Process for the preparation of glufosinate-ammonium

Abstract

A process for the preparation of glufosinate-ammonium or salts, enantiomers or mixtures of enantiomers in all proportions thereof, which is particularly suitable for the preparation of glufosinate-ammonium, substantially shortens the steps of the existing preparation process. In particular in the preparation of L-glufosinate-ammonium, the product can effectively maintain the ee value of the starting material.

Description

Invention Field

[0001] This invention relates to a method for preparing glufosinate. Background of the Invention

[0003] Glufosinate is an important herbicide. Invention Overview

[0005] This invention provides a method for preparing glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in all proportions, the method comprising the following steps:

[0006]

[0007] a) Make a compound of formula (II) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions.

[0008]

[0009] Reaction with one or more compounds of formula (III) or mixtures thereof;

[0010] The aforementioned mixture is a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V); or, a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (III); or, a mixture comprising one or more compounds of formula (V) and one or more compounds of formula (III); or, a mixture comprising one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V).

[0011]

[0012] b) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to give glufosinate (I) or its salt, enantiomers or mixtures of enantiomers in all proportions;

[0013] When PG is an amino protecting group, the step of removing the amino protecting group may also be included;

[0014] Where: LG is Hal 1 -OTs or

[0015] Hal 1 and Hal 2 Each can be a halogen, such as fluorine, chlorine, bromine, or iodine;

[0016] PG is a hydrogen or amino protecting group, preferably -C(=O)R, -C(=O)OR or -S(=O)2R;

[0017] A is -NHR1, -NR1R 1’ Or -OR1;

[0018] R, R1, R 1’ R2, R3, and R4 are each independently selected from C1-C6 alkyl groups, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl, 5-14-membered heteroaryl and 3-10-membered heterocyclic, and when the mixture contains a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture contains a mixture of one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V), R2 is any one of R3 and R4.

[0019] Chiral carbon atoms are marked with an asterisk (*).

[0020] The condition is that at least one of the following conditions is met:

[0021] 1) The compound of formula (II) is not

[0022] 2) The compound of formula (III) is not

[0023] 3) The compound of formula (IV) is not or

[0024] 4) The compound of formula (V) is not

[0025] The present invention further provides a preparation of enantiomeric glufosinate of formula (I).

[0026]

[0027] Or a method for preparing its salt, the method comprising the following steps:

[0028] a1) A compound of formula (II) or a salt thereof that is enantiomerically pure.

[0029]

[0030] Reaction with compound of formula (III),

[0031]

[0032] Or react with one or more compounds of formula (III) or mixtures thereof;

[0033] The aforementioned mixture is a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V); or, a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (III); or, a mixture comprising one or more compounds of formula (V) and one or more compounds of formula (III); or, a mixture comprising one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V).

[0034]

[0035] b1) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to obtain enantiomeric pure glufosinate (I) or its salt.

[0036] When PG is an amino protecting group, the step of removing the amino protecting group may also be included;

[0037] in:

[0038] LG is Hal 1 -OTs or

[0039] Hal 1 and Hal 2 Each can be a halogen, such as fluorine, chlorine, bromine, or iodine;

[0040] PG is a hydrogen or amino protecting group, preferably -C(=O)R, -C(=O)OR or -S(=O)2R;

[0041] A is -NHR1, -NR1R 1’ Or -OR1;

[0042] R, R1, R 1’ R2, R3, and R4 are each independently selected from C1-C6 alkyl groups, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl, 5-14-membered heteroaryl and 3-10-membered heterocyclic, and when the mixture contains a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture contains a mixture of one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V), R2 is any one of R3 and R4.

[0043] Chiral carbon atoms are marked with an asterisk (*).

[0044] The condition is that at least one of the following conditions is met:

[0045] 1) The compound of formula (II) is not

[0046] 2) The compound of formula (III) is not

[0047] 3) The compound of formula (IV) is not or

[0048] 4) The compound of formula (V) is not

[0049] In some specific embodiments, a compound of formula (III) is used.

[0050] In some specific embodiments, a mixture of a compound of formula (IV) and a compound of formula (V) is used, and a compound of formula (III) may also be added to the mixture in any proportion.

[0051] Furthermore, the aforementioned enantiomeric ratio is (L):(D)-enantiomer or (D):(L)-enantiomer in the range of 50.5:49.5 to 99.5:0.5.

[0052] Furthermore, the aforementioned enantiomeric ratios are (L):(D)-enantiomers ranging from 50.5:49.5 to 99.5:0.5.

[0053] In some embodiments, R is a C1-C6 alkyl group or C 6-10 Aryl group, preferably methyl, ethyl, tert-butyl, phenyl or p-methylphenyl.

[0054] In some embodiments, the aforementioned PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3, or

[0055] In some implementations, the aforementioned Hal 1 It can be chlorine, bromine, or iodine.

[0056] In some implementations, LG is chlorine, bromine, iodine, -OTs, or

[0057] In some implementations, the aforementioned Hal 2 It is chlorine.

[0058] In some implementation schemes, the aforementioned R1, R 1’ R2, R3, and R4 are each independently C1-C6 alkyl or C 6-12 Aryl group, preferably C1-C4 alkyl or benzyl.

[0059] In some implementations, the aforementioned R1 and R1’ Each can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or benzyl.

[0060] In some implementations, A is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0061] In some embodiments, the aforementioned R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, preferably n-propyl, isopropyl, or n-butyl.

[0062] In some embodiments, the aforementioned R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, preferably n-propyl, isopropyl, or n-butyl.

[0063] In some embodiments, the aforementioned R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl, preferably n-propyl, isopropyl, or n-butyl.

[0064] In some specific embodiments, the aforementioned mixture is a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), wherein the molar ratio of compounds of formula (IV) to compounds of formula (III) is (0.9–1.1):1 or (0.05–1.1):1; or the mixture is a mixture of one or more compounds of formula (V) and one or more compounds of formula (III), wherein the molar ratio of compounds of formula (V) to compounds of formula (III) is (0.9–1.1):1 or (0.05–1.1):1; or the mixture is a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V), wherein the molar ratio of compounds of formula (IV) to compounds of formula (V) is (0.9–1.1):1.

[0065] Furthermore, in the aforementioned step a) or a1), the reaction can occur at room temperature, and the reaction temperature can be 20 to 200°C. Considering the efficiency of the reaction, 90 to 140°C is preferred.

[0066] Furthermore, the aforementioned step a) or a1) is carried out in the presence of a base.

[0067] Furthermore, the base in step a) or a1) above is an organic base or ammonia.

[0068] Further, in step a) or a1), the organic base is selected from organic amines, pyridine, or pyridine derivatives having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle, piperidine, or piperidine derivatives having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle.

[0069] Furthermore, the aforementioned organic base is selected from triethylamine, piperidine, or pyridine.

[0070] Furthermore, in step a) or a1) above, the molar ratio of the base to the sum of the amounts of compound (III) and compound (V) is (1-10):1.

[0071] Furthermore, in the aforementioned step a) or a1), the reaction is carried out under solvent-free conditions or in an inert solvent.

[0072] Further, in step a) or a1), 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.

[0073] Further, in step a) or a1) above, the inert solvent is selected from any one or more of chlorobenzene, thallium, 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.

[0074] Further, in the aforementioned step a) or a1), the molar ratio of the compound of formula (III) or the mixture to the compound of formula (II) is 1:(0.8 to 10), preferably 1:(1 to 3); or the molar ratio of the compound of formula (II) to the compound of formula (III) or the mixture is 1:(0.8 to 10), preferably 1:(1 to 3).

[0075] Furthermore, the total reaction time of the aforementioned step a) or a1) is 0.5 hours to 25 hours, preferably 1 hour to 20 hours or 1 hour to 15 hours, and most preferably 1 hour to 5 hours.

[0076] Furthermore, in step b) or b1) above, an inorganic acid or an organic acid is added.

[0077] Furthermore, the aforementioned inorganic acid is hydrochloric acid or sulfuric acid.

[0078] Furthermore, in step b) or b1) above, the base is an inorganic base or an organic base.

[0079] Furthermore, the aforementioned alkali is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate.

[0080] Furthermore, the aforementioned base is NaOH, KOH, or Ba(OH)2.

[0081] Furthermore, in step b) or b1) above, the reaction temperature is 20–150 °C.

[0082] In some embodiments, the present invention provides compounds of formula (II) or salts thereof.

[0083]

[0084] The compounds of formula (II) are selected from:

[0085]

[0086] In some embodiments, the present invention provides the use of the above-described compounds in the preparation of glufosinate or its salts, or L-glufosinate or its salts.

[0087] The method of this invention is particularly suitable for the preparation of glufosinate, significantly shortening the steps of existing preparation processes. Especially in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when using enantiomeric pure raw materials (e.g., enantiomeric excess percentage (%ee) greater than 90%), the enantiomeric excess percentage (%ee) of the prepared L-glufosinate can be, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0088] Unless otherwise stated, the terms used in the specification and claims shall have the following meanings.

[0089] The term "amino protecting group" refers to a group that can be attached to a nitrogen atom of an amino group, thereby protecting the amino group from reaction and allowing it to be easily removed in subsequent reactions. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0090] Formula -C(=O)OR a The urethane group, wherein R a For example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; formula -C(=O)R b The amide group, wherein R b For example, methyl, ethyl, phenyl, trifluoromethyl, etc.; formula -S(=O)2-R c N-sulfonyl derivatives - groups, wherein R cExamples include toluene, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc.

[0091] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched groups with 1 to 18 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C1-C6 alkyl groups) are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. Alkyl groups can be substituted or unsubstituted; when substituted, the substituent can be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

[0092] C1-C4 alkyl groups are straight-chain or branched saturated hydrocarbon chains containing 1 to 4 carbon atoms. They can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl groups.

[0093] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spirocyclic, fused, or bridged systems (such as bicyclic [1.1.1]pentyl, bicyclic [2.2.1]heptyl, bicyclic [3.2.1]octyl, or bicyclic [5.2.0]nonyl, decahydronaphthyl, etc.), optionally substituted with one or more (such as one to three) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 "Cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl) with 3 to 10 cyclic carbon atoms, which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0094] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) atoms selected from C(=O), O, S, S(=O), S(=O)2, and NR. d Groups containing heteroatoms, wherein R d Represents a hydrogen atom or C 1-6 Alkyl or halogenated -C 1-6Alkyl group; the heterocyclic group may be attached to the remainder of the molecule by any one of the carbon atoms or a nitrogen atom (if present). In particular, 3-10 membered heterocyclic groups are groups having 3-10 carbon atoms and heteroatoms in the ring, such as, but not limited to, ethylene oxide, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolyl, pyrrolidone, imidazoalkyl, pyrazolyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0095] As used herein, the term "aryl" refers to a fully carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated π-electron system. For example, as used herein, the term "C 6-10 "Aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituented by one or more (such as 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, C). 1-6 Alkyl groups, etc., are substituted.

[0096] As used herein, the term "aralkyl" preferably refers to an aryl-substituted alkyl group, wherein the aryl group and the alkyl group are as defined herein. Typically, the aryl group may have 6-10 carbon atoms, and the alkyl group may have 1-6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0097] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic, or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13, or 14 ring atoms, particularly 1, 2, 3, 4, 5, 6, 9, or 10 carbon atoms, and containing at least one heteroatom that may be the same or different (the heteroatom being, for example, oxygen, nitrogen, or sulfur), and additionally, in each case, may be benzofused. Specifically, the heteroaryl group is selected from thienyl, furanyl, pyrroleyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiazolyl, etc., and their benzo[derivatives]; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo[derivatives].

[0098] As used in this article, “a mixture of enantiomers in all proportions” has the same meaning as “a mixture of enantiomers in any proportion”. Invention Details

[0100] Example 1a: General preparation method of compounds 1-5

[0101]

[0102] In a round-bottom flask, add L-homoserine lactone hydrochloride (1a-1) (ee value 99%, 0.1 mol), and alcohol (molar ratio of homoserine lactone hydrochloride to alcohol approximately 1:(10-15)). Lower the system temperature to 10°C and slowly add 0.3 mol of thionyl chloride. Maintain the system temperature at 10°C and stir the reaction for 30 min. Gradually raise the temperature to 35°C and stir the reaction for 20 h, continuously generating bubbles. Monitor the reaction progress using LC-MS or LC until the reaction is complete (some substrates require further heating to ensure complete reaction). Lower the system temperature to room temperature, remove the remaining thionyl chloride and solvent by vacuum distillation, and slurry the solid residue with 100 mL of a hexane / ethyl acetate mixture (volume ratio of hexane to ethyl acetate 2:1). Filter and collect the filter cake. Neutralize the wet product 1a-2 with ammonia water, adjust the pH to 7-8, extract with ethyl acetate, collect the organic phase, dry and concentrate to obtain the target product compound 1a-3.

[0103] Example 1b: Preparation of Compound 16

[0104]

[0105] Step 1

[0106] The synthesis was carried out using compound 16-1 as a starting material (its synthesis can be found in: Weitz, Iris S. et al., Journal of Organic Chemistry (1997), 62(8), 2527-2534). Compound 16-1 (40 mmol), DCM (20 ml), carbon tetrachloride (20 ml), and triphenylphosphine (120 mmol) were added to a round-bottom flask at room temperature and stirred for 2 h. TLC analysis showed complete reaction of the starting material, and compound 16-2 was obtained by column chromatography in 50% yield.

[0107] MS(ESI): m / z[M+H] + C 11 H 22 Calculated value of ClN2O3: 265.13; Measured value: 265.1.

[0108] 1 H NMR (400MHz, CDCl3) δ4.84 (td, J=8.8, 4.0Hz, 1H), 3.80–3.44 (m, 2H), 3.12 (s, 3H) ,2.97(s,3H),2.16–2.03(m,1H),1.96(ddt,J=14.5,8.9,5.6Hz,1H),1.43(s,9H).

[0109] Step 2

[0110] Compound 16-2 (20 mmol) was added to a round-bottom flask, followed by 1,4-dioxane (60 ml) and 36% HCl (16 ml). The mixture was stirred overnight at room temperature. The reaction solution was concentrated, neutralized with ammonia water, and the pH was adjusted to 7-8. The solution was extracted with ethyl acetate, dried, and concentrated to obtain compound 16.

[0111] The homoserine analogues listed below were prepared by the methods of Examples 1a and 1b, or by methods similar to those known in the art.

[0112]

[0113]

[0114]

[0115]

[0116] Example 2

[0117]

[0118] At -10℃, n-propanol (0.9 mol), triethylamine (0.9 mol), and n-hexane (450 ml) were added to a round-bottom flask. Methyl phosphorus dichloride (0.45 mol) was added dropwise using a constant-pressure dropping funnel over approximately 1 hour. The reaction was then carried out at 0℃ for 2 hours. The mixture was filtered, and the solid was washed with n-hexane (150 ml x 2). The mother liquor was evaporated under reduced pressure to remove the solvent, and then fractionated (at a temperature not exceeding 60℃) to obtain dipropyl methyl phosphite, a colorless liquid with a yield of 86% and a purity of 94%.

[0119] MS(ESI): m / z[M+H] + C7H 18 Calculated O2P value: 165.11; Measured value: 165.1.

[0120] 1 H NMR (400MHz, CDCl3) δ3.65(ddddt,J=10.0,6.2,5.0,3.5,1.7Hz,4H),1.51(q,J=7.1Hz,4H),1.12(dd,J=8.3,1.2Hz,3H),0.82(td,J=7.4,1.1Hz,6H).

[0121] 13 C NMR (100MHz, CDCl3) δ68.2, 24.6, 19.9, 10.2.

[0122] 31 P NMR (160MHz, CDCl3) δ 33.5.

[0123] Following a similar method described above, the following compounds were prepared:

[0124]

[0125]

[0126] Example 3

[0127]

[0128] Under a nitrogen atmosphere at -10°C, a chlorobenzene solution of compound (IV) (0.6 eq, 90% purity) was added to a round-bottom flask. A chlorobenzene solution of methyl phosphorus dichloride (0.6 eq, 98% purity) was then added dropwise using a constant-pressure dropping funnel at a rate of 1 d / s. After the addition was complete, the mixture was stirred for 10 min (at which point the corresponding compound (III) was formed). Hal 2 A chlorobenzene solution of compound (IIa) (1.0 eq) and triethylamine (1.2 eq, 98% purity) was continuously added dropwise at a rate of 4 d / s. After the addition was complete, the mixture was stirred for 30 min, heated to room temperature and stirred for 1 h, then heated to 90 °C and reacted for 12 h. After naturally cooling to room temperature, the mixture was filtered, and the filter cake was washed with chlorobenzene (150 mL x 3). The filtrate was then evaporated to dryness to obtain an intermediate. 100 mL of concentrated hydrochloric acid (36%) was added to the intermediate, and the mixture was heated to 90 °C and reacted for 10 h. MS analysis showed that the intermediate had disappeared. After naturally cooling to room temperature, the solvent was evaporated, and 95% ethanol (300 mL) was added and refluxed until the crude product was completely dissolved. The mixture was allowed to cool naturally to crystallize, filtered, and dried to obtain L-glufosinate hydrochloride.

[0129] According to the above method, L-glufosinate hydrochloride was prepared from the substrates in the table below, and the reaction yield and product ee value are shown in the table below.

[0130]

[0131] Example 4

[0132]

[0133] Under a nitrogen atmosphere and at -10°C, a chlorobenzene (6.0 kg) solution of diethyl methylphosphonite (861.7 g, 0.55 eq, 90% purity) was added to a 20 L double-walled glass reactor. A chlorobenzene (2.0 kg) solution of methyl phosphorus dichloride (679.5 g, 0.55 eq, 98% purity) was then added dropwise using a constant-pressure dropping funnel at a rate of 5 d / s. After the addition was complete, the mixture was stirred for 10 min (at which point chloro(ethoxy)(methyl)phosphine was generated). The compound of formula (IIa)-butyl ester (2.0 kg, 1.0 eq) and a solution of triethylamine (1.2 kg, 1.1 eq, 98% purity) in chlorobenzene (8.0 kg) were added dropwise at a rate of 10 d / s. After the addition was complete, the mixture was stirred for 30 min, heated to room temperature and stirred for another 30 min, then heated to 90 °C and reacted for 2 h. After naturally cooling to room temperature, the mixture was filtered, and the filter cake was washed with chlorobenzene (2.5 L x 2). The filtrate was then evaporated to dryness to obtain an intermediate. 4.2 kg of 36% wt. hydrochloric acid was added to the intermediate, and the mixture was heated to 95 °C and reacted for 10 h. The butanol produced during the reaction was distilled off simultaneously. MS analysis showed that the intermediate had disappeared. After naturally cooling to room temperature, the solvent was evaporated, and 95% ethanol (6 L) was added and refluxed until the crude product was completely dissolved. The mixture was allowed to cool naturally to crystallize, filtered, and dried to obtain a white L-glufosinate hydrochloride with a yield of 88% and an ee value of 98%.

[0134] In addition to those described herein, various modifications to the invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other disclosures) are incorporated herein by reference in their entirety.

Claims

1. A method for preparing glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in all proportions, characterized in that: The method includes the following steps: ， a) Make a compound of formula (II) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions. ， Reaction with one or more compounds of formula (III) or mixtures thereof; The mixture is a mixture comprising one or more formula (IV) compounds and one or more formula (V) compounds; or, a mixture comprising one or more formula (IV) compounds and one or more formula (III) compounds; or, a mixture comprising one or more formula (V) compounds and one or more formula (III) compounds; or, a mixture comprising one or more formula (III) compounds, one or more formula (IV) compounds and one or more formula (V) compounds; ； ； ； b) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to give glufosinate (I) or its salt, enantiomers or mixtures of enantiomers in all proportions; When PG is an amino protecting group, the step of removing the amino protecting group may also be included; in: LG is Hal 1 -OTs or ; Hal 1 and Hal 2 Each is an independent halogen selected from fluorine, chlorine, bromine or iodine; PG is a hydrogen or amino protecting group, wherein the amino protecting group is -C(=O)R, -C(=O)OR, or -S(=O)2R, wherein R is selected from C1-C6 alkyl groups, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; A is -NHR1, -NR1R 1’ Or -OR1; R1, R 1’ R2, R3, and R4 are each independently selected from C1-C6 alkyl groups, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl, 5-14-membered heteroaryl and 3-10-membered heterocyclic, and when the mixture contains a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture contains a mixture of one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V), R2 is any one of R3 and R4. Chiral carbon atoms are labeled ; The condition is that at least one of the following conditions is met: 1) The compound of formula (II) is not ; 2) The compound of formula (III) is not ; 3) The compound of formula (IV) is not ;or 4) The compound of formula (V) is not .

2. A method for preparing enantiomeric glufosinate or its salt of formula (I), characterized in that: The method includes the following steps: ， a1) A compound of formula (II) or a salt thereof that is enantiomerically pure ， Reaction with compound of formula (III), ， Or react with one or more compounds of formula (III) or mixtures thereof; The mixture is a mixture comprising one or more formula (IV) compounds and one or more formula (V) compounds; or, a mixture comprising one or more formula (IV) compounds and one or more formula (III) compounds; or, a mixture comprising one or more formula (V) compounds and one or more formula (III) compounds; or, a mixture comprising one or more formula (III) compounds, one or more formula (IV) compounds and one or more formula (V) compounds; ； ； ； b1) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to obtain enantiomeric pure glufosinate (I) or its salt. When PG is an amino protecting group, the step of removing the amino protecting group may also be included; in: LG is Hal 1 -OTs or ; Hal 1 and Hal 2 Each is an independent halogen selected from fluorine, chlorine, bromine or iodine; PG is a hydrogen or amino protecting group, wherein the amino protecting group is -C(=O)R, -C(=O)OR, or -S(=O)2R, wherein R is selected from C1-C6 alkyl groups, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; A is -NHR1, -NR1R 1’ Or -OR1; R1, R 1’ R2, R3, and R4 are each independently selected from C1-C6 alkyl groups, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl, 5-14-membered heteroaryl and 3-10-membered heterocyclic, and when the mixture contains a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture contains a mixture of one or more compounds of formula (III), one or more compounds of formula (IV) and one or more compounds of formula (V), R2 is any one of R3 and R4. Chiral carbon atoms are labeled ; The condition is that at least one of the following conditions is met: 1) The compound of formula (II) is not ; 2) The compound of formula (III) is not ; 3) The compound of formula (IV) is not ;or 4) The compound of formula (V) is not .

3. The method according to claim 1, characterized in that: The enantiomeric ratio is (L):(D)-enantiomer or (D):(L)-enantiomer in the range of 50.5:49.5 to 99.5:0.

5.

4. The method according to claim 3, characterized in that: The enantiomeric ratio is (L):(D)-enantiomers with a ratio of 50.5:49.5 to 99.5:0.

5.

5. The method according to claim 1 or 2, characterized in that: R is a C1-C6 alkyl group or C 6-10 Aryl.

6. The method according to claim 5, characterized in that: R is methyl, ethyl, tert-butyl, phenyl, or p-methylphenyl.

7. The method according to any one of claims 1-4, characterized in that: The PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3 or .

8. The method according to any one of claims 1-4, characterized in that: The Hal 1 It can be chlorine, bromine, or iodine.

9. The method according to any one of claims 1-4, characterized in that: LG represents chlorine, bromine, iodine, -OTs, or .

10. The method according to claim 9, characterized in that: LG represents chlorine, bromine, or iodine.

11. The method according to any one of claims 1-4, characterized in that: The Hal 2 It is chlorine.

12. The method according to any one of claims 1-4, characterized in that: The R1, R 1’ R2, R3, and R4 are each independently C1-C6 alkyl or C 6-12 Aryl group.

13. The method according to claim 12, characterized in that: The R1, R 1’ R1, R2, R3 and R4 are each independently C1-C4 alkyl or benzyl.

14. The method according to any one of claims 1-4, characterized in that: The R1 and R 1’ Each can be independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or benzyl.

15. The method according to any one of claims 1-4, characterized in that: A is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

16. The method according to any one of claims 1-4, characterized in that: R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

17. The method according to claim 16, characterized in that: R2 is n-propyl, isopropyl, or n-butyl.

18. The method according to any one of claims 1-4, characterized in that: R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

19. The method according to claim 18, characterized in that: R3 is n-propyl, isopropyl, or n-butyl.

20. The method according to any one of claims 1-4, characterized in that: R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl, or isobutyl.

21. The method according to claim 20, characterized in that: R4 is n-propyl, isopropyl, or n-butyl.

22. The method according to any one of claims 1-4, characterized in that: The mixture is a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), wherein the molar ratio of compounds of formula (IV) to compounds of formula (III) is (0.9~1.1):1; or the mixture is a mixture of one or more compounds of formula (V) and one or more compounds of formula (III), wherein the molar ratio of compounds of formula (V) to compounds of formula (III) is (0.9~1.1):1; or the mixture is a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V), wherein the molar ratio of compounds of formula (IV) to compounds of formula (V) is (0.9~1.1):

1.

23. The method according to any one of claims 1-4, characterized in that: The mixture is a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), wherein the molar ratio of compounds of formula (IV) to compounds of formula (III) is (0.05~1.1):1; or the mixture is a mixture of one or more compounds of formula (V) and one or more compounds of formula (III), wherein the molar ratio of compounds of formula (V) to compounds of formula (III) is (0.05~1.1):1; or the mixture is a mixture comprising one or more compounds of formula (IV) and one or more compounds of formula (V), wherein the molar ratio of compounds of formula (IV) to compounds of formula (V) is (0.9~1.1):

1.

24. The method according to any one of claims 1-4, characterized in that: In step a) or a1), the reaction temperature is 20~200℃.

25. The method according to claim 24, characterized in that: In step a) or a1), the reaction temperature is 90~140℃.

26. The method according to any one of claims 1-4, characterized in that: Step a) or a1) is carried out in the presence of a base.

27. The method according to claim 26, characterized in that: The base in step a) or a1) is an organic base or ammonia.

28. The method according to claim 27, characterized in that: In step a) or a1), the organic base is an organic amine.

29. The method according to claim 27, characterized in that: In step a) or a1), the organic base is selected from pyridine or a pyridine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle, piperidine or a piperidine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocycle.

30. The method according to claim 27, characterized in that: The organic base is selected from triethylamine, piperidine, or pyridine.

31. The method according to claim 26, characterized in that: In step a) or a1), the molar ratio of the base to the sum of the amounts of compound (III) and compound (V) is (1~10):

1.

32. The method according to any one of claims 1-4, characterized in that: In step a) or a1), the reaction is carried out under solvent-free conditions or in an inert solvent.

33. The method according to claim 32, characterized in that: In step a) or a1), the inert solvent is selected from one or more of amide solvents, hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents.

34. The method according to claim 32, characterized in that: In step a) or a1), the inert solvent is selected from one or more of amide solvents, halocarbon solvents, ether solvents or ester solvents.

35. The method according to claim 32, characterized in that: In step a) or a1), the inert solvent is a benzene-based solvent or a halogenated hydrocarbon solvent.

36. The method according to claim 32, characterized in that: In step a) or a1), the inert solvent is selected from any one or more of chlorobenzene, thiol, 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.

37. The method according to any one of claims 1-4, characterized in that: In step a) or a1), the molar ratio of compound (III) or the mixture to compound (II) is 1:(0.8~10); or the molar ratio of compound (II) to compound (III) or the mixture is 1:(0.8~10).

38. The method according to any one of claims 1-4, characterized in that: In step a) or a1), the molar ratio of compound (III) or the mixture to compound (II) is 1:(1~3); or the molar ratio of compound (II) to compound (III) or the mixture is 1:(1~3).

39. The method according to any one of claims 1-4, characterized in that: In step b) or b1), an inorganic acid or an organic acid is added.

40. The method according to claim 39, characterized in that: The inorganic acid is hydrochloric acid or sulfuric acid.

41. The method according to any one of claims 1-4, characterized in that: In step b) or b1), the base is an inorganic base or an organic base.

42. The method according to claim 41, characterized in that: The alkali is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate.

43. The method according to claim 42, characterized in that: The alkali is NaOH, KOH or Ba(OH)2.

44. The method according to any one of claims 1-4, characterized in that: In step b) or b1), the reaction temperature is 20~150℃.

45. The method according to any one of claims 1-4, characterized in that: The compounds of formula (II) are selected from: 。 46. ​​The method according to any one of claims 1-4, characterized in that: The compound of formula (IV) is , or , and / or the compound of formula (V) is .

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