Method for preparing glufosinate or its derivatives

Abstract

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

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present disclosure relates to a method for preparing glufosinate or a derivative thereof.

[0002] [Background of the invention] Glufosinate is a very potent, broad-spectrum, low-toxicity, non-selective (sterilant) organophosphate herbicide with specific systemic action developed by Hoechst in the 1980s. It can control annual or perennial dicotyledonous and grassy weeds. Glufosinate has two enantiomers (L- and D-). The herbicidal activity of L-glufosinate is twice as strong as that of racemic DL-glufosinate.

[0003] Existing methods for preparing glufosinate have many drawbacks (e.g., complicated processes, not suitable for large-scale production, use of highly toxic and / or expensive reagents).

[0004] [Summary of the Invention] The present disclosure provides methods for preparing glufosinate or its derivatives, the starting materials used in the methods being readily available and the process procedures being suitable for industrial-scale production.

[0005] In some embodiments, the present disclosure provides a method for preparing glufosinate of formula (I) or a salt thereof, its enantiomer, or a mixture of said enantiomers in all ratios, comprising: [ka] The method comprises the steps of: a) reacting a compound of formula (II) or a salt thereof, its enantiomer or a mixture of said enantiomers in all ratios with a compound of formula (III); [ka] b) reacting the intermediate, whether isolated or not, in the presence of water and an acid or a base to obtain glufosinate (I) or a salt thereof, an enantiomer thereof or a mixture of said enantiomers in all ratios; Including, When PG is an amino protecting group, the reaction may further include removing the amino protecting group, Where: X is halogen, -OAc, -OTs, -OMs or [ka] and Hal, Hal 1 and Hal 2 are each independently 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, 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, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 aralkyl, 5- to 14-membered heteroaryl, 3- to 10-membered heterocyclyl, or -Si(R5)(R6)(R7); R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 selected from the group consisting of aralkyl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl; R5, R6 and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12aralkyl, 5- to 14-membered heteroaryl, or 3- to 10-membered heterocyclyl; The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are each optionally 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, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7-C6 alkyl, C8-C6 alkyl, C9-C6 alkyl, C10-C6 alkyl, C11-C6 alkyl, C12-C6 alkenyl, C13-C6 alkynyl, C14-C6 alkyl, C15-C6 alkyl, C16-C6 alkyl, C17-C6 alkyl, C18-C6 alkyl, C19-C6 alkyl, C20-C6 alkenyl, C21-C6 alkynyl, C3-C6 alkyl, C19-C6 alkyl, C22-C6 alkenyl, C23-C6 alkynyl, C3-C6 alkyl, C18-C6 alkyl, C19-C6 alkyl, C24-C6 alkyl, C25-C6 alkyl, C26-C6 alkyl, C27-C6 alkyl, C28-C6 alkyl, C29-C6 alkyl, C30-C6 alkyl, C31-C6 alkyl, C32-C6 alkyl, C33-C6 alkyl, C34-C6 alkyl, C35-C6 alkyl, C36-C6 alkyl, C37-C6 alkyl, C38-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl, C38-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 substituted by one or more substituents independently selected from the group consisting of aralkyl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl; Asymmetric carbon atoms * It is displayed in The present invention provides a method comprising the steps of:

[0006] In some embodiments, the present disclosure provides a process for preparing a compound of formula (I)-1 or a salt thereof, its enantiomer, or a mixture of said enantiomers in all ratios, comprising: [ka] The method comprises the steps of: a) reacting a compound of formula (II) or a salt thereof, its enantiomer or a mixture of said enantiomers in all ratios with a compound of formula (III); [ka] b-1) reacting the intermediate, whether isolated or not, in the presence of ROH (i.e., in the absence of an acid or a base) to obtain glufosinate (I) or a salt thereof, an enantiomer thereof or a mixture of said enantiomers in all ratios; Including, When PG is an amino protecting group, the reaction may further include removing the amino protecting group, Where: X is halogen, -OAc, -OTs, -OMs or [ka] and Hal, Hal 1 and Hal 2 are each independently 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, 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, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl or -Si(R5)(R6)(R7); R4 is C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 selected from the group consisting of aralkyl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl; R5, R6 and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 aralkyl, 5- to 14-membered heteroaryl, or 3- to 10-membered heterocyclyl; R8 is H, C1-C6 alkyl, C3-C 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclyl; preferably, R8 is H or C1-C6 alkyl; more preferably, R8 is H, methyl or ethyl; The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are each optionally 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, C3-C6 alkyl, C4-C6 alkyl, C5-C6 alkyl, C6-C6 alkyl, C7-C6 alkyl, C8-C6 alkyl, C9-C6 alkyl, C10-C6 alkyl, C11-C6 alkyl, C12-C6 alkenyl, C13-C6 alkynyl, C14-C6 alkyl, C15-C6 alkyl, C16-C6 alkyl, C17-C6 alkyl, C18-C6 alkyl, C19-C6 alkyl, C20-C6 alkenyl, C21-C6 alkynyl, C3-C6 alkyl, C19-C6 alkyl, C22-C6 alkenyl, C23-C6 alkynyl, C3-C6 alkyl, C18-C6 alkyl, C19-C6 alkyl, C24-C6 alkyl, C25-C6 alkyl, C26-C6 alkyl, C27-C6 alkyl, C28-C6 alkyl, C29-C6 alkyl, C30-C6 alkyl, C31-C6 alkyl, C32-C6 alkyl, C33-C6 alkyl, C34-C6 alkyl, C35-C6 alkyl, C36-C6 alkyl, C37-C6 alkyl, C38-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl, C38-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl, C39-C6 alkyl 10 Cycloalkyl, C6-C 10 Aryl, C6-C 12 substituted by one or more substituents independently selected from the group consisting of aralkyl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl; Asymmetric carbon atoms * It is displayed in The present invention provides a method comprising the steps of:

[0007] In some embodiments, the compound of formula (II) in step a) above is enantiomerically pure, and the resulting glufosinate of formula (I) or a salt thereof, or a compound of formula (I)-1 or a salt thereof is also enantiomerically pure.

[0008] 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 obtained by the above method is (L):(D)-enantiomer or (D):(L)-enantiomer of 50.5:49.5 to 99.5:0.5.

[0009] In some embodiments, in the above method, the molar ratio of the compound of Formula (II) to the compound of Formula (III) is 2:1 or greater.

[0010] In some embodiments, in the above process, the molar ratio of the compound of formula (II) to the compound of formula (III) is from 0.2:1 to 10:1, preferably from 0.7:1 to 5:1.

[0011] 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.

[0012] In some embodiments, the compound of formula (III) or a solution thereof is added to the compound of formula (II) or a solution thereof in portions or all at once; or the compound of formula (II) or a solution thereof is added to the compound of formula (III) or a solution thereof in portions or all at once.

[0013] In some embodiments, X is chlorine, bromine, iodine, -OAc, -OTs, -OMs, or [ka] It is.

[0014] In some embodiments, X is chlorine.

[0015] In some embodiments, R1, R2, and R3 are each independently selected from hydrogen, C1-C6 alkyl, C6-C 10 Aryl or C6-C 12 It is aralkyl.

[0016] In some embodiments, R1, R2, and R3 are each independently C1-C6 alkyl, C6-C 10 Aryl or C6-C 12 It is aralkyl.

[0017] In some embodiments, R1, R2, and R3 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, phenyl, benzyl, phenylethyl, phenylpropyl, methylphenyl, ethylphenyl, propylphenyl, or naphthyl; more preferably ethyl.

[0018] In some embodiments, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0019] In some embodiments, Y is -OR1.

[0020] In some embodiments, R1 is ethyl or n-butyl.

[0021] In some embodiments, PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3, or [ka] It is.

[0022] In some embodiments, PG is hydrogen.

[0023] In some embodiments, the compound of formula (III) is dichloro(methyl)phosphane.

[0024] In some embodiments, the compound of formula (III) is the only phosphorus-containing reaction starting material.

[0025] In some embodiments, in step a), the reaction temperature is -50 to 200°C, preferably -20 to 140°C or 20 to 100°C.

[0026] In some embodiments, step a) is carried out in the presence of a base, the base being an inorganic base or an organic base; Preferably, the molar ratio of (the compound of formula (II) + the base) to the compound of formula (III) is at least 2.5:1, more preferably at least 3:1, and most preferably at least 4:1; 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, The organic base is preferably an organic base that does not contain active hydrogen, and the base that does not contain active hydrogen is preferably triethylamine, N,N-dimethylaniline or pyridine, and the triethylamine, N,N-dimethylaniline and pyridine optionally have 1 to 3 substituents bonded to one or more carbon atoms of the tertiary amine, and the substituents are halogen, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C3-C 10 Cycloalkyl and C6-C 10 aryl.

[0027] In some embodiments, when step a) is carried out in the presence of an active hydrogen-containing base (e.g., ammonia), the active hydrogen-containing base is added after mixing the compound of Formula (II) with all or a portion of the compound of Formula (III).

[0028] 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 or greater.

[0029] In some embodiments, 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, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

[0030] In some embodiments, in step b), an inorganic or organic acid is added.

[0031] In some embodiments, the inorganic acid is hydrochloric acid or sulfuric acid.

[0032] In some embodiments, in step b), the base is an inorganic base or an organic base; preferably, 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; more preferably, the base is NaOH, KOH, or Ba(OH).

[0033] In some embodiments, in step b), the reaction temperature is 20 to 150°C.

[0034] In some embodiments, in step b1), the reaction temperature is 0°C to 100°C, preferably 0°C to 80°C, and more preferably 20°C to 60°C or 30°C to 60°C.

[0035] The method of the present invention is particularly suitable for the preparation of glufosinate, substantially reducing the steps of the existing preparation process and providing excellent reaction yields. The compound of formula (III) used in the method of the present disclosure is readily available at low cost, making the method of the present disclosure suitable for industrial large-scale production.

[0036] In addition, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the starting material. For example, when an enantiomerically pure starting material (e.g., with an enantiomeric excess (% ee) of greater than 90%) is used, the enantiomeric excess (% ee) of the prepared L-glufosinate is, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0037] definition Unless otherwise specified, all technical and scientific terms used herein are intended to have the same meaning as commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology as commonly understood in the art, including modifications of those technologies or equivalent technical substitutions that are obvious to those skilled in the art. Although the following terms are believed to be readily understood by those skilled in the art, the following definitions are nevertheless provided to better illustrate the present invention.

[0038] As used herein, the terms "contain," "include," "comprise," "have," or "relate to," as well as other variations as used herein, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0039] The term "amino protecting group" refers to a group that can be attached to the nitrogen atom in an amino group to protect the amino group from participating in a reaction and can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following protecting groups: Formula -C(=O)OR a (In the formula, R a is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; b (In the formula, R bis, for example, methyl, ethyl, phenyl, trifluoromethyl, etc.); an amide group of the formula -S(=O)2-R c (In the formula, R c is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like.

[0040] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched groups, having 1 to 18 carbon atoms. Alkyl groups having 1 to 6 carbon atoms (i.e., C1-C6 alkyl), such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and pentyl, are preferred. Alkyl groups can be substituted or unsubstituted, and if substituted, the substituents can be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

[0041] C1-C4 alkyl is a straight or branched chain containing saturated hydrocarbon chain having 1 to 4 carbon atoms. It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

[0042] As used herein, the term "alkenyl" refers to a linear or branched monovalent hydrocarbyl ("C") group containing one or more double bonds and having 2 to 6 carbon atoms. 2~6 Alkenyl refers to, 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 as pure E (entgegen) forms, pure Z (zusammen) forms, or any mixture thereof.

[0043] As used herein, the term "alkynyl" refers to a monovalent hydrocarbyl containing one or more triple bonds and preferably having 2, 3, 4, 5 or 6 carbon atoms, for example, ethynyl or propynyl.

[0044] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., or bicyclic, including spiro, fused or bridged ring systems (e.g., bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthalene, etc.), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. Cycloalkyl has 3 to 15 carbon atoms. For example, the term "C3-C 10 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted by one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0045] As used herein, the term "heterocyclyl" refers to a heterocyclic ring having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and C(=O), O, S, S(=O), S(=O)2, and NR d (In the formula, R d is a hydrogen atom, C 1~6 Alkyl or C 1~6Heterocyclyl may be attached to the rest of the molecule via any one of a carbon atom or a nitrogen atom (if present). In particular, 3-10 membered heterocyclyl refers to a group having 3-10 carbon atoms and heteroatom(s) in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

[0046] 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 "C6-C 10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, e.g., phenyl or naphthyl. Aryl may have one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, -C 1~6 alkyl).

[0047] As used herein, the term "aralkyl" preferably refers to aryl-substituted alkyl, where aryl and alkyl 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.

[0048] 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, containing at least one heteroatom (e.g. O, N or S), which may be the same or different. Furthermore, in each case, the heteroaryl may be benzo-fused. In particular, the heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0049] As used herein, the term "substituted" means that one or more (e.g., 1, 2, 3, or 4) hydrogens on the specified atom have been replaced with one selected from the indicated group, provided that the replacement does not exceed the normal valence of the specified atom under the existing circumstances, 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.

[0050] As used herein, the term "base that does not contain an active hydrogen" refers to a base that does not contain groups such as NH, OH, SH, and PH in the molecule.

[0051] As used herein, a "mixture of enantiomers in all ratios" has the same meaning as a "mixture of enantiomers in any ratio."

[0052] [Detailed Description of the Invention] Example 1 [ka] A solution of chlorohomoserine ethyl ester (2.1 equiv, 162 g, 0.987 mol, ee value 99%) in chlorobenzene (835 g) and triethylamine (2.1 equiv, 100 g, 0.987 mol) were added to a 1 L four-neck flask, followed by nitrogen purge and lowering the temperature to 0° C. in an ice-water bath. A solution of MDP (1 equiv, 55 g, 0.47 mol) in chlorobenzene (127.4 g) was added to a constant pressure dropping funnel and dropwise addition was started while controlling the temperature at 0-5° C., and was completed in 1.5 h.

[0053] The resulting reaction solution was heated to 90° C. in an oil bath and reacted for 2 hours. After the reaction was completed, the reaction solution was naturally cooled to 30° C., filtered, and the filter cake was washed with chlorobenzene (200 g).

[0054] The filtrate was added with water (300 g) and stirred at 50° C. for 1 h, then 25% aqueous ammonia (40 g) was added to adjust the pH to 7. After neutralization, the phases were separated, and water (100 g) was added to the lower organic phase for secondary extraction. The aqueous phases were combined and concentrated under reduced pressure to a viscous state, to which 500 g of hydrochloric acid was added and heated to 100° C. for 8 h for hydrolysis. Samples were taken to determine the absolute amount and ee value of glufosinate acid in the reaction solution. Based on the theoretical yield of glufosinate acid (85.1 g) calculated from the amount of MDP, the yield of glufosinate acid was 92.6% and the ee value was 98%.

[0055] Example 2: [ka] A solution of chlorohomoserine ethyl ester (concentration 30% w / w, 2.1 equiv, 0.46 mol, ee: 99%) in chlorobenzene (255 g) and 46.7 g (2.1 equiv) of triethylamine were added to a 1 L four-neck flask and cooled to 0°C in an ice-water bath. Nitrogen flushing was performed three times. A solution of MDP (concentration 43.17% w / w, 1 equiv, 0.22 mol) in chlorobenzene (60.5 g) was added to a constant pressure dropping funnel and MDP was added dropwise under the protection of nitrogen, maintaining the temperature at 0-5°C during the dropwise addition over about 1.5 hours. After the dropwise addition was completed, the reaction mixture was warmed stepwise: first to 60°C and reacted for 1 hour, then to 80°C and reacted for 0.5 hour, then naturally cooled to 20-30°C. The mixture was suction filtered, the filter cake was washed with 110 g of chlorobenzene, and the filtrate was left for the next reaction.

[0056] The above filtrate was added to a 1 L four-neck flask along with 160 g water, warmed to 50°C and mechanically stirred for 1 h. Then, 20 g of aqueous ammonia (concentration 25% w / w, 1.33 equivalents, 0.29 mol) was added at 50°C to adjust the pH to 7-8, the mixture was stirred for 5 min and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g x 2). The aqueous phases were combined and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g of chlorobenzene. The final aqueous phase was subjected to further hydrolysis and the organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0057] The above final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state, to which 250 g of hydrochloric acid (concentration 30% w / w, 9.3 equivalents, 2.1 mol) was added and heated to 100°C for 8 hours for hydrolysis. A sample was taken to determine the absolute amount (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 92.6% and the ee value was 98%.

[0058] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. By calculation, the recovery rate of excess chlorohomoserine ethyl ester (1.1 equivalents) was determined to be 95% and the ee value was determined to be 96%.

[0059] Example 3: [ka] A solution of chlorohomoserine ethyl ester (concentration 40% w / w, 4.1 equiv, 0.91 mol, ee: 96.3%) in chlorobenzene (375 g) was added to a 1 L four-neck flask and cooled to 0°C in an ice-water bath. Nitrogen flushing was performed three times. A solution of MDP (concentration 43.17% w / w, 1 equiv, 0.22 mol) in chlorobenzene (60.5 g) was added to a constant pressure dropping funnel and MDP was added dropwise under the protection of nitrogen, maintaining the temperature at 0-5°C during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the reaction mixture was warmed stepwise: first to 60°C and reacted for 1 h, then to 80°C and reacted for 0.5 h, then naturally cooled.

[0060] The internal temperature was reduced to 60°C, 160 g of water was added, the temperature was adjusted to 50°C, and the reaction mixture was mechanically stirred for 1 h. 50 g of aqueous ammonia (concentration 25% w / w, 3.3 equivalents, 0.74 mol) was added at 50°C to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g x 2). The aqueous phases were combined and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g of chlorobenzene. The final aqueous phase was subjected to further hydrolysis and the organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0061] The above final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state, to which 250 g of hydrochloric acid (concentration 30% w / w, 9.3 equivalents, 2.1 mol) was added and heated to 100°C for 8 hours for hydrolysis. A sample was taken to determine the absolute amount (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 92.8% and the ee value was 93.8%.

[0062] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. By calculation, the recovery rate of excess chlorohomoserine ethyl ester (3.1 equivalents) was determined to be 98% and the ee value was determined to be 94%.

[0063] Example 4: [ka] A solution of chlorohomoserine ethyl ester (concentration 40% w / w, 2.75 equiv, 0.91 mol, ee: 96.3%) in chlorobenzene (375 g) was added to a 1 L four-neck flask and cooled to 0 °C in an ice-water bath. Nitrogen purge was performed three times. A solution of MDP (concentration 49% w / w, 2 / 3 equiv, 0.22 mol) in chlorobenzene (53 g) was added to a constant pressure dropping funnel and MDP was added dropwise under the protection of nitrogen while maintaining the temperature at 0-5 °C during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the mixture was stirred for 30 min and ammonia gas was pumped in at a rate of 200 mL / min for 45 min, which was stopped until the gas overflowed and the total amount of ammonia gas was 7.5 g (1.33 equiv, 0.44 mol). The temperature was then warmed to 15-20°C and the ammonia was removed under a vacuum of -0.095 MPa for 30 minutes while pumping in nitrogen. The reaction mixture was cooled to 0-10°C and a solution of MDP (49% w / w concentration, 1 / 3 equivalent, 0.11 mol) in additional chlorobenzene (13.2 g) was added dropwise. After the addition was complete, the reaction mixture was warmed stepwise: first to 60°C and reacted for 1 hour, then to 80°C and reacted for 0.5 hour, then naturally cooled.

[0064] The internal temperature was reduced to 60°C, 200 g of water was added, the internal temperature was adjusted to 50°C, and the reaction mixture was mechanically stirred for 1 h. 50 g of aqueous ammonia (concentration 25% w / w, 2.3 equivalents, 0.75 mol) was added at 50°C to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g x 2). The aqueous phases were combined and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g of chlorobenzene. The final aqueous phase was subjected to further hydrolysis and the organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0065] The above final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state, to which 373 g of hydrochloric acid (concentration 30% w / w, 9.3 equivalents, 3.07 mol) was added and heated to 100°C for 8 hours for hydrolysis. A sample was taken to determine the absolute amount (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 90.77% and the ee value was 92.3%.

[0066] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. The recovery rate of excess chlorohomoserine ethyl ester (1.75 equivalents) was calculated to be 95.2%, and the ee value was determined to be 93.5%.

[0067] Example 5: [ka] A solution of chlorohomoserine ethyl ester (concentration 41.5% w / w, 2.1 equiv, 0.35 mol, ee: 99%) in xylene (163.4 g) and 35.4 g (2.1 equiv) of triethylamine were added to a 1 L four-neck flask and cooled to 0°C in an ice-water bath. Nitrogen flushing was performed three times. A solution of MDP (concentration 50% w / w, 1 equiv, 0.165 mol) in xylene (38.7 g) was added to a constant pressure dropping funnel and MDP was added dropwise under the protection of nitrogen, maintaining the temperature at 0-5°C during the dropwise addition over about 1.5 hours. After the dropwise addition was completed, the reaction mixture was warmed stepwise: first to 60°C and reacted for 1 hour, then to 80°C and reacted for 0.5 hour, then naturally cooled to 20-30°C. The mixture was suction filtered, the filter cake was washed with 150 g of xylene, and the filtrate was left for the next reaction.

[0068] The above filtrate was added to a 1 L four-neck flask along with 180 g water, warmed to 50°C and mechanically stirred for 1 h. 20 g of aqueous ammonia (concentration 25% w / w, 1.78 equivalents, 0.29 mol) was added at 50°C to adjust the pH to 7-8, the mixture was stirred for 5 min and the phases were separated after neutralization. The product was in the aqueous phase. The upper organic phase was extracted with water (60 g x 2). The aqueous phases were combined and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g xylene. The final aqueous phase was subjected to further hydrolysis and the organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0069] The above final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state, to which 255 g of hydrochloric acid (concentration 30% w / w, 12.7 equivalents, 2.1 mol) was added and heated to 100°C for 8 hours for hydrolysis. A sample was taken to determine the absolute amount (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 87.5% and the ee value was 97.10%.

[0070] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. By calculation, the recovery rate of excess chlorohomoserine ethyl ester (1.1 equivalents) was determined to be 95% and the ee value was determined to be 98.25%.

[0071] Example 6: [ka] A solution of chlorohomoserine ethyl ester (concentration 38.54% w / w, 4.1 equiv, 0.935 mol, ee: 99.6%) in xylene (470.5 g) was added to a 1 L four-neck flask and cooled to 0-5°C in an ice-water bath. Nitrogen purge was performed three times. A solution of MDP (concentration 50% w / w, 1 equiv, 0.228 mol) in xylene (53.35 g) was added to a constant pressure dropping funnel and MDP was added dropwise under nitrogen protection while maintaining the temperature at 0-5°C during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the reaction mixture was warmed to 80°C and reacted for 2 h, then naturally cooled.

[0072] The internal temperature was reduced to 70°C, 160 g of water was added, the temperature was adjusted to 70°C, and the reaction mixture was mechanically stirred for 1 h. 50 g of aqueous ammonia (concentration 25% w / w, 3.2 equivalents, 0.74 mol) was added at 25-30°C to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The upper organic phase was extracted with water (60 g x 2). The aqueous phases were combined and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g of xylene. The final aqueous phase was subjected to further hydrolysis and the organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0073] The above final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state, to which 250 g of hydrochloric acid (concentration 30% w / w, 9.2 equivalents, 2.1 mol) was added and heated to 100°C for 8 hours for hydrolysis. A sample was taken to determine the absolute amount (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 88% and the ee value was 97.29%.

[0074] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. The recovery rate of excess chlorohomoserine ethyl ester (3.1 equivalents) was calculated to be 95.73%, and the ee value was determined to be 95.68%.

[0075] Example 7: [ka] A solution of chlorohomoserine ethyl ester (concentration 38.54% w / w, 2.75 equiv, 0.69 mol, ee: 99.6%) in xylene (370.9 g) was added to a 1 L four-neck flask and cooled to 0 °C in an ice-water bath. Nitrogen purge was performed three times. A solution of MDP (concentration 50% w / w, 2 / 3 equiv) in xylene (39.2 g) was added to a constant pressure dropping funnel and MDP was added dropwise under the protection of nitrogen while maintaining the temperature at 0-5 °C during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the mixture was stirred for 10-30 min and ammonia gas was pumped in at a rate of 200 mL / min for 30 min, which was stopped until the gas overflowed and the total amount of ammonia gas was 5.7 g (1.33 equiv, 0.33 mol). The temperature was then warmed to 15-20°C and ammonia was removed under a vacuum of -0.095 MPa for 20-30 min, with nitrogen pumped in. The reaction mixture was cooled to 0-10°C and a solution of MDP (concentration 50% w / w, 1 / 3 equivalent) in additional xylene (19.5 g) was added dropwise. The reaction mixture was warmed to 80°C and reacted for 0.5 h, then naturally cooled.

[0076] The internal temperature was lowered to 70°C, 180 g of water was added, the internal temperature was adjusted to 70°C, and the reaction mixture was mechanically stirred for 1 h. 50 g of aqueous ammonia (concentration 25% w / w, 2.96 equivalents, 0.74 mol) was added at 25-30°C to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The upper organic phase was extracted with water (60 g x 2). The aqueous phases were combined and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g of xylene. The final aqueous phase was subjected to further hydrolysis and the organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0077] The above final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state, to which 250 g of hydrochloric acid (concentration 30% w / w, 8.4 equivalents, 2.1 mol) was added and heated to 100°C for 8 hours for hydrolysis. A sample was taken to determine the absolute amount (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 85.2% and the ee value was 97.61%.

[0078] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. The recovery rate of excess chlorohomoserine ethyl ester (1.75 equivalents) was calculated to be 95.68%, and the ee value was determined to be 96.15%.

[0079] Example 8: [ka] A solution of chlorohomoserine ethyl ester (concentration 40% w / w, 2.75 equiv, 0.91 mol, ee: 96.3%) in chlorobenzene (375 g) was added to a 1 L four-neck flask and cooled to 0 °C in an ice-water bath. Nitrogen purge was performed three times. A solution of MDP (concentration 49% w / w, 2 / 3 equiv, 0.22 mol) in chlorobenzene (53 g) was added to a constant pressure dropping funnel and MDP was added dropwise under the protection of nitrogen while maintaining the temperature at 0-5 °C during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the mixture was stirred for 30 min and ammonia gas was pumped in at a rate of 200 mL / min for 45 min, which was stopped until the gas overflowed and the total amount of ammonia gas was 7.5 g (1.33 equiv, 0.44 mol). The temperature was then warmed to 15-20°C and the ammonia was removed under a vacuum of -0.095 MPa for 30 minutes while pumping in nitrogen. The reaction mixture was cooled to 0-10°C and a solution of MDP (49% w / w concentration, 1 / 3 equivalent, 0.11 mol) in additional chlorobenzene (13.2 g) was added dropwise. After the addition was complete, the reaction mixture was warmed stepwise: first to 60°C and reacted for 1 hour, then to 80°C and reacted for 0.5 hour, then naturally cooled.

[0080] The internal temperature was reduced to 60°C, 200 g of water was added, the internal temperature was adjusted to 50°C, and the reaction mixture was mechanically stirred for 1 h. 50 g of aqueous ammonia (concentration 25% w / w, 2.3 equivalents, 0.75 mol) was added at 50°C to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g x 2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g of chlorobenzene. The organic phase was kept for recovery of the starting material of chlorohomoserine ethyl ester.

[0081] A sample was taken to determine the absolute amount of MPNs (by LC). Based on the theoretical yield of MPNs calculated from the amount of MDP, the yield of MPNs was 77.5%.

[0082] A sample was taken to determine the absolute amount (by LC) and ee value of chlorohomoserine ethyl ester in the organic phase. The recovery rate of excess chlorohomoserine ethyl ester (1.75 equivalents) was calculated to be 97.8%, and the ee value was determined to be 95.3%.

[0083] In addition to those described herein, various modifications to the present invention will be apparent to those skilled in the art according to the above description. Such modifications are intended to fall within the scope of the appended claims. Each reference cited in this specification (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. 1. A process for preparing glufosinate of formula (I) or a salt thereof, its enantiomer or a mixture of said enantiomers in all ratios, comprising: 【Chemistry 1】 The method comprises the steps of: a) reacting a compound of formula (II) or a salt thereof, its enantiomer or a mixture of said enantiomers in all ratios with a compound of formula (III); 【Chemistry 2】 b) reacting the product of step a), whether it is isolated or not, in the presence of water and an acid or a base to obtain glufosinate (I) or a salt thereof, an enantiomer thereof or a mixture of said enantiomers in all ratios; Including, Where: X is a halogen; Hal １ and Hal ２ are each independently a halogen selected from fluorine, chlorine, bromine, and iodine; Y is -OR1; PG is hydrogen; R1 is C １ ~C ６ is alkyl, Asymmetric carbon atoms ＊ It is displayed in A method comprising:

2. 2. The method according to claim 1, wherein the compound of formula (II) in step a) has an enantiomeric excess (% ee) of more than 90% and the obtained glufosinate of formula (I) or a salt thereof also has an enantiomeric excess (% ee) of more than 90%.

3. The method according to claim 1, wherein the enantiomeric ratio of the glufosinate of formula (I) or a salt thereof is from 50.5:49.5 to 99.5:0.5 (L):(D)-enantiomers or (D):(L)-enantiomers.

4. 2. The process according to claim 1, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is 2:1 or more.

5. The method of claim 1, wherein in step a), 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.

6. The method of claim 1, 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 small portions or all at once; or the compound of formula (II) or a solution thereof is added to the compound of formula (III) or a solution thereof in small portions or all at once.

7. 2. The method of claim 1, wherein X is chlorine, bromine or iodine.

8. The method of claim 7, wherein X is chlorine.

9. The method of claim 1, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, or hexyl.

10. The method of claim 9, wherein R 1 is ethyl.

11. Y is -OCH ３ , -OCH ２ CH ３ , -OCH ２ CH ２ CH ３ , -OCH(CH ３ ) ２ , -OCH ２ CH ２ CH ２ CH ３ , or -OCH ２ CH (CH ３ 2. The method of claim 1 , wherein

12. Y is -OR １ and R １ The method of claim 1, wherein is ethyl or n-butyl.

13. 2. The method of claim 1, wherein the compound of formula (III) is dichloro(methyl)phosphane.

14. 2. The process of claim 1, wherein the compound of formula (III) is the only phosphorus-containing reaction starting material.

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

16. The method according to claim 1, wherein in step a), the reaction temperature is -20 to 140°C or 20 to 100°C.

17. 2. The process according to claim 1, wherein step a) is carried out in the presence of a base, said base being an inorganic base or an organic base.

18. The method of claim 17, wherein the molar ratio of (the compound of formula (II) + the base) to the compound of formula (III) is 2.5:1 or greater.

19. The method of claim 17, wherein the molar ratio of (the compound of formula (II) + the base) to the compound of formula (III) is 3:1 or greater.

20. The method of claim 17, wherein the molar ratio of (the compound of formula (II) + the base) to the compound of formula (III) is 4:1 or greater.

21. the inorganic base is 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; 18. The method of claim 17, wherein the organic base is an organic base that does not contain an active hydrogen.

22. 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, 22. The method of claim 21, wherein the organic base is an organic base that does not contain an active hydrogen, and the base that does not contain an active hydrogen is triethylamine, N,N-dimethylaniline, or pyridine, and the triethylamine, N,N-dimethylaniline, and pyridine optionally have 1 to 3 substituents bonded to one or more carbon atoms of the tertiary amine, the substituents being selected from halogen, -O-(C1-C6 alkyl), -NO2, -CN, C1-C6 alkyl, C3-C10 cycloalkyl, and C6-C10 aryl.

23. The method of claim 17, wherein step a) is carried out in the presence of an organic base containing active hydrogen, and the organic base containing active hydrogen is added after mixing the compound of formula (II) with all or a portion of the compound of formula (III).

24. The method of claim 17, wherein step a) is carried out in the presence of ammonia, and the ammonia is added after mixing the compound of formula (II) with all of the compound of formula (III).

25. 10. The process of claim 1, wherein step a) is carried out in the absence of an additional base.

26. The method of claim 25, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is 4:1 or more.

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

28. 28. The method of claim 27, wherein 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.

29. The method of claim 28, wherein the inert solvent is selected from any one or more of chlorobenzene, xylene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

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

31. 31. The method of claim 30, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

32. 2. The process according to claim 1, wherein in step b) the base is an inorganic base or an organic base.

33. 33. The method of claim 32, 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.

34. The base is NaOH, KOH or Ba(OH) ２ 34. The method of claim 33, wherein:

35. The process according to claim 1, wherein in step b), the reaction temperature is from 20 to 150° C.

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