Preparation method of glufosinate-ammonium or derivative thereof

Abstract

The present disclosure relates to a process for the preparation of glufosinate-ammonium or a derivative thereof comprising reacting a compound of formula (II) or a salt thereof, an enantiomer or a mixture of all proportions of enantiomers with a compound of formula (III) wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2: 1 and not less than 1: 1. According to the method, the steps of the existing preparation process are greatly shortened, the reaction yield is excellent, the used raw materials are easy to obtain, and the process operation is suitable for industrial scale production. # imgabs0 #

Description

Technical Field

[0001] The present disclosure relates to a method for preparing glufosinate or its derivatives. Background Art

[0002] Glufosinate is a highly efficient, broad-spectrum, low-toxic, non-selective (non-selective) organophosphorus herbicide with partial systemic action developed by Hoechst 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-glufosinate is twice that of the racemic DL-glufosinate.

[0003] Existing methods for preparing glufosinate have many defects (for example, the process is complex and not suitable for large-scale production; highly toxic and / or expensive reagents are used, etc.). Summary of the Invention

[0004] The present disclosure provides a method for preparing glufosinate or its derivatives, wherein the raw materials used in the method are easily available and the process operation is suitable for industrial-scale production.

[0005] In some embodiments, the present disclosure provides a method for preparing glufosinate of formula (I) or its salt, enantiomer or a mixture of enantiomers in all proportions, characterized in that: the method comprises the following steps:

[0006]

[0007] a) Reacting a compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in all proportions with a compound of formula (III), wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1:1;

[0008]

[0009] b) Reacting in the presence of water and an acid or a base to obtain glufosinate (I) or its salt, enantiomer or a mixture of enantiomers in all proportions, regardless of whether the intermediate is isolated;

[0010] When PG is an amino protecting group, it may further include a step of removing the amino protecting group;

[0011] Wherein:

[0012] X is halogen, -OAc, -OTs, -OMs or

[0013] Hal, Hal 1 and Hal 2 each independently is halogen, such as fluorine, chlorine, bromine or iodine;

[0014] Y is -OR1, -NH2, -NHR2 or -N(R2)(R3);

[0015] PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4;

[0016] R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic group or -Si(R5)(R6)(R7);

[0017] R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group;

[0018] R5, R6 and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic group;

[0019] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group;

[0020] The chiral carbon atom is marked with *.

[0021] In some embodiments, the present disclosure provides a method for preparing a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in all ratios thereof, characterized in that: the method comprises the following steps:

[0022]

[0023] a) React a compound of formula (II) or a salt, enantiomer or mixture of enantiomers in any ratio thereof with a compound of formula (III), wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1:1;

[0024]

[0025] b-1) Whether or not the intermediate is isolated, react in the presence of R8OH (i.e., in the absence of acid and base) to obtain a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in any ratio thereof;

[0026] When PG is an amino protecting group, it may further include the step of removing the amino protecting group;

[0027] Wherein:

[0028] X is halogen, -OAc, -OTs, -OMs or

[0029] Hal, Hal 1 and Hal 2 Each independently is halogen, such as fluorine, chlorine, bromine or iodine;

[0030] Y is -OR1, -NH2, -NHR2 or -N(R2)(R3);

[0031] PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4;

[0032] R1, R2 and R3 each independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic or -Si(R5)(R6)(R7);

[0033] R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic;

[0034] R5, R6 and R7 each independently are hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic;

[0035] R8 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic group; preferably, R8 is H or C1-C6 alkyl; more preferably, R8 is H, methyl or ethyl;

[0036] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group;

[0037] The chiral carbon atom is marked with *.

[0038] In some embodiments, the compound of formula (II) in step a) above is enantiomerically pure, and the obtained glufosinate-ammonium of formula (I) or its salt or the compound of formula (I)-1 or its salt is also enantiomerically pure.

[0039] In some embodiments, the enantiomeric ratio of the glufosinate-ammonium of formula (I) or its salt or the compound of formula (I)-1 or its salt obtained by the above method is 50.5:49.5 to 99.5:0.5 of (L):(D)-enantiomers or (D):(L)-enantiomers.

[0040] In some embodiments, in the above method, the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1.4:1.

[0041] In some embodiments, in the above method, the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1.6:1.

[0042] In some embodiments, in the above method, the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1.8:1.

[0043] In some embodiments, in the above method, the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 0.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1 or 1.9:1.

[0044] In some embodiments, in the above method, the molar ratio of the compound of formula (II) to the compound of formula (III) is 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1 or 1.9:1.

[0045] In some embodiments, the compound of formula (III) or its solution is added to the compound of formula (II) or its solution; or the compound of formula (II) or its solution is added to the compound of formula (III) or its solution.

[0046] In some embodiments, the compound of formula (III) or its solution is added to the compound of formula (II) or its solution in batches or at once; or the compound of formula (II) or its solution is added to the compound of formula (III) or its solution in batches or at once.

[0047] In some embodiments, X is chlorine, bromine, iodine, -OAc, -OTs, -OMs or

[0048] In some embodiments, X is chlorine.

[0049] In some embodiments, R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 aryl or C 6-12 aralkyl.

[0050] In some embodiments, R1, R2 and R3 are each independently C1-C6 alkyl, C 6-10 aryl or C 6-12 aralkyl.

[0051] In some embodiments, 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.

[0052] In some embodiments, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

[0053] In some embodiments, Y is -OR1.

[0054] In some embodiments, R1 is ethyl or n-butyl.

[0055] In some embodiments, PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3 or

[0056] In some embodiments, PG is hydrogen.

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

[0058] In some embodiments, the compound of formula (III) is the only phosphorus-containing reaction raw material.

[0059] In some embodiments, in step a), the reaction temperature is -50 to 200 °C, preferably -20 to 140 °C or 20 to 100 °C.

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

[0061] Preferably, the molar ratio of (compound of formula (II) + the above base) to the compound of formula (III) ≥ 2.5:1, more preferably ≥ 3:1, most preferably ≥ 4:1;

[0062] The inorganic base is preferably ammonia, alkali metal oxides, alkaline earth metal oxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates or alkaline earth metal bicarbonates; for example, potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide and magnesium oxide;

[0063] The organic base is preferably an organic base without active hydrogen, and the base without 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, and the substituents are selected from halogen, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C 3-10 cycloalkyl and C 6-10 aryl.

[0064] In some embodiments, when step a) is carried out in the presence of a base with active hydrogen (such as ammonia), the base with active hydrogen is added after mixing the compound of formula (II) with all or part of the compound of formula (III).

[0065] In some embodiments, when step a) is carried out in the absence of additional base, the molar ratio of the compound of formula (II) to the compound of formula (III) is preferably ≥1:1.

[0066] In some embodiments, step a) is carried out under solvent-free conditions or in an inert solvent;

[0067] Preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or ester solvents;

[0068] More preferably, the 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.

[0069] In some embodiments, in step b), an inorganic acid or an organic acid is added.

[0070] In some embodiments, the inorganic acid is hydrochloric acid or sulfuric acid.

[0071] In some embodiments, in step b), the base is an inorganic base or an organic base; the base is preferably 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; more preferably, the base is NaOH, KOH or Ba(OH)2.

[0072] In some embodiments, in step b), the reaction temperature is 20 to 150 °C.

[0073] In some embodiments, in step b1), the reaction temperature is 0 °C to 100 °C, preferably 0 °C to 80 °C, more preferably 20 °C to 60 °C or 30 °C to 60 °C.

[0074] The method of the present invention is particularly suitable for the preparation of glufosinate, greatly shortening the steps of the existing preparation process and having excellent reaction yields. The compound of formula (III) used in the method of the present disclosure is easy to obtain and low in cost, which makes the method of the present disclosure suitable for large-scale industrial production.

[0075] In addition, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when using an enantiopure raw material (such as an enantiomeric excess percentage (%ee) greater than 90%), the enantiomeric excess percentage (%ee) of the prepared L-glufosinate is, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0076] Definition

[0077] Unless otherwise defined, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by one of ordinary skill in the art. References to techniques used herein are intended to refer to techniques commonly understood in the art, including variations of those techniques or substitutions of equivalent techniques that are obvious to one of ordinary skill in the art. 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 invention.

[0078] As used herein, the terms "comprising," "including," "having," "containing," or "involving," and other variant forms thereof herein, are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0079] The term "amino protecting group" refers to a group that can be attached to the nitrogen atom of an amino group to protect the amino group from participating in a reaction and that can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0080] The carbamate group of the formula -C(=O)OR a wherein R a such as methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, and the like; the amide group of the formula -C(=O)R b wherein R b such as methyl, ethyl, phenyl, trifluoromethyl, and the like; the N-sulfonyl derivative-group of the formula -S(=O)2-R c wherein R c such as tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like.

[0081] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups having 1 to 18 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C1-C6 alkyl) are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituents can be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester or cyano.

[0082] C1-C4 alkyl is straight-chain or branched-chain and is a saturated hydrocarbon chain containing 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.

[0083] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group that contains one or more double bonds and has 2 - 6 carbon atoms ("C 2-6 alkenyl"). Examples of the alkenyl group include vinyl, 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 present invention contain an alkenyl group, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form or any mixture thereof.

[0084] As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group that contains one or more triple bonds and preferably has 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0085] 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[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.) which are optionally substituted by 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 having 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl) which are optionally substituted by 1 or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0086] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group 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(=O), O, S, S(=O), S(=O)2 and NR d wherein R d represents a hydrogen atom or C 1-6 alkyl or halo-C 1-6 alkyl; the heterocyclic group may be attached to the remainder of the molecule through any one of the carbon atoms or a nitrogen atom (if present). In particular, a 3- to 10-membered heterocyclic group is a group having 3 to 10 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, dioxolinyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

[0087] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-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 is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.).

[0088] As used herein, the term "aralkyl" preferably means an aryl-substituted alkyl, wherein the aryl and the alkyl are as defined herein. Generally, the aryl may have 6 to 10 carbon atoms, and the alkyl may have 1 to 6 carbon atoms. Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0089] 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, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least one heteroatom (said heteroatom being, for example, oxygen, nitrogen or sulfur), which may be the same or different, and which may additionally be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.

[0090] As used herein, the term "substituted" means that one or more (e.g., one, two, three or four) hydrogens on the specified atom are replaced by a selection from the indicated groups, provided that the normal valence of the specified atom in the current case is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only when such combinations form stable compounds.

[0091] As used herein, the term "base without active hydrogen" refers to a base that does not contain groups such as NH, OH, SH and PH in the molecule.

[0092] As used herein, "mixture of enantiomers in all ratios" has the same meaning as "mixture of enantiomers in any ratio". Detailed Description

[0093] Example 1

[0094]

[0095] Add a solution of ethyl chlorohomoserinate (162 g, 0.987 mol, ee value 99%) in chlorobenzene (835 g) and triethylamine (100 g, 0.987 mol) to a 1 L four-necked flask. After addition, replace the air with nitrogen and cool the mixture to 0 °C in an ice-water bath. Add MDP (115 g, 0.987 mol) to a constant pressure dropping funnel and start dropping while controlling the temperature at 0 - 5 °C. The dropping is completed in 1.5 h.

[0096] Heat the resulting reaction solution to 90 °C in an oil bath and react for 2 h. After the reaction is completed, cool the mixture to 30 °C naturally, filter by suction, and wash the filter cake with chlorobenzene (200 g).

[0097] Water (300 g) was added to the filtrate, and the mixture was stirred at 50 °C for 1 h. Then 25% ammonia water was added to adjust the pH to 7. After neutralization, the phases were separated, and the lower organic phase was extracted twice with water (100 g). The combined aqueous phases were concentrated under reduced pressure to a viscous state, 500 g of hydrochloric acid was added, and the temperature was raised to 100 °C for hydrolysis for 8 h. Samples were taken to determine the absolute content and ee value of glufosinate-ammonium acid in the reaction solution. Calculated based on the theoretical yield of glufosinate-ammonium acid from the MDP feed amount, the yield of glufosinate-ammonium acid was 40%, and the ee value was 98%.

[0098] Example 2:

[0099]

[0100] A solution of ethyl chlorohomoserinate (162 g, 0.987 mol, ee value 99%) in chlorobenzene (835 g) and triethylamine (100 g, 0.987 mol) were added to a 1 L four-necked flask. After addition, nitrogen replacement was carried out, and the temperature was lowered to 0 °C in an ice-water bath. MDP (82.4 g, 0.705 mol) was added to the constant-pressure dropping funnel, and the dropping was started while controlling the temperature at 0 - 5 °C. The dropping was completed in 1.5 h.

[0101] The obtained reaction solution was heated to 90 °C in an oil bath and reacted for 2 h. After the reaction was completed, the temperature was naturally lowered to 30 °C, and filtration was carried out. The filter cake was washed with chlorobenzene (200 g).

[0102] Water (300 g) was added to the filtrate, and the mixture was stirred at 50 °C for 1 h. Then 25% ammonia water was added to adjust the pH to 7. After neutralization, the phases were separated, and the lower organic phase was extracted twice with water (100 g). The combined aqueous phases were concentrated under reduced pressure to a viscous state, 500 g of hydrochloric acid was added, and the temperature was raised to 100 °C for hydrolysis for 8 h. Samples were taken to determine the absolute content and ee value of glufosinate-ammonium acid in the reaction solution. Calculated based on the theoretical yield of glufosinate-ammonium acid from the MDP feed amount, the yield of glufosinate-ammonium acid was 61%, and the ee value was 98%.

[0103] Example 3:

[0104]

[0105] A solution of ethyl chlorohomoserinate (162 g, 0.987 mol, ee value 99%) in chlorobenzene (835 g) and triethylamine (100 g, 0.987 mol) were added to a 1 L four-necked flask. After addition, nitrogen replacement was carried out, and the temperature was lowered to 0 °C in an ice-water bath. MDP (64.1 g, 0.55 mol) was added to the constant-pressure dropping funnel, and the dropping was started while controlling the temperature at 0 - 5 °C. The dropping was completed in 1.5 h.

[0106] The obtained reaction solution was heated to 90 °C in an oil bath and reacted for 2 h. After the reaction was completed, the temperature was naturally lowered to 30 °C, and filtration was carried out. The filter cake was washed with chlorobenzene (200 g).

[0107] Add water (300 g) to the filtrate, stir at 50 °C for 1 h, then add 25% ammonia water to adjust the pH to 7. After neutralization, separate the phases, and add water (100 g) to the lower organic phase for secondary extraction. After combining the aqueous phases, concentrate under reduced pressure to a viscous state, add 500 g of hydrochloric acid, heat up to 100 °C and hydrolyze for 8 h. Take a sample to measure the absolute content and ee value of glufosinate-ammonium acid in the reaction solution. Calculated based on the theoretical yield of glufosinate-ammonium acid with the feeding amount of MDP, the yield of glufosinate-ammonium acid is 81% and the ee value is 98%.

Claims

1. A process for preparing glufosinate of formula (I) or its salts, enantiomers or mixtures of enantiomers in all proportions, characterized in that: The method comprises the following steps: a) Reacting a compound of formula (II) or a salt, enantiomer or mixture of enantiomers in any proportion thereof with a compound of formula (III), wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1:1; b) Reacting in the presence of water and an acid or a base to obtain glufosinate (I) or a salt, enantiomer or mixture of enantiomers in any proportion thereof, whether or not the intermediate is isolated; When PG is an amino protecting group, it may further include a step of removing the amino protecting group; Wherein: X is halogen, -OAc, -OTs, -OMs or Hal, Hal 1 and Hal 2 each independently represents a halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4; R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic group, or -Si(R5)(R6)(R7); R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14-membered heteroaryl, and 3-10-membered heterocyclic group; R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14-membered heteroaryl, or 3-10-membered heterocyclic group; The above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group; The chiral carbon atom is marked with *.

2. A process for preparing a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in all proportions thereof, characterized in that: The method comprises the following steps: a) Reacting a compound of formula (II) or a salt, enantiomer or mixture of enantiomers in any proportion thereof with a compound of formula (III), wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1:1; b-1) Reacting in the presence of R8OH to obtain a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in any proportion thereof, whether or not the intermediate is isolated; When PG is an amino protecting group, it may further include a step of removing the amino protecting group; Wherein: X is halogen, -OAc, -OTs, -OMs or Hal, Hal 1 and Hal 2 each independently represents a halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4; R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14-membered heteroaryl, 3-10-membered heterocyclic group, or -Si(R5)(R6)(R7); R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14-membered heteroaryl and 3-10-membered heterocyclic group; R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14-membered heteroaryl, or 3-10-membered heterocyclic group; R8 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic group; preferably, R8 is H or C1-C6 alkyl; more preferably, R8 is H, methyl or ethyl; The above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group; The chiral carbon atom is marked with *.

3. The method according to claim 1 or 2, wherein the compound of formula (II) in step a) is enantiomerically pure, and the obtained glufosinate (I) or its salt or the compound of formula (I)-1 or its salt is also enantiomerically pure.

4. The method according to claim 1 or 2, wherein the enantiomeric ratio of glufosinate (I) or its salt or the compound of formula (I)-1 or its salt is (L):(D)-enantiomers or (D):(L)-enantiomers of 50.5:49.5 to 99.5:0.

5.

5. The method according to any one of claims 1-4, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is less than 2:1 and not less than 1.4:1, preferably less than 2:1 and not less than 1.6:1, more preferably less than 2:1 and not less than 1.8:

1.

6. The method according to any one of claims 1-5, wherein the compound of formula (III) or its solution is added to the compound of formula (II) or its solution; Alternatively, adding the compound of formula (II) or its solution to the compound of formula (III) or its solution; Preferably, adding the compound of formula (III) or its solution batchwise or at once to the compound of formula (II) or its solution; Alternatively, adding the compound of formula (II) or its solution batchwise or at once to the compound of formula (III) or its solution.

7. The method according to any one of claims 1-6, wherein X is chlorine, bromine, iodine, -OAc, -OTs, -OMs or Preferably, X is chlorine.

8. The method according to any one of claims 1-7, wherein R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 aryl or C 6-12 aralkyl; 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.

9. The method according to any one of claims 1-8, wherein Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

10. The method according to any one of claims 1-9, wherein Y is -OR1, and R1 is preferably ethyl or n-butyl.

11. The method according to any one of claims 1-10, wherein the PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3 or Preferably, PG is hydrogen.

12. The method according to any one of claims 1-11, wherein the compound of formula (III) is methylphosphorus dichloride.

13. The method according to any one of claims 1-12, wherein the compound of formula (III) is the only phosphorus-containing reaction raw material.

14. The method according to any one of claims 1-13, wherein in step a), the reaction temperature is -50 to 200 °C, preferably -20 to 140 °C or 20 to 100 °C.

15. The method according to any one of claims 1-14, wherein step a) is carried out in the presence of a base, and the base is an inorganic base or an organic base; Preferably, the molar ratio of (compound of formula (II) + the above base) to the compound of formula (III) ≥ 2.5:1, more preferably ≥ 3:1, most preferably ≥ 4:1; 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 without active hydrogen, and the base without 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, and the substituents are selected from halogen, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C 3-10 cycloalkyl and C 6-10 aryl.

16. The method according to any one of claims 1-14, wherein when step a) is carried out in the absence of an additional base, the molar ratio of the compound of formula (II) to the compound of formula (III) is preferably ≥ 4:

1.

17. The method according to any one of claims 1-16, wherein step a) is carried out under solvent-free conditions or in an inert solvent; Preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or ester solvents; More preferably, the 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.

18. The method according to any one of claims 1-17, wherein in step b), an inorganic acid or an organic acid is added.

19. The method according to claim 18, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

20. The method according to any one of claims 1-17, wherein in step b), the base is an inorganic base or an organic base.

21. The method according to claim 20, wherein the 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.

22. The method according to claim 21, wherein the base is NaOH, KOH or Ba(OH)₂.

23. The method according to any one of claims 1-22, wherein in step b), the reaction temperature is 20 to 150 °C.

24. The method according to claim 2, wherein in step b1), the reaction temperature is 0 °C to 100 °C, preferably 0 °C to 80 °C, more preferably 20 °C to 60 °C or 30 °C to 60 °C.

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