Preparation method for glufosinate or derivative thereof

Abstract

The present disclosure relates to a preparation method for a glufosinate or a derivative thereof. In particular, the present disclosure relates to a preparation method for a glufosinate of formula (I) or a salt, an enantiomer or a mixture of all proportions of enantiomers thereof. The method comprises preparing a compound of formula (III) from a compound of formula (II) or a salt, an enantiomer or a mixture of all proportions of enantiomers thereof; and preparing a glufosinate of formula (I) or a salt, an enantiomer or a mixture of all proportions of enantiomers thereof from the compound of formula (III).

Description

Process for the preparation of glufosinate or derivatives thereof Field of the invention

[0001] The present disclosure relates to a process for the preparation of glufosinate or derivatives thereof.

[0002] BACKGROUND

[0003] Glufosinate is a highly effective, broad-spectrum, low-toxicity, non-selective (total- kill) organophosphorus herbicide with partial systemic action developed by Hoechst AG in the 1980s. It can be used to control annual and perennial dicotyledonous and gramineous weeds. Glufosinate has two enantiomers, L-type and D-type, and the herbicidal activity of L-type glufosinate is twice that of racemic DL-type glufosinate.

[0004] The existing processes for the preparation of glufosinate have many defects (for example, the process is complex and not suitable for large-scale production; high-toxicity and / or expensive reagents are used, etc.).

[0005] SUMMARY

[0006] The present disclosure provides a process for the preparation of glufosinate or derivatives thereof, which uses raw materials that are easy to obtain and process operations that are suitable for industrial-scale production.

[0007] In some embodiments, the present disclosure provides a process for the preparation of glufosinate of formula (I) or salts, enantiomers or mixtures of enantiomers in all proportions thereof, characterized in that it comprises the following steps:

[0008] a) preparing a compound of formula (III) from a compound of formula (II) or salts, enantiomers or mixtures of enantiomers in all proportions thereof:

[0009] b) and then preparing glufosinate of formula (I) or salts, enantiomers or mixtures of enantiomers in all proportions thereof, from the compound of formula (III);

[0010] wherein:

[0011] X is halogen, -OAc, -OTs, -OMs or

[0012] Hal is halogen, for example fluorine, chlorine, bromine or iodine;

[0013] Y is -OR1, -NH2, -NHR2or -N(R2)(R3);

[0014] R1, R2and R3are each independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, or -Si(R4)(R5)(R6);

[0015] R4, R5, and R6are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl;

[0016] each of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -OH, =O, -O-(C1-C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)O-(C1-C6alkyl), -NH2, -NO2, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, and 3-10 membered heterocyclyl;

[0017] the chiral carbon atom is marked with *.

[0018] In some embodiments, the present disclosure provides a method of preparing a compound of Formula (I)-1, or a salt, an enantiomer, or a mixture of enantiomers in all proportions thereof, characterized in that the method comprises the steps of:

[0019] a) preparing a compound of Formula (III) from a compound of Formula (II), or a salt, an enantiomer, or a mixture of enantiomers in all proportions thereof:

[0020] b-1) obtaining a compound of Formula (I)-1, or a salt, an enantiomer, or a mixture of enantiomers in all proportions thereof, by reaction of a compound of Formula (III) with R7OH;

[0021] wherein:

[0022] X is halogen, -OAc, -OTs, -OMs, or

[0023] Hal is halogen, for example, fluorine, chlorine, bromine, or iodine;

[0024] Y is -OR1, -NH2, -NHR2, or -N(R2)(R3);

[0025] R1, R2, and R3are each independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, or -Si(R4)(R5)(R6);

[0026] R4, R5, and R6are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl;

[0027] R7is H, C1-C6alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl; preferably R7is H or C1-C6alkyl; more preferably R7is H, methyl, or ethyl;

[0028] each of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -OH, =O, -O-(C1-C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)O-(C1-C6alkyl), -NH2, -NO2, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, and 3-10 membered heterocyclyl;

[0029] the chiral carbon atom is marked with *.

[0030] In some embodiments, the present disclosure provides a method of preparing a compound of Formula (III) comprising the step of preparing the compound of Formula (III) from a compound of Formula (II):

[0031] wherein:

[0032] X is halogen, -OAc, -OTs, -OMs, or

[0033] Hal is halogen, for example, fluorine, chlorine, bromine, or iodine;

[0034] Y is -OR1, -NH2, -NHR2, or -N(R2)(R3);

[0035] R1, R2and R3are each independently C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, or -Si(R4)(R5)(R6);

[0036] R4, R5and R6are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl;

[0037] each of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, =0, -0-(Ci-C6alkyl), -C(=0)-(Ci-C6alkyl), -C(=0)OH, -C(=0)0-(Ci-C6alkyl), -NH2, -N02, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, and 3-10 membered heterocyclyl;

[0038] the chiral carbon atom is marked with *.

[0039] In some embodiments, the step a) comprises the following step c):

[0040] to prepare a compound of formula (V),

[0041] wherein:

[0042] Hal 1 and Hal 2 each independently halogen, for example fluorine, chlorine, bromine or iodine; and

[0043] X and Y are as defined herein.

[0044] In some embodiments, the step a) comprises the following step d) of converting the compound of formula (V) into a compound of formula (III) after step c).

[0045] In some embodiments, the compound of formula (II) in step a) is enantiomerically pure and the resulting glufosinate of formula (I) or a salt thereof or the compound of formula (I)-1 or a salt thereof or the compound of formula (III) or a salt thereof is also enantiomerically pure.

[0046] In some embodiments, the enantiomeric ratio of the glufosinate of formula (I) or a salt thereof or the compound of formula (I)-1 or a salt thereof or the compound of formula (III) or a salt thereof is 50.5:49.5 to 99.5:0.5 of the (L):(D)-enantiomer or the (D):(L)-enantiomer.

[0047] In some embodiments, in the above process, the molar ratio of the compound of formula (II) to the compound of formula (IV) is about 2:1 or higher (e.g. 3:1, 4:1 or 5:1).

[0048] In some embodiments, in the above process, the molar ratio of the compound of formula (II) to the compound of formula (III) is 0.2:1 to 10:1, preferably 0.7:1 to 5:1.

[0049] In some embodiments, in the above process, the compound of formula (IV) or a solution thereof is added to the compound of formula (II) or a solution thereof; or the compound of formula (II) or a solution thereof is added to the compound of formula (IV) or a solution thereof.

[0050] In preferred embodiments, in the above process, the compound of formula (IV) or a solution thereof is added to the compound of formula (II) or a solution thereof in portions or at once; or the compound of formula (II) or a solution thereof is added to the compound of formula (IV) or a solution thereof in portions or at once.

[0051] In some embodiments, X is chloro, bromo, iodo, -OAc, -OTs, -OMs or

[0052] In preferred embodiments, X is chloro.

[0053] In some embodiments, R1, R2and R3are each independently C1-C6alkyl, C 6-10 aryl or C 6-12 aralkyl.

[0054] In preferred embodiments, R1, R2and R3are each independently methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, t-butyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl, propylphenyl or naphthyl; more preferably ethyl.

[0055] In some embodiments, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0056] In some embodiments, Y is -OR1, R1is preferably ethyl or n-butyl, more preferably ethyl.

[0057] In some embodiments, the compound of formula (IV) is methylphosphinic dichloride.

[0058] In some embodiments, in the above process, the compound of formula (IV) is the only phosphorus-containing reaction material.

[0059] In some embodiments, in step c), the temperature of the reaction is between -30 and 30 °C, preferably between 0 and 10 °C.

[0060] In some embodiments, step c) is carried out in the presence of a base, which is an inorganic base or an organic base.

[0061] In preferred embodiments, the molar ratio of (compound of formula (II) + base as described above) to compound of formula (IV) is > 2.5:1, more preferably > 3:1, most preferably > 4:1 or > 5:1.

[0062] In preferred embodiments, the inorganic base is preferably ammonia, an alkali metal oxide, an alkaline earth metal oxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate; for example, potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide, and magnesium oxide.

[0063] In preferred embodiments, the organic base is preferably an organic base that does not contain a labile hydrogen, which is preferably triethylamine, N,N-dimethylaniline, or pyridine, which optionally has 1 to 3 substituents attached to one or more carbon atoms of the tertiary amine, which are selected from the group consisting of halogen, -OH, -0-(Ci-C6alkyl), -NH2, -NO2, -CN, Ci-C6alkyl, C 3-10 Cycloalkyl and C 6-10 Aryl.

[0064] In some embodiments, when step c) is carried out in the absence of additional base, the molar ratio of the compound of formula (II) to the compound of formula (IV) is preferably > 4:1.

[0065] In some embodiments, said step d) is converting the compound of formula (V) into the compound of formula (III) at a temperature of 50-150 °C, preferably about 50 °C-100 °C, more preferably about 60 °C-80 °C.

[0066] In some embodiments, said step c) and step d) are performed in one pot.

[0067] In some embodiments, said step a) is performed under solvent-free conditions or in an inert solvent.

[0068] In preferred embodiments, said inert solvent is selected from any one or more of a benzene-based solvent, an amide-based solvent, a hydrocarbon-based solvent, a halogenated hydrocarbon-based solvent, a sulfone or sulfoxide-based solvent, an ether-based solvent, or an ester-based solvent; preferably, said inert solvent is selected from any one or more of a benzene-based solvent, an amide-based solvent, a halogenated hydrocarbon-based solvent, an ether-based solvent, or an ester-based solvent.

[0069] In preferred embodiments, said inert solvent is selected from any one or more of chlorobenzene, xylene, mesitylene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, butyl acetate.

[0070] In some embodiments, said step b) is performed by hydrolyzing the compound of formula (III) under an acid catalyst.

[0071] In preferred embodiments, said acid is a mineral acid or an organic acid.

[0072] In preferred embodiments, said mineral acid is hydrochloric acid or sulfuric acid.

[0073] In some embodiments, said step b) is performed by hydrolyzing the compound of formula (III) under a base catalyst.

[0074] In preferred embodiments, said base is a mineral base or an organic base.

[0075] In preferred embodiments, said base is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate.

[0076] In preferred embodiments, said base is NaOH, KOH, or Ba(OH)2.

[0077] In some embodiments, in said step b), the temperature of the reaction is 20-150 °C, preferably 50-120 °C.

[0078] In some embodiments, in said step b-1), the temperature of the reaction is from 0°C to 100°C, preferably from 0°C to 80°C, more preferably from 20°C to 80°C or from 30°C to 70°C.

[0079] In some embodiments, the present disclosure provides a process for the preparation of glufosinate-ammonium of formula (I) or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof, characterized in that it comprises a reaction of preparation of glufosinate-ammonium of formula (I) or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof, from a compound of formula (III):

[0080] in which X and Y are as defined herein.

[0081] In a preferred embodiment, the reaction is carried out by hydrolysis under an acid catalyst, preferably hydrochloric acid, acetic acid or a Lewis acid.

[0082] In a preferred embodiment, the reaction is carried out at a temperature of from 20 to 150°C, preferably from 50 to 120°C.

[0083] In some embodiments, the present disclosure provides a process for the preparation of a compound of formula (I)-1 or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof, characterized in that it comprises a reaction of preparation of a compound of formula (I)-1 or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof, from a compound of formula (III):

[0084] in which X and Y are as defined herein.

[0085] In a preferred embodiment, the temperature of the reaction is from 0°C to 100°C, preferably from 0°C to 80°C, more preferably from 20°C to 80°C or from 30°C to 70°C.

[0086] In some embodiments, the present disclosure provides a compound of formula (V),

[0087] in which each group is as defined herein.

[0088] In a preferred embodiment, the compound of formula (V) is:

[0089] In some embodiments, the present disclosure provides a compound of formula (III),

[0090] in which:

[0091] each group is as defined herein;

[0092] In a preferred embodiment, the compound of formula (III) is:

[0093] The process of the present disclosure is particularly suitable for the preparation of glufosinate-ammonium, substantially shortening the steps of the existing preparation process and having an excellent reaction yield. The compound of formula (III) used in the process of the present disclosure is easily available and low cost, which makes the process of the present disclosure suitable for industrial mass production.

[0094] In addition, in the preparation of L-glufosinate-ammonium, the product can effectively maintain the ee value of the starting material. For example, when using a starting material that is enantiomerically pure (e.g., having a percent enantiomeric excess (%ee) of greater than 90%), the percent enantiomeric excess (%ee) of the prepared L-glufosinate-ammonium is, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0095] Definitions

[0096] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. Reference herein to technical terms used herein is intended to refer to the technical terms as commonly understood by those skilled in the art, including variations or substitutions of the techniques that are obvious to those skilled in the art or equivalent techniques. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the present application.

[0097] As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or "characterized by" and other variations thereof are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0098] The term "amino protecting group" refers to a group of formula -NRaRb, wherein Raand Rbare each independently hydrogen or lower alkyl, which can be attached to the nitrogen atom of an amino group so as to protect the amino group from participating in reactions and which can be readily removed in subsequent reactions. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0099] a urethane group of formula -C(=O)OR a wherein R a is, for example, methyl, ethyl, t-butyl, benzyl, phenethyl, CH2=CH-CH2-, and the like; an amide group of formula -C(=O)R b wherein R b is, for example, methyl, ethyl, phenyl, trifluoromethyl, and the like; an N-sulfonyl derivative group of formula -S(=O)2-R c wherein R csuch as tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like.

[0100] The term "alkyl" refers to saturated aliphatic hydrocarbon radicals including straight-chain and branched-chain groups of 1 to 18 carbon atoms. Preferred are alkyl groups containing 1 to 6 carbon atoms (i.e., C1-C6 alkyl), such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be halogen, nitro, sulfonyl, ether oxygen, ether sulfur, ester, thioester, or cyano.

[0101] C1-C4 alkyl is a straight-chain or branched saturated hydrocarbon chain comprising 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or t-butyl group.

[0102] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group which contains one or more double bonds and has 2-6 carbon atoms ("C 2-6 alkenyl"). The alkenyl group is, for example, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the application contain an alkenyl group, the compounds can exist as pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0103] As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, which preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

[0104] As used herein, the term "cycloalkyl" refers to saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon rings (e.g., monocyclic such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic including spiro, fused, or bridged systems (such as bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 cycloalkyl" refers to saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon rings of 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which are optionally substituted with 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0105] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, monovalent monocyclic or bicyclic radical having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) heteroatom-containing groups selected from C(=0), O, S, S(=0), S(=0)2, and NR d wherein R d represents a hydrogen atom or a C 1-6 alkyl group or a halo-C 1-6 alkyl group; the heterocyclyl group can be attached to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom, if present. In particular, a 3-10 membered heterocyclyl group is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl group.

[0106] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -N02, C 1-6 alkyl, etc.).

[0107] As used herein, the term "aralkyl" preferably means an aryl-substituted alkyl group, wherein the aryl and the alkyl groups are as defined herein. Typically, the aryl group can have 6-10 carbon atoms, and the alkyl group can have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0108] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which can be the same or different (the heteroatom is for example oxygen, nitrogen or sulfur), and which, in addition, can in each case be benzo-fused. In particular, the heteroaryl group is selected from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and the benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and the benzo derivatives thereof.

[0109] As used herein, the term "substituted" means that one or more (e.g. one, two, three or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that normal valency is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0110] As used herein, the term "base free of active hydrogen" means a base that does not contain NH, OH, SH and PH groups in the molecule.

[0111] As used herein, "mixtures of enantiomers in all proportions" is synonymous with "mixtures of enantiomers in any ratio".

[0112] DETAILED DESCRIPTION

[0113] Example 1

[0114] Step 1-2: Preparation of compound 3

[0115] Into a 2 L four-necked flask was added a solution of chloro-homoserine ethyl ester (compound 1, 2.0 eq, 165 g, 1.0 mol, ee value 99%) in toluene (800 g), and triethylamine (2.0 eq, 101 g, 1.0 mol) was added, and nitrogen substitution was performed after the addition was completed. MDP (1 eq, 58.5 g, 0.5 mol) was added dropwise through a constant pressure dropping funnel at a temperature of 0-10 °C, and the reaction was incubated for 0.5 h after the dropwise addition was completed. The triethylamine hydrochloride salt was filtered out under nitrogen protection to obtain a filtrate (which contained compound 2). The filtrate (compound 2) was incubated at 60 °C for 0.5 h and at 80 °C for 0.5 h to obtain a toluene solution of compound 3.

[0116] Mass of compound 3: [M+H] 339.2, 340.1, 341.1;

[0117] Compound 3 phosphorus spectrum:31P NMR (162 MHz, CDCI3) δ 68.32 (s), 66.79 (s).

[0118] Step 3-4: Preparation of L-glufosinate

[0119] To the above toluene solution of compound 3, add water (300 g) and stir at 65-70 °C for 1 hour to hydrolyze to give compound 4. Add 152 g of 25% ammonia water to neutralize and adjust the pH to 8, and separate the upper toluene phase (for recovery of compound 1). Add 600 g of hydrochloric acid to the water phase, and heat to 100 °C for 8 hours to hydrolyze. Take a sample to determine the absolute content and ee value of glufosinate acid in the reaction solution. The yield of glufosinate acid is 89.1% based on the amount of MDP charged, and the ee value is 96%.

[0120] Example 2

[0121] Step 1-2: Preparation of compound 3

[0122] Into a 2 L four-necked flask, add a toluene solution (1122 g) containing 55.36% w / w chloroacetylhomo-serine ester (compound 1, 4.02 eq, 621.12 g, 3.76 mol, ee value 98%), and add a toluene solution (200 g) containing MDP (1 eq, 109.98 g, 0.94 mol) dropwise through a constant pressure dropping funnel at a temperature of 0-10 °C. After the dropwise addition is completed, incubate the reaction for 0.5 hours. Heat to 60 °C for 0.5 hours, and then heat to 80 °C for 0.5 hours to obtain a toluene solution of compound 3.

[0123] Mass spectrum of compound 3: [M+H] 339.2, 340.1, 341.1;

[0124] Compound 3 phosphorus spectrum:31P NMR (162 MHz, CDCI3) δ 68.32 (s), 66.79 (s).

[0125] Step 3-4: Preparation of L-glufosinate

[0126] To the above toluene solution of compound 3, add water (430 g) and stir at 65-70 °C for 0.75 hours to hydrolyze to give compound 4. Add 152 g of 25% ammonia water to neutralize and adjust the pH to 8, and separate the upper toluene phase (for recovery of compound 1). Add 600 g of hydrochloric acid to the water phase, and heat to 100 °C for 8 hours to hydrolyze. Take a sample to determine the absolute content and ee value of glufosinate acid in the reaction solution. The yield of glufosinate acid is 89.1% based on the amount of MDP charged, and the ee value is 96%.

[0127] Various modifications of the application will be apparent to those skilled in the art from the foregoing description, which is intended to be illustrative only and not limiting. Such modifications are intended to fall within the scope of the appended claims. Each of the references cited in the present application, including all patents, patent applications, journal articles, books, and any other publications, are incorporated herein by reference in their entireties.

Claims

1. A method for preparing glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in all proportions, characterized in that: The method includes the following steps: a) Compound of formula (III) is prepared from a compound of formula (II) or its salt, enantiomer, or a mixture of enantiomers in all proportions: b) Prepare glufosinate of formula (I) or its salts, enantiomers or mixtures of enantiomers in all proportions from the compound of formula (III); in: X represents halogen, -OAc, -OTs, -OMs, or... Hal is a halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); R1, R2, and R3 are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6... 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R4)(R5)(R6); R4, R5, and R6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents independently selected from: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; Chiral carbon atoms are marked with an asterisk (*).

2. A method for preparing a compound of formula (I)-1 or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions, characterized in that: The method includes the following steps: a) Compound of formula (III) is prepared from a compound of formula (II) or its salt, enantiomer, or a mixture of enantiomers in all proportions: b-1) The compound of formula (III) is reacted with R7OH to obtain the compound of formula (I)-1 or its salt, enantiomer or mixture of enantiomers in all proportions; in: X represents halogen, -OAc, -OTs, -OMs, or... Hal is a halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); R1, R2, and R3 are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6... 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R4)(R5)(R6); R4, R5, and R6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl; R7 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl group, 5-14 membered heteroaryl group or 3-10 membered heterocyclic group; preferably, R7 is H or C1-C6 alkyl group; more preferably, R7 is H, methyl or ethyl group; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents independently selected from: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; Chiral carbon atoms are marked with an asterisk (*).

3. A method for preparing compound (III), comprising step a) of preparing compound (III) from compound (II): in: X represents halogen, -OAc, -OTs, -OMs, or... Hal is a halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); R1, R2, and R3 are each independently C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C6... 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R4)(R5)(R6); R4, R5, and R6 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents independently selected from: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; Chiral carbon atoms are marked with an asterisk (*).

4. The method according to any one of claims 1-3, characterized in that: Step a) includes the following step c): Compound (V) is prepared by reacting compound (II) with compound (IV). in: Hal 1 and Hal 2 Halogens, each independent of the other, such as fluorine, chlorine, bromine, or iodine; and X and Y are as defined in claim 1.

5. The method according to claim 4, characterized in that: Step a) includes step d) which converts compound (V) into compound (III) after step c).

6. The method according to any one of claims 1-5, wherein the compound of formula (II) in step a) is enantiomeric pure, and the resulting glufosinate of formula (I) or a salt thereof, or the compound of formula (I)-1 or a salt thereof, or the compound of formula (III) or a salt thereof, is also enantiomeric pure.

7. The method according to any one of claims 1-5, wherein the enantiomeric ratio of glufosinate of formula (I) or its salt, or the compound of formula (I)-1 or its salt, or the compound of formula (III) or its salt is (L):(D)-enantiomer or (D):(L)-enantiomer from 50.5:49.5 to 99.5:0.

5.

8. The method according to any one of claims 4-7, wherein the molar ratio of the compound of formula (II) to the compound of formula (IV) is about 2:1 or higher (e.g., 3:1, 4:1 or 5:1).

9. The method according to any one of claims 4-8, wherein the compound of formula (IV) or a solution thereof is added to the compound of formula (II) or a solution thereof; Alternatively, a compound of formula (II) or a solution thereof may be added to a compound of formula (IV) or a solution thereof; Preferably, the compound of formula (IV) or its solution is added to the compound of formula (II) or its solution in batches or all at once; Alternatively, the compound of formula (II) or its solution may be added in batches or all at once to the compound of formula (IV) or its solution.

10. The method according to any one of claims 1-9, wherein X is chlorine, bromine, iodine, -OAc, -OTs, -OMs, or Preferably, X is chlorine.

11. The method according to any one of claims 1-10, wherein R1, R2 and R3 are each independently C1-C6 alkyl, C 6-10 Aryl or C 6-12 Aryl alkyl groups; Preferably, R1, R2 and R3 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl, propylphenyl or naphthyl; more preferably ethyl.

12. The method according to any one of claims 1-11, wherein Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

13. The method according to any one of claims 1-12, wherein Y is -OR1, and R1 is preferably ethyl or n-butyl, more preferably ethyl.

14. The method according to any one of claims 4-13, wherein the compound of formula (IV) is methylphosphorus dichloride.

15. The method according to any one of claims 4-14, wherein the compound of formula (IV) is the only phosphorus-containing reactant.

16. The method according to any one of claims 4-15, wherein in step c), the reaction temperature is -30 to 30°C, preferably 0 to 10°C.

17. The method according to any one of claims 4-16, wherein step c) is carried out in the presence of a base, wherein the base is an inorganic base or an organic base; Preferably, the molar ratio of (compound of formula (II) + the above base) to compound of formula (IV) is ≥2.5:1, more preferably ≥3:1, and most preferably ≥4:1 or ≥5:1; The inorganic base is preferably ammonia, alkali metal oxide, alkaline earth metal oxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate, or alkaline earth metal bicarbonate; for example, potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide, and magnesium oxide. The organic base is preferably an organic base that does not contain active hydrogen. The base that does not contain active hydrogen is preferably triethylamine, N,N-dimethylaniline, or pyridine. The triethylamine, N,N-dimethylaniline, and pyridine optionally have 1 to 3 substituents attached to one or more carbon atoms of the tertiary amine. The substituents are selected from halogens, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C... 3-10 cycloalkyl and C 6-10 Aryl.

18. The method according to any one of claims 4-17, wherein when step c) is carried out in the absence of an additional base, the molar ratio of the compound of formula (II) to the compound of formula (IV) is preferably ≥4:

1.

19. The method according to any one of claims 5-18, characterized in that: Step d) involves converting compound (V) into compound (III) at a temperature of 50–150°C (preferably about 50°C–100°C, more preferably about 60°C–80°C).

20. The method according to any one of claims 5-19, characterized in that: Steps c) and d) are performed in one batch.

21. The method according to any one of claims 1-20, wherein step a) is carried out under solvent-free conditions or in an inert solvent; Preferably, the inert solvent is selected from one or more of benzene solvents, amide solvents, hydrocarbon solvents, halohydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from one or more of benzene solvents, amide solvents, halohydrocarbon solvents, ether solvents or ester solvents. More preferably, the inert solvent is selected from one or more of chlorobenzene, xylene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

22. The method according to any one of claims 1-21, wherein step b) is carried out by hydrolyzing compound (III) under an acid catalyst.

23. The method according to claim 22, wherein the acid is an inorganic acid or an organic acid.

24. The method according to claim 23, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

25. The method according to any one of claims 1-21, wherein step b) is carried out by hydrolyzing compound (III) under an alkaline catalyst.

26. The method according to claim 25, wherein the base is an inorganic base or an organic base.

27. The method according to claim 26, wherein the alkali is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate.

28. The method according to claim 27, wherein the base is NaOH, KOH or Ba(OH)2.

29. The method according to any one of claims 1-28, wherein in step b), the reaction temperature is 20-150°C, preferably 50-120°C.

30. The method according to claim 2, wherein in step b-1), the reaction temperature is 0°C to 100°C, preferably 0°C to 80°C, more preferably 20°C to 80°C or 30°C to 70°C.

31. A method for preparing glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in all proportions, characterized in that: The method comprises a reaction that prepares glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in all proportions from a compound of formula (III): Wherein X and Y are as defined in any one of claims 1-13; Preferably, the reaction is carried out by hydrolysis under an acid catalyst, which is preferably hydrochloric acid, acetic acid, or a Lewis acid; Preferably, the reaction is carried out at a temperature of 20–150°C, more preferably 50–120°C.

32. A method for preparing a compound of formula (I)-1 or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions, characterized in that: The method comprises a reaction in which compounds of formula (III) are prepared into compounds of formula (I)-1 or their salts, enantiomers, or mixtures of enantiomers in all proportions: Wherein X and Y are as defined in any one of claims 1-13; Preferably, the reaction temperature is 0°C to 100°C, more preferably 0°C to 80°C, and even more preferably 20°C to 80°C or 30°C to 70°C. Compound of formula (V), in: Each group is as defined in any one of claims 1-13; Preferably, the compound of formula (V) is:

34. Compound of formula (III), in: Each group is as defined in any one of claims 1-13; Preferably, the compound of formula (III) is:

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