Method for preparing glufosinate

Abstract

A preparation method for glufosinate or its salts, their enantiomers or mixtures of enantiomers in any ratio, which is particularly suitable for the preparation of glufosinate and greatly shortens the steps of the existing preparation process, especially in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material.

Description

Detailed Description of the Invention

[0001] [Field of the Invention] The present invention relates to a method for preparing glufosinate.

[0002] [Background of the invention] Glufosinate is an important herbicide.

[0003] [Summary of the Invention] The present invention relates to a process for preparing glufosinate of formula (I) or a salt thereof, its enantiomer or a mixture of enantiomers in all ratios, the process comprising: [ka] a) a compound of formula (II) or a salt thereof, its enantiomer or a mixture of its enantiomers in all ratios, [ka] with one or more compounds of formula (III) or a mixture thereof, the 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); [ka] b) reacting the intermediate, whether isolated or not, in the presence of water and an acid or a base to obtain glufosinate (I) or a salt thereof, an enantiomer thereof or a mixture of enantiomers in all ratios; Equipped with Wherein, when PG is an amino protecting group, the method may further include a step of removing the amino protecting group; Here, LG is Hal 1 , -OTs or [ka] and; Hal 1 and Hal 2 are each independently a halogen, e.g., fluorine, chlorine, bromine, or iodine; PG is hydrogen or an amino protecting group; the amino protecting group is preferably -C(=O)R, -C(=O)OR or -S(=O)R; A is -NHR1, -NR1R 1’ or -OR1; R, R1, R 1’ , R2, R3 and R4 are each independently C1 to C6 alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, C 6~12 R2 is selected from the group consisting of aralkyl, 5- to 14-membered heteroaryl and 3- to 10-membered heterocyclyl, and when the mixture comprises a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture comprises 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 either R3 or R4; Chiral carbon atoms * It is labeled with; However, the following conditions apply: 1) The compound of formula (II) [ka] isn't it; 2) The compound of formula (III) [ka] isn't it; 3) The compound of formula (IV) [ka] is not; or 4) The compound of formula (V) [ka] isn't it; The present invention provides a method in which at least one of the above is satisfied.

[0004] The present invention further relates to a process for preparing enantiomerically pure glufosinate of formula (I) or a salt thereof, comprising the steps of: [ka] The method comprises: a1) an enantiomerically pure compound of formula (II) or a salt thereof, [ka] A compound of formula (III), [ka] or one or more compounds or mixtures of formula (III); the 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); [ka] b1) reacting the intermediate, whether isolated or not, in the presence of water and an acid or a base to obtain enantiomerically pure glufosinate (I) or a salt thereof; Including, Wherein, when PG is an amino protecting group, the method may further include a step of removing the amino protecting group; Where: LG is Hal 1 , -OTs or [ka] and; Hal 1 and Hal 2 are each independently a halogen, e.g., fluorine, chlorine, bromine, or iodine; PG is hydrogen or an amino protecting group; the amino protecting group is preferably -C(=O)R, -C(=O)OR or -S(=O)R; A is -NHR1, -NR1R 1’ or -OR1; R, R1, R 1’ , R2, R3 and R4 are each independently C1 to C6 alkyl, C 3~10 Cycloalkyl, C 6~10 Aryl, C 6~12 R2 is selected from the group consisting of aralkyl, 5- to 14-membered heteroaryl and 3- to 10-membered heterocyclyl, and when the mixture comprises a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the mixture comprises 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 either R3 or R4; Chiral carbon atoms * It is labeled with; However, the following conditions apply: 1) The compound of formula (II) [ka] isn't it; 2) The compound of formula (III) [ka] isn't it; 3) The compound of formula (IV) [ka] is not; or 4) The compound of formula (V) [ka] isn't it; The present invention provides a method in which at least one of the above is satisfied.

[0005] In certain embodiments, one compound of formula (III) is used.

[0006] In certain embodiments, a mixture of one compound of formula (IV) and one compound of formula (V) is used, to which a compound of formula (III) can be further added in any ratio.

[0007] Further, the enantiomeric ratio, as the (L):(D)-enantiomers or (D):(L)-enantiomers, is 50.5:49.5 to 99.5:0.5.

[0008] Furthermore, the enantiomeric ratio, as the (L):(D)-enantiomers, is 50.5:49.5 to 99.5:0.5.

[0009] In some embodiments, R is C1-C6 alkyl or C6- 10 It is aryl, preferably methyl, ethyl, tert-butyl, phenyl or p-methylphenyl.

[0010] In some embodiments, the PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3, or [ka] It is.

[0011] In some embodiments, the Hal 1 is chlorine, bromine or iodine.

[0012] In some embodiments, LG is chlorine, bromine, iodine, -OTs or [ka] It is.

[0013] In some embodiments, the Hal 2 is chlorine.

[0014] In some embodiments, the R, R 1’ , R2, R3 and R4 are each independently C1 to C6 alkyl or C6 to C 12 It is aralkyl, and preferably C1 to C4 alkyl or benzyl.

[0015] In some embodiments, R and R 1’ are each independently ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or benzyl.

[0016] In some embodiments, A is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0017] In some embodiments, R2 is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably n-propyl, isopropyl or n-butyl.

[0018] In some embodiments, R3 is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably n-propyl, isopropyl or n-butyl.

[0019] In some embodiments, R4 is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl, preferably n-propyl, isopropyl or n-butyl.

[0020] In certain embodiments, the mixture is a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), where the molar ratio of the compounds of formula (IV) to the 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), where the molar ratio of the compounds of formula (V) to the 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), where the molar ratio of the compounds of formula (IV) to the compounds of formula (V) is (0.9-1.1):1.

[0021] Furthermore, in the above step a) or a1), the reaction can proceed at room temperature, and the reaction temperature can be 20 to 200° C., preferably 90 to 140° C., taking into consideration the reaction efficiency.

[0022] Furthermore, the above step a) or a1) is carried out in the presence of a base.

[0023] Furthermore, the base in the above step a) or a1) is an organic base or ammonia.

[0024] Furthermore, in the above step a) or a1), the organic base is selected from the group consisting of organic amines, pyridine derivatives having 1 to 3 substituents bonded to one or more carbon atoms in pyridine or a heterocycle, and piperidine derivatives having 1 to 3 substituents bonded to one or more carbon atoms in piperidine or a heterocycle.

[0025] Additionally, the organic base is selected from the group consisting of triethylamine, piperidine, or pyridine.

[0026] Furthermore, in the above step a) or a1), the molar ratio of the base to the total amount of the compound of formula (III) and the compound of formula (V) is (1-10):1.

[0027] Furthermore, in the above step a) or a1), the reaction is carried out under solvent-free conditions or in an inert solvent.

[0028] Furthermore, in the above 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.

[0029] Further, in the above step a) or a1), the inert solvent is selected from one or more of chlorobenzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

[0030] Further, in the above step a) or a1), the molar ratio of the compound or mixture of formula (III) to the compound of formula (II) is 1:(0.8-10), preferably 1:(1-3); or the molar ratio of the compound of formula (II) to the compound or mixture of formula (III) is 1:(0.8-10), preferably 1:(1-3).

[0031] Furthermore, the total reaction time of the above 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.

[0032] Furthermore, in the above step b) or b1), an inorganic acid or an organic acid is added.

[0033] Further, the inorganic acid is hydrochloric acid or sulfuric acid.

[0034] Furthermore, in the above step b) or b1), the base is an inorganic base or an organic base.

[0035] Further, 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.

[0036] Further, the base is NaOH, KOH or Ba(OH)2.

[0037] Furthermore, in the above step b) or b1), the reaction temperature is 20 to 150°C.

[0038] In some embodiments, the present disclosure provides a compound of formula (II): [ka] or a salt thereof, wherein the compound of formula (II) is [ka] The present invention provides a compound of formula (II) or a salt thereof, which is selected from the group consisting of:

[0039] In some embodiments, the present disclosure provides the use of the above compounds in the preparation of glufosinate or a salt thereof, or L-glufosinate or a salt thereof.

[0040] The method of the present invention is particularly suitable for preparing glufosinate, and substantially reduces the steps of existing preparation processes. In particular, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when an enantiomerically pure raw material (e.g., the enantiomeric excess (% ee) is more than 90%) is used, the enantiomeric excess (% ee) of the prepared L-glufosinate is, for example, more than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90% or 95%.

[0041] Unless otherwise stated, terms used in the specification and claims have the following meanings:

[0042] The term "amino protecting group" refers to a group that can be attached to the nitrogen atom in an amino group to protect the amino group from participating in a reaction and can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following protecting groups: Formula -C(=O)OR a (In the formula, R a is, for example, methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; b (In the formula, R b is methyl, ethyl, phenyl, trifluoromethyl, etc.); an amide group of the formula -S(=O)2-R c (In the formula, R c is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like.

[0043] The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight-chain and branched-chain groups, having 1 to 18 carbon atoms. Preferred are alkyls having 1 to 6 carbon atoms (i.e., C1-C6 alkyls), such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, and pentyl. Alkyl can be substituted or unsubstituted, and if substituted, the substituents can be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

[0044] C1-C4 alkyl is a straight or branched chain containing saturated hydrocarbon chain having 1 to 4 carbon atoms. It can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl.

[0045] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, etc., or bicyclic, including spiro, fused or bridged ring systems (bicyclo[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl or bicyclo[5.2.0]nonyl, decahydronaphthalene, etc.), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents. Cycloalkyl has 3 to 15 carbon atoms. For example, "C 3~10 The term "cycloalkyl" refers to a saturated monocyclic or polycyclic (e.g., bicyclic) hydrocarbon ring having 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with one or more (e.g., 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0046] As used herein, the term "heterocyclyl" refers to a heterocyclic ring having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms and, within the ring, C(=O), O, S, S(=O), S(=O), and NRd (In the formula, R d is a hydrogen atom, C 1~6 Alkyl or C 1~6 Heterocyclyl may be attached to the rest of the molecule via any one of the carbon atoms or nitrogen atoms (if present). In particular, 3- to 10-membered heterocyclyl refers to groups having 3-10 carbon atoms and heteroatom(s) in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidinonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0047] As used herein, the term "aryl" refers to an all-carbon monocyclic or fused-ring polycyclic aromatic group having a conjugated pi-electron system. For example, as used herein, "C 6~10 The term "aryl" refers to an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. Aryl can have one or more (e.g., 1 to 3) suitable substituents (e.g., halogen, -OH, -CN, -NO2, -C 1~6 alkyl).

[0048] The term "aralkyl" preferably refers to aryl-substituted alkyl, where aryl and alkyl are as defined herein. Typically, the aryl group may have 6 to 10 carbon atoms, and the alkyl group may have 1 to 6 carbon atoms. Exemplary aralkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, and phenylbutyl.

[0049] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, containing at least one heteroatom (such as O, N or S), which may be the same or different. Moreover, in each case, it may be benzo-fused. In particular, heteroaryl is selected from the group consisting of thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and benzo derivatives thereof; or pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and benzo derivatives thereof.

[0050] As used herein, a "mixture of enantiomers in all ratios" has the same meaning as a "mixture of enantiomers in any ratio."

[0051] [Detailed Description of the Invention] Example 1a: General method for the preparation of compounds 1-5 [ka] L-homoserine lactone hydrochloride (1a-1) (ee value 99%, 0.1 mol) was added to a round-bottom flask, followed by the addition of alcohol (the molar ratio of homoserine lactone hydrochloride to alcohol was approximately 1:(10-15)). The temperature of the system was lowered to 10°C, and thionyl chloride (0.3 mol) was slowly added dropwise. The temperature of the system was maintained at 10°C and stirred for 30 minutes. The temperature was gradually raised to 35°C, and the reaction was stirred for 20 hours, during which air bubbles were continuously generated. The reaction was monitored by LC-MS or LC until completion (it was necessary to raise the reaction temperature to completely react certain substrates). The temperature of the system was lowered to room temperature, and the remaining thionyl chloride and solvent were distilled off under reduced pressure, and the solid residue was slurried in 100 mL of a mixed solvent of n-hexane and ethyl acetate (the volume ratio of n-hexane to ethyl acetate was 2:1), and the filter cake was obtained by filtration. The wet product 1a-2 was neutralized with aqueous ammonia, the system was adjusted to pH 7-8, and extracted with ethyl acetate. The organic phase was collected, dried, and concentrated to obtain the target product compound 1a-3.

[0052] Example 1b: Preparation of Compound 16 [ka] Process 1 The synthesis was carried out using compound 16-1 as the starting material (see the synthesis described in Weitz, Iris S. et al., Journal of Organic Chemistry (1997), 62(8), pp. 2527-2534). At room temperature, compound 16-1 (40 mmol), DCM (20 ml), carbon tetrachloride (20 ml) and triphenylphosphine (120 mmol) were added to a round-bottom flask, and then stirred at room temperature for 2 hours. TLC showed that the raw material had undergone complete reaction, and compound 16-2 was obtained by column chromatography in 50% yield. MS (ESI): m / z [M+H] + C 11 H 22 Calculated for ClN2O3: 265.13; Found: 265.1. 1H NMR(400 MHz, CDCl3) δ 4.84 (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, 5.6 Hz, 1H), 1.43 (s, 9H).

[0053] Process 2 Compound 16-2 (20 mmol) was added to a round bottom flask, followed by 1,4-dioxane (60 ml) and 36% HCl (16 ml), and the reaction was stirred at room temperature overnight. The reaction solution was concentrated, then aqueous ammonia was added for neutralization and the pH was adjusted to 7-8. The mixture was extracted with ethyl acetate, dried, and concentrated to give compound 16.

[0054] The homoserine analogs in the table below were prepared by the methods of Example 1a, Example 1b, or analogous methods known in the art. [Table 1] TIFF0007620111000025.tif163149 TIFF0007620111000026.tif163149 TIFF0007620111000027.tif217149 TIFF0007620111000028.tif203149 TIFF0007620111000029.tif137149

[0055] Example 2 [ka] At -10°C, n-propanol (0.9mol), triethylamine (0.9mol) and n-hexane (450ml) were added to a round bottom flask, and dichloro(methyl)phosphane (0.45mol) was added dropwise via a constant pressure dropping funnel for about 1 hour. The reaction was warmed to 0°C and allowed to proceed for 2 hours for complete reaction. The mixture was filtered, the solid was washed with n-hexane (150ml x 2), and the mother liquor was evaporated under reduced pressure to remove the solvent. Dipropylmethylphosphonite (colorless liquid, yield: 86%, content: 94%) was obtained by fractionation (fractionation temperature is below 60°C). MS (ESI): m / z [M+H] + C7H 18 Calculated O2P: 165.11; Measured: 165.1. 1 H NMR(400 MHz, CDCl3) δ 3.65 (ddddt, J = 10.0,6.2, 5.0, 3.5, 1.7 Hz, 4H), 1.51 (q, J = 7.1 Hz, 4H), 1.12 (dd, J = 8.3, 1.2Hz, 3H), 0.82 (td, J = 7.4, 1.1 Hz, 6H). 13 C NMR(100 MHz, CDCl3) δ 68.2, 24.6, 19.9, 10.2. 31 P NMR(160 MHz, CDCl3) δ 33.5.

[0056] The following compounds were prepared following methods similar to those described above. [Table 2]

[0057] Example 3 [ka] Under nitrogen atmosphere at -10°C, a solution of the compound of formula (IV) (0.6 eq, 90% purity) in chlorobenzene was added to a round-bottom flask, and a solution of dichloro(methyl)phosphane (0.6 eq, 98% purity) in chlorobenzene was added dropwise at a rate of 1 d / s via a constant pressure dropping funnel. After the addition was complete, the reaction was stirred for 10 min (at which point the corresponding compound of formula (III) was formed). [ka] (wherein Hal 2 is chlorine, and R2 is R3 or R4). Then, a chlorobenzene solution of the compound of formula (IIa) (1.0 eq) and triethylamine (1.2 eq, 98% purity) was added thereto at a rate of 4 d / s, and stirring was continued for 30 minutes after the dropwise addition. The reaction was warmed to room temperature and stirred for 1 hour, then the temperature was raised to 90°C, and the reaction was continued for 12 hours. The reaction was naturally cooled to room temperature, suction filtered, and the filter cake was washed with chlorobenzene (150 mL x 3). The filtrate was rotary evaporated to remove chlorobenzene, resulting in the intermediate. 100 mL of concentrated hydrochloric acid (36%) was added to the intermediate, heated to 90°C, and the reaction was allowed to proceed for 10 hours. MS detection showed that the intermediate had disappeared, and the mixture was naturally cooled to room temperature, rotary evaporated to remove the solvent, and 95% ethanol (300 mL) was added. The solution was heated to reflux until the crude product was completely dissolved, then allowed to cool for crystallization, filtered, and dried to obtain L-glufosinate hydrochloride.

[0058] According to the above method, L-glufosinate hydrochloride was prepared from the substrates in the table below. The reaction yield and ee value of the product are shown in the table below. [Table 3] TIFF0007620111000035.tif91149

[0059] Example 4 [ka] Under nitrogen atmosphere and at -10°C, a solution of diethylmethylphosphonite (861.7 g, 0.55 eq, 90% purity) in chlorobenzene (6.0 kg) was added to a 20 L jacketed glass reactor, and a solution of dichloro(methyl)phosphane (679.5 g, 0.55 eq, 98% purity) in chlorobenzene (2.0 kg) was added dropwise at a rate of 5 d / s via a constant pressure dropping funnel. After the addition was complete, the reaction was stirred for 10 min (at which time chloro(ethoxy)(methyl)phosphane [ka] could be produced). Then, a solution of the compound of formula (IIa)-butyl ester (2.0 kg, 1.0 eq) and triethylamine (1.2 kg, 1.1 eq, 98% purity) in chlorobenzene (8.0 kg) was added thereto at a rate of 10 d / s, and stirring was continued for 30 minutes after the dropwise addition. The reaction was warmed to room temperature and stirred for 30 minutes, then the temperature was raised to 90°C, and the reaction was continued for 2 hours. The reaction was naturally cooled to room temperature, suction filtered, and the filter cake was washed with chlorobenzene (2.5 L x 2). The filtrate was rotary evaporated to remove chlorobenzene, resulting in the intermediate. 4.2 kg of 36% wt. hydrochloric acid was added to the intermediate, heated to 95°C, and the reaction was allowed to proceed for 10 hours, while the butanol produced was distilled off. MS detection showed that the intermediate had disappeared, and the mixture was naturally cooled to room temperature, rotary evaporated to remove the solvent, and 95% ethanol (6 L) was added. The solution was heated to reflux until the crude product was completely dissolved, then naturally cooled for crystallization, filtered, and dried to obtain L-glufosinate hydrochloride (white, 88% yield, 98% ee value).

[0060] In addition to those described herein, various modifications to the present invention will be apparent to those skilled in the art according to the above description. Such modifications are intended to be within the scope of the appended claims. Each reference cited in this specification (including all patents, patent applications, journal articles, books, and any other disclosures) is incorporated herein by reference in its entirety.

Claims

1. A process for preparing glufosinate of formula (I) or a salt thereof, its enantiomer or a mixture of enantiomers in all ratios, the process comprising: 【Chemistry 1】 a) a compound of formula (II) or a salt thereof, its enantiomer or a mixture of its enantiomers in all ratios, 【Chemistry 2】 with one or more compounds of formula (III) or a phosphorus-containing mixture, the phosphorus-containing 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); 【Chemistry 3】 b) reacting the product obtained in step a), whether it is isolated or not, in the presence of water and an acid or a base to obtain glufosinate (I) or a salt thereof, an enantiomer thereof or a mixture of enantiomers in all ratios; Equipped with Wherein, when PG is an amino protecting group, the method may further include a step of removing the amino protecting group; Here, LG is Hal １ , -OTs or 【Chemistry 4】 and Hal １ and Hal ２ are each independently fluorine, chlorine, bromine or iodine; PG is hydrogen or an amino protecting group; A is -NHR １ , -NR １ R １’ Or -OR １ and R １ , R １’ , R ２ , R ３ and R ４ are each independently １ ~C ６ Alkyl, C ３～１０ Cycloalkyl, C ６～１０ Aryl, C ６～１２ aralkyl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl; when the phosphorus-containing mixture comprises a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the phosphorus-containing mixture comprises 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), R ２ is R ３ Or R ４ either Chiral carbon atoms ＊ is labeled with; However, under the following conditions: 1) The compound of formula (II) 【Chemistry 5】 isn't it; 2) The compound of formula (III) 【Chemistry 6】 isn't it; 3) The compound of formula (IV) 【Chemistry 7】 is not; or 4) The compound of formula (V) 【Chemistry 8】 isn't it; At least one of the following is satisfied: A method comprising:

2. A process for preparing enantiomerically pure glufosinate of formula (I) or a salt thereof, comprising: 【Chemistry 9】 The method comprises: a1) reacting an enantiomerically pure compound of formula (II) or a salt thereof with 【Chemistry 10】 A compound of formula (III), 【Chemistry 11】 or one or more compounds of formula (III) or a phosphorus-containing mixture; the phosphorus-containing 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); 【Chemistry 12】 b1) reacting the product obtained in step a1), whether it is isolated or not, in the presence of water and an acid or a base to obtain enantiomerically pure glufosinate (I) or a salt thereof; Equipped with Wherein, when PG is an amino protecting group, the method may further include a step of removing the amino protecting group; Where: LG is Hal １ , -OTs or 【Chemistry 13】 and Hal １ and Hal ２ are each independently fluorine, chlorine, bromine or iodine; PG is hydrogen or an amino protecting group; A is -NHR １ , -NR １ R １’ Or -OR １ and R １ , R １’ , R ２ , R ３ and R ４ are each independently １ ~C ６ Alkyl, C ３～１０ Cycloalkyl, C ６～１０ Aryl, C ６～１２ aralkyl, 5- to 14-membered heteroaryl, and 3- to 10-membered heterocyclyl; when the phosphorus-containing mixture comprises a mixture of one or more compounds of formula (IV) and one or more compounds of formula (III), or when the phosphorus-containing mixture comprises 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), R ２ is R ３ Or R ４ either Chiral carbon atoms ＊ is labeled with; However, under the following conditions: 1) The compound of formula (II) 【Chemistry 14】 isn't it; 2) The compound of formula (III) 【Chemistry 15】 isn't it; 3) The compound of formula (IV) 【Chemistry 16】 is not; or 4) The compound of formula (V) 【Chemistry 17】 isn't it; At least one of the following is satisfied: A method comprising:

3. The method according to claim 1 or 2, wherein the amino protecting group is -C(=O)R, -C(=O)OR or -S(=O)2R, wherein R is selected from the group consisting of C1-C6 alkyl, C3-10 cycloalkyl, C6-10 aryl, C6-12 aralkyl, 5- to 14-membered heteroaryl and 3- to 10-membered heterocyclyl.

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

5. R is C １ ~C ６ Alkyl or C ６ ~ １０ The method according to claim 3, characterized in that it is aryl.

6. The method of claim 3, wherein R is methyl, ethyl, tert-butyl, phenyl or p-methylphenyl.

7. PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3 or 【Chemistry 18】 The method according to claim 1 or 2, characterized in that

8. Hal １ 3. The method according to claim 1 or 2, characterized in that is chlorine, bromine or iodine.

9. LG is -OTs or 【Chemistry 19】 The method according to claim 1 or 2, characterized in that 10. The method according to claim 1 or 2, wherein LG is chlorine, bromine or iodine.

11. The method according to claim 1 or 2, characterized in that Hal 2 is chlorine.

12. R １ , R １’ , R ２ , R ３ and R ４ However, each independently, C １ ~C ６ Alkyl or C ６ ~C １２ 3. The method according to claim 1 or 2, characterized in that the compound is aralkyl.

13. The method of claim 1 or 2, wherein R 1 , R 1′ , R 2 , R 3 and R 4 are each independently C 1 -C 4 alkyl or benzyl.

14. R １ and R １’ The method of claim 1 or 2, wherein each is independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, or benzyl.

15. The method according to claim 1 or 2, wherein A is --NHR 1 or --NR 1 R 1 .

16. The method according to claim 1 or 2, characterized in that A is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

17. R ２ 3. The process according to claim 1 or 2, characterized in that is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

18. The method according to claim 1 or 2, wherein R 3 is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

19. The method according to claim 1 or 2, wherein R 4 is methyl, ethyl, n-propyl, isopropyl, n-butyl or isobutyl.

20. The method according to claim 1 or 2, wherein R 2 or R 3 or R 4 is n-propyl, isopropyl or n-butyl.

21. The method of claim 1 or 2, wherein the phosphorus-containing 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 the compounds of formula (IV) to the compounds of formula (III) is (0.9-1.1):1 or (0.05-1.1):1; or the phosphorus-containing 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 the compounds of formula (V) to the compounds of formula (III) is (0.9-1.1):1 or (0.05-1.1):1; or the phosphorus-containing 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 the compounds of formula (IV) to the compounds of formula (V) is (0.9-1.1):

1.

22. The method according to claim 1 or 2, characterized in that in step a) or a1), the reaction temperature is from 20 to 200° C.

23. The method according to claim 1 or 2, characterized in that in step a) or a1), the reaction temperature is 90 to 140°C.

24. 3. The process according to claim 1 or 2, characterized in that step a) or a1) is carried out in the presence of a base.

25. 25. The process according to claim 24, characterized in that the base in step a) or a1) is an organic base selected from the group consisting of organic amines, pyridine derivatives having 1 to 3 substituents attached to one or more carbon atoms in the pyridine or heterocyclic ring, piperidine or piperidine derivatives having 1 to 3 substituents attached to one or more carbon atoms in the heterocyclic ring, or ammonia.

26. The method of claim 25, wherein the organic base is selected from the group consisting of triethylamine, piperidine or pyridine.

27. The method according to claim 24, characterized in that in step a) or a1), the molar ratio of the base to the total amount of the compound of formula (III) and the compound of formula (V) is (1-10):

1.

28. 3. The process according to claim 1 or 2, characterized in that in step a) or a1), the reaction is carried out under solvent-free conditions or in an inert solvent.

29. 29. The method according to claim 28, characterized in that 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.

30. The method according to claim 28, wherein in step a) or a1), the inert solvent is selected from one or more of a benzene solvent, an amide solvent, a halogenated hydrocarbon solvent, an ether solvent or an ester solvent.

31. 29. The process according to claim 28, characterized in that in step a) or a1), the inert solvent is selected from any one or more of chlorobenzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethylsulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

32. 3. The method according to claim 1 or 2, characterized in that in step a) or a1), the molar ratio of the compound of formula (III) or the phosphorus-containing mixture to the compound of formula (II) is 1:(0.8-10); or the molar ratio of the compound of formula (II) to the compound of formula (III) or the phosphorus-containing mixture is 1:(0.8-10).

33. The method of claim 1 or 2, characterized in that in step a) or a1), the molar ratio of the compound of formula (III) or the phosphorus-containing mixture to the compound of formula (II) is 1:(1-3); or the molar ratio of the compound of formula (II) to the compound of formula (III) or the phosphorus-containing mixture is 1:(1-3).

34. 3. The method according to claim 1 or 2, characterized in that in step b) or b1), an inorganic or organic acid is added.

35. The method according to claim 34, characterized in that the inorganic acid is hydrochloric acid or sulfuric acid.

36. 3. The process according to claim 1 or 2, characterized in that in step b) or b1), the base is an inorganic or organic base selected from the group consisting of alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates or alkaline earth metal bicarbonates.

37. The method according to claim 36, wherein in step b) or b1), the base is NaOH, KOH or Ba(OH) 2 .

38. 3. The process according to claim 1 or 2, characterized in that in step b) or b1), the reaction temperature is from 20 to 150° C.

39. The compound of formula (II) 【Table 1】 and / or The compound of formula (IV) 【Chemistry 20】 and / or The compound of formula (V) 【Chemistry 21】 The method according to claim 1 or 2, characterized in that

40. A compound of formula (II) or a salt thereof, 【Chemical 22】 The compound of formula (II) 【Chemistry 23】 or a salt thereof, selected from the group consisting of:

41. 41. Use of a compound according to claim 40 in the preparation of glufosinate or a salt thereof, or L-glufosinate or a salt thereof.

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