Preparation method of glufosinate-ammonium or its derivatives

Abstract

The present disclosure relates to a method for preparing glufosinate-ammonium or its derivatives.

Description

Technical Field

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

[0002] Glufosinate, developed by Hoechst in the 1980s, is a highly effective, broad-spectrum, low-toxic, non-selective (bacterial) organophosphorus herbicide with partial systemic action. It is used to control annual and perennial dicotyledonous and grass weeds. Glufosinate exists in two enantiomers, L- and D-forms. The herbicidal activity of L-form is twice that of the racemic DL-form.

[0003] Existing methods for preparing glufosinate-ammonium 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

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

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

[0006]

[0007] 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);

[0008]

[0009] 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 proportions, regardless of whether the intermediate is isolated or not;

[0010] When PG is an amino protecting group, the step of removing the amino protecting group may also be included;

[0011] in:

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

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

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

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

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

[0017] R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

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

[0019] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic 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;

[0020] Chiral carbon atoms are marked with *.

[0021] 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 proportions, characterized in that the method comprises the following steps:

[0022]

[0023] 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);

[0024]

[0025] 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;

[0026] When PG is an amino protecting group, the step of removing the amino protecting group may also be included;

[0027] in:

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

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

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

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

[0032] R1, R2 and R3 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);

[0033] R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 Cycloalkyl, C 6-10 Aryl, C 6-12 Aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[0034] 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;

[0035] R8 is H, C1-C6 alkyl, C3-10 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;

[0036] 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;

[0037] Chiral carbon atoms are marked with *.

[0038] 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.

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

[0040] 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.

[0041] 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.

[0042] 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.

[0043] 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.

[0044] In some embodiments, X is chloro, bromo, iodo, -OAc, -Ots, -Oms, or

[0045] In some embodiments, X is chlorine.

[0046] In some embodiments, R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 Aryl or C 6-12 Aralkyl.

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

[0048] 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.

[0049] In some embodiments, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0050] In some embodiments, said Y is -OR1.

[0051] In some embodiments, R1 is ethyl or n-butyl.

[0052] In some embodiments, the PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3 or

[0053] In some embodiments, PG is hydrogen.

[0054] In some embodiments, the compound of formula (III) is methylphosphonium dichloride.

[0055] In some embodiments, the compound of formula (III) is the only phosphorus-containing reaction starting material.

[0056] In some embodiments, in step a), the reaction temperature is -50 to 200°C, preferably -20 to 140°C or 20 to 100°C.

[0057] In some embodiments, step a) is performed in the presence of a base, which is an inorganic base or an organic base;

[0058] Preferably, the molar ratio of (compound of formula (II) + the above base) to the compound of formula (III) is ≥2.5:1, more preferably ≥3:1, most preferably ≥4:1;

[0059] 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;

[0060] 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.

[0061] In some embodiments, when 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).

[0062] In some embodiments, when 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.

[0063] In some embodiments, step a) is performed in the absence of a solvent or in an inert solvent;

[0064] 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;

[0065] 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.

[0066] In some embodiments, in step b), an inorganic acid or an organic acid is added.

[0067] In some embodiments, the inorganic acid is hydrochloric acid or sulfuric acid.

[0068] 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.

[0069] In some embodiments, in step b), the reaction temperature is 20-150°C.

[0070] 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.

[0071] The method of the present invention is particularly suitable for the preparation of glufosinate-ammonium, significantly shortening the steps of the existing preparation process and achieving excellent reaction yield. The compound of formula (III) used in the method of the present invention is readily available and inexpensive, making the method of the present invention suitable for industrial large-scale production.

[0072] In addition, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when using an enantiomerically pure raw material (e.g., an enantiomeric excess (%ee) greater than 90%), 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%.

[0073] definition

[0074] Unless otherwise defined, all technical and scientific terms used herein are intended to have the same meaning as those commonly understood by those skilled in the art. References to technology used herein are intended to refer to technology commonly understood in the art, including variations of technology or substitutions of equivalent technology that are obvious to those skilled in the art. While it is believed that the following terms are well understood by those skilled in the art, the following definitions are set forth to better explain the present invention.

[0075] As used herein, the terms "comprises," "comprising," "having," "containing," or "involving," and variations thereof herein, are inclusive or open-ended and do not exclude additional unrecited elements or method steps.

[0076] The term "amino protecting group" refers to a group that can be attached to the nitrogen atom of an amino group to protect the amino group from participating in the reaction and which can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0077] 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, where R b For example, methyl, ethyl, phenyl, trifluoromethyl, etc.; formula -S(=O)2-R c N-sulfonyl derivatives of - 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.

[0078] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight and branched groups having 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. When substituted, the substituent may be a halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano group.

[0079] 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.

[0080] 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 2-6 The 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.

[0081] 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.

[0082] 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 spirocyclic, fused or bridged systems (such as bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decalinyl, etc.), which is 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 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.

[0083] 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 Rd represents a hydrogen atom or C 1-6 Alkyl or halo-C 1-6 alkyl; 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, an 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.

[0084] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π electron system. For example, as used herein, the term "C 6-10 "Aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.) substituted.

[0085] As used herein, the term "aralkyl" preferably refers to an alkyl group 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, and phenylbutyl.

[0086] 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 be benzo-fused. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0087] As used herein, the term "substituted" refers to the replacement of one or more (e.g., one, two, three, or four) hydrogen atoms on the designated atom with a selected group selected from the indicated group, provided that the designated atom's normal valence in the present context is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are permissible only if such combinations form stable compounds.

[0088] As used herein, the term "base containing no active hydrogen" refers to a base that does not contain NH, OH, SH, PH, or other groups in the molecule.

[0089] As used herein, "a mixture of enantiomers in all proportions" has the same meaning as "a mixture of enantiomers in any proportion". DETAILED DESCRIPTION

[0090] Example 1

[0091]

[0092] To a 1L four-necked flask, a solution of ethyl chlorohomoserine (2.1eq, 162g, 0.987mol, ee value 99%) in chlorobenzene (835g) and triethylamine (2.1eq, 100g, 0.987mol) were added. After the addition was complete, the atmosphere was replaced with nitrogen and the temperature was cooled to 0°C in an ice-water bath. A solution of MDP (1eq, 55g, 0.47mol) in chlorobenzene (127.4g) was added to a constant pressure dropping funnel, and the temperature was controlled at 0-5°C and the addition was started dropwise. The addition was completed in 1.5h.

[0093] The resulting reaction solution was heated to 90° C. in an oil bath and reacted for 2 h. After the reaction was completed, the temperature was naturally lowered to 30° C. and filtered, and the filter cake was washed with chlorobenzene (200 g).

[0094] Water (300 g) was added to the filtrate, and the mixture was stirred at 50°C for 1 hour. 25% aqueous ammonia (40 g) was then added to adjust the pH to 7. After neutralization, the phases were separated, and the lower organic phase was extracted again with water (100 g). The aqueous phases were combined and concentrated under reduced pressure until viscous. 500 g of hydrochloric acid was added, and the temperature was raised to 100°C for hydrolysis for 8 hours. The reaction solution was sampled and the absolute content of glufosinate and the ee value were determined. Based on the theoretical glufosinate yield (85.1 g) based on the MDP feed, the glufosinate yield was 92.6% and the ee value was 98%.

[0095] Example 2:

[0096]

[0097] A 1L four-necked flask was charged with 255g of a chlorobenzene solution of ethyl chlorohomoserine (30% w / w, 2.1eq, 0.46mol, ee: 99%) and 46.7g (2.1eq) of triethylamine. The mixture was cooled to 0°C in an ice-water bath and replaced with nitrogen three times. A constant-pressure dropping funnel was charged with 60.5g of a chlorobenzene solution of MDP (43.17% w / w, 1eq, 0.22mol). MDP was added dropwise under nitrogen protection, with the temperature maintained at 0-5°C over approximately 1.5 hours. After the addition was complete, the reaction was heated in stages, first to 60°C for 1 hour, then to 80°C for 0.5 hour, and then cooled naturally to 20-30°C. The mixture was filtered, the filter cake washed with 110g of chlorobenzene, and the filtrate was retained for the next reaction.

[0098] The filtrate was added to a 1L four-necked flask, along with 160 g of water. The temperature was raised to 50°C and mechanically stirred for 1 hour. Then, 20 g of aqueous ammonia (25% w / w, 1.33 eq, 0.29 mol) was added at 50°C, the pH was adjusted to 7-8, and the mixture was stirred for 5 minutes. After neutralization, the phases were separated. The product was located in the aqueous phase. The lower organic phase was extracted with water (60 g x 2). The aqueous phases were combined and stripped with 100 g of chlorobenzene to remove the ethyl chlorohomoserine ester. The final aqueous phase was used for the next hydrolysis step, and the organic phase was retained for recovery of the raw material ethyl chlorohomoserine ester.

[0099] The final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state. 250 g of hydrochloric acid (30% w / w concentration, 9.3 eq, 2.1 mol) was added, and the mixture was heated to 100°C for hydrolysis for 8 h. The absolute content of glufosinate-ammonium (LC) and the ee value were then determined. Based on the theoretical glufosinate-ammonium yield based on the MDP feed, the yield of glufosinate-ammonium was 93.05%, and the ee value was 96.85%.

[0100] The absolute content (LC determination) and ee value of chlorohomoserine ethyl ester in the organic phase were determined by sampling, and the recovery rate of excess chlorohomoserine ethyl ester (1.1 eq) was calculated to be 95%, and the ee value was 96%.

[0101] Example 3:

[0102]

[0103] A 1L four-necked flask was charged with 375g of a chlorobenzene solution of ethyl chlorohomoserine (40% w / w, 4.1eq, 0.91mol, ee: 96.3%). The mixture was cooled to 0°C in an ice-water bath and replaced with nitrogen three times. A constant-pressure dropping funnel was charged with 60.5g of a chlorobenzene solution of MDP (43.17% w / w, 1eq, 0.22mol). MDP was added dropwise under nitrogen protection, maintaining the temperature between 0-5°C over approximately 1.5 hours. Following the addition, the reaction was heated in stages, first to 60°C for 1 hour, then to 80°C for 0.5 hour, and then cooled naturally.

[0104] The internal temperature was lowered to 60°C, 160 g of water was added, and the temperature was adjusted to 50°C. Mechanical stirring was carried out for 1 hour. 50 g of aqueous ammonia (25% w / w, 3.3 eq, 0.74 mol) was added at 50°C, the pH was adjusted to 7-8, and the mixture was stirred for 5 minutes. After neutralization, the phases were separated. The product was located in the aqueous phase. The lower organic phase was extracted with water (60 g x 2). The aqueous phases were combined and stripped with 100 g of chlorobenzene to remove the ethyl chlorohomoserine ester from the aqueous phase. The final aqueous phase was used for the next hydrolysis step, and the organic phase was retained for recovery of the raw material ethyl chlorohomoserine ester.

[0105] The final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state. 250 g of hydrochloric acid (30% w / w concentration, 9.3 eq, 2.1 mol) was added, and the mixture was heated to 100°C for hydrolysis for 8 h. The absolute content of glufosinate-ammonium (LC) and the ee value were then determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed, the yield of glufosinate-ammonium was 92.8%, and the ee value was 93.8%.

[0106] 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%.

[0107] Example 4:

[0108]

[0109] A 1L four-necked flask was charged with 375g of a chlorobenzene solution of ethyl chlorohomoserine (40% w / w, 2.75eq, 0.91mol, ee: 96.3%). The temperature was then cooled to 0°C in an ice-water bath and the atmosphere was replaced with nitrogen three times. A constant-pressure dropping funnel was charged with 53g of a chlorobenzene solution of MDP (49% w / w, 2 / 3eq, 0.22mol). MDP was added dropwise under nitrogen, maintaining the temperature at 0-5°C. The addition took approximately 1.5 hours. After the addition was complete, the mixture was stirred for 30 minutes. Ammonia gas was then introduced at a rate of 200mL / min for 45 minutes until gas escaped. The ammonia addition was stopped, resulting in a total of 7.5g (1.33eq, 0.44mol). The temperature was then raised to 15-20°C, and deamination was performed under vacuum at -0.095MPa for 30 minutes. The mixture was then filled with nitrogen. The temperature was lowered to 0-10°C, and 13.2 g of MDP chlorobenzene solution (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 h, then to 80°C for reaction for 0.5 h, and then the temperature was lowered naturally.

[0110] The internal temperature was lowered to 60°C, 200 g of water was added, the internal temperature was adjusted to 50°C, and 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, and the mixture was stirred for 5 min. After neutralization, the phases were separated and the product was located in the aqueous phase. The lower organic phase was extracted with water (60 g × 2), the aqueous phases were combined, and 100 g of chlorobenzene was used to back-extract the ethyl chlorohomoserine ester in the aqueous phase. The final aqueous phase was used for the next hydrolysis, and the organic phase was retained for the recovery of the raw material ethyl chlorohomoserine ester.

[0111] The final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state. 373 g of hydrochloric acid (30% w / w concentration, 9.3 eq, 3.07 mol) was added, and the mixture was heated to 100°C for hydrolysis for 8 h. The absolute content of glufosinate-ammonium (LC) and the ee value were then determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed, the yield of glufosinate-ammonium was 90.77%, and the ee value was 92.3%.

[0112] The absolute content (LC determination) and ee value of chlorohomoserine ethyl ester in the organic phase were determined by sampling, and the recovery rate of excess chlorohomoserine ethyl ester (1.75 eq) was calculated to be 95.2%, and the ee value was 93.5%.

[0113] Example 5:

[0114]

[0115] A 1L four-necked flask was charged with 163.4g of a xylene solution of butyl chlorohomoserine (41.5% w / w, 2.1eq, 0.35mol, ee: 99%) and 35.4g (2.1eq) of triethylamine. The mixture was cooled to 0°C in an ice-water bath and replaced with nitrogen three times. A constant-pressure dropping funnel was charged with 38.7g of a xylene solution of MDP (50% w / w, 1eq, 0.165mol) and MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5°C over approximately 1.5 hours. After the addition was complete, the reaction was heated in stages, first to 60°C for 1 hour, then to 80°C for 0.5 hour, and then cooled naturally to 20-30°C. The mixture was filtered, the filter cake washed with 150g of xylene, and the filtrate was retained for the next reaction.

[0116] The above filtrate was added to a 1L four-necked flask, 180 g of water was added, the temperature was raised to 50°C, 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, stirred for 5 min, and the phases were separated after neutralization. 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 back-extract the chlorohomoserine butyl ester in the aqueous phase. The final aqueous phase was used for the next hydrolysis, and the organic phase was retained for recovery of the raw material chlorohomoserine butyl ester.

[0117] The final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state. 255 g of hydrochloric acid (30% w / w concentration, 12.7 eq, 2.1 mol) was added, and the mixture was heated to 100° C. for hydrolysis for 8 h. The absolute content of glufosinate-ammonium (LC) and the ee value were then determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed, the yield of glufosinate-ammonium was 87.5%, and the ee value was 97.10%.

[0118] 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%.

[0119] Example 6:

[0120]

[0121] A 1L four-necked flask was charged with 470.5g of a xylene solution of butyl chlorohomoserine (38.54% w / w, 4.1eq, 0.935mol, ee: 99.6%). The mixture was cooled to 0-5°C in an ice-water bath and the atmosphere was replaced with nitrogen three times. A xylene solution of 53.35g of MDP (50% w / w, 1eq, 0.228mol) was added to a constant-pressure dropping funnel. MDP was added dropwise under nitrogen, maintaining the temperature at 0-5°C over approximately 1.5 hours. After the addition was complete, the mixture was heated to 80°C for 2 hours, then cooled naturally.

[0122] The internal temperature was lowered 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, the pH was adjusted to 7-8, and the mixture was 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 back-extract the chlorohomoserine butyl ester in the aqueous phase. The final aqueous phase was used for the next hydrolysis, and the organic phase was retained for the recovery of the raw material chlorohomoserine butyl ester.

[0123] The final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state. 250 g of hydrochloric acid (30% w / w concentration, 9.2 eq, 2.1 mol) was added, and the mixture was heated to 100°C for hydrolysis for 8 hours. The absolute content of glufosinate-ammonium (LC) and the ee value were then determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed, the yield of glufosinate-ammonium was 88%, and the ee value was 97.29%.

[0124] 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%.

[0125] Example 7:

[0126]

[0127] A 1L four-necked flask was charged with 370.9g of a xylene solution of butyl chlorohomoserine (38.54% w / w, 2.75 eq, 0.69 mol, ee: 99.6%). The temperature was then cooled to 0°C in an ice-water bath and the atmosphere was replaced with nitrogen three times. A constant-pressure dropping funnel was charged with 39.2g of a xylene solution of MDP (50% w / w, 2 / 3 eq) and added dropwise under nitrogen, maintaining the temperature at 0-5°C. The addition took approximately 1.5 hours. After the addition was complete, the mixture was stirred for 10-30 minutes. Ammonia gas was then introduced at a rate of 200 mL / min for 30 minutes until gas escaped. The ammonia addition was stopped, resulting in a total of 5.7g (1.33 eq, 0.33 mol). The temperature was then raised to 15-20°C, and deamination was performed under vacuum at -0.095 MPa for 20-30 minutes, followed by nitrogen purging. 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. The temperature was raised to 80°C and reacted for 2 h, and the temperature was lowered naturally.

[0128] The internal temperature was lowered 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 back-extract the chlorohomoserine butyl ester in the aqueous phase. The final aqueous phase was used for the next hydrolysis, and the organic phase was retained for the recovery of the raw material chlorohomoserine butyl ester.

[0129] The final aqueous phase was distilled under reduced pressure to remove most of the water and concentrated to a viscous state. 250 g of hydrochloric acid (30% w / w concentration, 8.4 eq, 2.1 mol) was added, and the mixture was heated to 100°C for hydrolysis for 8 h. The absolute content of glufosinate-ammonium (LC) and the ee value were then determined. Based on the theoretical yield of glufosinate-ammonium based on the MDP feed, the yield of glufosinate-ammonium was 85.2%, and the ee value was 97.61%.

[0130] 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%.

[0131] Example 8

[0132]

[0133] A 1L four-necked flask was charged with 375g of a chlorobenzene solution of ethyl chlorohomoserine (40% w / w, 2.75eq, 0.91mol, ee: 96.3%). The temperature was then cooled to 0°C in an ice-water bath and the atmosphere was replaced with nitrogen three times. A constant-pressure dropping funnel was charged with 53g of a chlorobenzene solution of MDP (49% w / w, 2 / 3eq, 0.22mol). MDP was added dropwise under nitrogen, maintaining the temperature at 0-5°C. The addition took approximately 1.5 hours. After the addition was complete, the mixture was stirred for 30 minutes. Ammonia gas was then introduced at a rate of 200mL / min for 45 minutes until gas escaped. The ammonia addition was stopped, resulting in a total of 7.5g (1.33eq, 0.44mol). The temperature was then raised to 15-20°C, and deamination was performed under vacuum at -0.095MPa for 30 minutes. The mixture was then filled with nitrogen. The temperature was lowered to 0-10°C, and 13.2 g of MDP chlorobenzene solution (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 h, then to 80°C for reaction for 0.5 h, and then the temperature was lowered naturally.

[0134] The internal temperature was lowered to 60°C, 200 g of water was added, the internal temperature was adjusted to 50°C, and 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, and the mixture was stirred for 5 min. After neutralization, the phases were separated and the product was located in the aqueous phase. 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 the ethyl chlorohomoserine ester in the aqueous phase, and the organic phase was retained for recovery of the raw material ethyl chlorohomoserine ester.

[0135] The absolute amount of MPN in the aqueous phase was determined by sampling (LC determination). The MPN yield was calculated based on the theoretical MPN yield based on the MDP feed amount, and was 77.5%.

[0136] 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%.

[0137] In addition to those described herein, various modifications of the present invention will be apparent to those skilled in the art from 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), wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is ≥2:1; 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 proportions, regardless of whether the intermediate is isolated or not; in: X is a halogen; Hal 1 and Hal 2 are each independently a halogen selected from fluorine, chlorine, bromine or iodine; Y is -OR1; PG is hydrogen; R1 is hydrogen or C1-C6 alkyl; Chiral carbon atoms are marked with *.

2. A process 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), wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is ≥2:1; 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 ratios, regardless of whether the intermediate is isolated or not; in: X is a halogen; Hal 1 and Hal 2 are each independently a halogen selected from fluorine, chlorine, bromine or iodine; Y is -OR1; PG is hydrogen; R1 is hydrogen or C1-C6 alkyl; R8 is H; Chiral carbon atoms are marked with *.

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

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

5.

5. The method according to claim 1 or 2, wherein 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.

6. The method according to claim 5, wherein 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.

7. The process according to any one of claims 1 or 2, wherein X is chlorine, bromine or iodine.

8. The process according to claim 7, wherein X is chlorine.

9. The method according to any one of claims 1 or 2, wherein R1 is a C1-C6 alkyl group.

10. The method according to claim 9, wherein R1 is methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl or hexyl. The method according to claim 10 , wherein R 1 is ethyl.

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

13. The method according to any one of claims 1 or 2, wherein Y is -OR1, and R1 is ethyl or n-butyl.

14. The method according to any one of claims 1 or 2, wherein the compound of formula (III) is methylphosphonium dichloride.

15. The process according to any one of claims 1 or 2, wherein the compound of formula (III) is the only phosphorus-containing reaction starting material.

16. The method according to any one of claims 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 any one of claims 1 or 2, wherein step a) is performed in the presence of a base, which is an inorganic base or an organic base.

20. The method according to claim 19, wherein the molar ratio of (the compound of formula (II) + the above-mentioned base) to the compound of formula (III) is ≥2.5:

1.

21. The method according to claim 20, wherein the molar ratio of (the compound of formula (II) + the above-mentioned base) to the compound of formula (III) is ≥3:

1.

22. The method according to claim 21, wherein the molar ratio of (the compound of formula (II) + the above-mentioned base) to the compound of formula (III) is ≥4:

1.

23. The method of claim 19, wherein 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.

24. The method of claim 19, 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 method according to claim 19 , wherein the organic base is an organic base that does not contain active hydrogen.

26. The method according to claim 25, wherein the organic base containing no active hydrogen is triethylamine, N,N-dimethylaniline or pyridine, wherein the triethylamine, N,N-dimethylaniline and pyridine optionally have 1 to 3 substituents attached to one or more carbon atoms of the tertiary amine, and the substituents are selected from halogen, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C 3-10 Cycloalkyl and C 6-10 Aryl.

27. The process according to any one of claims 1 or 2, wherein step a) is performed in the absence of an additional base.

28. The method according to claim 27, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is ≥4:

1.

29. The method according to any one of claims 1 or 2, wherein step a) is performed under solvent-free conditions or in an inert solvent.

30. The method according to claim 29, wherein the inert solvent is selected from any one or more of amide solvents, hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents.

31. The method according to claim 29, wherein the inert solvent is selected from any one or more of a benzene solvent, an amide solvent, a halogenated hydrocarbon solvent, an ether solvent or an ester solvent.

32. The method according to claim 29, wherein 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.

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

34. The method of claim 33, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

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

36. The process of claim 35, 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.

37. The method of claim 36, wherein the base is NaOH, KOH or Ba(OH)2.

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

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

40. The method according to claim 39, wherein in step b-1), the reaction temperature is 0°C to 80°C. The method according to claim 40, wherein in step b-1), the reaction temperature is 20°C to 60°C.

42. The method according to claim 41, wherein in step b-1), the reaction temperature is 30°C to 60°C.

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