METHODS OF PREPARING GLUFOSINATE

Abstract

Disclosed is a method of preparing glufosinate, and specifically a method of preparing glufosinate represented by formula (1) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising a step of hydrolyzing a compound of formula (III) to generate a compound of formula (1). Due to a distinctive reaction mechanism adopted in the method of the present disclosure, a halogenated hydrocarbon by-product in the Michaelis-Arbuzov reaction can be avoided and thus the destructive impact of the halogenated hydrocarbon by-product on ozone in the aerosphere can be prevented. Accordingly, the equipment and engineering investments required for the separation, purification, and collection of the foregoing by-product are eliminated, and the potential environmental and safety hazards brought by the foregoing by-product are also avoided.

##STR00001##

Claims

1. A method of preparing glufosinate represented by formula (I) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising: ##STR00047## hydrolyzing a compound of formula (III) to generate a compound of formula (I); ##STR00048## wherein: X.sup.1 is halogen; Y is OR.sup.3 or N(R.sup.4)(R.sup.5); R.sup.1 and R.sup.2 are each independently selected from hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.2-C.sub.6 alkenyl group, a C.sub.2-C.sub.6 alkynyl group, a C.sub.3-C.sub.6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a C.sub.6-C.sub.10 aryl group, or a five-membered to ten-membered heteroaryl group, or R.sup.1 and R.sup.2 form a three-membered to six-membered heterocycloalkyl group together with the N atom to which they are attached, wherein the C.sub.1-C.sub.6 alkyl group, the C.sub.2-C.sub.6 alkenyl group, the C.sub.2-C.sub.6 alkynyl group, the C.sub.3-C.sub.6 cycloalkyl group, the three-membered to six-membered heterocycloalkyl group, the C.sub.6-C.sub.10 aryl group, or the five-membered to ten-membered heteroaryl group is optionally substituted by halogen, a carboxyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a C.sub.1-C.sub.3 alkyl group, a C.sub.1-C.sub.3 haloalkyl group, a C.sub.1-C.sub.3 alkoxy group, a C.sub.3-C.sub.6 cycloalkyl group, or a C.sub.6-C.sub.10 aryl group; R.sup.3, R.sup.4, and R.sup.5 are each independently selected from hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.2-C.sub.6 alkenyl group, a C.sub.2-C.sub.6 alkynyl group, a C.sub.3-C.sub.6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a C.sub.6-C.sub.10 aryl group, or a five-membered to ten-membered heteroaryl group, or R.sup.4 and R.sup.5 form a three-membered to six-membered heterocycloalkyl group together with the N atom to which they are attached, wherein the C.sub.1-C.sub.6 alkyl group, the C.sub.2-C.sub.6 alkenyl group, the C.sub.2-C.sub.6 alkynyl group, the C.sub.3-C.sub.6 cycloalkyl group, the three-membered to six-membered heterocycloalkyl group, the C.sub.6-C.sub.10 aryl group, or the five-membered to ten-membered heteroaryl group is optionally substituted by halogen, a carboxyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a C.sub.1-C.sub.3 alkyl group, a C.sub.1-C.sub.3 haloalkyl group, a C.sub.1-C.sub.3 alkoxy group, a C.sub.3-C.sub.6 cycloalkyl group, or a C.sub.6-C.sub.10 aryl group; and * denotes a chiral carbon atom.

2. The method of claim 1, wherein the hydrolysis is performed in presence of an acid or an alkali.

3. The method of claim 2, wherein the acid is at least one selected from hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid, and acetic acid.

4. The method of claim 2, wherein the alkali is selected from hydroxide, carbonate, bicarbonate or basic carbonate of alkali metal or alkaline earth metal, ammonia, organic alkali, or organic amine.

5. The method of claim 1, wherein the hydrolysis is performed at a temperature of 30? C. to 140? C.

6. The method of claim 1, wherein the enantiomer of the glufosinate is L-glufosinate or D-glufosinate.

7. The method of claim 1, wherein the mixture of its enantiomers in any ratio comprises L-glufosinate and D-glufosinate in a ratio of 0.1:99.9 to 99.9:0.1.

8. The method of claim 1, wherein the halogen is selected from fluorine, chlorine, or bromine; the C.sub.1-C.sub.6 alkyl group is selected from a methyl group, an ethyl group, a propyl group, or an isopropyl group; the C.sub.2-C.sub.6 alkenyl group is selected from a vinyl group, a propenyl group, a 1-butenyl group, a 2-butenyl group, or an isobutenyl group; the C.sub.2-C.sub.6 alkynyl group is selected from an ethynyl group, a propynyl group, a 1-butynyl group, or 2-butynyl group; the C.sub.3-C.sub.6 cycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group; the three-membered to six-membered heterocycloalkyl group is selected from a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group comprising at least one heteroatom of N, O, or S; the C.sub.6-C.sub.10 aryl group is selected from a phenyl group or a naphthyl group; and/or the five-membered to ten-membered heteroaryl group is selected from a pyrazinyl group, a pyrazolyl group, a pyrrolyl group, a furyl group, a thienyl group, a thiazolyl group, or a pyridyl group.

9. The method of claim 1, wherein Ri, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each independently selected from hydrogen, a C.sub.1-C.sub.6 alkyl group, or a C.sub.3-C.sub.6 cycloalkyl group.

10. The method of claim 1, wherein the compound of formula (III) is prepared by subjecting a compound of formula (II) ##STR00049## to a reaction with any one of the following compounds or mixtures: a compound of formula (IV); a compound of formula (V); a compound of formula (IV) and a compound of formula (V); a compound of formula (IV) and a compound of formula (VII); a compound of formula (V) and a compound of formula (VII); or a compound of formula (IV), a compound of formula (V), and a compound of formula (VII); ##STR00050## wherein: X.sup.2 is halogen; R.sup.1, R.sup.2, X.sup.1, Y, and * are as defined in any one of claims 1, 8 or 9; and R.sup.9 and R.sup.10 are each independently selected from hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.2-C.sub.6 alkenyl group, a C.sub.2-C.sub.6 alkynyl group, a C.sub.3-C.sub.6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a C.sub.6-C.sub.10 aryl group, or a five-membered to ten-membered heteroaryl group, or R.sup.9 and R.sup.10 form a three-membered to six-membered heterocycloalkyl group together with the N atom to which they are attached, wherein the C.sub.1-C.sub.6 alkyl group, the C.sub.2-C.sub.6 alkenyl group, the C.sub.2-C.sub.6 alkynyl group, the C.sub.3-C.sub.6 cycloalkyl group, the three-membered to six-membered heterocycloalkyl group, the C.sub.6-C.sub.10 aryl group, or the five-membered to ten-membered heteroaryl group is optionally substituted by halogen, a carboxyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a C.sub.1-C.sub.3 alkyl group, a C.sub.1-C.sub.3 haloalkyl group, a C.sub.1-C.sub.3 alkoxy group, a C.sub.3-C.sub.6 cycloalkyl group, or a C.sub.6-C.sub.10 aryl group.

11. The method of claim 10, wherein the reaction is performed in presence of a deacid reagent.

12. The method of claim 11, wherein the deacid reagent is selected from NR.sup.11R.sup.12R.sup.13, wherein R.sup.1, R.sup.12, and R.sup.13 are each independently selected from hydrogen, a C.sub.1-C.sub.6 alkyl group, a C.sub.2-C.sub.6 alkenyl group, a C.sub.2-C.sub.6 alkynyl group, a C.sub.3-C.sub.6 cycloalkyl group, a three-membered to six-membered heterocycloalkyl group, a C.sub.6-C.sub.10 aryl group, or a five-membered to ten-membered heteroaryl group, or any two of R.sup.1, R.sup.12, and R.sup.13 form a three-membered to six-membered heterocycloalkyl group together with the N atom to which they are attached, wherein the C.sub.1-C.sub.6 alkyl group, the C.sub.2-C.sub.6 alkenyl group, the C.sub.2-C.sub.6 alkynyl group, the C.sub.3-C.sub.6 cycloalkyl group, the three-membered to six-membered heterocycloalkyl group, the C.sub.6-C.sub.10 aryl group, or the five-membered to ten-membered heteroaryl group is optionally substituted by halogen, a carboxyl group, a hydroxyl group, a cyano group, an amino group, a nitro group, a C.sub.1-C.sub.3 alkyl group, a C.sub.1-C.sub.3 haloalkyl group, a C.sub.1-C.sub.3 alkoxy group, a C.sub.3-C.sub.6 cycloalkyl group, or a C.sub.6-C.sub.10 aryl group.

13. The method of claim 11, wherein a molar ratio among the compound of formula (II), total usage of the compounds of formulas (IV), (V) and (VII), and the deacid reagent is 1: (0.9-5): (0.9-5).

14. The method of claim 10, wherein the reaction is performed in absence of a solvent or in presence of an organic solvent.

15. The method of claim 14, wherein the organic solvent is selected from an aromatic hydrocarbon solvent, an alkane solvent, a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, an amide solvent, or a sulfur-containing solvent.

16. The method of claim 10, wherein the reaction is performed at a temperature of ?20? C. to 10? C. for 1 to 15 hours, and then at 10? C. to 120? C. for 0.5 to 24 hours.

17. The method of claim 1, wherein the compound of formula (III) is prepared by a method comprising the following steps: a) subjecting a compound of formula (II) to a reaction with any one of the following compounds or mixtures: a compound of formula (IV); a compound of formula (V); a compound of formula (IV) and a compound of formula (V); a compound of formula (IV) and a compound of formula (VII); a compound of formula (V) and a compound of formula (VII); or a compound of formula (IV), a compound of formula (V), and a compound of formula (VII); ##STR00051## to obtain the compound of formula (VI); ##STR00052## and b) preparing the compound of formula (III) via a reaction with the compound of formula (VI); wherein X.sup.1, X.sup.2, Y, Ri, R.sup.2, R.sup.9, R.sup.10, and * are as defined in claim 10.

18. The method of claim 17, wherein the reaction in step a) is performed at a temperature of ?20? C. to 10? C. for 1 to 15 hours.

19. The method of claim 17, wherein the reaction in step b) is performed at a temperature of 10? C. to 120? C. for 0.5 to 24 hours.

20. A method of preparing glufosinate represented by formula (I) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising the following steps: ##STR00053## in absence of a solvent or in presence of an organic solvent, subjecting a compound of formula (II) ##STR00054## to a reaction with any one of the following compounds or mixtures: a compound of formula (IV); a compound of formula (V); a compound of formula (IV) and a compound of formula (V); a compound of formula (IV) and a compound of formula (VII); a compound of formula (V) and a compound of formula (VII); or a compound of formula (IV), a compound of formula (V), and a compound of formula (VII), to obtain an intermediate; and ##STR00055## hydrolyzing the intermediate under an acidic, neutral, or alkaline condition, to obtain a compound of formula (I); wherein X.sup.1, X.sup.2, Y, R.sup.1, R.sup.2, R.sup.9, R.sup.10, and * are as defined in claim 10.

21. A compound formula (III) or its salt or enantiomer, or a mixture of its enantiomers in any ratio; ##STR00056## wherein X.sup.1, Y, R.sup.1, R.sup.2, and * are as defined in any one of claims 1, 8 or 9.

22. The compound of formula (III) or its salt or enantiomer, or the mixture of its enantiomers in any ratio of claim 21, wherein the compound of formula (III) or its salt or enantiomer, or the mixture of its enantiomers in any ratio is prepared by the steps in the method of any one of claims 10 to 19.

23. A method of preparing a compound of formula (III) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising: ##STR00057## subjecting a compound of formula (II) ##STR00058## to a reaction with any one of the following compounds or mixtures: a compound of formula (IV); a compound of formula (V); a compound of formula (IV) and a compound of formula (V); a compound of formula (IV) and a compound of formula (VII); a compound of formula (V) and a compound of formula (VII); or a compound of formula (IV), a compound of formula (V), and a compound of formula (VII); ##STR00059## wherein X.sup.1, X.sup.2, Y, R.sup.1, R.sup.2, R.sup.9, R.sup.10, and * are as defined in claim 10.

24. A method of preparing a compound of formula (III) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising: ##STR00060## preparing the compound of formula (III) from a reaction with the compound of formula ##STR00061## wherein X.sup.1, Y, R.sup.1, R.sup.2, and * are as defined in claim 10.

25. A compound formula (VI) or its salt or enantiomer, or a mixture of its enantiomers in any ratio; ##STR00062## wherein X.sup.1, Y, R.sup.1, R.sup.2, and * are as defined in any one of claims 1, 8 or 9.

26. The compound of formula (VI) or its salt or enantiomer, or the mixture of its enantiomers in any ratio of claim 25, wherein the compound of formula (VI) or its salt or enantiomer, or the mixture of its enantiomers in any ratio is prepared by the steps in the method of any one of claims 17 to 19.

27. A method of preparing a compound of formula (VI) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising: ##STR00063## subjecting a compound of formula (II) ##STR00064## to a reaction with any one of the following compounds or mixtures: a compound of formula (IV); a compound of formula (V); a compound of formula (IV) and a compound of formula (V); a compound of formula (IV) and a compound of formula (VII); a compound of formula (V) and a compound of formula (VII); or a compound of formula (IV), a compound of formula (V), and a compound of formula (VII); ##STR00065## wherein XI, X.sup.2, Y, RI, R.sup.2, R.sup.9, R.sup.10, and * are as defined in claim 10.

28. A method of preparing a compound of formula (VI) or its salt or enantiomer, or a mixture of its enantiomers in any ratio, comprising: ##STR00066## subjecting a compound of formula (II); ##STR00067## to a reaction with a compound of formula (VII) and a compound of formula (VIII); ##STR00068## wherein X.sup.1, X.sup.2, Y, R.sup.1, R.sup.2, and * are as defined in claim 10.

29. A composition, comprising a compound of formula (IV) and a compound of formula (V); a compound of formula (IV) and a compound of formula (VII); or a compound of formula (IV), a compound of formula (V), and a compound of formula (VII); ##STR00069## wherein X.sup.2, R.sup.1, R.sup.2, R.sup.9, R.sup.10, and * are as defined in claim 10.

30. (canceled)

31. The method of claim 3, wherein the acid is selected from hydrochloric acid or sulfuric acid.

32. The method of claim 4, wherein the alkali is selected from sodium hydroxide or triethylamine.

33. The method of claim 5, wherein the hydrolysis is performed at a temperature of 70? C. to 110? C.

34. The method of claim 7, wherein the mixture of its enantiomers in any ratio comprises L-glufosinate and D-glufosinate in a ratio of 50:50 to 99.9:0.1.

35. The method of claim 9, wherein Ri, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are each independently selected from hydrogen, a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a tert-butyl group, a pentyl group, a hexyl group, a cyclopropyl group, a cyclobutyl group, a cyclopentyl group, or a cyclohexyl group.

36. The method of claim 13, wherein a molar ratio among the compound of formula (II), total usage of the compounds of formulas (IV), (V) and (VII), and the deacid reagent is 1: (1.05-1.5): (1.05-1.5).

37. The method of claim 15, wherein the organic solvent is at least one selected from toluene and chlorobenzene.

Description

DETAILED DESCRIPTION

[0089] The present disclosure is further described below with reference to examples, but these examples are not intended to limit the scope of the present disclosure. Unless otherwise stated, all reactants used in the examples are commercially available; and instruments and devices used in synthesis experiments and product analyses and detection are all conventional instruments and devices commonly used in organic syntheses.

Example 1: Synthesis of L-glufosinate hydrochloride (1-1)

[0090] ##STR00027##

(1) Synthesis of compound (IV-1)

[0091] ##STR00028##

[0092] Diethylamine (26.28 g, 0.359 mol, 2.1 eq.) was added into 100 g of toluene, the mixture was cooled to ?5? C. to 5? C. in a nitrogen atmosphere, and methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was then added dropwise with the temperature of the mixture maintained at ?5? C. to 5? C. After the addition was completed, compound (IV-1) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

[0093] m/z (ESI) 154.08 ([M+1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 144.57.

(2) Synthesis of compound (VI-1)

[0094] In a nitrogen atmosphere, the compound (II-1) (26.92 g, 0.163 mol, 0.95 eq.) and diethylamine (11.89 g, 0.163 mol, 0.95 eq.) was added successively into 50 g of toluene. After stirring evenly, the above compound (IV-1) was added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5 to 10? C., and the reaction was held for 2 hours after the dropwise addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-1), which can be directly used for the next reaction.

[0095] m/z (ESI) 283.11 ([M+1].sup.+, 100%).

(3) Synthesis of compound (III-1)

[0096] In a nitrogen atmosphere, the above compound (VI-1) solution was slowly heated to 80 to 85? C. for 10 hours to obtain a solution of compound (III-1), which can be directly used for the next reaction.

[0097] m/z (ESI) 247.18 ([M-C.sub.1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 71.40.

(4) Synthesis of compound (1-1)

[0098] Added 150 g of 30% hydrochloric acid into the above compound (III-1) solution and heated it to 95 to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 30.1 g of the target product (1-1), yield: 83.5%, assay: 98.1%, and 97.3% ee value.

[0099] m/z (ESI) 182.07 ([M+1].sup.+, 100%);

[0100] .sup.31P NMR (243 MHz, D.sub.2O) ?: 53.67;

[0101] .sup.1H NMR (600 MHz, D.sub.2O) ?: 4.10 (t, J=6.1 Hz, 1H), 2.25-2.05 (m, 2H), 1.99-1.75 (m, 2H), 1.47 (d, J=14.1 Hz, 3H);

[0102] .sup.13C NMR (151 MHz, D.sub.2O) 5:171.29, 52.96 (d, J=16.6 Hz), 25.25 (d, J=93.0 Hz), 22.72 (d, J=2.6 Hz), 13.61 (d, J=92.5 Hz).

Example 2: Synthesis of L-glufosinate hydrochloride (1-1)

[0103] ##STR00029##

(1) Synthesis of compound (IV-2)

[0104] ##STR00030##

[0105] Slowly added dimethylamine (16.20 g, 0.360 mol, 2.1 eq.) into 100 g of pre cooled toluene to ?5? C. to 5? C. in a nitrogen atmosphere, and then methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was added dropwise with the temperature of the mixture maintained at ?5? C. to 5? C. After the dropwise addition was completed, compound (IV-2) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

[0106] m/z (ESI) 126.04 ([M+1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 150.61.

(2) Synthesis of compound (VI-2)

[0107] In a nitrogen atmosphere, the compound (II-1) (27.20 g, 0.164 mol, 0.96 eq.) was added into 50 g of toluene. Dimethylamine (7.41 g, 0.164 mol, 0.96 eq.) was slowly added under ice bath cooling, and the inner temperature of the reaction solution was controlled at 5? C. to 10? C., then the above compound (IV-2) solution was added dropwise. The reaction was held for 2 hours after the dropwise addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-2), which can be directly used for the next reaction.

[0108] m/z (ESI) 255.12 ([M+1].sup.+, 100%).

(3) Synthesis of compound (III-2)

[0109] In a nitrogen atmosphere, the above compound (VI-2) solution was slowly heated to 80? C. to 85? C. for 7 hours to obtain a solution of compound (III-2), which can be directly used for the next reaction.

[0110] m/z (ESI) 219.14 ([M-C.sub.1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 78.20.

(4) Synthesis of compound (I-1)

[0111] Added 150 g of 30% hydrochloric acid into the above compound (III-2) solution and heated it to 95? C. to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 28.7 g of the target product (I-1), yield: 78.5%, assay: 97.6%, and 95.3% ee value.

Example 3: Synthesis of L-glufosinate hydrochloride (I-1)

[0112] ##STR00031##

(1) Synthesis of compound (V-1)

[0113] ##STR00032##

[0114] Diethylamine (51.30 g, 0.701 mol, 4.1 eq.) was added into 150 g of toluene, the mixture was cooled to ?5? C. to 5? C. in a nitrogen atmosphere, and methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was then added dropwise with the temperature of the mixture maintained at ?5? C. to 5? C. After the dropwise addition was completed, compound (V-1) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

[0115] m/z (ESI) 191.17 ([M+1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 79.29.

(2) Synthesis of compound (VI-1)

[0116] In a nitrogen atmosphere, the compound (II-2) (32.84 g, 0.163 mol, 0.95 eq.) was added into 50 g of toluene, and the above compound (V-1) was added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5? C. to 10? C. The reaction was held for 2 hours after the dripping was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-1), which can be directly used for the next reaction.

[0117] m/z (ESI) 283.13 ([M+1].sup.+, 100%).

(3) Synthesis of compound (III-1)

[0118] In a nitrogen atmosphere, the above compound (VI-1) solution was slowly heated to 80 to 85? C. for 10 hours to obtain a solution of compound (III-1), which can be directly used for the next reaction.

[0119] m/z (ESI) 247.17 ([M-C.sub.1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 71.10.

(4) Synthesis of compound (I-1)

[0120] Added 150 g of 30% hydrochloric acid into the above compound (III-1) solution and heated it to 95? C. to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 26.7 g of the target product (I-1), yield: 73.5%, assay: 97.5%, and 97.5% ee value.

Example 4: Synthesis of L-glufosinate hydrochloride (I-1)

[0121] ##STR00033##

(1) Synthesis of compound (V-2)

[0122] ##STR00034##

[0123] Slowly added dimethylamine (31.63 g, 0.701 mol, 4.1 eq.) into 150 g of toluene while lowering the temperature to ?5? C. to 5? C. under nitrogen protection. methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at ?5? C. to 5? C. After the dropwise addition was completed, compound (V-2) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

[0124] m/z (ESI) 135.09 ([M+1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 87.63.

(2) Synthesis of compound (VI-2)

[0125] In a nitrogen atmosphere, the compound (II-2) (32.84 g, 0.163 mol, 0.95 eq.) was added into 50 g of toluene, and the above compound (V-2) was added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5? C. to 10? C. The reaction was held for 2 hours after the dropwise addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-2), which can be directly used for the next reaction.

[0126] m/z (ESI) 255.11 ([M+1].sup.+, 100%).

(3) Synthesis of compound (III-2)

[0127] In a nitrogen atmosphere, the above compound (VI-2) solution was slowly heated to 80? C. to 85? C. for 8 hours to obtain a solution of compound (III-2), which can be directly used for the next reaction.

[0128] m/z (ESI) 219.12 ([M-C.sub.1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 77.90.

(4) Synthesis of compound (I-1)

[0129] Added 150 g of 30% hydrochloric acid into the above compound (III-2) solution and heated it to 95? C. to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 25.9 g of the target product (1-1), yield: 70.5%, assay: 96.2%, and 97.3% ee value.

Example 5: Synthesis of DL-glufosinate hydrochloride (1-2)

[0130] ##STR00035##

(1) Synthesis of compound (IV-1)

[0131] ##STR00036##

[0132] Diethylamine (27.53 g, 0.376 mol, 2.2 eq.) was added into 100 g of toluene, the mixture was cooled to ?5? C. to 5? C. in a nitrogen atmosphere, and methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was then added dropwise with the temperature of the mixture maintained at ?5? C. to 5? C. After the addition was completed, compound (IV-1) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

(2) Synthesis of compound (VI-3)

[0133] In a nitrogen atmosphere, the compound (11-3) (27.77 g, 0.168 mol, 0.98 eq.) and diethylamine (12.26 g, 0.168 mol, 0.98 eq.) was added successively into 50 g of toluene. After stirring evenly, the above compound (IV-1) was added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5? C. to 10? C., and the reaction was held for 2 hours after the addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-3), which can be directly used for the next reaction.

(3) Synthesis of compound (111-3)

[0134] In a nitrogen atmosphere, the above compound (VI-3) solution was slowly heated to 80? C. to 85? C. for 10 hours to obtain a solution of compound (111-3), which can be directly used for the next reaction.

(4) Synthesis of compound (1-2)

[0135] Added 150 g of 30% hydrochloric acid into the above compound (111-3) solution and heated it to 95 to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 30.2 g of the target product (1-2), yield: 81.5%, assay: 98.5%.

Example 6: Synthesis of DL-glufosinate hydrochloride (1-2)

[0136] ##STR00037##

(1) Synthesis of compound (IV-2)

[0137] ##STR00038##

[0138] Slowly added dimethylamine (16.20 g, 0.359 mol, 2.1 eq.) into 100 g of toluene while lowering the temperature to ?5 to 5? C. under nitrogen protection. methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was added dropwise while maintaining the system temperature at ?5 to 5? C. After the addition was completed, compound (IV-2) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

(2) Synthesis of compound (VI-4)

[0139] In a nitrogen atmosphere, the compound (11-3) (27.48 g, 0.166 mol, 0.97 eq.) was added into 50 g of toluene, then dimethylamine (7.48 g, 0.166 mol, 0.97 eq.) was slowly added under ice bath cooling, the inner temperature of the reaction solution was controlled at 5? C. to 10? C., then the above compound (IV-2) solution was added dropwise. The reaction was held for 2 hours after the dripping was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-4), which can be directly used for the next reaction.

(3) Synthesis of compound (111-4)

[0140] In a nitrogen atmosphere, the above compound (VI-4) solution was slowly heated to 80? C. to 85? C. for 6 hours to obtain a solution of compound (111-4), which can be directly used for the next reaction.

(4) Synthesis of compound (1-2)

[0141] Added 150 g of 30% hydrochloric acid into the above compound (111-4) solution and heated it to 95? C. to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 28.9 g of the target product (1-2), yield: 77.5%, assay: 96.8%.

Example 7: Synthesis of DL-glufosinate hydrochloride (1-2)

[0142] ##STR00039##

(1) Synthesis of compound (V-1)

[0143] ##STR00040##

[0144] Diethylamine (52.55 g, 0.719 mol, 4.2 eq.) was added into 150 g of toluene, the mixture was cooled to ?5? C. to 5? C. in a nitrogen atmosphere, and methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was then added dropwise with the temperature of the mixture maintained at ?5? C. to 5? C. After the addition was completed, compound (V-1) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

(2) Synthesis of compound (VI-3)

[0145] In a nitrogen atmosphere, the compound (11-4) (32.84 g, 0.163 mol, 0.95 eq.) was added into 50 g of toluene, and the above compound (V-1) was added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5? C. to 10? C. The reaction was held for 2 hours after the addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-3), which can be directly used for the next reaction.

(3) Synthesis of compound (111-3)

[0146] In a nitrogen atmosphere, the above compound (VI-3) solution was slowly heated to 80 to 85? C. for 10 hours to obtain a solution of compound (III-3), which can be directly used for the next reaction.

(4) Synthesis of compound (1-2)

[0147] Added 150 g of 30% hydrochloric acid into the above compound (III-3) solution and heated it to 95? C. to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 25.7 g of the target product (1-2), yield: 71.1%, assay: 97.8%.

Example 8: Synthesis of DL-glufosinate hydrochloride (1-2)

[0148] ##STR00041##

(1) Synthesis of compound (V-2)

[0149] ##STR00042##

[0150] Dimethylamine (31.24 g, 0.693 mol, 4.05 eq.) was slowly added into 150 g of toluene, the mixture was cooled to ?5? C. to 5? C. in a nitrogen atmosphere, and methyldichlorophosphine (20 g, 0.171 mol, 1.0 eq.) was then added dropwise with the temperature of the mixture maintained at ?5? C. to 5? C. After the addition was completed, compound (V-2) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

(2) Synthesis of compound (VI-4)

[0151] In a nitrogen atmosphere, the compound (II-4) (32.84 g, 0.163 mol, 0.95 eq.) was added into 50 g of toluene, and the above compound (V-2) was added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5? C. to 10? C. The reaction was held for 2 hours after the dropwise addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-4), which can be directly used for the next reaction.

(3) Synthesis of compound (III-4)

[0152] In a nitrogen atmosphere, the above compound (VI-4) solution was slowly heated to 80? C. to 85? C. for 8 hours to obtain a solution of compound (III-4), which can be directly used for the next reaction.

(4) Synthesis of compound (1-2)

[0153] Added 150 g of 30% hydrochloric acid into the above compound (III-4) solution and heated it to 95 to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 26.4 g of the target product (1-2), yield: 72.5%, assay: 97.2%.

Example 9: Synthesis of L-glufosinate hydrochloride (I-1)

[0154] ##STR00043##

(1) Synthesis of compound (VI-1)

[0155] In a nitrogen atmosphere, the compound (II-1) (40.37 g, 0.244 mol, 0.95 eq.) and diethylamine (57.24 g, 0.783 mol, 3.05 eq.) was added successively into 150 g of toluene. After stirring evenly, methyldichlorophosphine (30.0 g, 0.257 mol, 1.0 eq.) was then added dropwise under ice bath cooling. The inner temperature of the reaction solution was controlled at 5 to 10? C. The reaction was held for 2 hours after the dropwise addition was completed, nitrogen pressure filtration was then performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-1), which can be directly used for the next reaction.

(2) Synthesis of compound (III-1)

[0156] In a nitrogen atmosphere, the above compound (VI-1) solution was slowly heated to 80 to 85? C. for 10 hours to obtain a solution of compound (III-1), which can be directly used for the next reaction.

(3) Synthesis of compound (I-1)

[0157] Added 150 g of 30% hydrochloric acid into the above compound (III-1) solution and heated it to 95 to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 46.0 g of the target product (1-1), yield: 85.5%, assay: 98.5%, and 97.5% ee value.

Example 10: Synthesis of L-glufosinate hydrochloride (1-1)

[0158] ##STR00044##

(1) Synthesis of compound (VI-5)

[0159] In a nitrogen atmosphere, the compound (II-1) (33.78 g, 0.204 mol, 0.95 eq.) was added into 150 g of toluene. Methyldichlorophosphine (25.1 g, 0.215 mol, 1.0 eq.) was then added dropwise under ice bath cooling, simultaneously ammonia gas (18.46 g, 1.084 mol, 5.05 eq.) was slowly Injected into the mixture. The inner temperature of the reaction solution was controlled at 5? C. to 10? C. The reaction was held for 2 hours after the dropwise addition was completed, nitrogen pressure filtration was then performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-5), which can be directly used for the next reaction.

[0160] m/z (ESI) 227.07 ([M+1].sup.+, 100%).

(2) Synthesis of compound (111-5)

[0161] In a nitrogen atmosphere, the above compound (VI-5) solution was slowly heated to 60? C. to 65? C. for 10 hours to obtain a solution of compound (111-5), which can be directly used for the next reaction.

[0162] m/z (ESI) 191.11 ([M-C.sub.1].sup.+, 100%);

(3) Synthesis of compound (1-1)

[0163] Added 150 g of 30% hydrochloric acid into the above compound (111-5) solution and heated it to 95 to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 31.5 g of the target product (1-1), yield: 69.5%, assay: 97.5%, and 97.2% ee value.

Example 11: Synthesis of L-glufosinate hydrochloride (1-1)

[0164] ##STR00045##

(1) Synthesis of compound (IV-3)

[0165] ##STR00046##

[0166] N-methylaniline (50.73 g, 0.473 mol, 2.05 eq.) was dissolved in 100 g toluene, and cooled to ?5? C. to 5? C. under inert atmosphere, then methyldichlorophosphine (27 g, 0.231 mol, 1.0 eq.) was added dropwise while maintaining the inner temperature at ?5? C. to 5? C. After the addition was completed, the compound (IV-3) was obtained and directly used for the next reaction after 0.5 hour of reaction at a constant temperature.

[0167] m/z (CI) 188.05 ([M+1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 140.51.

(2) Synthesis of compound (VI-6)

[0168] In a nitrogen atmosphere, the compound (II-1) (37.48 g, 0.226 mol, 0.98 eq.) was added into 50 g of toluene, and N-methylaniline (24.25 g, 0.226 mol, 0.98 eq.) was added. After stirring evenly, the above compound (IV-3) solution was added dropwise under ice bath cooling, the inner temperature of the reaction solution was controlled at 5? C. to 10? C. The reaction was held for 5 hours after dropwise addition was completed. Nitrogen pressure filtration was performed, and the filter cake was washed twice with toluene. The combined filtrate was the solution of compound (VI-6), which can be directly used for the next reaction.

[0169] m/z (ESI) 317.13 ([M+1].sup.+, 100%).

(3) Synthesis of compound (III-6)

[0170] In a nitrogen atmosphere, the above compound (VI-6) solution was slowly heated to 80 to 85? C. for 12 hours to obtain a solution of compound (III-6), which can be directly used for the next reaction.

[0171] m/z (ESI) 281.15 ([M-C.sub.1].sup.+, 100%); .sup.31P NMR (33 MHz) ?: 60.31.

(4) Synthesis of compound (I-1)

[0172] Added 150 g of 30% hydrochloric acid into the above compound (III-6) solution and heated it to 95 to 105? C. for reaction. After the reaction was completed, the resulting mixture was distilled under reduced pressure, and then 150 g of absolute ethanol was added, the mixture was briefly boiled and cooled to crystallize, filtered and dried to obtain a white crystal, namely, 36.1 g of the target product (1-1), yield: 71.5%, assay: 97.5%, and 96.1% ee value.

[0173] The preferred embodiments of the present disclosure have been described in detail above. However, the present disclosure is not limited to the specific details in the above embodiments. Within the scope of the technical concept of the present disclosure, many simple modifications can be made to the technical solution of the present disclosure, all of which fall within the claimed scope of the present disclosure.

[0174] Furthermore, it should be noted that various specific technical features described in the above specific embodiments can be combined in any suitable way without contradiction. In order to avoid unnecessary repetition, the present disclosure will not explain various possible combinations separately.

[0175] Furthermore, any combination can be made among various embodiments of the present disclosure, as long as it does not violate the idea of the present disclosure, it should also be regarded as the disclosure of the present disclosure.