A method for preparing glufosinate

Abstract

The present application relates to a preparation method of glufosinate. Specifically, it relates to a method for preparing glufosinate represented by formula (I) or a salt, an enantiomer or a mixture of enantiomers in any ratio thereof, which comprises reacting a compound of formula (II) with a compound of formula (III), and hydrolyzing the reaction product to obtain the compound of formula (I). The method of the present application has higher substrate reactivity, milder conditions for the construction of P-C bond, lower reaction temperature, and can reduce the racemization of L-form at high temperature, thereby improving the retention of L-form during the preparation of L-glufosinate.

Description

Technical Field

[0001] This application relates to the field of pesticides and herbicides, and more specifically, to a method for preparing glufosinate. Background Technology

[0002] Glufosinate, chemically known as 4-[hydroxy(methyl)phosphono]-DL-homoalanine, was developed and produced by Hoechst AG in Germany. It is a glutamine synthesis inhibitor and a non-selective contact herbicide. Its mechanism of action involves inhibiting the activity of glutamine synthase in plants, leading to impaired glutamine synthesis, disrupted nitrogen metabolism, and accumulation of ammonium ions, thereby interfering with plant metabolism and causing plant death.

[0003] Glufosinate molecules contain a chiral carbon and have two different configurations, namely L-glufosinate and D-glufosinate. Only the L-isomer has herbicidal activity and is easily decomposed in soil. It has less toxicity to humans and animals, which can significantly reduce environmental pressure. Moreover, its activity and efficacy against resistant weeds are superior to ordinary glufosinate.

[0004] With the ban on paraquat and the growing problem of glyphosate resistance, coupled with the widespread introduction of glufosinate resistance genes into dozens of crops globally, including rice, wheat, corn, sugar beets, tobacco, soybeans, cotton, potatoes, tomatoes, rapeseed, and sugarcane, the replacement of glufosinate with the other two has accelerated. Although the vast majority of commercially available glufosinate currently on the market is still its racemic form, with technological innovation and progress, L-glufosinate's entry into the mainstream market is unstoppable.

[0005] Existing methods for preparing chiral pure L-glufosinate mainly include chemical and biological methods. Chemical methods include chemical resolution and chemical synthesis.

[0006] Chemical resolution involves using chiral resolving reagents to separate racemic D,L-glufosinate or its derivatives synthesized by external chemical methods, thereby obtaining optically pure L-glufosinate. Patent specification WO1995023805A1 discloses a method for obtaining single [L]- or [D]-homoalanine-4-yl-(methyl)phosphonic acid and its salts through racemic resolution of D,L-homoalanine-4-yl-(methyl)phosphonic acid by salting out a chiral base such as quinine or cinchonine with one of the diastereomers. This method requires expensive chiral resolving reagents, has low yields, and lacks significant advantages for industrialization.

[0007] The chemical synthesis of L-glufosinate can be further subdivided into: asymmetric synthesis and total synthesis using natural or fermented L-amino acids as raw materials. The latter, because it does not require the construction of chiral centers in the amino acid structure, offers a more direct and simpler synthetic route and better preservation of the ee value compared to other methods, and is increasingly attracting attention from relevant enterprises and research institutions both domestically and internationally.

[0008] The patent specification with publication number US5442088A discloses a method for obtaining L-glufosinate hydrochloride by using L-homoserine lactone or its derivatives as raw materials through ring-opening chlorination, esterification, condensation with methyl phosphite diester, and finally hydrolysis and purification.

[0009]

[0010] This multi-step reaction unit is easy to operate, but the chlorinated substrates used in the Arbuzov reaction have low reactivity and require higher temperatures to proceed. At the same time, the chlorinated alkane byproducts further react with methyl phosphite at high temperatures, increasing the unit consumption. Additionally, at this temperature, the L-type ee value decreases to some extent due to the racemization of some raw materials or products.

[0011] The patent specification with publication number CN113490671B discloses that: using amino-protected or unprotected haloserine esters as raw materials, condensing them with methylphosphonic acid monochloro esters to obtain an intermediate, and then hydrolyzing it to obtain L-glufosinate.

[0012]

[0013] This method uses homoserine as a raw material and synthesizes it through multiple steps such as cyclization, chlorination, esterification, and protection by protecting groups, which involves a relatively long reaction process.

[0014] In recent years, with the ban on paraquat and the problem of glyphosate resistance, the demand for glufosinate has been increasing. Therefore, developing a glufosinate synthesis method with mild reaction conditions, higher yield, lower cost and simple operation is of great significance for reducing the amount of herbicide used and increasing its efficiency. Summary of the Invention

[0015] For the sake of brevity, the term “compound of formula (N) (such as compound of formula (II))” as used below may also encompass any optical isomer, geometric isomer, tautomer or mixture of isomers of compound of formula (N), or an agriculturally acceptable salt.

[0016] The term "optical isomer" refers to the various isomers formed when a compound has one or more chiral centers, each of which can exist in either an R or S configuration. Optical isomers include all diastereomers, enantiomers, meso compounds, racemates, or mixtures thereof. For example, optical isomers can be separated by chiral chromatography or by chiral synthesis.

[0017] The term "geometric isomer" refers to the fact that when a compound contains a double bond, it can exist as cis isomers, trans isomers, E-isomers, and Z-isomers. Geometric isomers include cis isomers, trans isomers, E-isomers, Z-isomers, or mixtures thereof.

[0018] The term "tautomer" refers to an isomer that results from the rapid movement of an atom in a molecule to two different positions. Those skilled in the art will understand that tautomers can interconvert and may coexist in an equilibrium state under certain conditions.

[0019] Unless otherwise specified, references to “compound of formula (N)” (such as compound of formula (II)) also include isotopically labeled compounds obtained by replacing any atom of that compound with its isotopic atom. That is, the present invention includes all agriculturally acceptable isotopically labeled compounds of formula (N) wherein one or more atoms are replaced by atoms having the same atomic number as atoms commonly found in nature but with different atomic masses or mass numbers.

[0020] Examples of isotopes suitable for inclusion in the compounds of this 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, an isotope of fluorine, such as 18 F, an isotope of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, an isotope of oxygen, such as 15 O、 17 O and 18 O, and isotopes of sulfur, such as 35 S.

[0021] Isotope-labeled compounds of formula (N) can generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotope-labeling reagent instead of the previously used unlabeled reagent, in a manner similar to that described in the examples and preparations appended herein.

[0022] Compounds of formula (N) may exist in the form of agriculturally acceptable salts, such as acid addition salts and / or base addition salts of compounds of formula (N). Unless otherwise specified, “agriculturally acceptable salts” as used herein includes acid addition salts or base addition salts that may appear in compounds of formula (N).

[0023] Agriculturally acceptable salts of 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 include, but are not limited to: acetates, adipates, aspartates, benzoates, benzenesulfonates, bicarbonates / carbonates, hydrogen sulfates / sulfates, borates, camphor sulfonates, citrates, cyclohexylamine sulfonates, ethanedisulfonates, formates, fumarates, gluconate, glucuronates, glucuronates, hexafluorophosphates, 2-(4-hydroxybenzyl)benzoates, hydrochlorides / chlorides, hydrobromines / bromines, hydroiodides / iodides, 2-hydroxyethanesulfonates, lactates, malates, maleates, malonates, methanesulfonates, methyl sulfates, naphthalates, 2-naphthalenesulfonates, nicotinates, nitrates, orotates, oxalates, hexadecates, phosphates / hydrogen phosphates / dihydrogen phosphates, pyroglutamates, gluconate, stearates, salicylates, tannins, tartrates, toluenesulfonates, and trifluoroacetates. Suitable base addition salts are formed by bases that form non-toxic salts. Examples 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. They can also form acid and base hemisalts, 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.

[0024] Some compounds of the present invention may exist in both unsolvated and solvated forms (including hydrated forms). Generally, compounds of formula (N) are included within the scope of the present invention, whether they exist in solvated or unsolvated forms.

[0025] Some compounds of the present invention may exist in different crystal forms or amorphous forms. Regardless of the form in which they exist, compounds of formula (N) are included within the scope of the present invention.

[0026] To avoid ambiguity, the terms used in this article are defined below. Unless otherwise stated, the meanings of the terms used in this article are as follows.

[0027] When 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.

[0028] When used in this document, the term "independently" means that when there are more than one substituent, these substituents may be the same or different.

[0029] When used herein, the terms “optional” or “optionally” indicate that the event described may or may not occur. For example, “optionally substituted” means that the group may be unsubstituted or substituted.

[0030] As used herein, the term "heteroatom" refers to oxygen (O), nitrogen (N), or S (O). m (where m can be 0, 1 or 2, i.e. sulfur atom S, or sulfoxide SO, or sulfonyl S(O)2).

[0031] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight-chain and branched groups. 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 group having 1-6 carbon atoms. The term "C1-C6 alkyl" includes, in its definition, the term "C1-C6 alkyl". 1-6 "alkyl", "C1-C3 alkyl" and "C1-C4 alkyl". Examples of alkyl groups 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.

[0032] As used herein, the term "C3-C6 cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms forming a ring. For example, C3-C6 cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0033] As used herein, the term "n-membered heterocyclic alkyl" refers to a cycloalkyl group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, wherein the heteroatoms are selected from at least one of N, O, and S. For example, tri- to six-membered heterocyclic alkyl groups include, but are not limited to, oxobutane, thiobutane, azabutane, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothioran, piperidine, morpholine, and piperazine.

[0034] When used in this document, the term "C6-C" 10 "Aryl" refers to an aryl group having an aromatic ring containing 6-10 carbon atoms, preferably phenyl.

[0035] As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m carbon atoms forming an aromatic ring and (nm) heteroatoms forming an aromatic ring, wherein the heteroatoms are selected from at least one of N, O, and S. For example, five- to ten-membered heteroaryls include, but are not limited to, pyrazines, pyrazoles, pyrroles, furans, thiophenes, thiazoles, and pyridines.

[0036] As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (at most fully haloalkyl, 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 (at most fully haloalkyl, 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 one, two, or three halogen substituents. Examples of haloalkyl groups include: CF3, C2F5, CHF2, CH2F, CH2CF3, CH2Cl, etc.

[0037] In this document, the ranges related to the number of substituents, carbon atoms, and ring atoms represent a list of all integers within that range, and the range is merely a simplified representation. 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 ranges related to the number of substituents, carbon atoms, and ring atoms also encompass any of their subranges, and each subrange is also considered to be disclosed herein.

[0038] In a first aspect, this application provides a method for preparing glufosinate-ammonium of formula (I) or a salt thereof, enantiomers, or mixtures of enantiomers in any proportion, comprising the following steps:

[0039]

[0040] 1) React a compound of formula (II) or its salt, enantiomers, or mixtures of enantiomers in any proportion with a compound of formula (III).

[0041]

[0042] as well as

[0043] 2) Hydrolyze the reaction product of step 1) to obtain compound (I).

[0044] in,

[0045] X is a halogen;

[0046] Y is -OR 3 or -N(R) 4 (R) 5 );

[0047] Z is a hydrogen or amino protecting group;

[0048] R 1 and R 2Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or penta- to deca-aryl, or R 1 and R 2 Together with the N atom to which it is attached, it forms a three- to six-membered heterocyclic alkyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups are optionally surrounded by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C6-C 10 Aryl substitution;

[0049] R 3 and R 6 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or penta- to deca-aryl, or R 7 and R 8 Together with the N atom to which it is attached, it forms a three- to six-membered heterocyclic alkyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups are optionally surrounded by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C6-C 10 Aryl substitution;

[0050] R 4 and R 5 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or penta- to deca-aryl, or R 4 and R 5 Together with the N atom to which it is attached, it forms a three- to six-membered heterocyclic alkyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups are optionally surrounded by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C6-C 10 Aryl substitution; and

[0051] *Used to identify chiral carbon atoms.

[0052] As used herein, "amino protecting group" refers to a protecting group applied to the amino group before a reaction in a multifunctional organic compound to ensure that the reaction occurs only at the desired group and to prevent the amino group from being affected. The amino protecting group can be selected from various amino protecting groups known in the art, and those skilled in the art are capable of adjusting and selecting it according to actual needs. In one embodiment of the invention, the amino protecting group can be selected from one or more of the following: -C(O)R 7 -C(O)OR 8 -CH2R 9 and -SO2R 10 , where R 7 R 8 R 9 and R 10 Each is independently selected from C1-C6 alkyl, C3-C6 cycloalkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups. Preferably, the amino protecting group can be ethoxycarbonyl.

[0053] According to the present invention, the compound of formula (I) may exist as a single enantiomer. For example, in one embodiment of the present invention, the compound of formula (I) may be pure L-glufosinate or D-glufosinate. Alternatively, the compound of formula (I) may also exist as a mixture of enantiomers, wherein the enantiomers may each exist in any proportion within the enantiomer mixture. For example, in one embodiment of the present invention, the mixture of any proportion of enantiomers of the compound of formula (I) comprises 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) of the present invention may preferably be present in a larger proportion in the enantiomer mixture. For example, in one embodiment, the mixture of enantiomers of the compound of formula (I) in any proportion contains 50:50 to 99.9:0.1 (e.g., 60:40, 70:30, 80:20, 90:10, 95:5 or 99:1, etc.) of L-glufosinate and D-glufosinate.

[0054] As a preferred embodiment of the compound of formula (II) and the amino protecting group, R 1 R 2 R 3 R 4 R 5 R 6 R 7 R 8 R 9 and R 10Each can be independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or C6-C 10 Aryl, preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or phenyl. Additionally, in a preferred embodiment, when used herein, the halogen may be selected from fluorine, chlorine, or bromine; the C1-C6 alkyl may be selected from methyl, ethyl, propyl, or isopropyl; the C2-C6 alkenyl may be selected from vinyl, propenyl, 1-butenyl, 2-butenyl, or isobutenyl; the C2-C6 ynyl may be selected from ethynyl, propynyl, 1-butynyl, or 2-butynyl; the C3-C6 cycloalkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl; the three- to six-membered heterocyclic alkyl may be selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl containing at least one heteroatom of N, O, and S; C6-C 10 The aryl group may be selected from phenyl or naphthyl; and / or the five- to ten-membered heteroaryl group may be selected from pyrazinyl, pyrazolyl, pyrroleyl, furanyl, thiophenyl, thiazolyl or pyridyl.

[0055] As an alternative to compound (II), R 1 R 2 R 3 R 4 R 5 and R 6 They can also be selected independently from -Si(R) 14 (R) 15 (R) 16 ), where R 14 R 15 and R 16 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 aryl or five- to ten-membered heteroaryl, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocycloalkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups are optionally surrounded by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C6-C 10 Aryl substitution.

[0056] Furthermore, the preparation method of the first aspect of the present invention may further include the step of preparing the compound of formula (III). In one embodiment of the present invention, the compound of formula (III) may be composed of a compound comprising formula (IV) and HOR. 6Compounds of formula (V) and (VII); compounds of formula (VI), (VII) and HOR 6 It is prepared by reacting a compound of formula (VI), formula (VII), and formula (VIII) together.

[0057]

[0058] Among them, R 1 R 2 R 6 And X as defined above.

[0059] In the steps for preparing compounds of formula (III) as described above, the compounds of formulas (IV-VIII) used can be added to the reaction system as initial reactants, or they can be further obtained by in-situ reactions of other compounds. For example, compound (IV) can be obtained by in-situ reaction of compound (VI) and compound (VII); or compound (V) can be obtained by in-situ reaction of compound (VI) and compound (VIII). Furthermore, in the various steps for preparing compounds of formula (III) described above, there are no restrictions on the order in which the raw materials are added, that is, the raw materials can be added to the reaction system in any order.

[0060] According to the present invention, the steps for preparing compound (III) as described above can preferably be carried out in the presence of an acid-binding agent. Specifically, the acid-binding agent can be selected from NR. 11 R 12 R 13 , where R 11 R 12 and R 13 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or penta- to deca-aryl, or R 11 R 12 and R 13 Any two of the atoms in the group, together with the N atoms they are attached to, form a three- to six-membered heterocyclic alkyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups are optionally surrounded by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C6-C 10Aryl substitution. It is worth noting that since compound (VII) conforms to the general formula for acid-binding agents described above, and thus also meets the requirements for being an acid-binding agent, when compound (VII) has already been added to the reaction system, it is preferable to add an excess of compound (VII) as an acid-binding agent present in the reaction. In a preferred embodiment of the present invention, the acid-binding agent may be selected from at least one of an excess of compound (VII), ammonia, triethylamine, morpholine, and piperidine. Furthermore, the amounts of each reactant and the reaction conditions in this reaction 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 composition to the acid-binding agent may be 1:0.01-5, preferably 1:0.1-1.5.

[0061] Further, 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 invention, the organic solvent is selected from aromatic solvents (e.g., benzene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halobenzene, or dihalobenzene), alkane solvents (e.g., n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane), halocarbon solvents (e.g., dichloromethane, dichloroethane, chloroform, or carbon tetrachloride), and ether solvents (e.g., tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl...). The organic solvent can be selected from at least one of toluene and chlorobenzene. The solvents used include ethers, methylcyclopentyl ether, ethylene glycol dimethyl ether, dioxane or diethylene glycol dimethyl ether), ester solvents (e.g., ethyl acetate, isopropyl acetate or butyl acetate), amide solvents (e.g., N,N-dimethylformamide, N,N-dimethylacetamide, hexamethylphosphoric triamine, N-methylpyrrolidone or 1,3-dimethyl-2-imidazolinone), or sulfur-containing solvents (e.g., dimethyl sulfoxide or sulfolane). Preferably, the organic solvent is selected from at least one of toluene and chlorobenzene. In another embodiment of the invention, the reaction in step 1) can be carried out at a temperature of -10-130°C (e.g., -5°C, 0°C, 5°C, 10°C, 20°C, 40°C, 60°C, 80°C, 100°C or 120°C, etc.) for 1-25 hours (e.g., 2h, 4h, 6h, 12h, 18h or 24h, etc.).

[0062] Furthermore, for step 2), the hydrolysis can be carried out directly under neutral conditions, i.e., the hydrolysis reaction can be performed directly in the presence of water. Alternatively, the hydrolysis can 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 of alkali metals or alkaline earth metals, carbonates, bicarbonates or basic carbonates, ammonia, organic bases, and organic amines, preferably sodium hydroxide or triethylamine. In one embodiment of the invention, the hydrolysis can be carried out at a temperature of, for example, 30-140°C (e.g., 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, or 130°C, etc.), preferably 60-110°C.

[0063] In a second aspect, this application provides a composition comprising a compound of formula (IV) and HOR. 6 Compounds of formula (V) and (VII); compounds of formula (VI), (VII) and HOR 6 ; or compounds of formula (VI), formula (VII), and formula (VIII),

[0064]

[0065] Among them, R 1 R 2 R 6 And X as defined above.

[0066] In a third aspect, this application provides the use of the composition of the second aspect in a preparation of glufosinate or a salt thereof, an enantiomer, or a mixture of enantiomers in any proportion as represented by formula (I).

[0067]

[0068] Those skilled in the art will understand that the definitions and preferences described in one aspect of this application also apply to other aspects. Those skilled in the art will appreciate that embodiments of various aspects of this application can be combined in various ways without departing from the subject matter and spirit of this application, and these combinations are also included within the scope of this application.

[0069] Research has revealed that, compared to existing technologies, the present invention offers at least the following advantages:

[0070] 1. Higher substrate reactivity allows for milder PC bond construction conditions, with reaction temperatures reduced by 30–70°C compared to the former. This reduces racemization of the L-configuration at high temperatures during L-glufosinate preparation, thus improving the purity of the L-configuration in the product; and

[0071] 2. The raw materials can be prepared and used in situ, eliminating the need for the synthesis and distillation purification steps of methyl phosphite. Furthermore, the preparation of the raw materials is simple, and the parameter selection process for the reaction of phosphorus dichloride with amines offers a wide range of options and high tolerance for error. Detailed Implementation

[0072] The invention is further illustrated below with reference to specific embodiments; however, these embodiments do not limit the scope of the invention. Unless otherwise stated, all reactants used in the embodiments were obtained commercially; the instruments and equipment used in the synthesis experiments and product analysis were conventional instruments and equipment commonly used in organic synthesis.

[0073] Example 1: Synthesis of L-Glufosinate Hydrochloride (I-1)

[0074] 1) Synthesis of compound (III-1)

[0075]

[0076] Diethylamine (72.70 g, 0.994 mol, 2.0 eq.) was added to 406.7 g of toluene. Under nitrogen protection, the mixture was cooled to -5 to 5 °C, and methyl phosphorus dichloride (58.1 g, 0.497 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 to 5 °C. After the addition was complete, an anhydrous ethanol solution (62.21 g) of diethylamine (38.17 g, 0.522 mol, 1.05 eq.) was added dropwise. The reaction was maintained at this temperature for 0.5 hours to obtain compound (III-1). The mixture was filtered to remove salt, and the filtrate was used directly for the next reaction.

[0077] m / z(ESI) 164.13([M+1] + , 100%); 31 P NMR (33MHz) δ: 135.25ppm.

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

[0079]

[0080] Under nitrogen protection, compound (II-1) (112.21 g, 0.472 mol, 0.95 eq.) was added to the filtrate of compound (III-1) and the temperature was slowly raised to 85-90 °C and maintained for 12 h.

[0081] Add 435.8 g of 30% hydrochloric acid to the above-mentioned solution, allow it to stand and separate into layers, and heat the aqueous phase to 90-95°C for reflux reaction. After the reaction is complete, remove the solvent by vacuum distillation to dryness, add 435.8 g of anhydrous ethanol, heat to reflux, cool to crystallize, filter and dry to obtain a white solid, which is 84.4 g of the target product (I-1), with a yield of 80.5%, a purity of 98.0%, and an ee value of 97.0%.

[0082] m / z(ESI) 182.07([M+1] + , 100%);

[0083] 31 P NMR (243MHz, D2O) δ: 53.67;

[0084] 1 H NMR (600MHz, D2O) δ: 4.10 (t, J=6.1Hz, 1H), 2.25-2.05 (m, 2H), 1.99-1.75 (m, 2H), 1.47 (d, J=14.1Hz, 3H);

[0085] 13 C NMR (151 MHz, D2O) δ: 171.29, 52.96 (d, J = 16.6 Hz), 25.25 (d, J = 93.0 Hz), 22.72 (d, J = 2.6 Hz), 13.61 (d, J = 92.5 Hz).

[0086] Example 2: Synthesis of L-Glufosinate Hydrochloride (I-1)

[0087] 1) Synthesis of compound (III-2)

[0088]

[0089] Aniline (88.90 g, 0.955 mol, 2.0 eq.) was added to 390.6 g of toluene. Under nitrogen protection, the mixture was cooled to -5 to 5 °C, and methyl phosphorus dichloride (55.8 g, 0.477 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 to 5 °C. After the addition was complete, an anhydrous ethanol solution (69.76 g) of aniline (46.67 g, 0.501 mol, 1.05 eq.) was added dropwise. The reaction was maintained at this temperature for 0.5 hours to obtain compound (III-2). The mixture was filtered to remove salt, and the filtrate was used directly for the next reaction.

[0090] m / z(ESI) 184.10([M+1] + , 100%); 31 P NMR (33MHz) δ: 112.50ppm.

[0091] 2) Synthesis of compound (I-1)

[0092]

[0093] Under nitrogen protection, compound (II-2) (77.47 g, 0.468 mol, 0.98 eq.) was added to the filtrate of compound (III-2) and the temperature was slowly raised to 85-90 °C and maintained for 12 h.

[0094] Add 418.5 g of 30% hydrochloric acid to the above-mentioned solution, allow it to stand and separate into layers, and heat the aqueous phase to 90-95°C under reflux. After the reaction is complete, remove the solvent by vacuum distillation to dryness, add 418.5 g of anhydrous ethanol, heat to reflux, cool to crystallize, filter and dry to obtain a white solid, which is 79.1 g of the target product (I-1), with a yield of 75.5%, a purity of 97.1%, and an ee value of 96.6%.

[0095] Example 3: Synthesis of L-Glufosinate Hydrochloride (I-1)

[0096] 1) Synthesis of compound (III-3)

[0097]

[0098] N-methylaniline (103.58 g, 0.967 mol, 2.0 eq.) was added to 395.5 g of toluene. Under nitrogen protection, the mixture was cooled to -5 to 5 °C, and methyl phosphorus dichloride (56.5 g, 0.483 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 to 5 °C. After the addition was complete, an anhydrous ethanol solution (77.76 g) of N-methylaniline (54.38 g, 0.507 mol, 1.05 eq.) was added dropwise. The reaction was maintained at this temperature for 0.5 hours to obtain compound (III-3). The mixture was filtered to remove salt, and the filtrate was used directly for the next reaction.

[0099] m / z(ESI) 198.13([M+1] + , 100%); 31 P NMR (33MHz) δ: 133.28ppm.

[0100] 2) Synthesis of compound (I-1)

[0101]

[0102] Under nitrogen protection, compound (II-2) (76.04 g, 0.459 mol, 0.95 eq.) was added to the filtrate of compound (III-3) and the temperature was slowly raised to 85-90 °C and maintained for 12 h.

[0103] Add 423.8 g of 30% hydrochloric acid to the above-mentioned solution, allow it to stand and separate into layers, and heat the aqueous phase to 90-95°C for reflux reaction. After the reaction is complete, remove the solvent by vacuum distillation to dryness, add 423.8 g of anhydrous ethanol, heat to reflux, cool to crystallize, filter and dry to obtain a white solid, which is 87.1 g of the target product (I-1), with a yield of 85.5%, a purity of 98.1%, and an ee value of 97.2%.

[0104] Example 4: Synthesis of L-Glufosinate Hydrochloride (I-1)

[0105] 1) Synthesis of compound (III-3)

[0106]

[0107] N-methylaniline (104.86 g, 0.979 mol, 2.0 eq.) was added to 400.4 g of toluene. Under nitrogen protection, the mixture was cooled to -5 to 5 °C, and methyl phosphorus dichloride (57.2 g, 0.489 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at -5 to 5 °C. After the addition was complete, an anhydrous ethanol solution (78.19 g) of N-methylaniline (54.53 g, 0.509 mol, 1.04 eq.) was added dropwise. The reaction was maintained at this temperature for 0.5 hours to obtain compound (III-3). The mixture was filtered to remove salt, and the filtrate was used directly for the next reaction.

[0108] 2) Synthesis of compound (I-1)

[0109]

[0110] Under nitrogen protection, compound (1I-3) (93.93 g, 0.465 mol, 0.95 eq.) was added to the filtrate of compound (III-3) above, and the temperature was slowly raised to 85-90 °C and maintained for 12 h.

[0111] Add 429.0 g of 30% hydrochloric acid to the above-mentioned solution, allow it to stand and separate into layers, and heat the aqueous phase to 90-95°C under reflux. After the reaction is complete, remove the solvent by vacuum distillation to dryness, add 429.0 g of anhydrous ethanol, heat to reflux, cool to crystallize, filter and dry to obtain a white solid, which is 91.3 g of the target product (I-1), with a yield of 88.5%, a purity of 98.0%, and an ee value of 97.1%.

[0112] 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 solution of the present invention, and these simple modifications all fall within the protection scope of the present invention.

[0113] It should also be noted that the various specific technical features described in the above specific embodiments can be combined in any suitable manner without contradiction. In order to avoid unnecessary repetition, the present invention will not describe the various possible combinations separately.

[0114] Furthermore, various different embodiments of the present invention can be combined in any way, as long as they do not violate the spirit of the present invention, they should also be regarded as the content disclosed by the present invention.

Claims

1. A method for preparing glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in any proportion, comprising the following steps: 1) React the compound of formula (II) or its salt, enantiomers, or mixtures of enantiomers in any proportion with the compound of formula (III) in the presence of an organic solvent at a temperature of 30-130°C. as well as 2) The reaction product of step 1) is hydrolyzed in the presence of acid or base to obtain compound (I). in, X is a halogen; Y is -OR 3 ; Z is a hydrogen or amino protecting group; the amino protecting group is selected from -C(O)R 7 , where R 7 Selected from C1-C6 alkyl groups; R 1 and R 2 Each is independently selected from hydrogen, C1-C6 alkyl, or C6-C 10 Aryl; R 3 and R 6 Each is independently selected from C1-C6 alkyl groups; and *Used to identify chiral carbon atoms.

2. The method according to claim 1, wherein, The amino protecting group is selected from ethoxycarbonyl.

3. The method according to claim 1, wherein, The enantiomers of the glufosinate are L-glufosinate or D-glufosinate, and / or a mixture of any proportion of the enantiomers of the glufosinate 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 any proportion of enantiomers of glufosinate comprises L-glufosinate and D-glufosinate in a ratio of 50:50 to 99.9:0.

1.

5. The method according to claim 1, wherein, Halogens are selected from fluorine, chlorine, or bromine; C1-C6 alkyl groups are selected from methyl, ethyl, propyl, or isopropyl; C6-C 10 The aryl group is selected from phenyl or naphthyl.

6. The method according to claim 1, wherein, The R 1 R 2 Each is independently selected from hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, or phenyl; R 3 R 6 R 7 Each is independently selected from methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, or hexyl.

7. The method according to claim 1, wherein, The compound of formula (III) is prepared from a composition comprising the following compounds: compound of formula (IV) and HOR. 6 Compounds of formula (V) and compounds of formula (VII); Compounds of formula (VI), compounds of formula (VII), and HOR 6 ; Or compounds of formula (VI), formula (VII), and formula (VIII), Among them, R 1 R 2 R 6 And X as defined in claim 1; the reaction is carried out in the presence of an acid-binding agent.

8. The method according to claim 7, wherein, The acid-binding agent is selected from NR. 11 R 12 R 13 , where R 11 R 12 and R 13 Each is independently selected from hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or penta- to deca-aryl, or R 11 R 12 and R 13 Any two of the atoms in the group, together with the N atoms they are attached to, form a three- to six-membered heterocyclic alkyl group, wherein the C1-C6 alkyl, C2-C6 alkenyl, C2-C6 ynyl, C3-C6 cycloalkyl, three- to six-membered heterocyclic alkyl, C6-C 10 Aryl or five- to ten-membered heteroaryl groups are optionally surrounded by halogen, carboxyl, hydroxyl, cyano, amino, nitro, C1-C3 alkyl, C1-C3 haloalkyl, C1-C3 alkoxy, C3-C6 cycloalkyl, or C6-C 10 Aryl substitution.

9. The method according to claim 7 or 8, wherein, The molar ratio of the composition to the acid-binding agent is 1:0.01-5.

10. The method according to claim 9, wherein, The molar ratio of the composition to the acid-binding agent is 1:0.1-1.

5.

11. The method according to claim 1, wherein, In step 1), the organic solvent is selected from at least one of aromatic solvents, alkane solvents, halogenated hydrocarbon solvents, ether solvents, ester solvents, amide solvents, and sulfur-containing solvents; and / or, In step 2), 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; and / or the base is selected from hydroxides of alkali metals or alkaline earth metals, carbonates, bicarbonates or basic carbonates, ammonia, organic bases or organic amines.

12. The method according to claim 11, wherein, In step 1), the organic solvent is selected from at least one of toluene and chlorobenzene; and / or, In step 2), the acid is selected from hydrochloric acid or sulfuric acid; and / or the base is selected from sodium hydroxide or triethylamine.

13. The method according to claim 12, wherein, In step 1), the reaction is carried out for 1-25 hours; and / or, In step 2), the hydrolysis is carried out at a temperature of 30-140°C for 0.5-36 hours.

14. The method according to claim 13, wherein, In step 1), the reaction is carried out at a temperature of 30-95°C; and / or, In step 2), the hydrolysis is carried out at a temperature of 60-110°C.

15. Use of a composition in glufosinate or a salt thereof, enantiomer or mixture of enantiomers in any proportion as represented by formula (I), The composition comprises: a compound of formula (IV) and HOR 6 Compounds of formula (V) and compounds of formula (VII); Compounds of formula (VI), compounds of formula (VII), and HOR 6 ; Or compounds of formula (VI), formula (VII), and formula (VIII); Among them, R 1 R 2 R 6 X and * are as defined in claim 1.

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