Process for the preparation of glufosinate or its derivatives

Abstract

The present disclosure relates to a process for preparing glufosinate or a derivative thereof.

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380013473.2, filed on March 24, 2023, entitled "Preparation method of glufosinate or its derivatives". Technical Field

[0002] This disclosure relates to a method for preparing glufosinate or its derivatives. Background Technology

[0003] Glufosinate, developed by Hearst Corporation in the 1980s, is a highly effective, broad-spectrum, low-toxicity, non-selective (non-selective) organophosphorus herbicide with partial systemic activity. It can be used to control annual and perennial dicotyledonous and grassy weeds. Glufosinate exists in two enantiomers, L- and D-, with L-glufosinate exhibiting twice the herbicidal activity of racemic DL-glufosinate.

[0004] Existing methods for preparing glufosinate have many drawbacks (e.g., complex processes, unsuitable for large-scale production; use of highly toxic and / or expensive reagents, etc.). Summary of the Invention

[0005] This disclosure provides a method for preparing glufosinate or its derivatives, wherein the raw materials used in the method are readily available and the process is suitable for industrial-scale production.

[0006] In some embodiments, this disclosure provides a method for preparing glufosinate of formula (I) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions, characterized in that the method comprises the following steps:

[0007]

[0008] a) Reacting a compound of formula (II) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions with a compound of formula (III);

[0009]

[0010] b) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to give glufosinate (I) or its salt, enantiomers or mixtures of enantiomers in all proportions;

[0011] When PG is an amino protecting group, the step of removing the amino protecting group may also be included;

[0012] in:

[0013] X represents halogen, -OAc, -OTs, -OMs, or...

[0014] Hal、Hal 1and Hal 2 Each can be a halogen, such as fluorine, chlorine, bromine, or iodine;

[0015] Y is -OR1, -NH2, -NHR2 or -N(R2)(R3);

[0016] PG is a hydrogen or amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4;

[0017] 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 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R5)(R6)(R7);

[0018] R4 is selected from 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;

[0019] 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 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl;

[0020] 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;

[0021] Chiral carbon atoms are marked with an asterisk (*).

[0022] In some embodiments, this disclosure provides 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 the following steps:

[0023]

[0024] a) Reacting a compound of formula (II) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions with a compound of formula (III);

[0025]

[0026] b-1) Regardless of whether the intermediate is separated, the reaction in the presence of R8OH (i.e. in the absence of acid and base) yields a compound of formula (I)-1 or its salt, enantiomers or mixtures of enantiomers in all proportions.

[0027] When PG is an amino protecting group, the step of removing the amino protecting group may also be included;

[0028] in:

[0029] X represents halogen, -OAc, -OTs, -OMs, or...

[0030] Hal、Hal 1 and Hal 2 Each can be a halogen, such as fluorine, chlorine, bromine, or iodine;

[0031] Y is -OR1, -NH2, -NHR2 or -N(R2)(R3);

[0032] PG is a hydrogen or amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4;

[0033] 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 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R5)(R6)(R7);

[0034] R4 is selected from 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;

[0035] 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 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl;

[0036] R8 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 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;

[0037] 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;

[0038] Chiral carbon atoms are marked with an asterisk (*).

[0039] In some embodiments, the compound of formula (II) in step a) above is enantiomeric pure, and the resulting glufosinate of formula (I) or its salt or the compound of formula (I)-1 or its salt is also enantiomeric pure.

[0040] In some embodiments, the enantiomeric ratio of the glufosinate of formula (I) or its salt, or the compound of formula (I)-1 or its salt, prepared by the above method is (L):(D)-enantiomer or (D):(L)-enantiomer, from 50.5:49.5 to 99.5:0.5.

[0041] In some embodiments, the molar ratio of compound (II) to compound (III) in the above method is ≥2:1.

[0042] In some embodiments, in the above method, the molar ratio of compound (II) to compound (III) is 0.2:1 to 10:1, preferably 0.7:1 to 5:1.

[0043] In some embodiments, a compound of formula (III) or a solution thereof is added to a compound of formula (II) or a solution thereof; or a compound of formula (II) or a solution thereof is added to a compound of formula (III) or a solution thereof.

[0044] In some embodiments, the compound of formula (III) or a solution thereof is added in batches or in a single step to the compound of formula (II) or a solution thereof; or the compound of formula (II) or a solution thereof is added in batches or in a single step to the compound of formula (III) or a solution thereof.

[0045] In some implementations, X is chlorine, bromine, iodine, -OAc, -Ots, -Oms, or...

[0046] In some implementations, X is chlorine.

[0047] In some embodiments, R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 Aryl or C 6-12 Aryl group.

[0048] In some embodiments, R1, R2, and R3 are each independently C1-C6 alkyl, C 6-10 Aryl or C 6-12 Aryl group.

[0049] 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.

[0050] In some implementations, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0051] In some implementations, Y is -OR1.

[0052] In some implementations, R1 is ethyl or n-butyl.

[0053] In some embodiments, the PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3, or

[0054] In some implementations, PG is hydrogen.

[0055] In some embodiments, the compound of formula (III) is methyl phosphorus dichloride.

[0056] In some embodiments, the compound of formula (III) is the only phosphorus-containing reactant.

[0057] In some embodiments, in step a), the reaction temperature is -50 to 200°C, preferably -20 to 140°C or 20 to 100°C.

[0058] In some embodiments, step a) is carried out in the presence of a base, which is an inorganic or organic base;

[0059] Preferably, the molar ratio of (compound of formula (II) + the above base) to compound of formula (III) is ≥2.5:1, more preferably ≥3:1, and most preferably ≥4:1;

[0060] 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.

[0061] 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.

[0062] In some embodiments, when step a) is carried out in the presence of a base containing active hydrogen (e.g., ammonia), the base containing active hydrogen is added after the compound of formula (II) is mixed with all or part of the compound of formula (III).

[0063] In some embodiments, 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.

[0064] In some embodiments, step a) is carried out under solvent-free conditions or in an inert solvent;

[0065] 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.

[0066] 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.

[0067] In some implementations, an inorganic acid or an organic acid is added in step b).

[0068] In some embodiments, the inorganic acid is hydrochloric acid or sulfuric acid.

[0069] 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.

[0070] In some implementations, the reaction temperature in step b) is 20–150°C.

[0071] 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.

[0072] The method of this invention is particularly suitable for the preparation of glufosinate, significantly shortening the steps of existing preparation processes and achieving excellent reaction yields. The compounds of formula (III) used in the method of this disclosure are readily available and inexpensive, making the method suitable for large-scale industrial production.

[0073] Furthermore, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when using enantiomeric pure raw materials (e.g., enantiomeric excess percentage (%ee) greater than 90%), the enantiomeric excess percentage (%ee) of the prepared L-glufosinate can be, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0074] definition

[0075] Unless otherwise defined, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by one of ordinary skill in the art. References to technical terms herein refer to techniques commonly understood in the art, including variations or equivalent substitutions of techniques that are obvious to one of ordinary skill in the art. While it is believed that the following terms will be well understood by one of ordinary skill in the art, the following definitions are set forth to better explain the invention.

[0076] As used herein, the terms “including,” “comprising,” “having,” “containing,” or “involving,” and their other variations herein, are inclusive or open-ended and do not exclude other unlisted elements or method steps.

[0077] The term "amino protecting group" refers to a group that can be attached to a nitrogen atom of an amino group, thereby protecting the amino group from reaction and allowing it to be easily removed in subsequent reactions. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0078] Formula -C(=O)OR a The urethane group, wherein R a For example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; formula -C(=O)R b The amide group, wherein R b For example, methyl, ethyl, phenyl, trifluoromethyl, etc.; formula -S(=O)2-R c N-sulfonyl derivatives - groups, wherein R c Examples include toluene, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc.

[0079] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 18 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups) are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

[0080] C1-C4 alkyl groups are straight-chain or branched saturated hydrocarbon chains containing 1 to 4 carbon atoms. They can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl groups.

[0081] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbon group containing one or more double bonds and having 2–6 carbon atoms ("C"). 2-6The alkenyl group is, for example, 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 may exist in pure E (iso-side) form, pure Z (iso-side) form, or any mixture thereof.

[0082] As used herein, the term "alkynyl" refers to a monovalent hydrocarbon group containing one or more triple bonds, preferably having 2, 3, 4, 5 or 6 carbon atoms, such as ethynyl or propynyl.

[0083] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 10 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0084] 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) atoms selected from C(=O), O, S, S(=O), S(=O)2, and NR. d Groups containing heteroatoms, wherein R d Represents a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6Alkyl group; the heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, 3-10 membered heterocyclic groups are groups having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0085] 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" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituented by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0086] As used herein, the term "aralkyl" preferably refers to an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6-10 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0087] 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, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc., and their benzo[derivatives]; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives].

[0088] As used herein, the term "substitution" refers to the selective replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on a specified atom by a designated group, provided that the substitution does not exceed the normal valence of the specified atom in the present case and that the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form a stable compound.

[0089] As used in this article, the term "base without active hydrogen" refers to a base whose molecule does not contain groups such as NH, OH, SH, and PH.

[0090] As used in this article, “a mixture of enantiomers in all proportions” has the same meaning as “a mixture of enantiomers in any proportion”. Detailed Implementation

[0091] Example 1

[0092]

[0093] Add a chlorobenzene (835g) solution of chlorohomoserine ethyl ester (2.1eq, 162g, 0.987mol, ee value 99%) and triethylamine (2.1eq, 100g, 0.987mol) to a 1L four-necked flask. After the addition is complete, purge with nitrogen and cool to 0℃ in an ice-water bath. Add a chlorobenzene (127.4g) solution of MDP (1eq, 55g, 0.47mol) to a constant pressure dropping funnel. Start adding the solution at 0-5℃ and complete the addition in 1.5h.

[0094] The resulting reaction solution was heated to 90°C in an oil bath and reacted for 2 hours. After the reaction was completed, it was allowed to cool naturally to 30°C, filtered, and the filter cake was washed with chlorobenzene (200g).

[0095] Water (300g) was added to the filtrate, and the mixture was stirred at 50℃ for 1 hour. Then, 25% ammonia (40g) was added to adjust the pH to 7. After neutralization, the phases were separated, and the lower organic phase was extracted a second time with water (100g). The aqueous phases were combined and concentrated under reduced pressure to a viscous state. 500g of hydrochloric acid was added, and the mixture was heated to 100℃ for 8 hours to hydrolyze. Samples were taken to determine the absolute content and ee value of glufosinate in the reaction solution. Based on the theoretical yield of glufosinate (85.1g) of MDP feed, the glufosinate yield was 92.6%, and the ee value was 98%.

[0096] Example 2:

[0097]

[0098] 255g of a chlorobenzene solution of chlorohomoserine ethyl ester (concentration 30% w / w, 2.1 eq, 0.46 mol, ee: 99%) and 46.7g (2.1 eq) of triethylamine were added to a 1L four-necked flask. The mixture was cooled to 0℃ in an ice-water bath and purged with nitrogen three times. 60.5g of a chlorobenzene solution of MDP (concentration 43.17% w / w, 1 eq, 0.22 mol) was added to a constant-pressure dropping funnel. MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5℃ during the addition process, which took approximately 1.5 hours. After the addition was complete, a staged heating reaction was adopted: first, the temperature was raised to 60℃ for 1 hour, then to 80℃ for 0.5 hours, and then allowed to cool naturally to 20-30℃. The mixture was then filtered, and the filter cake was washed with 110g of chlorobenzene. The filtrate was reserved for the next reaction step.

[0099] The above filtrate was added to a 1L four-necked flask, followed by 160g of water. The mixture was heated to 50℃ and mechanically stirred for 1 hour. Then, 20g of ammonia (25% w / w, 1.33 eq, 0.29 mol) was added at 50℃ to adjust the pH to 7-8. The mixture was stirred for 5 minutes, neutralized, and then separated into phases. The product was in the aqueous phase. The lower organic phase was extracted with water (60g × 2). The aqueous phases were combined, and the aqueous phase was back-extracted with 100g of chlorobenzene to obtain ethyl chlorohomoserine from the aqueous phase. The final aqueous phase was used for the next hydrolysis step, while the organic phase was retained for the recovery of the raw material ethyl chlorohomoserine.

[0100] The final aqueous phase was subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, and then 250 g of hydrochloric acid (30% w / w, 9.3 eq, 2.1 mol) was added. The mixture was then heated to 100℃ for 8 hours for hydrolysis. Samples were taken to determine the absolute content (LC determination) and ee value of glufosinate. Based on the theoretical yield of glufosinate using the MDP feed amount, the glufosinate yield was 93.05%, and the ee value was 96.85%.

[0101] The absolute content (LC determination) and ee value of chlorohomoserine ethyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine ethyl ester (1.1 eq) was calculated to be 95%, and the ee value was 96%.

[0102] Example 3:

[0103]

[0104] 375g of a chlorobenzene solution of chlorohomoserine ethyl ester (concentration 40% w / w, 4.1 eq, 0.91 mol, ee: 96.3%) was added to a 1L four-necked flask and cooled to 0℃ in an ice-water bath, followed by nitrogen purging three times. 60.5g of a chlorobenzene solution of MDP (concentration 43.17% w / w, 1 eq, 0.22 mol) was added to a constant-pressure dropping funnel. MDP was added dropwise under nitrogen protection, with the temperature controlled between 0-5℃ during the addition process, which took approximately 1.5 hours. After the addition was complete, a staged heating reaction was adopted: first, the temperature was raised to 60℃ for 1 hour, then to 80℃ for 0.5 hours, and finally allowed to cool naturally.

[0105] The internal temperature was lowered to 60℃, 160g of water was added, and the temperature was adjusted to 50℃. Mechanical stirring was performed for 1 hour. At 50℃, 50g of ammonia (25% w / w, 3.3 eq, 0.74 mol) was added, and the pH was adjusted to 7-8. Stirring was continued for 5 minutes, and the mixture was neutralized and then separated into phases. The product was in the aqueous phase. The lower organic phase was extracted with water (60g × 2). The aqueous phases were combined, and the aqueous phase was back-extracted with 100g of chlorobenzene to obtain ethyl chlorohomoserine. The final aqueous phase was used for the next hydrolysis step, while the retained organic phase was used for the recovery of the raw material ethyl chlorohomoserine.

[0106] The final aqueous phase was subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, and then 250 g of hydrochloric acid (30% w / w, 9.3 eq, 2.1 mol) was added. The mixture was then heated to 100℃ for 8 hours for hydrolysis. Samples were taken to determine the absolute content (LC determination) and ee value of glufosinate. Based on the theoretical yield of glufosinate using the MDP feed amount, the glufosinate yield was 92.8%, and the ee value was 93.8%.

[0107] The absolute content (LC determination) and ee value of chlorohomoserine ethyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine ethyl ester (3.1 eq) was calculated to be 98%, and the ee value was 94%.

[0108] Example 4:

[0109]

[0110] 375g of a chlorobenzene solution of chlorohomoserine ethyl ester (concentration 40% w / w, 2.75 eq, 0.91 mol, ee: 96.3%) was added to a 1L four-necked flask and cooled to 0℃ in an ice-water bath, followed by nitrogen purging three times. 53g of a chlorobenzene solution of MDP (concentration 49% w / w, 2 / 3 eq, 0.22 mol) was added to a constant-pressure dropping funnel, and MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5℃ during the addition process, which took approximately 1.5 hours. After the addition was complete, the mixture was stirred for 30 minutes, and ammonia gas was passed through at a rate of 200 mL / min for 45 minutes until gas overflowed. The ammonia flow was then stopped, with a total ammonia volume of 7.5g (1.33 eq, 0.44 mol). The temperature was then raised to 15-20℃, and the mixture was subjected to a vacuum of -0.095 MPa for 30 minutes to remove ammonia, followed by nitrogen purging. Cool down to 0-10℃, then add 13.2g of chlorobenzene solution of MDP (concentration 49% w / w, 1 / 3 eq, 0.11mol) dropwise. After the addition is complete, adopt a staged heating reaction, first heating to 60℃ for 1h, then heating to 80℃ for 0.5h, and then cooling down naturally.

[0111] The internal temperature was lowered to 60℃, 200g of water was added, and the internal temperature was adjusted to 50℃. The reaction was mechanically stirred for 1 hour. At 50℃, 50g of ammonia water (concentration 25% w / w, 2.3 eq, 0.75 mol) was added, the pH was adjusted to 7-8, and the mixture was stirred for 5 minutes. After neutralization, the phases were separated. The product was in the aqueous phase. The lower organic phase was extracted with water (60g × 2). The aqueous phases were combined, and the aqueous phase was back-extracted with 100g of chlorobenzene to obtain ethyl chlorohomoserine from the aqueous phase. The final aqueous phase was used for the next step of hydrolysis, and the organic phase was retained for the recovery of the raw material ethyl chlorohomoserine.

[0112] The final aqueous phase was subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, and then 373 g of hydrochloric acid (30% w / w, 9.3 eq, 3.07 mol) was added. The mixture was then heated to 100℃ for 8 hours for hydrolysis. Samples were taken to determine the absolute content (LC determination) and ee value of glufosinate. Based on the theoretical yield of glufosinate using the MDP feed amount, the glufosinate yield was 90.77%, and the ee value was 92.3%.

[0113] The absolute content (LC determination) and ee value of chlorohomoserine ethyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine ethyl ester (1.75 eq) was calculated to be 95.2%, and the ee value was 93.5%.

[0114] Example 5:

[0115]

[0116] 163.4 g of xylene solution of chlorohomoserine butyl ester (concentration 41.5% w / w, 2.1 eq, 0.35 mol, ee: 99%) and 35.4 g (2.1 eq) of triethylamine were added to a 1 L four-necked flask. The mixture was cooled to 0 °C in an ice-water bath and purged with nitrogen three times. 38.7 g of xylene solution of MDP (concentration 50% w / w, 1 eq, 0.165 mol) was added to a constant-pressure dropping funnel. MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5 °C during the addition process, which took approximately 1.5 h. After the addition was complete, a staged heating reaction was adopted: first, the temperature was raised to 60 °C and reacted for 1 h, then raised to 80 °C and reacted for 0.5 h, and then naturally cooled to 20-30 °C. The mixture was filtered, and the filter cake was washed with 150 g of xylene. The filtrate was reserved for the next reaction step.

[0117] Add the above filtrate to a 1L four-necked flask, add 180g of water, heat to 50℃, and mechanically stir for 1h. At 50℃, add 20g of ammonia (concentration 25% w / w, 1.78eq, 0.29mol), adjust the pH to 7-8, stir for 5min, neutralize, and separate the phases. The product is in the aqueous phase. Extract the upper organic phase with water (60g×2), combine the aqueous phases, and back-extract the chlorohomoserine butyl ester from the aqueous phase with 100g of xylene. The final aqueous phase is used for the next step of hydrolysis, and the organic phase is retained for the recovery of the raw material chlorohomoserine butyl ester.

[0118] The final aqueous phase was subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, and then 255 g of hydrochloric acid (concentration 30% w / w, 12.7 eq, 2.1 mol) was added. The mixture was then heated to 100℃ for 8 hours for hydrolysis. Samples were taken to determine the absolute content (LC determination) and ee value of glufosinate. Based on the theoretical yield of glufosinate using the MDP feed amount, the glufosinate yield was 87.5%, and the ee value was 97.10%.

[0119] The absolute content (LC determination) and ee value of chlorohomoserine butyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine butyl ester (1.1 eq) was calculated to be 95%, and the ee value was 98.25%.

[0120] Example 6:

[0121]

[0122] 470.5 g of xylene solution containing chlorohomoserine butyl ester (concentration 38.54% w / w, 4.1 eq, 0.935 mol, ee: 99.6%) was added to a 1 L four-necked flask. The mixture was cooled to 0-5 °C in an ice-water bath and purged with nitrogen three times. 53.35 g of xylene solution containing MDP (concentration 50% w / w, 1 eq, 0.228 mol) was added to a constant-pressure dropping funnel. MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5 °C during the addition process, which took approximately 1.5 h. After the addition was complete, the temperature was raised to 80 °C and the reaction proceeded for 2 h, followed by natural cooling.

[0123] The internal temperature was lowered to 70℃, 160g of water was added, the temperature was adjusted to 70℃, and mechanical stirring was carried out for 1 hour. At 25-30℃, 50g of ammonia water (concentration 25% w / w, 3.2 eq, 0.74 mol) was added to adjust the pH to 7-8, and the mixture was stirred for 5 minutes. After neutralization, the phases were separated, and the product was in the aqueous phase. The upper organic phase was extracted with water (60g × 2). The aqueous phases were combined, and the aqueous phase was back-extracted with 100g of xylene to obtain chlorohomoserine butyl ester. The final aqueous phase was used for the next step of hydrolysis, and the organic phase was retained for the recovery of the raw material chlorohomoserine butyl ester.

[0124] The final aqueous phase was subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, and then 250 g of hydrochloric acid (30% w / w, 9.2 eq, 2.1 mol) was added. The mixture was then heated to 100℃ for 8 hours for hydrolysis. Samples were taken to determine the absolute content (LC determination) and ee value of glufosinate. Based on the theoretical yield of glufosinate using the MDP feed amount, the glufosinate yield was 88%, and the ee value was 97.29%.

[0125] The absolute content (LC determination) and ee value of chlorohomoserine butyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine butyl ester (3.1 eq) was calculated to be 95.73% and the ee value was 95.68%.

[0126] Example 7:

[0127]

[0128] 370.9 g of xylene solution of chlorohomoserine butyl ester (concentration 38.54% w / w, 2.75 eq, 0.69 mol, ee: 99.6%) was added to a 1 L four-necked flask and cooled to 0 °C in an ice-water bath, followed by nitrogen purging three times. 39.2 g of xylene solution of MDP (concentration 50% w / w, 2 / 3 eq) was added to a constant-pressure dropping funnel, and MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5 °C during the addition process, which took approximately 1.5 h. After the addition was complete, the mixture was stirred for 10-30 min, and ammonia gas was passed through at a rate of 200 mL / min for 30 min until gas overflowed. The ammonia flow was then stopped, with a total ammonia volume of 5.7 g (1.33 eq, 0.33 mol). The temperature was then raised to 15-20 °C, and the mixture was subjected to a vacuum of -0.095 MPa to remove ammonia for 20-30 min, followed by nitrogen purging. Cool to 0-10℃, then add 19.5g of xylene solution of MDP (concentration 50% w / w, 1 / 3 eq), heat to 80℃ and react for 2 hours, then allow to cool naturally.

[0129] The internal temperature was lowered to 70℃, 180g of water was added, the temperature was adjusted to 70℃, and mechanical stirring was carried out for 1 hour. At 25-30℃, 50g of ammonia water (concentration 25% w / w, 2.96 eq, 0.74 mol) was added, the pH was adjusted to 7-8, and the mixture was stirred for 5 minutes. After neutralization, the phases were separated, and the product was in the aqueous phase. The upper organic phase was extracted with water (60g × 2). The aqueous phases were combined, and the aqueous phase was back-extracted with 100g of xylene to obtain chlorohomoserine butyl ester. The final aqueous phase was used for the next step of hydrolysis, and the organic phase was retained for the recovery of the raw material chlorohomoserine butyl ester.

[0130] The final aqueous phase was subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, and then 250 g of hydrochloric acid (30% w / w, 8.4 eq, 2.1 mol) was added. The mixture was then heated to 100℃ for 8 hours for hydrolysis. Samples were taken to determine the absolute content (LC determination) and ee value of glufosinate. Based on the theoretical yield of glufosinate using the MDP feed amount, the glufosinate yield was 85.2%, and the ee value was 97.61%.

[0131] The absolute content (LC determination) and ee value of chlorohomoserine butyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine butyl ester (1.75 eq) was calculated to be 95.68%, and the ee value was 96.15%.

[0132] Example 8

[0133]

[0134] 375g of a chlorobenzene solution of chlorohomoserine ethyl ester (concentration 40% w / w, 2.75 eq, 0.91 mol, ee: 96.3%) was added to a 1L four-necked flask and cooled to 0℃ in an ice-water bath, followed by nitrogen purging three times. 53g of a chlorobenzene solution of MDP (concentration 49% w / w, 2 / 3 eq, 0.22 mol) was added to a constant-pressure dropping funnel, and MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5℃ during the addition process, which took approximately 1.5 hours. After the addition was complete, the mixture was stirred for 30 minutes, and ammonia gas was passed through at a rate of 200 mL / min for 45 minutes until gas overflowed. The ammonia flow was then stopped, with a total ammonia volume of 7.5g (1.33 eq, 0.44 mol). The temperature was then raised to 15-20℃, and the mixture was subjected to a vacuum of -0.095 MPa for 30 minutes to remove ammonia, followed by nitrogen purging. Cool to 0-10℃, then add 13.2g of chlorobenzene solution of MDP (concentration 49% w / w, 1 / 3 eq, 0.11mol) dropwise. After the addition is complete, adopt a staged heating reaction: first heat to 60℃ for 1h, then heat to 80℃ for 0.5h, and then cool naturally.

[0135] The internal temperature was lowered to 60℃, 200g of water was added, and the internal temperature was adjusted to 50℃. The reaction was mechanically stirred for 1 hour. At 50℃, 50g of ammonia water (concentration 25% w / w, 2.3 eq, 0.75 mol) was added, the pH was adjusted to 7-8, and the mixture was stirred for 5 minutes. After neutralization, the phases were separated. The product was in the aqueous phase. The lower organic phase was extracted with water (60g × 2), and the aqueous phases were combined. The aqueous phase was back-extracted with 100g of chlorobenzene to obtain ethyl chlorohomoserine from the aqueous phase. The organic phase was retained for the recovery of the raw material ethyl chlorohomoserine.

[0136] The absolute content of MPN in the above aqueous phase was determined by LC. Based on the theoretical yield of MPN using the MDP feed amount, the MPN yield was 77.5%.

[0137] The absolute content (LC determination) and ee value of chlorohomoserine ethyl ester in the above organic phase were determined by sampling. The recovery rate of excess chlorohomoserine ethyl ester (1.75 eq) was calculated to be 97.8%, and the ee value was 95.3%.

[0138] In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A method for preparing glufosinate of formula (I) or its salts, enantiomers thereof, or mixtures of enantiomers in all proportions, characterized in that: The method includes the following steps: ， a) Reacting a compound of formula (II) or a salt thereof, its enantiomers, or a mixture of enantiomers in all proportions with a compound of formula (III), wherein the compound of formula (III) is the only phosphorus-containing reactant, and Step a) is carried out in the presence of a base, wherein the base is an inorganic or organic base, wherein the molar ratio of (compound of formula (II) + base) to compound of formula (III) is ≥2.5:1; or step a) is carried out in the absence of an additional base; ， b) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to give glufosinate (I) or its salt, its enantiomers or mixtures of all proportions of enantiomers. in: X is a halogen; Hal 1 and Hal 2 Each is an independent halogen selected from fluorine, chlorine, bromine, and iodine; Y is -OR1; PG stands for hydrogen; R1 is hydrogen or a C1-C6 alkyl group; Chiral carbon atoms are labeled ; When step a) is carried out in the presence of ammonia, the ammonia is added after the compound of formula (II) is mixed with all the compounds of formula (III); When step a) is carried out in the presence of other bases containing active hydrogen, the base containing active hydrogen is added after the compound of formula (II) is mixed with all or part of the compound of formula (III).

2. A method for preparing a compound of formula (I)-1 or a salt thereof, an enantiomer thereof, or a mixture of enantiomers in all proportions, characterized in that: The method includes the following steps: ， a) Reacting a compound of formula (II) or a salt thereof, its enantiomers, or a mixture of enantiomers in all proportions with a compound of formula (III), and Step a) is carried out in the presence of a base, wherein the base is an inorganic or organic base, wherein the molar ratio of (compound of formula (II) + base) to compound of formula (III) is ≥2.5:1; or step a) is carried out in the absence of an additional base; ， b-1) Regardless of whether the intermediate is separated, the reaction in the presence of R8OH yields a compound of formula (I)-1 or a salt thereof, its enantiomers or a mixture of enantiomers in all proportions. in: X is a halogen; Hal 1 and Hal 2 Each is an independent halogen selected from fluorine, chlorine, bromine, and iodine; Y is -OR1; PG stands for hydrogen; R1 is hydrogen or a C1-C6 alkyl group; R8 is H; Chiral carbon atoms are labeled .

3. The method according to claim 1 or 2, 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, is also enantiomeric pure.

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

5.

5. The method according to claim 1 or 2, wherein the molar ratio of compound (II) to compound (III) is ≥2:

1.

6. The method according to claim 1 or 2, wherein in step a), the compound of formula (III) 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 (III) or a solution thereof.

7. The method according to claim 6, wherein in step a), the compound of formula (III) or a solution thereof is added to the compound of formula (II) or a solution thereof in batches or in one go; or the compound of formula (II) or a solution thereof is added to the compound of formula (III) or a solution thereof in batches or in one go.

8. The method according to claim 1 or 2, wherein X is chlorine, bromine or iodine.

9. The method according to claim 8, wherein X is chlorine.

10. The method according to claim 1 or 2, wherein R1 is a C1-C6 alkyl group.

11. The method according to claim 10, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, or hexyl.

12. The method of claim 11, wherein R1 is ethyl.

13. The method according to claim 1 or 2, wherein Y is -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3 or -OCH2CH(CH3)2.

14. The method according to claim 1 or 2, wherein Y is -OR1 and R1 is ethyl or n-butyl.

15. The method according to claim 1 or 2, wherein the compound of formula (III) is methyl phosphorus dichloride.

16. The method according to claim 1 or 2, wherein in step a), the reaction temperature is -50 to 200°C.

17. The method according to claim 16, wherein in step a), the reaction temperature is -20 to 140°C.

18. The method according to claim 17, wherein in step a), the reaction temperature is 20~100°C.

19. The method according to claim 1 or 2, wherein the molar ratio of (compound of formula (II) + base) to compound of formula (III) is ≥3:

1.

20. The method according to claim 19, wherein the molar ratio of (compound of formula (II) + base) to compound of formula (III) is ≥4:

1.

21. The method according to claim 1 or 2, wherein the inorganic base is ammonia, alkali metal oxide, alkaline earth metal oxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate. The organic base is an organic base that does not contain active hydrogen.

22. The method according to claim 21, wherein the inorganic base is potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide, or magnesium oxide; The organic base is an organic base that does not contain active hydrogen, and the organic base that does not contain active hydrogen is triethylamine, N,N-dimethylaniline, or pyridine, and 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 being selected from halogens, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C 3-10 cycloalkyl and C 6-10 Aryl.

23. The method according to claim 1 or 2, 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 ≥4:

1.

24. The method according to claim 1 or 2, wherein step a) is carried out under solvent-free conditions or in an inert solvent.

25. The method according to claim 24, wherein the inert solvent is selected from one or more of amide solvents, hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents and ester solvents.

26. The method of claim 24, wherein the inert solvent is selected from benzene solvents or halogenated hydrocarbon solvents.

27. The method according to claim 24, wherein 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.

28. The method according to claim 1, wherein in step b), an inorganic acid or an organic acid is added.

29. The method according to claim 28, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

30. The method according to claim 1, wherein in step b), the base is an inorganic base or an organic base.

31. The method according to claim 30, 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.

32. The method according to claim 31, wherein the base is NaOH, KOH or Ba(OH)2.

33. The method according to claim 1, wherein in step b), the reaction temperature is 20~150°C.

34. The method according to claim 2, wherein in step b-1), the reaction temperature is from 0°C to 100°C.

35. The method according to claim 2, wherein in step b-1), the reaction temperature is from 0°C to 80°C.

36. The method according to claim 2, wherein in step b-1), the reaction temperature is 20°C to 60°C.

37. The method according to claim 2, wherein in step b-1), the reaction temperature is 30°C to 60°C.

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