Preparation method of glufosinate-ammonium or derivative thereof

Abstract

The present disclosure relates to processes for the preparation of glufosinate-ammonium or derivatives thereof.

Description

[0001] This application is a divisional application of Chinese patent application 202380013473.2, filed on March 24, 2023, with the invention name “Method for preparing glufosinate or its derivatives”. Technical Field

[0002] The present disclosure relates to a method for preparing glufosinate-ammonium or a derivative thereof. Background Art

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

[0004] Existing methods for preparing glufosinate-ammonium have many defects (eg, complex processes, not suitable for large-scale production, use of highly toxic and / or expensive reagents, etc.). Summary of the invention

[0005] The present disclosure provides a method for preparing glufosinate-ammonium or its derivatives. The raw materials used in the method are easy to obtain, and the process operation is suitable for industrial-scale production.

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

[0007]

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

[0009]

[0010] b) reacting in the presence of water and an acid or base to obtain glufosinate (I) or a salt thereof, an enantiomer or a mixture of enantiomers in all ratios, regardless of whether the intermediate is isolated or not;

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

[0012] in:

[0013] X is halogen, -OAc, -OTs, -OMs or

[0014] Hal 1and Hal 2 are each independently halogen, such as fluorine, chlorine, bromine or iodine;

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

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

[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 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl 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 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[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 Aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclic group;

[0020] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[0021] Chiral carbon atoms are marked with *.

[0022] In some embodiments, the present 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 ratios, characterized in that the method comprises the following steps:

[0023]

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

[0025]

[0026] b-1) reacting in the presence of R8OH (i.e. in the absence of acid and base) to obtain a compound of formula (I)-1 or a salt thereof, an enantiomer or a mixture of enantiomers in all ratios, regardless of whether the intermediate is isolated or not;

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

[0028] in:

[0029] X is halogen, -OAc, -OTs, -OMs or

[0030] Hal 1 and Hal 2 are each independently halogen, such as fluorine, chlorine, bromine or iodine;

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

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

[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 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl 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 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[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 Aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclic group;

[0036] R8 is H, C1-C6 alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclyl; preferably, R8 is H or C1-C6 alkyl; more preferably, R8 is H, methyl or ethyl;

[0037] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[0038] Chiral carbon atoms are marked with *.

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

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

[0041] 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.

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

[0043] In some embodiments, 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.

[0044] In some embodiments, the compound of formula (III) or its solution is added to the compound of formula (II) or its solution in batches or all at once; or the compound of formula (II) or its solution is added to the compound of formula (III) or its solution in batches or all at once.

[0045] In some embodiments, X is chloro, bromo, iodo, -OAc, -Ots, -Oms, or

[0046] In some embodiments, 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 Aralkyl.

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

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

[0051] In some embodiments, said Y is -OR1.

[0052] In some embodiments, 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 embodiments, 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 reaction starting material.

[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 performed in the presence of a base, which is an inorganic base or an organic base;

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

[0060] 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;

[0061] The organic base is preferably an organic base without active hydrogen, and the base without active hydrogen is preferably triethylamine, N,N-dimethylaniline or pyridine, and the triethylamine, N,N-dimethylaniline and pyridine optionally have 1 to 3 substituents connected to one or more carbon atoms of the tertiary amine, and the substituents are selected from halogen, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C 3-10 Cycloalkyl and C 6-10 Aryl.

[0062] In some embodiments, when the step a) is performed in the presence of a base containing active hydrogen (eg, 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 the step a) is performed 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 performed under solvent-free conditions or in an inert solvent;

[0065] 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;

[0066] More preferably, the inert solvent is selected from any 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 embodiments, in step b), an inorganic acid or an organic acid is added.

[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 embodiments, in step b), the reaction temperature 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 the present invention is particularly suitable for the preparation of glufosinate-ammonium, greatly shortens the steps of the existing preparation process, and has an excellent reaction yield. The compound of formula (III) used in the method of the present invention is easy to obtain and low in cost, which makes the method of the present invention suitable for large-scale industrial production.

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

[0074] definition

[0075] Unless otherwise defined, the meanings of all technical terms and scientific terms used herein are intended to be the same as those generally understood by those skilled in the art. Reference to the technology used herein is intended to refer to the technology generally understood in the art, including those changes in technology that are obvious to those skilled in the art or replacement of equivalent technology. Although it is believed that the following terms are well understood by those skilled in the art, the following definitions are still set forth to better explain the present invention.

[0076] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and other variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0077] The term "amino protecting group" refers to a group that can be attached to the nitrogen atom on the amino group to protect the amino group from participating in the reaction and which can be easily removed in the subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0078] Formula -C(=O)OR a A carbamate group, wherein R a For example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; formula -C(=O)R b An 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 For example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl, 2,3,6-trimethyl-4-methoxybenzene, and the like.

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

[0080] C1-C4 alkyl is a straight or branched, saturated hydrocarbon chain containing 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.

[0081] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon radical containing one or more double bonds and having 2 to 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 be present in the pure E (entgegen) form, the pure Z (zusammen) form or any mixture thereof.

[0082] As used herein, the term "alkynyl" denotes 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., a monocyclic ring such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or a bicyclic ring, including a spirocyclic, fused or bridged system (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring carbon atoms (for example cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl), which is optionally substituted by 1 or more (such as 1 to 3) suitable substituents, for example methyl substituted cyclopropyl.

[0084] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8 or 9 carbon atoms and one or more (e.g., one, two, three or four) selected from C(=O), O, S, S(=O), S(=O)2 and NR d A heteroatom-containing group, wherein R d Represents a hydrogen atom or C 1-6 Alkyl or halo-C 1-6alkyl; the heterocyclyl may be attached to the rest of the molecule via any of the carbon atoms or the nitrogen atom, if present. In particular, a 3-10 membered heterocyclyl is a group having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, an oxirane, an aziridine, an azetidinyl, an oxetanyl, a tetrahydrofuranyl, a dioxolyl, a pyrrolidinyl, a pyrrolidonyl, an imidazolidinyl, a pyrazolidinyl, a pyrrolinyl, a tetrahydropyranyl, a piperidinyl, a morpholinyl, a dithianyl, a thiomorpholinyl, a piperazinyl or a trithianyl.

[0085] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. 6-10 "Aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by 1 or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0086] As used herein, the term "aralkyl" preferably refers to an alkyl substituted with an aryl 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, 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, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which may be identical or different (the heteroatom being, for example, oxygen, nitrogen or sulfur) and, in each case, may additionally be benzo-fused. In particular, heteroaryl is selected from thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0088] As used herein, the term "substitution" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogens on the designated atom with a selection from the indicated group, provided that the normal valence of the designated atom in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permitted only if such combinations form stable compounds.

[0089] As used herein, the term "base not containing active hydrogen" refers to a base that does not contain groups such as NH, OH, SH and PH in the molecule.

[0090] As used herein, "a mixture of enantiomers in all ratios" has the same meaning as "a mixture of enantiomers in any ratio". DETAILED DESCRIPTION

[0091] Example 1

[0092]

[0093] To a 1L four-necked flask, add a solution of ethyl chlorohomoserine (2.1eq, 162g, 0.987mol, ee value 99%) in chlorobenzene (835g) and triethylamine (2.1eq, 100g, 0.987mol). After the addition is completed, replace with nitrogen and cool to 0°C in an ice-water bath. Add a solution of MDP (1eq, 55g, 0.47mol) in chlorobenzene (127.4g) to a constant pressure dropping funnel, control the temperature at 0-5°C and start adding dropwise, which will be completed in 1.5h.

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

[0095] Add water (300g) to the filtrate, stir at 50℃ for 1h, then add 25% ammonia water (40g) to adjust the pH to 7, separate the phases after neutralization, and add water (100g) to the lower organic phase for secondary extraction. After the aqueous phases are combined, they are concentrated under reduced pressure to a viscous state, add 500g hydrochloric acid, heat to 100℃ for hydrolysis for 8h, and take samples to determine the absolute content and ee value of glufosinate in the reaction solution. Calculated based on the theoretical yield of glufosinate (85.1g) of glufosinate based on the MDP feed amount, the yield of glufosinate is 92.6% and the ee value is 98%.

[0096] Embodiment 2:

[0097]

[0098] 255g of chlorobenzene solution of ethyl chlorohomoserine (concentration 30% w / w, 2.1eq, 0.46mol, ee: 99%) and 46.7g (2.1eq) of triethylamine were added to a 1L four-necked flask, cooled to 0°C in an ice-water bath, and replaced with nitrogen three times; 60.5g of chlorobenzene solution of MDP (concentration 43.17% w / w, 1eq, 0.22mol) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, and the temperature was controlled at 0-5°C during the addition process, and the time was about 1.5h. After the addition was completed, a staged temperature increase reaction was adopted, first heated to 60°C for reaction for 1h, then heated to 80°C for reaction for 0.5h, and then naturally cooled to 20-30°C, filtered, the filter cake was washed with 110g of chlorobenzene, and the filtrate was reserved for the next step of reaction.

[0099] Add the above filtrate to a 1L four-necked flask, add 160g of water, heat to 50°C, and stir mechanically for 1h; then, add 20g of ammonia water (concentration 25% w / w, 1.33eq, 0.29mol) at 50°C, adjust the pH to 7-8, stir for 5min, and separate the phases after neutralization. The product is located in the aqueous phase, and the lower organic phase is extracted with water (60g×2). The aqueous phases are combined, and 100g of chlorobenzene is used to extract the ethyl chlorohomoserine in the aqueous phase. 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 ethyl chlorohomoserine.

[0100] The final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and 250 g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 2.1 mol) was added, and the temperature was raised to 100° C. for hydrolysis for 8 h, and then the absolute content of glufosinate ammonium (LC determination) and ee value were determined. Based on the theoretical yield of glufosinate ammonium based on the MDP feed amount, the yield of glufosinate ammonium was 93.05%, and the ee value was 96.85%.

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

[0102] Embodiment 3:

[0103]

[0104] 375g of chlorobenzene solution of ethyl chlorohomoserine (concentration 40% w / w, 4.1eq, 0.91mol, ee: 96.3%) was added to a 1L four-necked flask, cooled to 0°C in an ice-water bath, and replaced with nitrogen three times; 60.5g of chlorobenzene solution of MDP (concentration 43.17% w / w, 1eq, 0.22mol) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, and the temperature was controlled at 0-5°C during the addition process, which took about 1.5h. After the addition was completed, a staged temperature increase reaction was adopted, firstly the temperature was increased to 60°C for reaction for 1h, then the temperature was increased to 80°C for reaction for 0.5h, and then the temperature was naturally decreased.

[0105] The internal temperature was reduced to 60°C, 160g of water was added, the temperature was adjusted to 50°C, mechanical stirring was performed for 1h, 50g of ammonia water (concentration 25% w / w, 3.3eq, 0.74mol) was added at 50°C, the pH was adjusted to 7-8, stirring was performed for 5min, and the phases were separated after neutralization. The product was located in the aqueous phase, and the lower organic phase was extracted with water (60g×2), the aqueous phases were combined, and 100g of chlorobenzene was used to extract the ethyl chlorohomoserine in 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.

[0106] The final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and 250 g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 2.1 mol) was added, and the temperature was raised to 100° C. for hydrolysis for 8 h, and then the absolute content of glufosinate ammonium (LC determination) and ee value were determined. Based on the theoretical yield of glufosinate ammonium based on the MDP feed amount, the yield of glufosinate ammonium was 92.8%, and the ee value was 93.8%.

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

[0108] Embodiment 4:

[0109]

[0110] 375g of chlorobenzene solution of ethyl chlorohomoserine ester (concentration 40% w / w, 2.75eq, 0.91mol, ee: 96.3%) was added to a 1L four-necked flask, cooled to 0°C in an ice-water bath, and replaced with nitrogen three times; 53g of chlorobenzene solution of MDP (concentration 49% w / w, 2 / 3eq, 0.22mol) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, and the temperature was controlled at 0-5°C during the addition process, and it took about 1.5h. After the addition was completed, it was stirred for 30min, and ammonia was introduced at a rate of 200mL / min for 45min until gas overflowed, and the ammonia was stopped, and the total amount of ammonia was 7.5g (1.33eq, 0.44mol); then the temperature was raised to 15-20°C, vacuum-0.095MPa deamination was performed for 30min, and nitrogen was filled. The temperature was lowered to 0-10°C, and 13.2 g of chlorobenzene solution of MDP (concentration 49% w / w, 1 / 3 eq, 0.11 mol) was added dropwise. After completion of the addition, the temperature was raised in stages, first to 60°C for reaction for 1 hour, then to 80°C for reaction for 0.5 hour, and then the temperature was lowered naturally.

[0111] The internal temperature was reduced to 60°C, 200 g of water was added, the internal temperature was adjusted to 50°C, the reaction was mechanically stirred for 1 h, 50 g of aqueous ammonia (concentration 25% w / w, 2.3 eq, 0.75 mol) was added at 50°C, the pH was adjusted to 7-8, stirred for 5 min, and the phases were separated after neutralization. The product was located in the aqueous phase, and the lower organic phase was extracted with water (60 g × 2). The aqueous phases were combined and 100 g of chlorobenzene was used to extract 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 recovery of the raw material ethyl chlorohomoserine.

[0112] The final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and 373 g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 3.07 mol) was added. After heating to 100° C. for 8 h of hydrolysis, the absolute content of glufosinate ammonium (LC determination) and ee value were determined. Based on the theoretical yield of glufosinate ammonium based on the MDP feed amount, the yield of glufosinate ammonium was 90.77% and the ee value was 92.3%.

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

[0114] Embodiment 5:

[0115]

[0116] Add 163.4g xylene solution of butyl chlorohomoserine (concentration 41.5% w / w, 2.1eq, 0.35mol, ee: 99%) and 35.4g (2.1eq) of triethylamine to a 1L four-necked flask, cool to 0°C in an ice-water bath, and replace with nitrogen three times; add 38.7g of MDP xylene solution (concentration 50% w / w, 1eq, 0.165mol) to a constant pressure dropping funnel, add MDP dropwise under nitrogen protection, and control the temperature at 0-5°C during the addition process, which takes about 1.5h. After the addition is completed, adopt a staged temperature increase reaction, first heat to 60°C for 1h, then heat to 80°C for 0.5h, then naturally cool to 20-30°C, filter, wash the filter cake with 150g xylene, and keep the filtrate for the next step of reaction.

[0117] The above filtrate was added to a 1L four-necked flask, and 180 g of water was added. The temperature was raised to 50°C and mechanically stirred for 1 h. 20 g of aqueous ammonia (concentration 25% w / w, 1.78 eq, 0.29 mol) was added at 50°C, the pH was adjusted to 7-8, and stirred for 5 min. After neutralization, the phases were separated and the product was located in the aqueous phase. The upper organic phase was extracted with water (60 g × 2). The aqueous phases were combined and 100 g of xylene was used to extract butyl 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 butyl chlorohomoserine.

[0118] The final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and 255 g of hydrochloric acid (concentration 30% w / w, 12.7 eq, 2.1 mol) was added. After heating to 100° C. for 8 hours of hydrolysis, the absolute content of glufosinate-ammonium (LC determination) and ee value were determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed amount, the yield of glufosinate-ammonium 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 organic phase were determined by sampling, and the recovery rate of excess chlorohomoserine butyl ester (1.1 eq) was calculated to be 95%, and the ee value was 98.25%.

[0120] Embodiment 6:

[0121]

[0122] 470.5 g of xylene solution of butyl chlorohomoserine (concentration 38.54% w / w, 4.1 eq, 0.935 mol, ee: 99.6%) was added to a 1L four-necked flask, cooled to 0-5°C in an ice-water bath, and replaced with nitrogen three times; 53.35 g of xylene solution of MDP (concentration 50% w / w, 1 eq, 0.228 mol) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, and the temperature was controlled at 0-5°C during the addition process, which took about 1.5 hours. After the addition was completed, the temperature was raised to 80°C for reaction for 2 hours, and the temperature was naturally lowered.

[0123] The internal temperature was reduced to 70°C, 160 g of water was added, the temperature was adjusted to 70°C, mechanical stirring was carried out for 1 h, 50 g of aqueous ammonia (concentration 25% w / w, 3.2 eq, 0.74 mol) was added at 25-30°C to adjust the pH to 7-8, stirred for 5 min, and separated into phases after neutralization. The product was located in the aqueous phase, and the upper organic phase was extracted with water (60 g × 2). The aqueous phases were combined and 100 g of xylene was used to extract butyl 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 butyl chlorohomoserine.

[0124] The final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and 250 g of hydrochloric acid (concentration 30% w / w, 9.2 eq, 2.1 mol) was added, and the temperature was raised to 100° C. for hydrolysis for 8 hours, and then the absolute content of glufosinate-ammonium (LC determination) and ee value were determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed amount, the yield of glufosinate-ammonium was 88%, and the ee value was 97.29%.

[0125] The absolute content (LC determination) and ee value of chlorohomoserine butyl ester in the organic phase were determined by sampling, and 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] Embodiment 7:

[0127]

[0128] 370.9g of xylene solution of butyl chlorohomoserine ester (concentration 38.54% w / w, 2.75eq, 0.69mol, ee: 99.6%) was added to a 1L four-necked flask, cooled to 0°C in an ice-water bath, and replaced with nitrogen three times; 39.2g of xylene solution of MDP (concentration 50% w / w, 2 / 3eq) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, and the temperature was controlled at 0-5°C during the addition process, which took about 1.5h. After the addition was completed, it was stirred for 10-30min, and ammonia was introduced at a rate of 200mL / min for 30min until gas overflowed, and the ammonia was stopped, and the total amount of ammonia was 5.7g (1.33eq, 0.33mol); then the temperature was raised to 15-20°C, vacuum-0.095MPa deamination was performed for 20-30min, and nitrogen was introduced. The temperature was lowered to 0-10°C, and 19.5 g of a xylene solution of MDP (concentration 50% w / w, 1 / 3 eq) was added dropwise, and the temperature was raised to 80°C for reaction for 2 h, and the temperature was lowered naturally.

[0129] The internal temperature was reduced to 70°C, 180 g of water was added, the temperature was adjusted to 70°C, mechanical stirring was carried out for 1 h, 50 g of aqueous ammonia (concentration 25% w / w, 2.96 eq, 0.74 mol) was added at 25-30°C, the pH was adjusted to 7-8, stirred for 5 min, and the phases were separated after neutralization. The product was located in the aqueous phase, and the upper organic phase was extracted with water (60 g × 2). The aqueous phases were combined and 100 g of xylene was used to extract butyl chlorohomoserine from the aqueous phase. The final aqueous phase was used for the next step of hydrolysis, and the organic phase was retained for recovery of the raw material butyl chlorohomoserine.

[0130] The final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and 250 g of hydrochloric acid (concentration 30% w / w, 8.4 eq, 2.1 mol) was added, and the temperature was raised to 100° C. for hydrolysis for 8 h, and then the absolute content of glufosinate ammonium (LC determination) and ee value were determined. Based on the theoretical yield of glufosinate ammonium based on the MDP feed amount, the yield of glufosinate ammonium 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 organic phase were determined by sampling, and 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 chlorobenzene solution of ethyl chlorohomoserine ester (concentration 40% w / w, 2.75eq, 0.91mol, ee: 96.3%) was added to a 1L four-necked flask, cooled to 0°C in an ice-water bath, and replaced with nitrogen three times; 53g of chlorobenzene solution of MDP (concentration 49% w / w, 2 / 3eq, 0.22mol) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, and the temperature was controlled at 0-5°C during the addition process, and it took about 1.5h. After the addition was completed, it was stirred for 30min, and ammonia was introduced at a rate of 200mL / min for 45min until gas overflowed, and the ammonia was stopped, and the total amount of ammonia was 7.5g (1.33eq, 0.44mol); then the temperature was raised to 15-20°C, vacuum-0.095MPa deamination was performed for 30min, and nitrogen was filled. The temperature was lowered to 0-10°C, and 13.2 g of chlorobenzene solution of MDP (concentration 49% w / w, 1 / 3 eq, 0.11 mol) was added dropwise. After completion of the addition, the temperature was raised in stages, first to 60°C for reaction for 1 hour, then to 80°C for reaction for 0.5 hour, and then the temperature was lowered naturally.

[0135] The internal temperature was reduced to 60°C, 200 g of water was added, the internal temperature was adjusted to 50°C, the reaction was mechanically stirred for 1 h, 50 g of aqueous ammonia (concentration 25% w / w, 2.3 eq, 0.75 mol) was added at 50°C, the pH was adjusted to 7-8, stirred for 5 min, and the phases were separated after neutralization. The product was located in the aqueous phase, and the lower organic phase was extracted with water (60 g × 2), and the aqueous phases were combined; 100 g of chlorobenzene was used to extract ethyl chlorohomoserine from the aqueous phase, and the organic phase was retained for recovery of the raw material ethyl chlorohomoserine.

[0136] The absolute content of MPN in the aqueous phase was determined by sampling (LC determination). The MPN yield was calculated based on the theoretical yield of MPN based on the MDP feed amount, and was 77.5%.

[0137] The absolute content (LC determination) and ee value of ethyl chlorohomoserine ester in the organic phase were determined by sampling, and the recovery rate of excess ethyl chlorohomoserine 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 of the present 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. Each reference cited in this application (including all patents, patent applications, journal articles, books and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A method for preparing glufosinate-ammonium or its salts, enantiomers or mixtures of enantiomers in all proportions of formula (I), characterized in that: The method comprises the following steps: a) reacting a compound of formula (II) or a salt, an enantiomer or a mixture of enantiomers in all ratios thereof with a compound of formula (III); b) reacting in the presence of water and an acid or base to obtain glufosinate (I) or a salt thereof, an enantiomer or a mixture of enantiomers in all ratios, regardless of whether the intermediate is isolated or not; When PG is an amino protecting group, the step of removing the amino protecting group may also be included; in: X is halogen, -OAc, -OTs, -OMs or Hal 1 and Hal 2 are each independently halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4; R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl or -Si(R5)(R6)(R7); R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl; R5, R6 and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclic group; The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl; Chiral carbon atoms are marked with *.

2. A method for preparing a compound of formula (I)-1 or a salt thereof, an enantiomer or a mixture of enantiomers in all proportions, characterized in that: The method comprises the following steps: a) reacting a compound of formula (II) or a salt, an enantiomer or a mixture of enantiomers in all ratios thereof with a compound of formula (III); b-1) reacting in the presence of R8OH to obtain a compound of formula (I)-1 or a salt thereof, an enantiomer or a mixture of enantiomers in all proportions, regardless of whether the intermediate is isolated or not; When PG is an amino protecting group, the step of removing the amino protecting group may also be included; in: X is halogen, -OAc, -OTs, -OMs or Hal 1 and Hal 2 are each independently halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4; R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl or -Si(R5)(R6)(R7); R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl; R5, R6 and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclic group; R8 is H, C1-C6 alkyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl or 3-10 membered 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 heterocyclic groups are each optionally substituted by one or more substituents independently selected from the following: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl; Chiral carbon atoms are marked with *.

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