Preparation method of glufosinate or derivatives thereof

Abstract

The present disclosure relates to the preparation method of glufosinate or derivatives thereof.

Claims

1. A method for preparing glufosinate of formula (I) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios, characterized in that the method comprises the following steps: ##STR00017## a) reacting a compound of formula (II) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios with a compound of formula (III); ##STR00018## b) reacting the intermediate, no matter whether it is isolated or not, in the presence of water and an acid or a base to obtain the glufosinate (I) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios; when PG is an amino protecting group, a step of removing the amino protecting group can be further comprised; wherein: X is halogen, OAc, -OTs, -OMs or ##STR00019## Hal, Hal.sup.1 and Hal.sup.2 are each independently halogen, e.g., fluorine, chlorine, bromine or iodine; Y is OR.sub.1, NH.sub.2, NHR.sub.2 or N(R.sub.2)(R.sub.3); PG is hydrogen or an amino protecting group, and the amino protecting group preferably is C(?O)R.sub.4, C(?O)OR.sub.4 or S(?O).sub.2R.sub.4; R.sub.1, R.sub.2 and R.sub.3 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl, 3-10-membered heterocyclyl or Si(R.sub.5)(R.sub.6)(R.sub.7); R.sub.4 is selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl and 3-10-membered heterocyclyl; R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclyl; the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the group consisting of: halogen, OH, O, O(C.sub.1-C.sub.6 alkyl), C(?O)(C.sub.1-C.sub.6 alkyl), C(?O)OH, C(?O)O(C.sub.1-C.sub.6 alkyl), NH.sub.2, NO.sub.2, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl and 3-10-membered heterocyclyl; the chiral carbon atom is labeled with *.

2. A method for preparing a compound of formula (I)-1 or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios, characterized in that the method comprises the following steps: ##STR00020## a) reacting a compound of formula (II) or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios with a compound of formula (III); ##STR00021## b-1) reacting the intermediate, no matter whether it is isolated or not, in the presence of R.sub.8OH, to obtain the compound of formula (I)-1 or a salt, an enantiomer thereof or a mixture of the enantiomers in all ratios; when PG is an amino protecting group, a step of removing the amino protecting group can be further comprised; wherein: X is halogen, OAc, -OTs, -OMs or ##STR00022## Hal, Hal.sup.1 and Hal.sup.2 are each independently halogen, e.g., fluorine, chlorine, bromine or iodine; Y is OR.sub.1, NH.sub.2, NHR.sub.2 or N(R.sub.2)(R.sub.3); PG is hydrogen or an amino protecting group, and the amino protecting group preferably is C(?O)R.sub.4, C(?O)OR.sub.4 or S(?O).sub.2R.sub.4; R.sub.1, R.sub.2 and R.sub.3 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl, 3-10-membered heterocyclyl or Si(R.sub.5)(R.sub.6)(R.sub.7); R.sub.4 is selected from the group consisting of C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl and 3-10-membered heterocyclyl; R.sub.5, R.sub.6 and R.sub.7 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclyl; R.sub.8 is H, C.sub.1-C.sub.6 alkyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl or 3-10-membered heterocyclyl; preferably, R.sub.8 is H or C.sub.1-C.sub.6 alkyl; more preferably, Ra is H, methyl or ethyl; the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl are each optionally substituted by one or more substituents independently selected from the group consisting of: halogen, OH, ?O, O(C.sub.1-C.sub.6 alkyl), C(?O)(C.sub.1-C.sub.6 alkyl), C(?O)OH, C(?O)O(C.sub.1-C.sub.6 alkyl), NH.sub.2, NO.sub.2, CN, C.sub.1-C.sub.6 alkyl, C.sub.2-C.sub.6 alkenyl, C.sub.2-C.sub.6 alkynyl, C.sub.3-10 cycloalkyl, C.sub.6-10 aryl, C.sub.6-12 aralkyl, 5-14-membered heteroaryl and 3-10-membered heterocyclyl; the chiral carbon atom is labeled with *.

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

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

5. The method according to claim 1, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) is ?2:1.

6. The method according to claim 1, wherein the compound of formula (III) or a solution thereof is added to the compound of formula (II) or a solution thereof; or the compound of formula (II) or a solution thereof is added to the compound of formula (III) or a solution thereof; preferably, the compound of formula (III) or a solution thereof is added to the compound of formula (II) or a solution thereof in portions or in one portion; or the compound of formula (II) or a solution thereof is added to the compound of formula (III) or a solution thereof in portions or in one portion.

7. The method according to claim 1, wherein X is chlorine, bromine, iodine, OAc, -OTs, -OMs or ##STR00023## preferably, X is chlorine.

8. The method according to claim 1, wherein R.sub.1, R.sub.2 and R.sub.3 are each independently hydrogen, C.sub.1-C.sub.6 alkyl, C.sub.6-10 aryl or C.sub.6-12 aralkyl; preferably, R.sub.1, R.sub.2 and R.sub.3 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, phenyl, benzyl, phenylethyl, phenylpropyl, methylphenyl, ethylphenyl, propylphenyl or naphthyl; and more preferably ethyl.

9. The method according to claim 1, wherein Y is NHCH.sub.2CH.sub.2CH.sub.2CH.sub.3, N(CH.sub.3).sub.2, OCH.sub.3, OCH.sub.2CH.sub.3, OCH.sub.2CH.sub.2CH.sub.3, OCH(CH.sub.3).sub.2, OCH.sub.2CH.sub.2CH.sub.2CH.sub.3, OCH.sub.2CH(CH.sub.3).sub.2 or -OBn.

10. The method according to claim 1, wherein the Y is OR.sub.1, and R.sub.1 preferably is ethyl or n-butyl.

11. The method according to claim 1, wherein the PG is hydrogen, C(?O)CH.sub.3, C(O)Ph, C(O)OC.sub.2H.sub.5, C(?O)OC(CH.sub.3).sub.3 or ##STR00024## preferably, PG is hydrogen.

12. The method according to claim 1, wherein the compound of formula (III) is dichloro(methyl)phosphane.

13. The method according to claim 1, wherein the compound of formula (III) is the only phosphorus-containing reaction starting material.

14. The method according to claim 1, wherein in the step a), the reaction temperature is ?50?200? C., preferably is ?20?140? C. or 20?100? C.

15. The method according to claim 1, wherein the step a) is carried out in the presence of a base, and the base is an inorganic base or an organic base; preferably, the molar ratio of (the compound of formula (II)+the above base) to the compound of formula (III) is ?2.5:1, more preferably ?3:1, and most preferably ?4:1; the inorganic base is preferably ammonia, alkali metal oxide, alkaline earth metal oxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate; e.g., potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide and magnesium oxide; the organic base is preferably an organic base containing no active hydrogen, and the base containing no active hydrogen is preferably triethylamine, N,N-dimethylaniline or pyridine, and the triethylamine, N,N-dimethylaniline and pyridine optionally have 1-3 substituents attached to one or more carbon atoms of the tertiary amine, and the substituents are selected from halogen, OH, O(C.sub.1-C.sub.6 alkyl), NH.sub.2, NO.sub.2, CN, C.sub.1-C.sub.6 alkyl, C.sub.3-10 cycloalkyl and C.sub.6-10 aryl.

16. The method according to claim 1, wherein when the step a) is carried out in the absence of an additional base, the molar ratio of the compound of formula (II) to the compound of formula (III) is preferably ?4:1.

17. The method according to claim 1, wherein the step a) is carried out under a solvent-free condition or in an inert solvent; preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, hydrocarbon solvents, halogenated hydrocarbon solvents, sulfone or sulfoxide solvents, ether solvents or ester solvents; preferably, the inert solvent is selected from any one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or ester solvents; more preferably, the inert solvent is selected from any one or more of chlorobenzene, xylene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.

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

19. The method according to claim 18, wherein the inorganic acid is hydrochloric acid or sulfuric acid.

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

21. The method according to claim 20, wherein the base is alkali metal hydroxide, alkaline earth metal hydroxide, alkali metal carbonate, alkaline earth metal carbonate, alkali metal bicarbonate or alkaline earth metal bicarbonate.

22. The method according to claim 21, wherein the base is NaOH, KOH or Ba(OH).sub.2.

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

24. The method according to claim 2, wherein in the step b1), the reaction temperature is 0? C. to 100? C., preferably 0? C. to 80? C., more preferably 20? C. to 60? C. or 30? C. to 60? C.

Description

DETAILED DESCRIPTION OF THE INVENTION

Example 1

[0085] ##STR00009##

[0086] A solution of chlorohomoserine ethyl ester (2.1 eq, 162 g, 0.987 mol, ee value 99%) in chlorobenzene (835 g) and triethylamine (2.1 eq, 100 g, 0.987 mol) were added to a 1 L four-necked flask, nitrogen replacement was carried out after the addition, and the temperature was reduced to 0? C. in an ice water bath. A solution of MDP (1 eq, 55 g, 0.47 mol) in chlorobenzene (127.4 g) was added to a constant pressure dropping funnel, and the dropping was started while controlling the temperature at 0-5? C. and completed in 1.5 hours.

[0087] The resulting reaction solution was heated to 90? C. in an oil bath and reacted for 2 hours. After the reaction was completed, it was naturally cooled to 30? C. and filtrated, and the filter cake was washed with chlorobenzene (200 g).

[0088] The filtrate was added with water (300 g), stirred at 50? C. for 1 hour, and then 25% ammonia water (40 g) was added to adjust the pH to 7. Phases was separated after the neutralization, and water (100 g) was added to the lower organic phase for secondary extraction. The aqueous phases were combined, concentrated under reduced pressure to a viscous state, 500 g hydrochloric acid was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content and ee value of glufosinate acid in the reaction solution. Based on the theoretical yield of glufosinate acid (85.1 g) calculated from the amount of MDP, the yield of glufosinate acid was 92.6%, and the ee value was 98%.

Example 2

[0089] ##STR00010##

[0090] A solution of chlorohomoserine ethyl ester (concentration 30% w/w, 2.1 eq, 0.46 mol, ee: 99%) in chlorobenzene (255 g) and 46.7 g triethylamine (2.1 eq) were added to a 1 L four-necked flask, and cooled to 0? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration 43.17% w/w, 1 eq, 0.22 mol) in chlorobenzene (60.5 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the reaction was warmed in stages: firstly warmed to 60? C. and reacted for 1 h, then warmed to 80? C. and reacted for 0.5 h, and then naturally cooled to 20-30? C. The mixture was filtered with suction, the filter cake was washed with 110 g chlorobenzene, and the filtrate was left for the next reaction.

[0091] The above filtrate was added to a 1 L four-necked flask, added with 160 g water, warmed to 50? C., and mechanically stirred for 1 h. Then, 20 g ammonia water (concentration 25% w/w, 1.33 eq, 0.29 mol) was added at 50? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g chlorobenzene. The final aqueous phase was subject to the next hydrolysis, and the organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0092] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, 250 g hydrochloric acid (concentration 30% w/w, 9.3 eq, 2.1 mol) was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 92.6%, and the ee value was 98%.

[0093] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (1.1 eq) was 95% and the ee value was 96%.

Example 3

[0094] ##STR00011##

[0095] A solution of chlorohomoserine ethyl ester (concentration 40% w/w, 4.1 eq, 0.91 mol, ee: 96.3%) in chlorobenzene (375 g) was added to a 1 L four-necked flask, and cooled to 0? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration 43.17% w/w, 1 eq, 0.22 mol) in chlorobenzene (60.5 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the reaction was warmed in stages: firstly warmed to 60? C. and reacted for 1 h, then warmed to 80? C. and reacted for 0.5 h, and then naturally cooled.

[0096] The internal temperature was lowered to 60? C., 160 g water was added, the temperature was adjusted to 50? C., and the reaction was mechanically stirred for 1 h. 50 g ammonia water (concentration 25% w/w, 3.3 eq, 0.74 mol) was added at 50? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g chlorobenzene. The final aqueous phase was subject to the next hydrolysis, and the organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0097] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, 250 g hydrochloric acid (concentration 30% w/w, 9.3 eq, 2.1 mol) was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 92.8%, and the ee value was 93.8%.

[0098] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (3.1 eq) was 98% and the ee value was 94%.

Example 4

[0099] ##STR00012##

[0100] A solution of chlorohomoserine ethyl ester (concentration 40% w/w, 2.75 eq, 0.91 mol, ee: 96.3%) in chlorobenzene (375 g) was added to a 1 L four-necked flask, and cooled to 0? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration: 49% w/w, 2/3 eq, 0.22 mol) in chlorobenzene (53 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the mixture was stirred for 30 min, ammonia gas was pumped in at a rate of 200 mL/min for 45 min, which was stopped until gas overflowed, and the total amount of ammonia gas was 7.5 g (1.33 eq, 0.44 mol). Then the temperature was warmed to 15-20? C., ammonia was removed under vacuum of ?0.095 MPa for 30 min, and nitrogen was pumped in. The reaction was cooled to 0-10? C., and a further solution of MDP (concentration 49% w/w, 1/3 eq, 0.11 mol) in chlorobenzene (13.2 g) was dropwise added. After the dropwise addition was completed, the reaction was warmed in stages: firstly warmed to 60? C. and reacted for 1 h, then warmed to 80? C. and reacted for 0.5 h, and then naturally cooled.

[0101] The internal temperature was lowered to 60? C., 200 g water was added, the internal temperature was adjusted to 50? C., and the reaction was mechanically stirred for 1 h. 50 g ammonia water (concentration 25% w/w, 2.3 eq, 0.75 mol) was added at 50? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g chlorobenzene. The final aqueous phase was subject to the next hydrolysis, and the organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0102] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, 373 g hydrochloric acid (concentration 30% w/w, 9.3 eq, 3.07 mol) was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 90.77%, and the ee value was 92.3%.

[0103] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (1.75 eq) was 95.2% and the ee value was 93.5%.

Example 5

[0104] ##STR00013##

[0105] A solution of chlorohomoserine ethyl ester (concentration 41.5% w/w, 2.1 eq, 0.35 mol, ee: 99%) in xylene (163.4 g) and 35.4 g triethylamine (2.1 eq) were added to a 1 L four-necked flask, and cooled to 0? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration 50% w/w, 1 eq, 0.165 mol) in xylene (38.7 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the reaction was warmed in stages: firstly warmed to 60? C. and reacted for 1 h, then warmed to 80? C. and reacted for 0.5 h, and then naturally cooled to 20-30? C. The mixture was filtered with suction, the filter cake was washed with 150 g xylene, and the filtrate was left for the next reaction.

[0106] The above filtrate was added to a 1 L four-necked flask, added with 180 g water, warmed to 50? C., and mechanically stirred for 1 h. 20 g ammonia water (concentration 25% w/w, 1.78 eq, 0.29 mol) was added at 50? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The upper organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g xylene. The final aqueous phase was subject to the next hydrolysis, and the organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0107] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, 255 g hydrochloric acid (concentration 30% w/w, 12.7 eq, 2.1 mol) was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 87.5%, and the ee value was 97.10%.

[0108] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (1.1 eq) was 95% and the ee value was 98.25%.

Example 6

[0109] ##STR00014##

[0110] A solution of chlorohomoserine ethyl ester (concentration 38.54% w/w, 4.1 eq, 0.935 mol, ee: 99.6%) in xylene (470.5 g) was added to a 1 L four-necked flask, and cooled to 0-5? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration 50% w/w, 1 eq, 0.228 mol) in xylene (53.35 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the reaction was warmed to 80? C. and reacted for 2 h, and then naturally cooled.

[0111] The internal temperature was lowered to 70? C., 160 g water was added, the temperature was adjusted to 70? C., and the reaction was mechanically stirred for 1 h. 50 g ammonia water (concentration 25% w/w, 3.2 eq, 0.74 mol) was added at 25-30? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The upper organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g xylene. The final aqueous phase was subject to the next hydrolysis, and the organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0112] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, 250 g hydrochloric acid (concentration 30% w/w, 9.2 eq, 2. 1 mol) was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 88%, and the ee value was 97.29%.

[0113] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (3.1 eq) was 95.73% and the ee value was 95.68%.

Example 7

[0114] ##STR00015##

[0115] A solution of chlorohomoserine ethyl ester (concentration 38.54% w/w, 2.75 eq, 0.69 mol, ee: 99.6%) in xylene (370.9 g) was added to a 1 L four-necked flask, and cooled to 0? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration 50% w/w, 2/3 eq) in xylene (39.2 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the mixture was stirred for 10-30 min, ammonia gas was pumped in at a rate of 200 mL/min for 30 min, which was stopped until gas overflowed, and the total amount of ammonia gas was 5.7 g (1.33 eq, 0.33 mol). Then the temperature was warmed to 15-20? C., ammonia was removed under vacuum of ?0.095 MPa for 20-30 min, and nitrogen was pumped in. The reaction was cooled to 0-10? C., and a further solution of MDP (concentration 50% w/w, 1/3 eq) in xylene (19.5 g) was dropwise added. The reaction was warmed to 80? C. and reacted for 0.5 h, and then naturally cooled.

[0116] The internal temperature was lowered to 70? C., 180 g water was added, the internal temperature was adjusted to 70? C., and the reaction was mechanically stirred for 1 h. 50 g ammonia water (concentration 25% w/w, 2.96 eq, 0.74 mol) was added at 25-30? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The upper organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g xylene. The final aqueous phase was subject to the next hydrolysis, and the organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0117] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, 250 g hydrochloric acid (concentration 30% w/w, 8.4 eq, 2.1 mol) was added thereto, and heated to 100? C. for hydrolysis for 8 hours. A sample was taken to determine the absolute content (by LC) and ee value of glufosinate acid. Based on the theoretical yield of glufosinate acid calculated from the amount of MDP, the yield of glufosinate acid was 85.2%, and the ee value was 97.61%.

[0118] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (1.75 eq) was 95.68% and the ee value was 96.15%.

Example 8

[0119] ##STR00016##

[0120] A solution of chlorohomoserine ethyl ester (concentration 40% w/w, 2.75 eq, 0.91 mol, ee: 96.3%) in chlorobenzene (375 g) was added to a 1 L four-necked flask, and cooled to 0? C. in an ice water bath. Nitrogen replacement was performed for three times. A solution of MDP (concentration: 49% w/w, 2/3 eq, 0.22 mol) in chlorobenzene (53 g) was added to a constant pressure dropping funnel, and MDP was added dropwise under the protection of nitrogen, while keeping the temperature at 0-5? C. during the dropwise addition over about 1.5 h. After the dropwise addition was completed, the mixture was stirred for 30 min, ammonia gas was pumped in at a rate of 200 mL/min for 45 min, which was stopped until gas overflowed, and the total amount of ammonia gas was 7.5 g (1.33 eq, 0.44 mol). Then the temperature was warmed to 15-20? C., ammonia was removed under vacuum of ?0.095 MPa for 30 min, and nitrogen was pumped in. The reaction was cooled to 0-10? C., and a further solution of MDP (concentration 49% w/w, 1/3 eq, 0.11 mol) in chlorobenzene (13.2 g) was dropwise added. After the dropwise addition was completed, the reaction was warmed in stages: firstly warmed to 60? C. and reacted for 1 h, then warmed to 80? C. and reacted for 0.5 h, and then naturally cooled.

[0121] The internal temperature was lowered to 60? C., 200 g water was added, the internal temperature was adjusted to 50? C., and the reaction was mechanically stirred for 1 h. 50 g ammonia water (concentration 25% w/w, 2.3 eq, 0.75 mol) was added at 50? C. to adjust the pH to 7-8, the mixture was stirred for 5 min, and the phases were separated after neutralization. The product was in the aqueous phase. The lower organic phase was extracted with water (60 g?2). The aqueous phases were combined, and the chlorohomoserine ethyl ester in the aqueous phase was back-extracted with 100 g chlorobenzene. The organic phase was kept for the recovery of the starting material of chlorohomoserine ethyl ester.

[0122] A sample was taken to determine the absolute content (by LC) of MPN. Based on the theoretical yield of MPN calculated from the amount of MDP, the yield of MPN was 77.5%.

[0123] A sample was taken to determine the absolute content (by LC) and ee value of chlorohomoserine ethyl ester in the above-mentioned organic phase. Upon calculation, it was determined that the recovery rate of the excess chlorohomoserine ethyl ester (1.75 eq) was 97.8% and the ee value was 95.3%.

[0124] In addition to those described herein, according to the foregoing description, various modifications to the present invention would be apparent to those skilled in the art. Such modifications are intended to fall within the scope of the appended claims. Each reference cited herein (including all patents, patent applications, journal articles, books and any other disclosures) are incorporated herein by reference in its entirety.