Preparation method of glufosinate-ammonium or derivative thereof

Abstract

The present disclosure relates to processes for the preparation of glufosinate-ammonium or derivatives thereof.

Description

TECHNICAL FIELD

[0001] The present disclosure relates to a method for preparing glufosinate or a derivative thereof. BACKGROUND

[0002] Glufosinate is a highly effective, broad-spectrum, low-toxicity, non-selective (total-kill) organophosphorus herbicide with partial systemic action developed by Hoechst AG in the 1980s. It can be used to control annual and perennial dicotyledonous and gramineous weeds. Glufosinate has two enantiomers, L-type and D-type, and the herbicidal activity of L-type glufosinate is twice that of racemic DL-type glufosinate.

[0003] The existing methods for preparing glufosinate have many defects (e.g., complex process, not suitable for large-scale production; use of highly toxic and / or expensive reagents, etc.). SUMMARY

[0004] The present disclosure provides a method for preparing glufosinate or a derivative thereof, which uses raw materials that are easy to obtain and process operations that are suitable for industrial-scale production.

[0005] In some embodiments, the present disclosure provides a method for preparing glufosinate of formula (I) or a salt, an enantiomer, or a mixture of enantiomers in all proportions thereof, characterized in that the method comprises the following steps:

[0006]

[0007] a) reacting a compound of formula (II) or a salt, an enantiomer, or a mixture of enantiomers in all proportions thereof, with a compound of formula (III);

[0008]

[0009] b) whether or not the intermediate is isolated, reacting in the presence of water and an acid or a base to obtain glufosinate (I) or a salt, an enantiomer, or a mixture of enantiomers in all proportions thereof;

[0010] When PG is an amino protecting group, the method can further comprise a step of removing the amino protecting group;

[0011] wherein:

[0012] X is halogen, -OAc, -OTs, -OMs, or

[0013] Hal, Hal 1 and Hal 2 each independently is halogen, for example fluorine, chlorine, bromine, or iodine;

[0014] Y is -OR1, -NH2, -NHR2, or -N(R2)(R3);

[0015] PG is hydrogen or an amino protecting group, preferably -C(=O)R4, -C(=O)OR4, or -S(=O)2R4;

[0016] R1, R2, and R3 are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl, or -Si(R5)(R6)(R7);

[0017] R4is selected from the group consisting of C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, and 3-10 membered heterocyclyl;

[0018] R5, R6, and R7are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, or 3-10 membered heterocyclyl;

[0019] each of the above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclyl groups is optionally substituted with one or more substituents independently selected from the group consisting of halogen, -OH, =O, -O-(C1-C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)O-(C1-C6alkyl), -NH2, -NO2, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, and 3-10 membered heterocyclyl;

[0020] the chiral carbon atom is marked with *.

[0021] In some embodiments, the present disclosure provides a method of preparing a compound of Formula (I)-1, or a salt, enantiomer, or mixture of enantiomers in all proportions thereof, characterized in that the method comprises the following steps:

[0022]

[0023] a) reacting a compound of formula (II) or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof, with a compound of formula (III);

[0024]

[0025] b-1) whether or not the intermediate is isolated, reacting in the presence of R8OH (i.e. in the absence of an acid and a base) to give a compound of formula (I)-1 or a salt, an enantiomer or a mixture of enantiomers in all proportions thereof;

[0026] when PG is an amino protecting group, the process can further comprise the step of removing the amino protecting group;

[0027] wherein:

[0028] X is halogen, -OAc, -OTs, -OMs or

[0029] Hal, Hal 1 and Hal 2 each independently halogen, for example fluorine, chlorine, bromine or iodine;

[0030] Y is -OR1, -NH2, -NHR2or -N(R2)(R3);

[0031] PG is hydrogen or an amino protecting group, which is preferably -C(=O)R4, -C(=O)OR4or -S(=O)2R4;

[0032] R1, R2and R3are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclyl or -Si(R5)(R6)(R7);

[0033] R4is selected from C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[0034] R5, R6and R7are each independently hydrogen, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclyl;

[0035] R8is H, C1-C6alkyl, C3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclyl; preferably, R8is H or C1-C6alkyl; more preferably, R8is H, methyl or ethyl;

[0036] each of the above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclyl is optionally substituted with one or more substituents independently selected from halogen, -OH, =O, -O-(C1-C6alkyl), -C(=O)-(C1-C6alkyl), -C(=O)OH, -C(=O)O-(C1-C6alkyl), -NH2, -NO2, -CN, C1-C6alkyl, C2-C6alkenyl, C2-C6alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclyl;

[0037] The chiral carbon atom is marked with *.

[0038] In some embodiments, the compound of formula (II) in step a) above is enantiomerically pure and the resulting glufosinate ammonium of formula (I) or a salt thereof or the compound of formula (I)-1 or a salt thereof is also enantiomerically pure.

[0039] In some embodiments, the enantiomeric ratio of the glufosinate ammonium of formula (I) or a salt thereof or the compound of formula (I)-1 or a salt thereof obtained by the above-mentioned process is 50.5:49.5 to 99.5:0.5 of (L):(D)-enantiomer or (D):(L)-enantiomer.

[0040] In some embodiments, in the above-mentioned process, the molar ratio of the compound of formula (II) to the compound of formula (III) is > 2:1.

[0041] In some embodiments, in the above-mentioned process, the molar ratio of the compound of formula (II) to the compound of formula (III) is 0.2:1 to 10:1, preferably 0.7:1 to 5:1.

[0042] In some embodiments, 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.

[0043] In some embodiments, the compound of formula (III) or a solution thereof is added to the compound of formula (II) or a solution thereof in portions or all at once; 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 all at once.

[0044] In some embodiments, X is chloro, bromo, iodo, -OAc, -Ots, -Oms, or

[0045] In some embodiments, X is chloro.

[0046] In some embodiments, R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 aryl, or C 6-12 aralkyl.

[0047] In some embodiments, R1, R2, and R3 are each independently C1-C6 alkyl, C 6-10 aryl, or C 6-12 aralkyl.

[0048] In some embodiments, R1, R2, and R3 are each independently methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, t-butyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl, propylphenyl, or naphthyl; more preferably, ethyl.

[0049] In some embodiments, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2, or -OBn.

[0050] In some embodiments, Y is -OR1.

[0051] In some embodiments, R1 is ethyl or n-butyl.

[0052] In some embodiments, PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3, or

[0053] In some embodiments, PG is hydrogen.

[0054] In some embodiments, the compound of formula (III) is methylphosphorus dichloride.

[0055] In some embodiments, the compound of formula (III) is the only phosphorus-containing reactant.

[0056] In some embodiments, the temperature of the reaction in step a) is from -50 to 200 °C, preferably from -20 to 140 °C or from 20 to 100 °C.

[0057] In some embodiments, said step a) is carried out in the presence of a base, said base being an inorganic base or an organic base;

[0058] Preferably, the molar ratio of (compound of formula (II) + base as described above) to compound of formula (III) is > 2.5:1, more preferably > 3:1, most preferably > 4:1.

[0059] Said inorganic base is preferably ammonia, an alkali metal oxide, an alkaline earth metal oxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate or an alkaline earth metal bicarbonate; for example, potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide and magnesium oxide.

[0060] Said organic base is preferably an organic base free of active hydrogen, said base free of active hydrogen is preferably triethylamine, N,N-dimethylaniline or pyridine, said triethylamine, N,N-dimethylaniline and pyridine optionally having 1 to 3 substituents attached to one or more carbon atoms of the tertiary amine, said substituents being selected from the group consisting of halogen, -OH, -0-(Ci-C6-alkyl), -NH2, -NO2, -CN, Ci-C6-alkyl, C 3-10 Cycloalkyl and C 6-10 Aryl.

[0061] In some embodiments, when said step a) is carried out in the presence of a base containing active hydrogen (for example ammonia), said base containing active hydrogen is added after mixing of said compound of formula (II) with all or part of the compound of formula (III).

[0062] In some embodiments, when said step a) is carried out in the absence of an additional base, the molar ratio of said compound of formula (II) to said compound of formula (III) is preferably > 4:1.

[0063] In some embodiments, said step a) is carried out in the absence of a solvent or in an inert solvent.

[0064] Preferably, said inert solvent is selected from any one or more of a benzene-based solvent, an amide-based solvent, a hydrocarbon-based solvent, a halogenated hydrocarbon-based solvent, a sulfone or sulfoxide-based solvent, an ether-based solvent or an ester-based solvent; preferably, said inert solvent is selected from any one or more of a benzene-based solvent, an amide-based solvent, a halogenated hydrocarbon-based solvent, an ether-based solvent or an ester-based solvent.

[0065] More preferably, said inert solvent is selected from any one or more of chlorobenzene, xylenes, mesitylene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, N-methylpyrrolidone, N,N-dimethylformamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, butyl acetate.

[0066] In some embodiments, in the step b), an inorganic acid or an organic acid is added.

[0067] In some embodiments, the inorganic acid is hydrochloric acid or sulfuric acid.

[0068] In some embodiments, in the step b), the base is an inorganic base or an organic base; preferably, the base is an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal carbonate, an alkaline earth metal carbonate, an alkali metal bicarbonate, or an alkaline earth metal bicarbonate; more preferably, the base is NaOH, KOH, or Ba(OH)2.

[0069] In some embodiments, in the step b), the temperature of the reaction is 20-150 °C.

[0070] In some embodiments, in the step b1), the temperature of the reaction 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.

[0071] The method of the present disclosure is particularly suitable for the preparation of glufosinate-ammonium, substantially shortening the steps of the existing preparation process and having excellent reaction yield. The compound of formula (III) used in the method of the present disclosure is easy to obtain and low in cost, which makes the method of the present disclosure suitable for large-scale industrial production.

[0072] In addition, in the preparation of L-glufosinate-ammonium, the product can effectively maintain the ee value of the raw material. For example, when using a raw material that is enantiomerically pure (e.g., having a percent enantiomeric excess (%ee) of greater than 90%), the percent enantiomeric excess (%ee) of the prepared L-glufosinate-ammonium is, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0073] Definitions

[0074] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. References herein to technical terms used herein are intended to refer to the technical terms as commonly understood in the art, including variations or substitutions of those technical terms that would be apparent to one of ordinary skill in the art. Although the following terms are believed to be well understood by one of ordinary skill in the art, the following definitions are set forth to better clarify the application.

[0075] As used herein, the terms "comprises", "comprising", "includes", "including", "has", "having", "contains", "containing", or "encompasses", "encompassing", and other variations thereof, are inclusive or open-ended and do not exclude additional, unrecited elements or method steps.

[0076] The term "amino protecting group" refers to a group that can be attached to a nitrogen atom of an amino group to protect the amino group from participating in reactions and which can be readily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0077] carbamate groups of the formula -C(=0)OR a wherein R a is, for example, methyl, ethyl, t-butyl, benzyl, phenethyl, CH2=CH-CH2-, and the like; amide groups of the formula -C(=0)R b wherein R b is, for example, methyl, ethyl, phenyl, trifluoromethyl, and the like; N-sulfonyl derivative groups of the formula -S(=0)2-R c wherein R c is, for example, tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, and the like.

[0078] The term "alkyl" refers to saturated aliphatic hydrocarbon radicals including straight chain and branched chain groups of 1 to 18 carbon atoms. Preferred are alkyl groups containing 1 to 6 carbon atoms (i.e., C1-C6 alkyl), such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, t-butyl, pentyl, and the like. The alkyl group can be substituted or unsubstituted, and when substituted, the substituents can be halogen, nitro, sulfonyl, ether oxygen, ether sulfur, ester, thioester, or cyano.

[0079] C1-C4 alkyl is a straight chain or branched chain, saturated hydrocarbon chain comprising 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or t-butyl group.

[0080] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group that contains one or more double bonds and that has from 2 to 6 carbon atoms ("C 2-6 alkenyl"). The alkenyl group is, for example, ethenyl, 1-propenyl, 2-propenyl, 2-butenyl, 3-butenyl, 2-pentenyl, 3-pentenyl, 4-pentenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, 2-methyl-2-propenyl, and 4-methyl-3-pentenyl. When the compounds of the application contain an alkenyl group, the compounds can exist in pure E (entgegen) form, pure Z (zusammen) form, or in any mixture thereof.

[0081] As used herein, the term "alkynyl" means a monovalent hydrocarbon group that contains one or more triple bonds and that preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

[0082] As used herein, the term "cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring (e.g., monocyclic, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, cyclononyl, or bicyclic, including spiro, fused, or bridged systems (such as bicyclo[l. l. l]pentyl, bicyclo[2.2. l]heptyl, bicyclo[3.2. l]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, and the like), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents. The cycloalkyl group has 3 to 15 carbon atoms. For example, the term "C 3-10 cycloalkyl" refers to a saturated monocyclic or polycyclic (such as bicyclic) hydrocarbon ring of 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with 1 or more (such as 1 to 3) suitable substituents, for example, methyl-substituted cyclopropyl.

[0083] As used herein, the term "heterocyclyl" refers to a saturated or unsaturated, monovalent monocyclic or bicyclic radical having 2, 3, 4, 5, 6, 7, 8, or 9 carbon atoms in the ring and one or more (e.g., one, two, three, or four) heteroatoms in the ring selected from C(=0), O, S, S(=0), S(=0)2, and NR d , wherein R d represents a hydrogen atom or C 1-6 alkyl or halo-C 1-6 alkyl; the heterocyclyl group can be attached to the remainder of the molecule through any one of the carbon atoms or the nitrogen atom, if present. In particular, 3-10 membered heterocyclyl is a radical having 3-10 carbon atoms and heteroatoms in the ring, for example, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuranyl, dioxolinyl, pyrrolidinyl, pyrrolidonyl, imidazolidinyl, pyrazolidinyl, pyrrolinyl, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl, or trithianyl.

[0084] As used herein, the term "aryl" refers to an all-carbon, monocyclic or fused ring polycyclic, aromatic group having a conjugated pi-electron system. For example, as used herein, the term "C 6-10 aryl" means an aromatic group containing 6 to 10 carbon atoms, such as phenyl or naphthyl. The aryl group is optionally substituted with 1 or more (such as 1 to 3) suitable substituents (e.g., halo, -OH, -CN, -NO2, C 1-6 alkyl, and the like).

[0085] As used herein, the term "arylalkyl" preferably denotes an aryl-substituted alkyl group, wherein the aryl and the alkyl are as defined herein. Typically, the aryl group can have 6 to 10 carbon atoms and the alkyl group can have 1 to 6 carbon atoms. Exemplary arylalkyl groups include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0086] As used herein, the term "heteroaryl" denotes a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, in particular 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and which contains at least one heteroatom which can be the same or different (the heteroatom is, for example, oxygen, nitrogen or sulfur), and, in addition, can in each case be benzo-fused. In particular, the heteroaryl group is selected from the group consisting of thienyl, furanyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl and the like, and benzo derivatives thereof; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl and the like, and benzo derivatives thereof.

[0087] As used herein, the term "substituted" means that one or more (e.g. one, two, three or four) hydrogens on the designated atom are replaced with a selection from the indicated group, provided that normal valency is not exceeded and that the substitution results in a stable compound. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds.

[0088] As used herein, the term "base free of active hydrogen" means a base which does not contain groups such as NH, OH, SH and PH in its molecule.

[0089] As used herein, "mixtures of enantiomers in all proportions" is synonymous with "mixtures of enantiomers in any ratio". DETAILED DESCRIPTION

[0090] Example 1

[0091]

[0092] Into a 1 L four-necked flask was added a solution of ethyl chloromethylhistidine (2.1 eq, 162 g, 0.987 mol, 99% ee) in chlorobenzene (835 g) and triethylamine (2.1 eq, 100 g, 0.987 mol), nitrogen was replaced after addition, and the temperature was lowered to 0 °C with 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 temperature was controlled at 0-5 °C to start the dropwise addition, which was completed in 1.5 h.

[0093] The obtained reaction solution was warmed to 90°C in an oil bath, and reacted for 2 hours. After the reaction was completed, the temperature was naturally lowered to 30°C, and the filter cake was washed with chlorobenzene (200 g).

[0094] Water (300 g) was added to the filtrate, and stirred at 50°C for 1 hour. Then, 25% ammonia water (40 g) was added to adjust the pH to 7. After neutralization, the phases were separated, and water (100 g) was added to the lower organic phase for secondary extraction. The water phases were combined and concentrated under reduced pressure to a viscous state. Hydrochloric acid (500 g) was added, and the temperature was raised to 100°C for hydrolysis for 8 hours. The absolute content and ee value of glufosinate in the reaction solution were determined by sampling. Based on the theoretical yield of glufosinate (85.1 g) calculated from the amount of MDP fed, the yield of glufosinate was 92.6%, and the ee value was 98%.

[0095] Example 2:

[0096]

[0097] Chlorobenzene solution of chloroethyldiaminopropionate 255 g (concentration 30% w / w, 2.1 eq, 0.46 mol, ee: 99%) and triethylamine 46.7 g (2.1 eq) were added to a 1 L four-necked flask, and cooled to 0°C in an ice water bath. Nitrogen was replaced for three times. MDP chlorobenzene solution 60.5 g (concentration 43.17% w / w, 1 eq, 0.22 mol) was added to a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection. The temperature was controlled at 0-5°C during the dropping process, and the dropping process took about 1.5 hours. After the dropping was completed, the temperature was raised to 60°C for 1 hour, then to 80°C for 0.5 hour, and then naturally lowered to 20-30°C. The filter cake was washed with 110 g of chlorobenzene, and the filtrate was reserved for the next reaction.

[0098] The filtrate was added to a 1 L four-necked flask, and water 160 g was added. The temperature was raised to 50°C, and mechanically stirred for 1 hour. Then, ammonia water 20 g (concentration 25% w / w, 1.33 eq, 0.29 mol) was added at 50°C to adjust the pH to 7-8, and stirred for 5 minutes. After neutralization, the phases were separated. The product was in the water phase, and water was added to the lower organic phase for extraction (60 g x 2). The water phases were combined, and chlorobenzene 100 g was used to extract chloroethyldiaminopropionate from the water phase. The final water phase was used for the next hydrolysis, and the organic phase was reserved for the recovery of chloroethyldiaminopropionate.

[0099] The final water phase was distilled under reduced pressure to remove most of the water, and concentrated to a viscous state. Hydrochloric acid 250 g (concentration 30% w / w, 9.3 eq, 2.1 mol) was added, and the temperature was raised to 100°C for hydrolysis for 8 hours. The absolute content (LC determination) and ee value of glufosinate were determined by sampling. Based on the theoretical yield of glufosinate calculated from the amount of MDP fed, the yield of glufosinate was 93.05%, and the ee value was 96.85%.

[0100] The absolute content (LC determination) and ee value of the chlorohomospermidine ethyl ester in the above organic phase were determined by sampling, and the recovery rate of the excess chlorohomospermidine ethyl ester (1.1 eq) was calculated to be 95%, and the ee value was 96%.

[0101] Example 3:

[0102]

[0103] A 1L four-necked flask was charged with a chlorobenzene solution of chlorohomospermidine ethyl ester 375g (concentration 40% w / w, 4.1 eq, 0.91 mol, ee: 96.3%), cooled to 0°C in an ice water bath, and replaced with nitrogen three times; a constant pressure dropping funnel was charged with a chlorobenzene solution of MDP 60.5g (concentration 43.17% w / w, 1 eq, 0.22 mol), and MDP was added dropwise under nitrogen protection, with the temperature controlled at 0-5°C during the addition, which took about 1.5h. After the addition was completed, the reaction was carried out by staged temperature increase, first increased to 60°C for 1h, then increased to 80°C for 0.5h, and then naturally cooled.

[0104] When the internal temperature dropped to 60°C, 160g of water was added, the temperature was adjusted to 50°C, and mechanical stirring was carried out for 1h. Then 50g of ammonia water (concentration 25% w / w, 3.3 eq, 0.74 mol) was added at 50°C, the pH was adjusted to 7-8, and stirring was carried out for 5min. After neutralization, the phases were separated. The product was in the aqueous phase, the lower organic phase was extracted with water (60g x 2), the chlorohomospermidine ethyl ester in the aqueous phase was back-extracted with chlorobenzene 100g, the final aqueous phase was used for the next step of hydrolysis, and the organic phase was reserved for the recovery of chlorohomospermidine ethyl ester.

[0105] The above final aqueous phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, and then 250g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 2.1 mol) was added. After hydrolysis at 100°C for 8h, the absolute content (LC determination) and ee value of the glufosfamide were determined by sampling. Based on the theoretical yield of glufosfamide calculated from the amount of MDP charged, the yield of glufosfamide was 92.8%, and the ee value was 93.8%.

[0106] The absolute content (LC determination) and ee value of the chlorohomospermidine ethyl ester in the above organic phase were determined by sampling, and the recovery rate of the excess chlorohomospermidine ethyl ester (3.1 eq) was calculated to be 98%, and the ee value was 94%.

[0107] Example 4:

[0108]

[0109] 1 L four-mouth flask was charged with chloroformyl ethyl ester in chlorobenzene solution 375 g (concentration 40% w / w, 2.75 eq, 0.91 mol, ee: 96.3%), ice water bath was used to cool the temperature to 0°C, and nitrogen was used to replace the air for three times; MDP in chlorobenzene solution 53 g (concentration 49% w / w, 2 / 3 eq, 0.22 mol) was added into a constant pressure dropping funnel, and MDP was added dropwise under nitrogen protection, the temperature was controlled at 0-5°C during the dropping process, and the dropping process took about 1.5 h. After the dropping process was completed, the mixture was stirred for 30 min, and ammonia was introduced at a rate of 200 mL / min for 45 min until gas overflowed, the ammonia introduction was stopped, and the total amount of ammonia was 7.5 g (1.33 eq, 0.44 mol); then the temperature was increased to 15-20°C, and ammonia was removed under vacuum at -0.095 MPa for 30 min, and nitrogen was introduced.

[0110] When the internal temperature decreased to 60°C, water 200 g was added, the internal temperature was adjusted to 50°C, and the reaction was stirred for 1 h at 50°C. Ammonia water 50 g (concentration 25% w / w, 2.3 eq, 0.75 mol) was added at 50°C, the pH was adjusted to 7-8, and the mixture was stirred for 5 min. After neutralization, the phases were separated, the product was in the water phase, the lower organic phase was extracted with water (60 g x 2), the water phases were combined, chlorobenzene 100 g was used to extract the chloroformyl ethyl ester in the water phase, the final water phase was used for the next step of hydrolysis, and the organic phase was reserved for the recovery of chloroformyl ethyl ester.

[0111] The final water phase was subjected to vacuum distillation, most of the water was removed, and the mixture was concentrated to a viscous state. Hydrochloric acid 373 g (concentration 30% w / w, 9.3 eq, 3.07 mol) was added, the temperature was increased to 100°C, and the mixture was hydrolyzed for 8 h. The absolute content (LC determination) and ee value of glufosinate-ammonium in the sample were determined. The yield of glufosinate-ammonium was 90.77% and the ee value was 92.3% based on the theoretical yield of glufosinate-ammonium calculated from the amount of MDP used.

[0112] The absolute content (LC determination) and ee value of chloroformyl ethyl ester in the above-mentioned organic phase were determined, and the recovery rate of excess chloroformyl ethyl ester (1.75 eq) was calculated to be 95.2% with an ee value of 93.5%.

[0113] Example 5:

[0114]

[0115] 1 L four-mouth flask, add chloro-homoserine butyl ester xylene solution 163.4 g (concentration 41.5% w / w, 2.1 eq, 0.35 mol, ee: 99%), triethylamine 35.4 g (2.1 eq), ice water bath cooling to 0°C, nitrogen replacement three times; constant pressure dropping funnel, add MDP xylene solution 38.7 g (concentration 50% w / w, 1 eq, 0.165 mol), drop MDP under nitrogen protection, temperature control at 0-5°C during drop, time 1.5 h or so. After drop, use staged temperature rise reaction, first rise to 60°C for 1 h, then rise to 80°C for 0.5 h, then naturally cool to 20-30°C, suction filtration, filter cake washed with 150 g xylene, filtrate reserved for next step reaction.

[0116] 1 L four-mouth flask, add above filtrate, add water 180 g, rise to 50°C, mechanical stirring for 1 h, 50°C add ammonia water 20 g (concentration 25% w / w, 1.78 eq, 0.29 mol), adjust pH to 7-8, stir for 5 min, after neutralization, phase separation, product in water phase, add water to extract upper organic phase (60 g x 2), combine water phases, extract water phase chloro-homoserine butyl ester with xylene 100 g, final water phase used for next step hydrolysis, retain organic phase for recovery of chloro-homoserine butyl ester raw material.

[0117] Above final water phase, remove most water by reduced pressure distillation, concentrate to viscous state, add hydrochloric acid 255 g (concentration 30% w / w, 12.7 eq, 2.1 mol), rise to 100°C for 8 h, take sample to determine glufosinate acid absolute content (LC determination) and ee value. Calculate glufosinate acid yield 87.5% and ee value 97.10% based on MDP feed amount glufosinate acid theoretical yield.

[0118] Take sample to determine absolute content of chloro-homoserine butyl ester in above organic phase (LC determination) and ee value, calculate excess chloro-homoserine butyl ester (1.1 eq) recovery 95% and ee value 98.25%.

[0119] Example 6:

[0120]

[0121] 1 L four-mouth flask was charged with chloro-homoserine butyl ester in xylene solution 470.5 g (concentration 38.54% w / w, 4.1 eq, 0.935 mol, ee: 99.6%), ice water bath was used to cool the temperature to 0-5°C, nitrogen was used to replace the air for three times; 53.35 g MDP in xylene solution (concentration 50% w / w, 1 eq, 0.228 mol) was charged in a constant pressure dropping funnel, MDP was added dropwise under nitrogen protection, the temperature was controlled at 0-5°C during the dropping process, which took about 1.5 h. After the dropping was completed, the temperature was increased to 80°C and reacted for 2 h, and then naturally cooled down.

[0122] When the internal temperature dropped to 70°C, 160 g of water was added, the temperature was adjusted to 70°C, and mechanical stirring was performed for 1 h. Then, 50 g of 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, and stirred for 5 min. After neutralization, the product was in the water phase, and the upper organic phase was extracted with water (60 g x 2). The water phase was combined and extracted with 100 g of xylene to extract the chloro-homoserine butyl ester from the water phase. The final water phase was used for the next step of hydrolysis, and the organic phase was reserved for the recovery of chloro-homoserine butyl ester.

[0123] The above final water phase was distilled under reduced pressure to remove most of the water, and concentrated to a viscous state. Then, 250 g of hydrochloric acid (concentration 30% w / w, 9.2 eq, 2.1 mol) was added, and the temperature was increased to 100°C for hydrolysis for 8 h. The absolute content (LC determination) and ee value of glufosinate-ammonium were determined by sampling. The yield of glufosinate-ammonium was 88% and the ee value was 97.29% based on the theoretical yield of glufosinate-ammonium calculated from the amount of MDP fed.

[0124] The absolute content (LC determination) and ee value of chloro-homoserine butyl ester in the above organic phase were determined by sampling, and the recovery rate of excess chloro-homoserine butyl ester (3.1 eq) was calculated to be 95.73% with an ee value of 95.68%.

[0125] Example 7:

[0126]

[0127] 1 L four-necked flask was charged with chloroammonium butyl ester in xylene solution 370.9 g (concentration 38.54% w / w, 2.75 eq, 0.69 mol, ee: 99.6%), cooled to 0°C with ice water bath, replaced with nitrogen for three times; a constant pressure dropping funnel was charged with MDP in xylene solution 39.2 g (concentration 50% w / w, 2 / 3 eq), added MDP drop by drop under nitrogen protection, the temperature was controlled at 0-5°C during the dropping process, which took about 1.5 h. After the dropping was completed, stirred for 10-30 min, passed in ammonia gas at a rate of 200 mL / min for 30 min until gas overflowed, stopped passing in ammonia, the total amount of ammonia was 5.7 g (1.33 eq, 0.33 mol); then increased to 15-20°C, removed ammonia under vacuum-0.095 MPa for 20-30 min, filled in nitrogen. Cooled to 0-10°C, added MDP in xylene solution 19.5 g (concentration 50% w / w, 1 / 3 eq) again, increased to 80°C and reacted for 2 h, then naturally cooled down.

[0128] When the internal temperature dropped to 70°C, added water 180 g, adjusted the temperature to 70°C, mechanically stirred for 1 h, added ammonia water 50 g (concentration 25% w / w, 2.96 eq, 0.74 mol) at 25-30°C, adjusted the pH to 7-8, stirred for 5 min, after neutralization, the product was in the water phase, the upper organic phase was extracted with water (60 g x 2), the water phases were combined, the chloroammonium butyl ester in the water phase was back-extracted with xylene 100 g, the final water phase was used for the next step of hydrolysis, and the organic phase was reserved for the recovery of chloroammonium butyl ester.

[0129] The final water phase was distilled under reduced pressure to remove most of the water, concentrated to a viscous state, added hydrochloric acid 250 g (concentration 30% w / w, 8.4 eq, 2.1 mol), increased to 100°C and hydrolyzed for 8 h, then sampled to determine the absolute content of glufosinate acid (determined by LC) and ee value. According to the theoretical yield of glufosinate acid calculated based on the amount of MDP fed, the yield of glufosinate acid was 85.2%, and the ee value was 97.61%.

[0130] The absolute content of chloroammonium butyl ester in the above-mentioned organic phase was determined by sampling (determined by LC) and ee value, and the recovery rate of excess chloroammonium butyl ester (1.75 eq) was calculated to be 95.68%, and the ee value was 96.15%.

[0131] Example 8

[0132]

[0133] 1 L four-necked flask was charged with chloroformyl ethyl ester in chlorobenzene 375 g (concentration 40% w / w, 2.75 eq, 0.91 mol, ee: 96.3%), cooled to 0°C with ice water bath, replaced with nitrogen for three times; MDP in chlorobenzene 53 g (concentration 49% w / w, 2 / 3 eq, 0.22 mol) was added into a constant pressure dropping funnel, and then added dropwise under nitrogen protection, the temperature was controlled at 0-5°C during the dropping process, and the dropping process took about 1.5 h. After the dropping process was completed, the stirring was continued for 30 min, and then ammonia was bubbled into the flask at a rate of 200 mL / min for 45 min until gas overflowed, the ammonia bubbling was stopped, and the total amount of ammonia was 7.5 g (1.33 eq, 0.44 mol); the temperature was then increased to 15-20°C, and then the ammonia was removed under vacuum at -0.095 MPa for 30 min, and then nitrogen was filled into the flask. The temperature was then decreased to 0-10°C, and then MDP in chlorobenzene 13.2 g (concentration 49% w / w, 1 / 3 eq, 0.11 mol) was added dropwise, and then the reaction was carried out by increasing the temperature in stages, i.e., the temperature was first increased to 60°C for 1 h, and then the temperature was increased to 80°C for 0.5 h, and then the temperature was decreased naturally.

[0134] When the internal temperature decreased to 60°C, water 200 g was added, the internal temperature was adjusted to 50°C, and then the reaction was carried out under mechanical stirring for 1 h, and then ammonia water 50 g (concentration 25% w / w, 2.3 eq, 0.75 mol) was added at 50°C, the pH was adjusted to 7-8, the stirring was continued for 5 min, the phase separation was carried out after neutralization, the product was in the water phase, and the lower organic phase was extracted with water (60 g x 2), and then the water phases were combined; chloroformyl ethyl ester in the water phase was extracted with chlorobenzene 100 g, and then the organic phase was reserved for the recovery of chloroformyl ethyl ester.

[0135] The absolute content of MPN in the above water phase was determined by sampling (LC determination), and the yield of MPN was calculated based on the theoretical yield of MPN with the amount of MDP used as the raw material, and the yield of MPN was 77.5%.

[0136] The absolute content of chloroformyl ethyl ester in the above organic phase was determined by sampling (LC determination), and the ee value was determined, and then the recovery rate of excess chloroformyl ethyl ester (1.75 eq) was calculated to be 97.8%, and the ee value was 95.3%.

[0137] Various modifications of the application will be apparent to those skilled in the art from the foregoing description, which modifications are intended to fall within the scope of the application. Each of the references cited in this application, including all patents, patent applications, journal articles, books, and any other publications, are incorporated by reference herein in their entireties.

Claims

1. A method for preparing glufosinate of formula (I) or its salts, enantiomers, or mixtures of enantiomers in all proportions, characterized in that: The method includes the following steps: a) Reacting a compound of formula (II) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions with a compound of formula (III); b) Regardless of whether the intermediate is separated, the reaction is carried out in the presence of water and acid or base to give glufosinate (I) or its salt, enantiomers or mixtures of enantiomers in all proportions; When PG is an amino protecting group, the step of removing the amino protecting group may also be included; in: X is a halogen, -OAc, -OTs, -OMs, or Hal. Hal、Hal 1 and Hal 2 Each can be a halogen, such as fluorine, chlorine, bromine, or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is a hydrogen or amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4; R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R5)(R6)(R7); R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents independently selected from: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; Chiral carbon atoms are marked with an asterisk (*).

2. A method for preparing a compound of formula (I)-1 or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions, characterized in that: The method includes the following steps: a) Reacting a compound of formula (II) or a salt thereof, an enantiomer, or a mixture of enantiomers in all proportions with a compound of formula (III); b-1) Regardless of whether the intermediate is separated, the reaction in the presence of R8OH yields a compound of formula (I)-1 or its salt, enantiomers or mixtures of enantiomers in all proportions; When PG is an amino protecting group, the step of removing the amino protecting group may also be included; in: X is a halogen, -OAc, -OTs, -OMs, or Hal. Hal、Hal 1 and Hal 2 Each can be a halogen, such as fluorine, chlorine, bromine, or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is a hydrogen or amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4; R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, 3-10 membered heterocyclic groups or -Si(R5)(R6)(R7); R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; R5, R6, and R7 are each independently hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic alkyl; R8 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl alkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic group; preferably, R8 is H or C1-C6 alkyl; more preferably, R8 is H, methyl or ethyl; The aforementioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl, and heterocyclic groups are each optionally substituted by one or more substituents independently selected from: halogen, -OH, =O, -O-(C1-C6 alkyl), -C(=O)-(C1-C6 alkyl), -C(=O)OH, -C(=O)O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 Aryl, C 6-12 Aryl groups, 5-14 membered heteroaryl groups, and 3-10 membered heterocyclic groups; Chiral carbon atoms are marked with an asterisk (*).

3. The method according to claim 1 or 2, wherein the compound of formula (II) in step a) is enantiomeric pure, and the resulting glufosinate of formula (I) or a salt thereof, or the compound of formula (I)-1 or a salt thereof, is also enantiomeric pure.

4. The method according to claim 1 or 2, wherein the enantiomeric ratio of glufosinate of formula (I) or its salt or the compound of formula (I)-1 or its salt is (L):(D)-enantiomer or (D):(L)-enantiomer from 50.5:49.5 to 99.5:0.

5.

5. The method according to any one of claims 1-4, wherein the molar ratio of compound (II) to compound (III) is ≥2:

1.

6. The method according to any one of claims 1-5, wherein the compound of formula (III) or a solution thereof is added to the compound of formula (II) or a solution thereof; Alternatively, a compound of formula (II) or a solution thereof may be added to a compound of formula (III) or a solution thereof; Preferably, the compound of formula (III) or its solution is added to the compound of formula (II) or its solution in batches or all at once; Alternatively, the compound of formula (II) or its solution may be added in batches or all at once to the compound of formula (III) or its solution.

7. The method according to any one of claims 1-6, wherein X is chlorine, bromine, iodine, -OAc, -OTs, -OMs, or... Preferably, X is chlorine.

8. The method according to any one of claims 1-7, wherein R1, R2, and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 Aryl or C 6-12 Aryl alkyl groups; Preferably, R1, R2 and R3 are each independently methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl, ethylphenyl, propylphenyl or naphthyl; more preferably ethyl.

9. The method according to any one of claims 1-8, wherein Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

10. The method according to any one of claims 1-9, wherein Y is -OR1, and R1 is preferably ethyl or n-butyl.

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