L-GLUFOSINATE DERIVATIVE, COMPOSITION COMPRISING SAME, PREPARATION METHOD THEREFOR AND USE THEREOF

Abstract

Provided is a method for preparing the L-glufosinate of formula (I) or a derivative thereof.

##STR00001##

Claims

1. A method for preparing a compound of Formula (I), ##STR00018## wherein the method comprises reacting a compound of Formula (III) with ROH, ##STR00019## wherein: Y is OR.sub.1, NH.sub.2, NHR.sub.2, or N(R.sub.2)(R.sub.3); R is H, substituted or unsubstituted alkyl having 1-6 carbon atoms, substituted or unsubstituted alkenyl having 2-6 carbon atoms, substituted or unsubstituted alkynyl having 2-6 carbon atoms, substituted or unsubstituted cycloalkyl having 3-10 carbon atoms, substituted or unsubstituted heterocyclyl having 2-10 carbon atoms, substituted or unsubstituted aryl having 6-20 carbon atoms, substituted or unsubstituted aralkyl having 6-20 carbon atoms, or substituted or unsubstituted heteroaryl having 2-10 carbon atoms; preferably, R is H or substituted or unsubstituted alkyl having 1 to 6 carbon atoms; more preferably, R is H, methyl or ethyl; R.sub.1, R.sub.2 and R.sub.3 are each independently substituted or unsubstituted alkyl having 1-6 carbon atoms, substituted or unsubstituted alkenyl having 2-6 carbon atoms, substituted or unsubstituted alkynyl having 2-6 carbon atoms, substituted or unsubstituted cycloalkyl having 3-10 carbon atoms, substituted or unsubstituted heterocyclyl having 2-10 carbon atoms, substituted or unsubstituted aryl having 6-20 carbon atoms, substituted or unsubstituted aralkyl having 6-20 carbon atoms, or substituted or unsubstituted heteroaryl having 2-10 carbon atoms, or Si(R.sub.4)(R.sub.5)(R.sub.6); R.sub.4, R.sub.5 and R.sub.6 are each independently substituted or unsubstituted alkyl having 1-6 carbon atoms, or substituted or unsubstituted aryl having 6-20 carbon atoms; substituents for the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, aralkyl, and heteroaryl groups are each independently halogen, carboxyl, amino, nitro, cyano, alkyl having 1-6 carbon atoms, aryl having 6-10 carbon atoms, or cycloalkyl having 3-10 carbon atoms.

2. The method according to claim 1, wherein the compound of Formula (III) is prepared from a compound of Formula (V): ##STR00020## wherein: X is halogen, OTs, or Hal ##STR00021## Hal, at each occurrence, is each independently halogen selected from F, Cl, Br or I; Y is as defined in claim 1; R.sub.7 is H, substituted or unsubstituted alkyl having 1-6 carbon atoms, substituted or unsubstituted alkenyl having 2-6 carbon atoms, or substituted or unsubstituted alkynyl having 2-6 carbon atoms, and substituents for the alkyl, alkenyl and alkynyl groups are each independently halogen, carboxyl, amino, nitro, cyano, alkyl having 1-6 carbon atoms, aryl having 6-10 carbon atoms or cycloalkyl having 3-10 carbon atoms.

3. The method according to claim 2, wherein the compound of Formula (V) is prepared by reacting a compound of Formula (II) ##STR00022## with one or more compounds of Formula (IV) or a mixture; the mixture being a mixture comprising one or more compounds of Formula (IV)-1 and one or more compounds of Formula (IV)-2; or a mixture comprising one or more compounds of Formula (IV)-1 and one or more compounds of Formula (IV); or a mixture comprising one or more compounds of Formula (IV)-2 and one or more compounds of Formula (IV); or a mixture comprising one or more compounds of Formula (IV), one or more compounds of Formula (IV)-1 and one or more compounds of Formula (IV)-2; ##STR00023## wherein X, Hal and R.sub.7 are as defined in claim 2.

4. The method according to claim 1, wherein R.sub.1, R.sub.2, and R.sub.3 are each independently methyl, ethyl, propyl (e.g., n-propyl, isopropyl), butyl (e.g., n-butyl, isobutyl, or tert-butyl), pentyl, hexyl, benzyl, phenyl or naphthyl, preferably ethyl, n-propyl, isopropyl or n-butyl, more preferably ethyl; preferably, 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.

5. The method according to claim 2, wherein R.sub.7 is methyl, ethyl, propyl, butyl, pentyl or hexyl, preferably ethyl.

6. The method according to claim 3, wherein in the reaction for preparing the compound of Formula (V), the reaction temperature is 30 C. to 30 C.

7. The method according to claim 3, wherein in the reaction for preparing the compound of Formula (V), the mixture is a mixture of one or more compounds of Formula (IV)-1 and one or more compounds of Formula (IV), and the molar ratio of the compounds of Formula (IV)-1 to the compounds of Formula (IV) 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 (IV)-2 and one or more compounds of Formula (IV), and the molar ratio of the compounds of Formula (IV)-2 to the compounds of Formula (IV) 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)-1 and one or more compounds of Formula (IV)-2, and the molar ratio of the compounds of Formula (IV)-1 to the compounds of Formula (IV)-2 is (0.9-1.1):1.

8. The method according to claim 3, wherein the reaction for preparing the compound of Formula (V) is performed in the presence of a base.

9. The method according to claim 8, wherein the base employed in the reaction for preparing the compound of Formula (V) is an organic base or ammonia.

10. The method according to claim 9, wherein in the reaction for preparing the compound of Formula (V), the organic base is selected from the group consisting of organic amine, pyridine or a pyridine derivative having 1-3 substituents attached to one or more carbon atoms in the heterocycle, piperidine or a piperidine derivative having 1-3 substituents attached to one or more carbon atoms in the heterocycle; preferably, the above substituents are selected from the group consisting of 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.

11. The method according to claim 10, wherein the organic base is selected from the group consisting of N,N-dimethylaniline, triethylamine, piperidine or pyridine.

12. The method according to claim 3, wherein the reaction for preparing the compound of Formula (V) is carried out under a solvent-free condition or in an inert solvent; 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.

13. The method according to claim 12, wherein the inert solvent is selected from any one or more of chlorobenzene, 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.

14. The method according to claim 3, wherein in the reaction for preparing the compound of Formula (V), the molar ratio of the compound of Formula (IV) or the mixture to the compound of Formula (II) is 1:(0.5-10), preferably 1:(1-3); or the molar ratio of the compound of Formula (II) to the compound of Formula (IV) or the mixture is 1:(0.5-10), preferably 1:(1-3).

15. The method according to claim 2, wherein the reaction for preparing the compound of Formula (III) comprises heating the compound of Formula (V) at a temperature of 50 C. to 150 C.

16. The method according to claim 3, wherein the reaction for preparing the compound of Formula (V) and the reaction for preparing the compound of Formula (III) are a one-pot process.

17. The method according to claim 1, wherein the compound of Formula (I) has an enantiomeric excess (ee) value of greater than 50%.

18. The method according to claim 17, wherein the compound of Formula (I) has an ee value of greater than 90%.

19. The method according to claim 1, wherein the reaction between the compound of Formula (III) and ROH is performed at a temperature of from 0 C. to 100 C., e.g., at a temperature of from 0 C. to 80 C., from 0 C. to 60 C., from 0 C. to 40 C., from 0 C. to 30 C., from 0 C. to 20 C., from 30 C. to 80 C., or from 30 C. to 60 C.

Description

DETAILED DESCRIPTION OF THE INVENTION

[0057] Chlorohomoserine alkyl esters used in the following examples may be prepared by a method similar to that disclosed in CN 110845347 A. The remaining reagents (e.g., MDP and MDEP) are all commercially available.

[0058] The product content recited in the examples is the absolute content of the pure product in the product obtained, which was determined by HPLC (an external standard method).

Example 1

##STR00008##

[0059] A solution of diethyl methylphosphonite (MDEP, 68.8 g, 455.4 mmol, 0.53 eq, and a purity of 90%) in chlorobenzene (300 g) was added to a round-bottom flask under nitrogen atmosphere at 10 C., and a solution of dichloro(methyl)phosphane (MDP, 54.4 g, 455.4 mmol, 0.53 eq, and a purity of 98%) in chlorobenzene (200 g) was added dropwise through a constant-pressure funnel at a dripping rate of 1 d/s. After the dropwise addition was completed, stirring was continued for 10 minutes (MCP was generated in the reaction solution at this time). A solution of chlorohomoserine ethyl ester (150 g, 867.5 mmol, 1.0 eq, a purity of 96%, and an ee value of 99%) and triethylamine (107.5 g, 1041 mmol, 1.2 eq, and a purity of 98%) in chlorobenzene (500 g) was added dropwise thereto at a dripping rate of 4 d/s. After the dropwise addition was completed, stirring was continued for 30 minutes. The reaction was then warmed to room temperature and stirred for 1 hour, followed by reaction at 90 C. for 3 h until complete reaction. The mixture was naturally cooled to room temperature, and filtered with suction. The filter cake was washed with chlorobenzene (150 mL3), and the filtrate was rotary evaporated to remove chlorobenzene, thereby obtaining a pale yellow viscous liquid, which is the crude MPO product.

[0060] A mixture of water (62.5 g, 3470 mmol) and acetonitrile (125 g) was added dropwise to the crude MPO product at 10 C. The reaction was stirred for 1 h until a solid precipitated out. Acetonitrile (594 g) was then added, and the solution was stirred at room temperature (about 15 C.) until a large amount of solid precipitated out. The solid was filtered and dried to afford MPN (white solid, 145.9 g, content: 90%).

[0061] Data for characterizing the structure of the product are shown below: [0062] MS (ESI): m/z [M+H].sup.+ calcd for C7H17NO4P: 210.09; found: 210.1. [0063] .sup.1H NMR (400 MHz, DMSO-d.sub.6) : 4.34-4.11 (m, 2H), 4.00 (t, J=5.8 Hz, 1H), 2.28-1.92 (m, 2H), 1.77-1.48 (m, 2H), 1.23 (t, J=7.1 Hz, 3H), 1.17 (d, J=13.8 Hz, 3H). [0064] .sup.13C NMR (100 MHz, DMSO-d.sub.6) 169.5, 61.7, 52.4, 52.3, 27.6, 26.7, 23.8, 16.3, 15.3, 14.0. [0065] .sup.31P NMR (160 MHz, DMSO-d.sub.6) 38.9.

Example 2

##STR00009##

[0066] A solution of diethyl methylphosphite (MDEP, 34.7 g, 227.6 mmol, 0.53 eq, and a purity of 90%) in chlorobenzene (300 g) was added to a round-bottomed flask under nitrogen atmosphere at 10 C., and a solution of dichloro(methyl)phosphane (MDP, 27.2 g, 227.6 mmol, 0.53 eq, and a purity of 98%) in chlorobenzene (200 g) was added dropwise through a constant-pressure funnel at a dripping rate of 1 d/s. After the dropwise addition was completed, stirring was continued for 10 min (MCP was generated in the reaction solution at this time). A solution of chlorohomoserine isopropyl ester (82.0 g, 433.6 mmol, 1.0 eq, a purity of 95%, and an ee value of 99%) and triethylamine (53.8 g, 520.5 mmol, 1.2 eq, and a purity of 98%) in chlorobenzene (300 g) was added dropwise thereto at a dripping rate of 4 d/s. After the dropwise addition was completed, stirring was continued for 30 minutes. The reaction was then warmed to room temperature and stirred for 1 hour, followed by reaction at 90 C. for 3 h until complete reaction. The mixture was naturally cooled to room temperature, and filtered with suction. The filter cake was washed with chlorobenzene (150 mL3), and the filtrate was rotary evaporated to remove chlorobenzene, thereby obtaining a pale yellow viscous liquid, which is the crude MPO-iPr product.

[0067] A mixture of water (31.2 g, 1734.4 mmol) and acetonitrile (62.4 g) was added dropwise to the crude MPO-iPr product at 10 C. The reaction was stirred for 1 h until a solid precipitated out. Acetonitrile (296.4 g) was then added, and the solution was stirred at room temperature (about 15 C.) until a large amount of solid precipitated out. The solid was filtered and dried to afford MPN-iPr (white solid, 79.4 g, content: 91%).

[0068] Data for characterizing the structure of the product are shown below: [0069] MS (ESI): m/z [M+H].sup.+ calcd for C8H19NO4P: 224.10; found: 224.1. [0070] .sup.1H NMR (600 MHz, Chloroform-d) 5.10 (p, J=6.3 Hz, 1H), 3.82 (dd, J=7.5, 2.9 Hz, 1H), 2.41-2.31 (m, 1H), 2.26 (dddq, J=15.6, 11.9, 8.0, 4.5, 4.0 Hz, 1H), 1.77-1.60 (m, 2H), 1.31-1.23 (m, 9H). [0071] .sup.13C NMR (150 MHz, Chloroform-d) 169.2, 70.0, 53.1, 29.1, 28.5, 23.8, 21.9, 17.1, 16.5. [0072] .sup.31P NMR (240 MHz, Chloroform-d) 36.8.

Example 3

##STR00010##

[0073] A solution of diethyl methylphosphonite (MDEP, 22.9 g, 151.8 mmol, 0.53 eq, and a purity of 90%) in chlorobenzene (100 g) was added to a round-bottom flask under nitrogen atmosphere at 10 C., and a solution of dichloro(methyl)phosphane (MDP, 18.1 g, 151.8 mmol, 0.53 eq, and a purity of 98%) in chlorobenzene (67 g) was added dropwise through a constant-pressure funnel at a dripping rate of 1 d/s. After the dropwise addition was completed, stirring was continued for 10 minutes (MCP was generated in the reaction solution at this time). A solution of chlorohomoserine ethyl ester (50 g, 289.1 mmol, 1.0 eq, a purity of 96%, and an ee value of 99%) and triethylamine (35.8 g, 347.0 mmol, 1.2 eq, and a purity of 98%) in chlorobenzene (167 g) was added dropwise thereto at a dripping rate of 4 d/s. After the dropwise addition was completed, stirring was continued for 30 minutes. The reaction was then warmed to room temperature and stirred for 1 hour, followed by reaction at 90 C. for 3 h until complete reaction. The mixture was naturally cooled to room temperature, and filtered with suction. The filter cake was washed with chlorobenzene (50 mL3).

[0074] A mixture of water (20.8 g, 1156.4 mmol) and acetonitrile (20.8 g) was added to the MPO filtrate, and the mixture was rotary evaporated until a solid precipitated out. The rotary evaporation was stopped, acetonitrile (250 g) containing 5% by weight of water was added, the mixture was stirred, and a large amount of solid precipitated out. The solid was filtered and dried to afford MPN (a white solid, 41.8 g, content: 94%).

Example 4

##STR00011##

[0075] A solution of diethyl methylphosphonite (MDEP, 22.9 kg, and a purity of 95%) in chlorobenzene (80 kg) was added to a reactor under nitrogen atmosphere at 10 C. to 15 C., and dichloro(methyl)phosphane (MDP, 19.1 kg, and a purity of 98%) was added dropwise over 2 h. After the dropwise addition was completed, stirring was continued for 30 minutes (MCP was generated in the reaction solution at this time). The reaction solution was added dropwise to a solution of chlorohomoserine ethyl ester (50 kg, a purity of 96%, and an ee value of 99%) and triethylamine (35.8 kg, and a purity of 98%) in chlorobenzene (232 kg) over 5 h. After the dropwise addition was completed, the reaction was warmed to 90 C. and allowed to proceed for 3 h until complete reaction. The mixture was naturally cooled to room temperature and centrifuged. The filter cake was thoroughly washed with chlorobenzene.

[0076] A mixture of water (10 kg) and acetonitrile (20 kg) was added to the MPO filtrate at 60 C., the mixture was stirred for 30 minutes and then the solvent was distilled until a solid precipitated out. Acetonitrile (25 kg) containing 5% by weight of water was added, the mixture was stirred, and a large amount of solid precipitated out. The solid was filtered and dried to afford MPN (a white solid, 57.5 kg, content: 96%, yield 91%, ee 99%), the MPN remained in the mother liquor was 3.2%.

Example 5

##STR00012##

[0077] A solution of diethyl methylphosphonite (MDEP, 11.5 kg, and a purity of 95%) in chlorobenzene (40 kg) was added to a reactor under nitrogen atmosphere at 10 C. to 15 C., and dichloro(methyl)phosphane (MDP, 10.1 kg, and a purity of 98%) was added dropwise over 1 h. After the dropwise addition was completed, stirring was continued for 30 minutes (MCP was generated in the reaction solution at this time). The reaction solution was added dropwise to a solution of chlorohomoserine ethyl ester (25 kg, a purity of 96%, and an ee value of 99%) in chlorobenzene (232 kg) over 3 h, while 3 kg ammonia gas was pumped in for neutralization. After the dropwise addition was completed, the reaction was warmed to 90 C. and allowed to proceed for 3 h until complete reaction. The mixture was naturally cooled to room temperature and centrifuged. The filter cake was thoroughly washed with chlorobenzene.

[0078] A mixture of water (5 kg) and acetonitrile (25 kg) was added to the MPO filtrate at 40 C., the mixture was stirred for 30 minutes and then the solvent was distilled until a large amount of solid precipitated out. The solid was filtered and dried to afford MPN (a white solid, 28.1 kg, content: 96%, yield 89%, ee 99%), the MPN remained in the mother liquor was 2.8%.

Example 6

##STR00013##

[0079] A solution of diethyl methylphosphonite (MDEP, 22.9 g, 151.8 mmol, 0.53 eq, and a purity of 90%) in chlorobenzene (100 g) was added to a round-bottom flask under nitrogen atmosphere at 10 C., and a solution of dichloro(methyl)phosphane (MDP, 18.1 g, 151.8 mmol, 0.53 eq, and a purity of 98%) in chlorobenzene (67 g) was added dropwise through a constant-pressure funnel at a dripping rate of 1 d/s. After the dropwise addition was completed, stirring was continued for 10 minutes (MCP was generated in the reaction solution at this time). A solution of chlorohomoserine ethyl ester (50 g, 289.1 mmol, 1.0 eq, a purity of 96%, and an ee value of 99%) and triethylamine (35.8 g, 347.0 mmol, 1.2 eq, and a purity of 98%) in chlorobenzene (167 g) was added dropwise thereto at a dripping rate of 4 d/s. After the dropwise addition was completed, stirring was continued for 30 minutes. The reaction was then warmed to room temperature and stirred for 1 hour, followed by reaction at 90 C. for 3 h until complete reaction. The mixture was naturally cooled to room temperature, and filtered with suction. The filter cake was washed with chlorobenzene (50 mL3).

[0080] Absolute ethanol (40 g, 867.3 mmol) was added to the MPO filtrate at 10 C. The reaction was stirred for 1 h and distilled under reduced pressure to afford MPN-Et (a pale yellow viscous liquid, 76.8 g, content: 75%, yield 84%, ee 98.7%).

Example 7

##STR00014##

[0081] MPN (70 g, 301.2 mmol, a purity of 90%) was added to a round-bottom flask, and 36% concentrated hydrochloric acid (315 mL) was added dropwise. The reaction was slowly heated to reflux until complete reaction of the starting materials. The solvent was evaporated to dryness, 95% ethanol (240 mL) and water (24 mL) were added, and the mixture was refluxed until the product is completely dissolved. The solution was cooled to allow precipitation of the solid. The solid was filtered and dried to afford the L-glufosinate hydrochloride salt (a white solid, yield of the pure product 92.4%, content 96.6%, an ee value of 98%).

Example 8

##STR00015##

[0082] MPN (70 g, 301.2 mmol, a purity of 90%) was added to a round-bottom flask, and 36% concentrated hydrochloric acid (315 mL) was added dropwise. The reaction was slowly heated to reflux until complete reaction of the starting materials. The solvent was evaporated to dryness, water (63 g) was added, followed by dropwise addition of ammonia water (59 g) to adjust the pH to 7-8. The solvent was then evaporated to dryness, the residue was dissolved by adding methanol, filtered to remove ammonium chloride, and the filtrate was refluxed for 2 h. The mixture was cooled to 15 C. to allow precipitation of the solid. The solid was filtered and dried to afford the L-glufosinate ammonium salt (a white solid, yield of the pure product 84.4%, content 96%, an ee value of 98%).

Example 9

##STR00016##

[0083] MPN-Et (70 g, 221.4 mmol, a purity of 75%) was added to a round-bottom flask, and 36% concentrated hydrochloric acid (315 mL) was added dropwise. The reaction was slowly heated to reflux until complete reaction of the starting materials. The solvent was evaporated to dryness, 95% ethanol (200 mL) and water (20 mL) were added, and the mixture was refluxed until the product is completely dissolved. The solution was cooled to allow precipitation of the solid. The solid was filtered and dried to afford the L-glufosinate hydrochloride salt (a white solid, yield of the pure product 91.3%, content 93.2%, an ee value of 97%).

Example 10

##STR00017##

[0084] MPN (28.7 kg, and a purity of 96%) was added to a reactor, and 30% concentrated hydrochloric acid (143.5 kg) was added. The reaction was slowly heated to 100 C. and allowed to proceed at this temperature while being distilled. Upon complete reaction of the starting materials, the solvent was evaporated to dryness, 95% ethanol (72 kg) was added, and the mixture was stirred. Upon cooling, a large amount of solid precipitated out. The solid was filtered and dried to afford the L-glufosinate hydrochloride salt (a white solid, 28.4 kg, yield of the pure product 91.7%, content 96.2%, an ee value of 99%), the amount of the L-glufosinate hydrochloride salt remained in the mother liquor was 3.6%.

[0085] 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.