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthalenecarboxylates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, palmitates, phosphates / monohydrogen phosphates / dihydrogen phosphates, pyroglutamates, glucosaccharinates, stearates, salicylates, tannates, tartrates, toluenesulfonates, and trifluoroacetates. Suitable base addition salts are formed from bases that form non-toxic salts. Examples thereof include, but are not limited to: ammonium salts, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, lithium, tromethamine, and zinc salts. Hemisalts of acids and bases can also be formed, such as hemisulfates and hemicalcium salts. Methods for preparing agriculturally acceptable salts of the compounds described herein are known to those skilled in the art.

[0025] Certain compounds of the present invention can exist in non-solvated forms as well as solvated forms (including hydrated forms). Generally, compounds of formula (N) are included within the scope of the present invention whether they exist in solvated form or in unsolvated form.

[0026] Certain compounds of the present invention can exist in different crystalline forms or amorphous forms, and compounds of formula (N) are included within the scope of the present invention regardless of the form in which they exist.

[0027] To avoid ambiguity, the terms used in this text are defined below. Unless otherwise specified, the meanings of the terms used herein are as follows.

[0028] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in a group are independently replaced by the corresponding number of substituents.

[0029] As used herein, the term "independently" means that when the number of substituents exceeds one, these substituents can be the same or different.

[0030] As used herein, the term "optionally" or "optionally" means that the event it describes can occur or not occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

[0031] As used herein, the term "heteroatom" represents oxygen (O), nitrogen (N), or S(O) m (where m can be 0, 1, or 2, i.e., sulfur atom S, or sulfoxide group SO, or sulfonyl group S(O)2).

[0032] As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight-chain and branched-chain. In some embodiments, the alkyl group has, for example, 1-6 or 1-3 carbon atoms. For example, the term "C1-C6 alkyl" refers to a straight-chain or branched-chain group having 1-6 carbon atoms. The term "C1-C6 alkyl" includes the terms "C 1-6 alkyl", "C1-C3 alkyl", and "C1-C4 alkyl" in its definition. Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, etc.

[0033] As used herein, the term "C3-C6 cycloalkyl" refers to a cycloalkyl having 3 to 6 ring-forming carbon atoms. For example, C3-C6 cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0034] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl having m ring-forming carbon atoms and (n-m) ring-forming heteroatoms, where the heteroatoms are selected from at least one of N, O, and S. For example, three- to six-membered heterocycloalkyl includes, but is not limited to, oxetane, thiolane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine.

[0035] As used herein, the term "C6-C 10 aryl" refers to an aryl group having an aromatic ring containing 6 to 10 carbon atoms, preferably a phenyl group.

[0036] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (n - m) heteroatoms forming an aromatic ring, said heteroatoms being selected from at least one of N, O, and S. For example, 5- to 10-membered heteroaryl groups include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine.

[0037] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). For example, the term "C1-C6 haloalkyl" refers to a C1-C6 alkyl group having one or more halogen substituents (up to a perhaloalkyl group, i.e., each hydrogen atom of the alkyl group is replaced by a halogen atom). As another example, the term "C1 haloalkyl" refers to a methyl group having 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include: CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, etc.

[0038] In this article, the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms represent the individual listing of all integers within that range, and the range is only used as a simplified notation. For example: "1-4 substituents" means 1, 2, 3, or 4 substituents; "3-8 carbon atoms" means 3, 4, 5, 6, 7, or 8 carbon atoms. Therefore, the number ranges related to the number of substituents, the number of carbon atoms, and the number of ring atoms also cover any of its sub-ranges, and each sub-range is also considered to be disclosed herein.

[0039] In view of the above technical problems and the deficiencies existing in the art, the present invention provides a method for preparing glufosinate or its salt, enantiomer, or a mixture of enantiomers in any proportion represented by formula (I), which comprises the following steps:

[0040]

[0041] 1) Reacting a compound of formula (II) or its salt, enantiomer, or a mixture of enantiomers in any proportion with an alcohol compound or a phenol compound,

[0042]

[0043] and

[0044] 2) Separating by-products from the reaction product of step 1), and then performing hydrolysis to obtain the compound of formula (I),

[0045] Among them,

[0046] X is a halogen;

[0047] Y is -OR 3 or -N(R 4 )(R 5 );

[0048] R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, or R 1 and R 2 together with the N atom to which they are attached form a 3- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by a halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or C6-C 10 aryl;

[0049] R 3 , R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, or R 4 and R 5 together with the N atom to which they are attached form a 3- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by a halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or C6-C 10 aryl; and

[0050] * is used to identify a chiral carbon atom.

[0051] According to the present invention, the compound of formula (I) can exist in the form of a single enantiomer. For example, in one embodiment of the present invention, the compound of formula (I) can be pure L-glufosinate or D-glufosinate. Additionally, the compound of formula (I) can also exist in the form of a mixture of enantiomers, and the enantiomers can each exist in any proportion in the enantiomer mixture. For example, in one embodiment of the present invention, a mixture of enantiomers of the compound of formula (I) in any proportion contains L-glufosinate and D-glufosinate in a ratio of 0.1:99.9 to 99.9:0.1. However, since only L-glufosinate is active, the L-enantiomer of the compound of formula (I) in the present invention can also preferably exist in a larger proportion in the enantiomer mixture. For example, in one embodiment, a mixture of enantiomers of the compound of formula (I) in any proportion contains L-glufosinate and D-glufosinate in a ratio of 50:50 to 99.9:0.1 (such as 60:40, 70:30, 80:20, 90:10, 95:5, 96:4, 97:3, 98:2, or 99:1, etc.).

[0052] As a preferred embodiment of the compound of formula (II), R 1 、R 2 、R 3 、R 4 and R 5 can each independently be selected from hydrogen, C1-C6 alkyl, or C3-C6 cycloalkyl, preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. More preferably, in the compound of formula (II), X is selected from chlorine, R 1 and R 2 are independently selected from hydrogen, methyl, ethyl, or phenyl, Y is selected from OR 4 and R 4 is selected from hydrogen, methyl, ethyl, or isopropyl. Additionally, in a preferred embodiment, when used herein, halogen can be selected from fluorine, chlorine, or bromine; C1-C6 alkyl can be selected from methyl, ethyl, propyl, or isopropyl; C2-C6 alkenyl can be selected from vinyl, propenyl, 1-butenyl, 2-butenyl, or isobutenyl; C2-C6 alkynyl can be selected from ethynyl, propynyl, 1-butynyl, or 2-butynyl; C3-C6 cycloalkyl can be selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; three- to six-membered heterocycloalkyl can be selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl containing at least one heteroatom selected from N, O, and S; C6-C 10 aryl can be selected from phenyl or naphthyl; and / or five- to ten-membered heteroaryl can be selected from pyrazinyl, pyrazolyl, pyrrolyl, furyl, thienyl, thiazolyl, or pyridyl.

[0053] As an alternative to the compound of formula (II), R1 , R 2 , R 3 , R 4 and R 5 may also each independently be selected from -Si(R 8 )(R 9 )(R 10 ), where R 8 , R 9 and R 10 are each independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heteroalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl, where the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C6 cycloalkyl, 3- to 6-membered heteroalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl is optionally substituted by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or C6-C 10 aryl.

[0054] Furthermore, the preparation method of the present invention may further include the step of preparing the compound of formula (II). More specifically, the steps of the preparation method of the compound of formula (II) can be carried out by the steps described in another patent application CN202310033931.0 of the present applicant, and the entire content of this application is incorporated herein by reference.

[0055] In addition, the alcohol compound or phenol compound used in step 1) can be common alcohol compounds or phenol compounds in the art, without particular limitation. In one embodiment of the present invention, the alcohol compound can be a monohydric alcohol or a polyhydric alcohol (such as a dihydric alcohol, a trihydric alcohol, etc.), or can be a monosaccharide, a disaccharide or a polysaccharide compound (such as glucose, sucrose or starch, etc.); preferably, the alcohol compound can be glucose or a compound represented by R 6 (OH) n , where R 6 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, and n is any integer from 1 to 3; more preferably, the alcohol compound can be methanol, ethanol, isopropanol, ethylene glycol, glycerol or glucose. In another embodiment of the present invention, the phenol compound can be a compound represented by R 7 (OH) m , where R 7 is selected from C6-C 10 aryl or 5- to 10-membered heteroaryl, and m is any integer from 1 to 3; preferably, the phenol compound is represented by R7 (OH) m The represented compound, wherein R 7 is phenyl, and m is any integer from 1 to 3; more preferably, the phenolic compound is phenol.

[0056] In the above step 1), for the amounts of each reactant and the reaction conditions in the step of reacting the compound of formula (II) with an alcohol or a phenolic compound as described above, they can be adjusted according to actual needs and the knowledge of those skilled in the art. In one embodiment of the present invention, the molar ratio of the compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in any proportion to the alcohol compound or the phenolic compound is 1:0.5 - 100, preferably 1:2 - 20 (such as 1:3, 1:4, 1:5, 1:8, 1:10, 1:12, 1:15, 1:18 or 1:20, etc.). In another embodiment of the present invention, the reaction can be carried out at a temperature of 20 - 130 °C (such as 30 °C, 40 °C, 50 °C, 60 °C, 65 °C, 70 °C, 75 °C, 80 °C, 90 °C, 100 °C, 110 °C or 120 °C, etc.), preferably at a temperature of 60 - 80 °C, and the reaction time can be 1 - 20 hours (such as 2 h, 4 h, 5 h, 6 h, 8 h, 10 h, 12 h, 18 h or 20 h, etc.).

[0057] In the above step 1), the reaction of the compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in any proportion with the alcohol compound or the phenolic compound can optionally be carried out in the presence of an acid, wherein the acid can preferably be at least one of hydrogen chloride, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid and acetic acid, and can be further preferably hydrogen chloride, hydrochloric acid or sulfuric acid. In a more preferred embodiment, the molar ratio of the compound of formula (II) to the hydrogen ion in the acid is 1:0.1 - 10 (such as 1:0.1, 1:0.2, 1:0.5, 1:0.9, 1:1, 1:1.1, 1:1.2, 1:1.5, 1:1.8, 1:2, 1:5 or 1:10, etc.), preferably 1:0.9 - 2. That is to say, according to the different stoichiometric numbers, the molar amount of the acid used can be adjusted accordingly.

[0058] The above step (1) can be carried out in the absence of a solvent or in the presence of an organic solvent. In one embodiment of the present invention, the organic solvent is selected from aromatic solvents (such as benzene, xylene, mesitylene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halogenated benzene or dihalogenated benzene), alkane solvents (such as n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane), halogenated hydrocarbon solvents (such as dichloromethane, dichloroethane, chloroform or carbon tetrachloride), ether solvents (such as tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methylcyclopentyl ether, ethylene glycol dimethyl ether, dioxane or diethylene glycol dimethyl ether), ester solvents (such as ethyl acetate, isopropyl acetate or butyl acetate), amide solvents (such as N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone or 1,3-dimethyl-2-imidazolidinone) or sulfur-containing solvents (such as dimethyl sulfoxide or sulfolane). Preferably, the organic solvent is selected from at least one of toluene and chlorobenzene.

[0059] Further, in the above step (1), after the reaction of the compound of formula (II) with an alcohol or a phenolic compound is completed, the by-products can be optionally separated, such as removing low-boiling substances or performing solid-liquid separation, wherein the by-products are HN(R 1 )(R 2 ) or its salt, which can be recycled after recovery treatment, and the filtrate can be directly used for the next reaction. Therefore, in one embodiment of the present invention, the by-product HN(R 1 )(R 2 ) or its salt is preferably recycled.

[0060] In step (2), the hydrolysis can be directly carried out under neutral conditions, that is, the hydrolysis reaction can be directly carried out in the presence of water. Additionally, the hydrolysis can also preferably be carried out in the presence of an acid or a base. More specifically, the acid can be selected from at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid and acetic acid, preferably hydrochloric acid or sulfuric acid; the base can be selected from hydroxides, carbonates, bicarbonates or basic carbonates of alkali metals or alkaline earth metals, ammonia water, organic bases, organic amines, preferably sodium hydroxide or triethylamine. Additionally, in one embodiment of the present invention, the hydrolysis can be carried out at a temperature of, for example, 30-140 °C (such as 40 °C, 50 °C, 60 °C, 70 °C, 80 °C, 90 °C, 100 °C, 110 °C, 120 °C or 130 °C, etc.), preferably 70-110 °C.

[0061] Those skilled in the art can understand that the definitions and preferred options described in one aspect of the present application are equally applicable to other aspects. Those skilled in the art can understand that the embodiments of various aspects of the present application can be combined in various ways without departing from the subject and idea of the present application, and these combinations are also included within the scope of the present application.

[0062] It has been found through research that compared with the prior art, the present invention has at least the following beneficial effects:

[0063] 1. The by-product HN(R 1 )(R 2 ) or its salt can be separated and recovered with a recovery rate of more than 90%. The obtained by-product can be sold externally or recycled after further purification, which greatly reduces the raw material cost and reduces the discharge of three wastes; and

[0064] 2. Since the by-product can be separated and recovered before hydrolysis, the difficulty of final product separation and purification is greatly reduced, the product yield is significantly improved, the content is slightly increased, and the ee value is maintained. Specific Embodiments

[0065] The present invention will be further described below in conjunction with embodiments; however, these embodiments do not limit the scope of the present invention. Unless otherwise stated, all reactants used in each embodiment are obtained through commercial channels; the instruments and equipment used in synthetic experiments and product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.

[0066] Example 1: Synthesis of L-glufosinate hydrochloride (I-1)

[0067]

[0068] 1) Synthesis of compound (II-1)

[0069] Diethylamine (67.77 g, 0.927 mol, 2.12 eq.) was added to 255.5 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and methylphosphonous dichloride (51.1 g, 0.437 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction was maintained for 0.5 hour to obtain a reaction solution of N,N-diethyl-methylphosphoramidite monochloride [CAS No.: 40467-94-5] for standby.

[0070] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (69.78 g, 0.421 mol, 0.96 eq) was added to 209.4 g of toluene, and then diethylamine (30.82 g, 0.421 mol, 0.96 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphoramidite monochloride was added under ice bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the reaction was maintained for 2 hours. The temperature was slowly raised to 80 - 85 °C and the reaction was maintained for 10 hours. Filtered under nitrogen pressure, the filter cake was washed twice with toluene, and the filtrates were combined to obtain a reaction solution of compound (II-1), which could be directly used for the next step of the reaction.

[0071] 2) Synthesis of compound (I-1)

[0072] To the reaction solution of the above compound (II-1), ethanol (97.06 g, 2.107 mol, 4.82 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances and by-products under reduced pressure, 383.3 g of 30% hydrochloric acid was added. After stirring for 0.5 hour, the mixture was allowed to stand for liquid separation, and the aqueous phase was heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 383.3 g of absolute ethanol was added, the temperature was raised to reflux until clear, and then cooled for crystallization. The product was filtered by suction and dried to obtain 83.6 g of a white solid, which was the target product (I-1) with a yield of 89.5%, a content of 98.2%, and 97.4% ee.

[0073] Example 2: Synthesis of L-glufosinate hydrochloride (I-1)

[0074]

[0075] 1) Synthesis of compound (II-1)

[0076] Diethylamine (68.01 g, 0.930 mol, 2.14 eq.) was added to 254.0 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (50.80 g, 0.435 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 0.5 hour to obtain a reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby.

[0077] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutanoate [CAS No.: 777033-03-1] (69.09 g, 0.417 mol, 0.96 eq.) was added to 207.3 g of toluene, and then diethylamine (30.51 g, 0.417 mol, 0.96 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice-bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 2 hours. Then the temperature was slowly raised to 80 - 85 °C and kept at this temperature for reaction for 10 hours. The product was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain a reaction solution of compound (II-1), which could be directly used for the next step of reaction.

[0078] 2) Synthesis of compound (I-1)

[0079] To the reaction solution of the above compound (II-1), 112.82 g of a pre-prepared ethanol solution containing hydrogen chloride (16.73 g, 0.459 mol, 1.06 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances under reduced pressure, it was cooled to room temperature, and the by-product salt was obtained by suction filtration. 381.0 g of 30% hydrochloric acid was added to the filtrate, and after stirring for 0.5 hour, it was allowed to stand for liquid separation. The aqueous phase was heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 381.0 g of anhydrous ethanol was added, the temperature was raised to reflux until clear, and then it was cooled for crystallization. After suction filtration and drying, 84.4 g of a white solid, which is the target product (I-1), was obtained, with a yield of 91.4%, a content of 98.3%, and 97.5% ee.

[0080] Example 3: Synthesis of L-glufosinate hydrochloride (I-1)

[0081]

[0082] 1) Synthesis of compound (II-1)

[0083] Diethylamine (68.63 g, 0.938 mol, 2.13 eq.) was added to 257.5 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (51.5 g, 0.441 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was completed, the reaction was kept at a constant temperature for 0.5 hour to obtain a reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby.

[0084] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (69.53 g, 0.420 mol, 0.95 eq.) was added to 208.6 g of toluene, and then diethylamine (30.70 g, 0.420 mol, 0.95 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice-bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was completed, the reaction was kept at a constant temperature for 2 hours, and then slowly heated to 80 - 85 °C and kept at a constant temperature for 10 hours. It was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain a reaction solution of compound (II-1), which can be directly used for the next step of the reaction.

[0085] 2) Synthesis of compound (I-1)

[0086] To the reaction solution of the above compound (II-1), phenol (79.02 g, 0.840 mol, 1.91 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances and by-products under reduced pressure, 386.3 g of 30% hydrochloric acid was added. After stirring for 0.5 hour, the mixture was allowed to stand for liquid separation, and the aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 386.3 g of absolute ethanol was added, the temperature was raised to reflux until clear, then cooled for crystallization, filtered by suction, and dried to obtain a white solid, which was the target product (I-1) with a yield of 85.4%, a content of 98.1%, and 97.4% ee, weighing 79.5 g.

[0087] Comparative Example 1: Synthesis of L-glufosinate hydrochloride (I-1)

[0088]

[0089] 1) Synthesis of compound (II-1)

[0090] Diethylamine (66.08 g, 0.904 mol, 2.1 eq.) was added to 251.5 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and methylphosphonous dichloride (50.30 g, 0.430 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 0.5 hour to obtain a reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby.

[0091] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (67.69 g, 0.409 mol, 0.95 eq.) was added to 203.1 g of toluene, and then diethylamine (29.89 g, 0.409 mol, 0.95 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice-bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 2 hours, and then slowly heated to 80 - 85 °C and kept at the same temperature for reaction for 10 hours. Filtered under nitrogen pressure, the filter cake was washed twice with toluene, and the filtrates were combined to obtain a solution of compound (II-1), which could be directly used for the next step of reaction.

[0092] 2) Synthesis of compound (I-1)

[0093] To the above solution of compound (II-1), 377.3 g of 30% hydrochloric acid was added, and the aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed by distillation under reduced pressure until dryness. 377.3 g of absolute ethanol was added, the temperature was raised to reflux until clear, then cooled for crystallization, filtered by suction, and dried to obtain a white solid, which was the target product (I-1) with a yield of 81.8%, a content of 97.8%, and 97.2% ee, weighing 74.4 g.

[0094] Example 4: Synthesis of L-glufosinate hydrochloride (I-1)

[0095]

[0096] 1) Synthesis of compound (II-1)

[0097] Diethylamine (137.20 g, 1.876 mol, 4.25 eq.) was added to 258.0 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (51.6 g, 0.441 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction was kept at the same temperature for 0.5 h, and then slowly heated to an internal temperature of 80 - 85 °C. A 255.3 g toluene suspension of (2S)-2-amino-4-chlorobutyric acid ethyl ester hydrochloride [CAS No.: 162955-16-0] (85.09 g, 0.421 mol, 0.95 eq) was added dropwise. After the addition was complete, the reaction was continued to be kept at the same temperature for 10 h, and then filtered under nitrogen pressure. The filter cake was washed twice with toluene, and the filtrates were combined to obtain the reaction solution of compound (II-1), which could be directly used for the next step of the reaction.

[0098] 2) Synthesis of compound (I-1)

[0099] Ethanol (96.99 g, 2.105 mol, 4.77 eq.) was added to the above reaction solution of compound (II-1), and the mixture was heated to 70 - 80 °C for reaction for 5 h. After low-boiling substances and by-products were removed under reduced pressure, 387.0 g of 30% hydrochloric acid was added, and the mixture was stirred for 0.5 h and then allowed to stand for liquid separation. The aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 387.0 g of absolute ethanol was added, the mixture was heated to reflux until clear, cooled for crystallization, filtered by suction, and dried to obtain a white solid, which was the target product (I-1) with a yield of 90.2%, a content of 98.0%, and an ee value of 97.3% (84.3 g).

[0100] Example 5: Synthesis of L-glufosinate hydrochloride (I-1)

[0101]

[0102] 1) Synthesis of compound (II-1)

[0103] Diethylamine (133.48 g, 1.825 mol, 4.2 eq.) was added to 254.0 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (50.8 g, 0.435 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction mixture was kept at this temperature for 0.5 h, and then slowly heated to an internal temperature of 80 - 85 °C. A toluene suspension (252.9 g) of (2S)-2-amino-4-chlorobutyric acid ethyl ester hydrochloride [CAS No.: 162955-16-0] (84.30 g, 0.417 mol, 0.96 eq) was added dropwise. After the addition was complete, the reaction was continued at this temperature for 10 h. The mixture was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain the reaction solution of compound (Ⅱ-1), which could be directly used for the next step of the reaction.

[0104] 2) Synthesis of compound (I-1)

[0105] To the above reaction solution of compound (Ⅱ-1), 112.82 g of an ethanol solution containing hydrogen chloride (16.73 g, 0.459 mol, 1.06 eq) was added. The mixture was heated to 70 - 80 °C and reacted for 5 h. After removing the low-boiling substances under reduced pressure, it was cooled to room temperature. The by-product salt was obtained by suction filtration. 381.0 g of 30% hydrochloric acid was added to the filtrate, and the mixture was stirred for 0.5 h and then allowed to stand for liquid separation. The aqueous phase was heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 381.0 g of absolute ethanol was added, and the mixture was heated to reflux until clear. After cooling, crystallization occurred. The product was filtered by suction and dried to obtain 86.3 g of a white solid, which was the target product (I-1) with a yield of 93.4%, a content of 98.2%, and 97.2% ee.

[0106] Comparative Example 2: Synthesis of L-glufosinate hydrochloride (I-1)

[0107]

[0108] 1) Synthesis of compound (II-1)

[0109] Diethylamine (128.51 g, 1.757 mol, 4.1 eq.) was added to 250.5 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (50.10 g, 0.429 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction mixture was kept at this temperature for 0.5 h, and then slowly heated to an internal temperature of 80 - 85 °C. A toluene suspension (246.8 g) of (2S)-2-amino-4-chlorobutyric acid ethyl ester hydrochloride [CAS No.: 162955-16-0] (82.27 g, 0.407 mol, 0.95 eq) was added dropwise. After the addition was complete, the reaction was continued at this temperature for 10 h. The mixture was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain the reaction solution of compound (Ⅱ-1), which could be directly used for the next step of the reaction.

[0110] 2) Synthesis of Compound (I-1)

[0111] To the reaction solution of the above compound (II-1), 375.8 g of 30% hydrochloric acid was added. After stirring for 0.5 h, the mixture was allowed to stand for liquid separation. The aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 375.8 g of absolute ethanol was added, and the temperature was raised to reflux until clear. After cooling, crystallization occurred. Filtration was carried out by suction and drying to obtain 77.9 g of a white solid, which was the target product (I-1) with a yield of 85.4%, a content of 97.1%, and 97.0% ee.

[0112] Example 6: Synthesis of DL-glufosinate hydrochloride (I-2)

[0113]

[0114] 1) Synthesis of Compound (II-2)

[0115] Diethylamine (73.67 g, 1.007 mol, 2.3 eq.) was added to 256.0 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (51.20 g, 0.438 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction was kept at the same temperature for 0.5 h to obtain a reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby use.

[0116] Under nitrogen protection, ethyl 2-amino-4-chlorobutyrate [CAS No.: 806595-35-7] (71.30 g, 0.430 mol, 0.98 eq.) was added to 213.9 g of toluene, and then diethylamine (31.49 g, 0.430 mol, 0.98 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the reaction was kept at the same temperature for 2 h, and then slowly heated to 80 - 85 °C and kept at this temperature for 10 h. Filtration was carried out under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain a reaction solution of compound (II-2), which could be directly used for the next step of the reaction.

[0117] 2) Synthesis of Compound (I-2)

[0118] To the reaction solution of the above compound (II-2), ethanol (99.17 g, 2.152 mol, 4.92 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances and by-products under reduced pressure, 384.0 g of 30% hydrochloric acid was added. After stirring for 0.5 hour, the mixture was allowed to stand and separate into layers. The aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 384.0 g of absolute ethanol was added, the temperature was raised to reflux until clear, then cooled for crystallization. Filtration was carried out by suction and drying to obtain 85.4 g of a white solid, which was the target product (I-2) with a yield of 89.8% and a content of 98.5%.

[0119] Example 7: Synthesis of DL-glufosinate hydrochloride (I-2)

[0120]

[0121] 1) Synthesis of compound (II-2)

[0122] Diethylamine (72.95 g, 0.997 mol, 2.3 eq.) was added to 253.5 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and methylphosphonous dichloride (50.7 g, 0.434 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction was carried out at the same temperature for 0.5 hour to obtain the reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby.

[0123] Under nitrogen protection, ethyl 2-amino-4-chlorobutyrate [CAS No.: 806595-35-7] (70.67 g, 0.427 mol, 0.98 eq.) was added to 212.0 g of toluene, and then diethylamine (31.21 g, 0.427 mol, 0.98 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice-bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the reaction was carried out at the same temperature for 2 hours, and then slowly heated to 80 - 85 °C and maintained for reaction for 10 hours. Filtration was carried out under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain the reaction solution of compound (II-2), which could be directly used for the next step of reaction.

[0124] 2) Synthesis of compound (I-2)

[0125] To the reaction solution of the above compound (II-2), 116.19 g of a pre-prepared ethanol solution containing hydrogen chloride (17.89 g, 0.491 mol, 1.13 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances under reduced pressure, it was cooled to room temperature, and the by-product salt was obtained by suction filtration. 380.3 g of 30% hydrochloric acid was added to the filtrate, stirred for 0.5 hour, and then allowed to stand for liquid separation. The aqueous phase was heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 380.3 g of absolute ethanol was added, heated to reflux until clear, cooled for crystallization, suction filtered, and dried to obtain 87.9 g of a white solid, which was the target product (I-2) with a yield of 93.3% and a content of 98.6%.

[0126] Example 8: Synthesis of DL-glufosinate hydrochloride (I-2)

[0127]

[0128] 1) Synthesis of compound (II-2)

[0129] Diethylamine (72.59 g, 0.992 mol, 2.24 eq.) was added to 259.0 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and methylphosphonous dichloride (51.80 g, 0.443 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction was carried out at a constant temperature for 0.5 hour to obtain a reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby use.

[0130] Under nitrogen protection, ethyl 2-amino-4-chlorobutyrate [CAS No.: 806595-35-7] (72.65 g, 0.439 mol, 0.99 eq.) was added to 218.0 g of toluene, and then diethylamine (32.08 g, 0.439 mol, 0.99 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice bath cooling, controlling the internal temperature of the system at 5 - 10 °C. After the addition was complete, the reaction was carried out at a constant temperature for 2 hours, and then slowly heated to 80 - 85 °C and maintained at a constant temperature for 10 hours. Filtered under nitrogen pressure, the filter cake was washed twice with toluene, and the filtrates were combined to obtain a reaction solution of compound (II-2), which could be directly used for the next step of the reaction.

[0131] 2) Synthesis of compound (I-2)

[0132] To the reaction solution of the above compound (II-2), glycerol (81.61 g, 0.886 mol, 2.0 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances and by-products under reduced pressure, 388.5 g of 30% hydrochloric acid was added. After stirring for 0.5 hour, the mixture was allowed to stand for liquid separation, and the aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 388.5 g of absolute ethanol was added, the temperature was raised to reflux until clear, and then cooled for crystallization. The product was filtered by suction and dried to obtain 82.7 g of a white solid, which was the target product (I-2) with a yield of 85.3% and a content of 98.4%.

[0133] Comparative Example 3: Synthesis of DL-glufosinate hydrochloride (I-2)

[0134]

[0135] 1) Synthesis of compound (II-2)

[0136] Diethylamine (69.37 g, 0.948 mol, 2.2 eq.) was added to 252.0 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (50.4 g, 0.431 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 0.5 hour to obtain the reaction solution of N,N-diethyl-methylphosphonamidous chloride [CAS No.: 40467-94-5] for standby use.

[0137] Under nitrogen protection, ethyl 2-amino-4-chlorobutyrate [CAS No.: 806595-35-7] (69.97 g, 0.422 mol, 0.98 eq.) was added to 209.9 g of toluene, and then diethylamine (30.90 g, 0.422 mol, 0.98 eq.) was added. After stirring evenly, the above-prepared reaction solution of N,N-diethyl-methylphosphonamidous chloride was added under ice-bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 2 hours, and then slowly heated to 80 - 85 °C and kept at this temperature for reaction for 10 hours. The product was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain the reaction solution of compound (II-2), which could be directly used for the next step of reaction.

[0138] 2) Synthesis of compound (I-2)

[0139] To the reaction solution of the above compound (II-2), 378.0 g of 30% hydrochloric acid was added. After stirring for 0.5 hour, the mixture was allowed to stand for liquid separation, and the aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 378.0 g of absolute ethanol was added, the temperature was raised to reflux until clear, and then cooled for crystallization. The product was filtered by suction and dried to obtain 76.3 g of a white solid, which was the target product (I-2) with a yield of 81.7% and a content of 98.4%.

[0140] Example 9: Synthesis of L-glufosinate hydrochloride (I-1)

[0141]

[0142] 1) Synthesis of compound (II-3)

[0143] Add N-methylaniline (96.21 g, 0.898 mol, 2.05 eq.) to 358.4 g of toluene. Under nitrogen protection, cool the temperature to -5 - 5 °C, and start to dropwise add methylphosphonous dichloride (51.20 g, 0.438 mol, 1.0 eq.) while maintaining the system temperature at -5 - 5 °C. After the addition is complete, keep the reaction at a constant temperature for 0.5 hour to obtain N-methyl-N-phenyl-methylphosphonamidous chloride [CAS No.: 91275-60-4] for standby use.

[0144] Under nitrogen protection, add ethyl (2S)-2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (71.23 g, 0.430 mol, 0.98 eq) to 356.1 g of toluene, add N-methylaniline (46.09 g, 0.430 mol, 0.98 eq.), stir evenly, and then add the above-prepared reaction solution of N-methyl-N-phenyl-methylphosphonamidous chloride under ice bath cooling, control the internal temperature of the system at 5 - 10 °C. After the addition is complete, keep the reaction at a constant temperature for 2 hours. Slowly raise the temperature to 80 - 85 °C and keep the reaction at a constant temperature for 10 hours. Filter under nitrogen pressure, wash the filter cake twice with toluene, and combine the filtrates to obtain the reaction solution of compound (Ⅱ-3), which can be directly used for the next step of the reaction.

[0145] 2) Synthesis of compound (I-1)

[0146] Add ethanol (99.06 g, 2.150 mol, 4.91 eq.) to the above reaction solution of compound (Ⅱ-3), heat to 70 - 80 °C and react for 5 hours. After decompressing to remove low-boiling substances and by-products, add 384.0 g of 30% hydrochloric acid, stir for 0.5 hour and then let it stand for liquid separation. Take the aqueous phase and heat it to 95 - 105 °C for reaction. After the reaction is completed, decompress and evaporate to dryness, add 384.0 g of absolute ethanol, heat to reflux to dissolve clearly, cool to crystallize, filter by suction and dry to obtain a white solid, which is the target product (I-1) 78.4 g, with a yield of 82.1%, a content of 98.0%, and 97.1% ee.

[0147] Example 10: Synthesis of L-glufosinate hydrochloride (I-1)

[0148]

[0149] 1) Synthesis of compound (II-3)

[0150] N-Methylaniline (99.13 g, 0.925 mol, 2.1 eq.) was added to 360.5 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methylphosphonous dichloride (51.50 g, 0.441 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction mixture was kept at the same temperature for 0.5 h to obtain N-methyl-N-phenyl-methylphosphonamidous chloride [CAS No.: 91275-60-4] for standby.

[0151] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (72.23 g, 0.436 mol, 0.99 eq) was added to 361.1 g of toluene, and then N-methylaniline (49.07 g, 0.458 mol, 1.04 eq.) was added. After stirring evenly, the above-prepared reaction solution of N-methyl-N-phenyl-methylphosphonamidous chloride was added under ice-bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the reaction mixture was kept at the same temperature for 2 h. Then, the temperature was slowly raised to 80 - 85 °C and the reaction mixture was kept at this temperature for 10 h. The reaction mixture was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain the reaction solution of compound (Ⅱ-3), which could be directly used for the next step of the reaction.

[0152] 2) Synthesis of compound (I-1)

[0153] To the reaction solution of the above compound (Ⅱ-3), 118.0 g of a pre-prepared ethanol solution containing hydrogen chloride (17.49 g, 0.480 mol, 1.09 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 h. After removing the low-boiling substances under reduced pressure, the mixture was cooled to room temperature, and the by-product salt was obtained by suction filtration. 386.3 g of 30% hydrochloric acid was added to the filtrate, and the mixture was stirred for 0.5 h and then allowed to stand for liquid separation. The aqueous phase was heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. 386.3 g of absolute ethanol was added, and the mixture was heated to reflux until clear. After cooling, crystallization occurred, and the product was obtained by suction filtration and drying. The white solid obtained was the target product (I-1), with a yield of 85.8%, a content of 98.2%, and an ee value of 97.2%, weighing 82.9 g.

[0154] Example 11: Synthesis of L-glufosinate hydrochloride (I-1)

[0155]

[0156] 1) Synthesis of compound (II-3)

[0157] N-Methylaniline (94.52 g, 0.882 mol, 2.03 eq.) was added to 355.6 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methyldichlorophosphine (50.80 g, 0.435 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the reaction mixture was kept at a constant temperature for 0.5 hour to obtain N-methyl-N-phenyl-methylphosphonamidous chloride [CAS No.: 91275-60-4] for standby.

[0158] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (69.81 g, 0.421 mol, 0.97 eq) was added to 349.0 g of toluene, and then N-methylaniline (47.42 g, 0.443 mol, 1.02 eq.) was added. After stirring evenly, the above-prepared reaction solution of N-methyl-N-phenyl-methylphosphonamidous chloride was added under ice bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the reaction mixture was kept at a constant temperature for 2 hours. Then, the temperature was slowly raised to 80 - 85 °C and kept at a constant temperature for 10 hours. After filtration under nitrogen pressure, the filter cake was washed twice with toluene, and the filtrates were combined to obtain the reaction solution of compound (Ⅱ-3), which could be directly used for the next step of the reaction.

[0159] 2) Synthesis of compound (I-1)

[0160] To the reaction solution of the above compound (Ⅱ-3), glucose (51.70 g, 0.478 mol, 1.1 eq.) was added, and the mixture was heated to 70 - 80 °C and reacted for 5 hours. After removing low-boiling substances and by-products under reduced pressure, 381.0 g of 30% hydrochloric acid was added. After stirring for 0.5 hour, the mixture was allowed to stand and separate into layers. The aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. Then, 381.0 g of absolute ethanol was added, and the mixture was heated to reflux until clear. After cooling, crystallization occurred, and the product was filtered, dried to obtain a white solid, which was the target product (I-1) with a yield of 71.9 g, a yield of 76.7%, a content of 97.8%, and 96.9% ee.

[0161] Comparative Example 4: Synthesis of L-glufosinate hydrochloride (I-1)

[0162]

[0163] 1) Synthesis of compound (II-3)

[0164] N-Methylaniline (94.14 g, 0.878 mol, 2.05 eq.) was added to 350.7 g of toluene. Under nitrogen protection, the temperature was lowered to -5 - 5 °C, and then methyldichlorophosphine (50.10 g, 0.429 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 - 5 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 0.5 h to obtain N-methyl-N-phenyl-methylphosphonamidous chloride [CAS No.: 91275-60-4] for standby use.

[0165] Under nitrogen protection, (2S)-ethyl 2-amino-4-chlorobutyrate [CAS No.: 777033-03-1] (69.55 g, 0.420 mol, 0.98 eq) was added to 347.8 g of toluene, and then N-methylaniline (45.00 g, 0.420 mol, 0.98 eq.) was added. After stirring evenly, the above-prepared reaction solution of N-methyl-N-phenyl-methylphosphonamidous chloride was added under ice bath cooling, and the internal temperature of the system was controlled at 5 - 10 °C. After the addition was complete, the mixture was kept at the same temperature for reaction for 2 h. Then the temperature was slowly raised to 80 - 85 °C and kept at this temperature for reaction for 10 h. It was filtered under nitrogen pressure, and the filter cake was washed twice with toluene. The filtrates were combined to obtain the reaction solution of compound (Ⅱ-3), which could be directly used for the next reaction.

[0166] 2) Synthesis of compound (I-1)

[0167] To the reaction solution of the above compound (Ⅱ-3), 375.8 g of 30% hydrochloric acid was added. After stirring for 0.5 h, the mixture was allowed to stand for liquid separation, and the aqueous phase was taken and heated to 95 - 105 °C for reaction. After the reaction was completed, the solvent was removed under reduced pressure until dryness. Then 375.8 g of absolute ethanol was added, and the mixture was heated to reflux until clear. After cooling, crystallization occurred. It was filtered by suction and dried to obtain a white solid, which was the target product (I-1) with a yield of 72.5%, a content of 97.5%, and an ee value of 96.8% (67.9 g).

[0168] The preferred embodiments of the present invention have been described in detail above. However, the present invention is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present invention, various simple modifications can be made to the technical solutions of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0169] In addition, it should be noted that, in the case of no contradiction, the various specific technical features described in the above specific embodiments can be combined in any appropriate way. To avoid unnecessary repetition, the present invention will not separately describe various possible combination methods.

[0170] In addition, any combination can be made between various different embodiments of the present invention as long as it does not violate the idea of the present invention, and it should also be regarded as the content disclosed by the present invention.

Claims

1. A method for preparing glufosinate or its salt, enantiomer or a mixture of enantiomers in any ratio represented by formula (I), which comprises the following steps: 1) Reacting a compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in any ratio with an alcohol compound or a phenol compound, and 2) Separating by-products from the reaction product of step 1) and then performing hydrolysis to obtain the compound of formula (I), wherein, X is a halogen; Y is -OR 3 or -N(R 4 )(R 5 )); R 1 and R 2 each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl or C6-C 10 aryl, or R 1 and R 2 together with the N atom to which it is attached form a 3- to 6-membered heterocycloalkyl, wherein the C1-C6 alkyl, C3-C6 cycloalkyl, 3- to 6-membered heterocycloalkyl or C6-C 10 aryl is optionally substituted by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or C6-C 10 aryl; R 3 , R 4 and R 5 Each is independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, three-membered to six-membered heterocycloalkyl or C6-C 10 Aryl, or R 4 and R 5 Together with the nitrogen atom to which it is attached, it forms a three-membered to six-membered heterocycloalkyl group, wherein the C1-C6 alkyl group, C3-C6 cycloalkyl group, three-membered to six-membered heterocycloalkyl group or C6-C 10 The aryl group is optionally substituted with halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl or C6-C 10 Aryl substituted; and * is used to identify chiral carbon atoms.

2. The method according to claim 1, wherein The enantiomers of glufosinate are L-glufosinate or D-glufosinate.

3. The method according to claim 1, wherein, The mixture of enantiomers of glufosinate in any ratio contains L-glufosinate and D-glufosinate in a ratio of 0.1:99.9 to 99.9:0.

1.

4. The method according to claim 3, wherein, The mixture of enantiomers of glufosinate in any ratio contains L-glufosinate and D-glufosinate in a ratio of 50:50 to 99.9:0.

1.

5. The method according to claim 1, wherein, the halogen is selected from fluorine, chlorine or bromine; C1-C6 alkyl is selected from methyl, ethyl, propyl or isopropyl; C3-C6 cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a three- to six-membered heterocycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl containing at least one heteroatom among N, O and S; and / or C6-C 10 The aryl group is selected from phenyl or naphthyl.

6. The method according to claim 1, wherein, Said R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, C1-C6 alkyl or C3-C6 cycloalkyl.

7. The method according to claim 6, wherein The said R 1 , R 2 , R 3 , R 4 and R 5 are each independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

8. The method according to claim 1, wherein the alcohol compound is a monohydric alcohol or a polyhydric alcohol, or a monosaccharide, disaccharide or polysaccharide compound.

9. The method according to claim 8, wherein The alcohol compound is glucose or a compound represented by R 6 (OH) n , where R 6 is selected from C1-C6 alkyl or C3-C6 cycloalkyl, and n is any integer from 1 to 3.

10. The method according to claim 9, wherein, The alcohol compound is methanol, ethanol, isopropanol, ethylene glycol, glycerol or glucose.

11. The method according to claim 1, wherein, The phenolic compound is a compound represented by R 7 (OH) m , where R 7 is selected from C6-C 10 aryl or a 5- to 10-membered heteroaryl, and m is any integer from 1 to 3.

12. The method according to claim 11, wherein, The phenolic compound is a compound represented by R 7 (OH) m , where R 7 is phenyl and m is any integer from 1 to 3.

13. The method according to claim 12, wherein, The phenol compound is phenol.

14. The method according to claim 1, wherein For step 1), the molar ratio of the compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in any ratio to the alcohol compound or the phenol compound is 1:0.5 - 100.

15. The method according to claim 14, wherein The molar ratio of the compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in any ratio to the alcohol compound or the phenol compound is 1:2 - 20.

16. The method according to claim 1, wherein For step 1), the reaction is carried out in the absence of a solvent or in the presence of an organic solvent.

17. The method according to claim 16, wherein, The organic solvent is selected from aromatic solvents, alkane solvents, halogenated hydrocarbon solvents, ether solvents, ester solvents, amide solvents or sulfur-containing solvents.

18. The method according to claim 17, wherein, The organic solvent is selected from at least one of toluene and chlorobenzene.

19. The method according to claim 1, wherein Step 1) is carried out in the presence of an acid.

20. The method according to claim 19, wherein, The acid is at least one of hydrogen chloride, hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid and acetic acid.

21. The method according to claim 20, wherein The acid is hydrogen chloride, hydrochloric acid or sulfuric acid.

22. The method according to claim 19, wherein The molar ratio of the compound of formula (II) to the hydrogen ion in the acid is 1:0.1 - 10.

23. The method according to claim 22, wherein, The molar ratio of the compound of formula (II) to the hydrogen ion in the acid is 1:0.9 - 2.

24. The method according to claim 1, wherein Step 1) is carried out at a temperature of 20 - 130 °C; and / or the hydrolysis in step 2) is carried out at a temperature of 30 - 140 °C.

25. The method according to claim 1, wherein, Step 1) is carried out at a temperature of 60 - 80 °C; and / or the hydrolysis in step 2) is carried out at a temperature of 70 - 110 °C.

26. The method according to claim 1, wherein, The hydrolysis is carried out in the presence of an acid or a base.

27. The method according to claim 26, wherein, The acid is selected from at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid and acetic acid.

28. The method according to claim 27, wherein, The acid is selected from hydrochloric acid or sulfuric acid.

29. The method according to claim 26, wherein, The base is selected from hydroxides, carbonates, bicarbonates or basic carbonates of alkali metals or alkaline earth metals, ammonia water, organic bases or organic amines.

30. The method according to claim 29, wherein The base is selected from sodium hydroxide or triethylamine.

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