Preparation method of glufosinate-ammonium or derivative thereof

Abstract

# imgabs0. The present disclosure relates to a process for the preparation of glufosinate-ammonium or a derivative thereof. In particular, the present invention relates to a process for the preparation of a compound of formula (I)-1 or a salt, enantiomer or a mixture of all proportions of enantiomers thereof, said process comprising the step of reacting a compound of formula (II) or a salt, enantiomer or a mixture of all proportions of enantiomers thereof with a compound of formula (III).

Description

[0001] This application is a divisional application of Chinese Patent Application No. 202380013473.2, titled "Preparation Method of Glufosinate or Its Derivatives", filed on March 24, 2023. Technical Field

[0002] The present disclosure relates to a preparation method of glufosinate or its derivatives. Background Art

[0003] Glufosinate is a highly effective, broad-spectrum, low-toxic, non-selective (non-selective) organophosphorus herbicide with partial systemic action developed by Hoechst 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-glufosinate is twice that of the racemic DL-glufosinate.

[0004] Existing preparation methods of glufosinate have many defects (for example, the process is complex and not suitable for large-scale production; highly toxic and / or expensive reagents are used, etc.). Summary of the Invention

[0005] The present disclosure provides a preparation method of glufosinate or its derivatives, and the raw materials used in the method are easy to obtain, and the process operation is suitable for industrial-scale production.

[0006] In some embodiments, the present disclosure provides a preparation method of glufosinate of formula (I) or its salt, enantiomer or a mixture of enantiomers in all proportions, characterized in that: the method comprises the following steps:

[0007]

[0008] a) Reacting a compound of formula (II) or its salt, enantiomer or a mixture of enantiomers in all proportions with a compound of formula (III);

[0009]

[0010] b) Reacting in the presence of water and an acid or a base to obtain glufosinate (I) or its salt, enantiomer or a mixture of enantiomers in all proportions, regardless of whether the intermediate is separated;

[0011] When PG is an amino protecting group, it may further include a step of removing the amino protecting group;

[0012] Wherein:

[0013] X is halogen, -OAc, -OTs, -OMs or

[0014] Hal, Hal 1and Hal 2 Each independently is a halogen, such as fluorine, chlorine, bromine or iodine;

[0015] Y is -OR1, -NH2, -NHR2 or -N(R2)(R3);

[0016] PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4;

[0017] R1, R2 and R3 each independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic group or -Si(R5)(R6)(R7);

[0018] R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group;

[0019] R5, R6 and R7 each independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic group;

[0020] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group;

[0021] The chiral carbon atom is marked with *.

[0022] In some embodiments, the present disclosure provides a method for preparing a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in all ratios thereof, characterized in that: the method comprises the following steps:

[0023]

[0024] a) React a compound of formula (II) or a salt, enantiomer or mixture of enantiomers in any ratio thereof with a compound of formula (III);

[0025]

[0026] b-1) Whether or not the intermediate is isolated, react in the presence of R8OH (i.e., in the absence of acid and base) to obtain a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in any ratio thereof;

[0027] When PG is an amino protecting group, it may further include the step of removing the amino protecting group;

[0028] Wherein:

[0029] X is halogen, -OAc, -OTs, -OMs or

[0030] Hal, Hal 1 and Hal 2 each independently is halogen, such as fluorine, chlorine, bromine or iodine;

[0031] Y is -OR1, -NH2, -NHR2 or -N(R2)(R3);

[0032] PG is hydrogen or an amino protecting group, and the amino protecting group is preferably -C(=O)R4, -C(=O)OR4 or -S(=O)2R4;

[0033] R1, R2 and R3 each independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl, 3-10 membered heterocyclic or -Si(R5)(R6)(R7);

[0034] R4 is selected from C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic;

[0035] R5, R6 and R7 each independently is hydrogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 5-14 membered heteroaryl or 3-10 membered heterocyclic;

[0036] R8 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 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;

[0037] The above alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14-membered heteroaryl and 3-10-membered heterocyclic group;

[0038] The chiral carbon atom is marked with *.

[0039] In some embodiments, the compound of formula (II) in step a) above is enantiomerically pure, and the resulting glufosinate-ammonium of formula (I) or its salt or the compound of formula (I)-1 or its salt is also enantiomerically pure.

[0040] In some embodiments, the enantiomeric ratio of the glufosinate-ammonium of formula (I) or its salt or the compound of formula (I)-1 or its salt obtained by the above method is 50.5:49.5 to 99.5:0.5 of (L):(D)-enantiomers or (D):(L)-enantiomers.

[0041] In some embodiments, in the above method, the molar ratio of the compound of formula (II) to the compound of formula (III) ≥ 2:1.

[0042] In some embodiments, in the above method, 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.

[0043] In some embodiments, the compound of formula (III) or its solution is added to the compound of formula (II) or its solution; or the compound of formula (II) or its solution is added to the compound of formula (III) or its solution.

[0044] In some embodiments, the compound of formula (III) or its solution is added to the compound of formula (II) or its solution in batches or at once; or the compound of formula (II) or its solution is added to the compound of formula (III) or its solution in batches or at once.

[0045] In some embodiments, X is chlorine, bromine, iodine, -OAc, -Ots, -Oms or

[0046] In some embodiments, X is chlorine.

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

[0048] In some embodiments, R1, R2 and R3 are each independently C1-C6 alkyl, C 6-10 aryl or C 6-12 aralkyl.

[0049] In some embodiments, 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.

[0050] In some embodiments, Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

[0051] In some embodiments, Y is -OR1.

[0052] In some embodiments, R1 is ethyl or n-butyl.

[0053] In some embodiments, PG is hydrogen, -C(=O)CH3, -C(=O)Ph, -C(=O)OC2H5, -C(=O)OC(CH3)3 or

[0054] In some embodiments, PG is hydrogen.

[0055] In some embodiments, the compound of formula (III) is methylphosphonous dichloride.

[0056] In some embodiments, the compound of formula (III) is the only phosphorus-containing reaction raw material.

[0057] In some embodiments, in step a), the reaction temperature is -50 to 200 °C, preferably -20 to 140 °C or 20 to 100 °C.

[0058] In some embodiments, step a) is carried out in the presence of a base, and the base is an inorganic base or an organic base;

[0059] Preferably, the molar ratio of (compound of formula (II) + the above base) to the compound of formula (III) ≥ 2.5:1, more preferably ≥ 3:1, and most preferably ≥ 4:1;

[0060] The inorganic base is preferably ammonia, alkali metal oxides, alkaline earth metal oxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal bicarbonates or alkaline earth metal bicarbonates; for example, potassium bicarbonate, sodium bicarbonate, lithium carbonate, potassium carbonate, sodium carbonate, cesium carbonate, calcium carbonate, magnesium carbonate, calcium oxide and magnesium oxide;

[0061] The organic base is preferably an organic base without active hydrogen, and the base without active hydrogen is preferably triethylamine, N,N-dimethylaniline or pyridine. The triethylamine, N,N-dimethylaniline and pyridine optionally have 1 to 3 substituents attached to one or more carbon atoms of the tertiary amine, and the substituents are selected from halogen, -OH, -O-(C1-C6 alkyl), -NH2, -NO2, -CN, C1-C6 alkyl, C 3-10 cycloalkyl and C 6-10 aryl.

[0062] In some embodiments, when step a) is carried out in the presence of a base with active hydrogen (such as ammonia), the base with active hydrogen is added after mixing the compound of formula (II) with all or part of the compound of formula (III).

[0063] In some embodiments, when 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.

[0064] In some embodiments, step a) is carried out under solvent-free conditions or in an inert solvent;

[0065] 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;

[0066] 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.

[0067] In some embodiments, in step b), an inorganic acid or an organic acid is added.

[0068] In some embodiments, the inorganic acid is hydrochloric acid or sulfuric acid.

[0069] In some embodiments, in step b), the base is an inorganic base or an organic base; the base is preferably a hydroxide of an alkali metal, a hydroxide of an alkaline earth metal, a carbonate of an alkali metal, a carbonate of an alkaline earth metal, a bicarbonate of an alkali metal, or a bicarbonate of an alkaline earth metal; more preferably, the base is NaOH, KOH, or Ba(OH)₂.

[0070] In some embodiments, in step b), the reaction temperature is 20 to 150 °C.

[0071] In some embodiments, in step b1), the reaction temperature is from 0 °C to 100 °C, preferably from 0 °C to 80 °C, more preferably from 20 °C to 60 °C or from 30 °C to 60 °C.

[0072] The method of the present invention is particularly suitable for the preparation of glufosinate, greatly shortening the steps of the existing preparation process and having excellent reaction yields. The compound of formula (III) used in the method of the present disclosure is easily obtained and low in cost, which makes the method of the present disclosure suitable for large-scale industrial production.

[0073] In addition, in the preparation of L-glufosinate, the product can effectively maintain the ee value of the raw material. For example, when using an enantiopure raw material (e.g., enantiomeric excess percentage (%ee) greater than 90%), the enantiomeric excess percentage (%ee) of the prepared L-glufosinate is, for example, greater than 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, or 95%.

[0074] Definition

[0075] Unless otherwise defined, the meanings of all technical and scientific terms used herein are intended to be the same as those commonly understood by one of ordinary skill in the art. References to techniques used herein refer to techniques commonly understood in the art, including variations of those techniques that are obvious to one of ordinary skill in the art or substitutions of equivalent techniques. 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 explain the present invention.

[0076] As used herein, the terms "comprising", "including", "having", "containing", or "involving" and other variant forms thereof in this text are inclusive or open-ended and do not exclude other unrecited elements or method steps.

[0077] The term "amino protecting group" refers to a group that can be attached to the nitrogen atom of an amino group to protect the amino group from participating in reactions and can be easily removed in subsequent reactions. Suitable amino protecting groups include, but are not limited to, the following protecting groups:

[0078] The carbamate group of the formula -C(=O)OR a wherein R a such as methyl, ethyl, tert-butyl, benzyl, phenethyl, CH2=CH-CH2-, etc.; the amide group of the formula -C(=O)R b wherein R b such as methyl, ethyl, phenyl, trifluoromethyl, etc.; the N-sulfonyl derivative-group of the formula -S(=O)2-R c wherein R c such as tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxybenzene, etc.

[0079] The term "alkyl" refers to a saturated aliphatic hydrocarbon group, including straight-chain and branched-chain groups having 1 to 18 carbon atoms. Alkyl groups containing 1 to 6 carbon atoms (i.e., C1-C6 alkyl) are preferred, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl, etc. The alkyl group can be substituted or unsubstituted. When substituted, the substituents can be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.

[0080] C1-C4 alkyl is straight-chain or branched-chain and contains a saturated hydrocarbon chain having 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, or tert-butyl group.

[0081] As used herein, the term "alkenyl" means a linear or branched monovalent hydrocarbon group that contains one or more double bonds and has 2-6 carbon atoms ("C 2-6"Alkenyl"). The alkenyl is, for example, vinyl, 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 present invention contain alkenyl, the compounds may exist in pure E (entgegen) form, pure Z (zusammen) form, or any mixture thereof.

[0082] As used herein, the term "alkynyl" denotes a monovalent hydrocarbon group containing one or more triple bonds, which preferably has 2, 3, 4, 5, or 6 carbon atoms, such as ethynyl or propynyl.

[0083] 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[1.1.1]pentyl, bicyclo[2.2.1]heptyl, bicyclo[3.2.1]octyl, or bicyclo[5.2.0]nonyl, decahydronaphthyl, etc.), which is optionally substituted with one or more (such as 1 to 3) suitable substituents. The cycloalkyl 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 having 3 to 10 ring-forming carbon atoms (e.g., cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl), which is optionally substituted with one or more (such as 1 to 3) suitable substituents, such as methyl-substituted cyclopropyl.

[0084] As used herein, the term "heterocyclic group" refers to a saturated or unsaturated monovalent monocyclic or bicyclic group 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) heteroatom-containing groups selected from C(=O), O, S, S(=O), S(=O)2, and NR d wherein R d represents a hydrogen atom or C 1-6 alkyl or halo-C 1-6Alkyl; the heterocyclic group may be attached to the remainder of the molecule through any of the carbon atoms or a nitrogen atom (if present). In particular, a 3- to 10-membered heterocyclic group is a group having 3 to 10 carbon atoms and heteroatoms in the ring, such as, but not limited to, oxiranyl, aziridinyl, azetidinyl, oxetanyl, tetrahydrofuryl, dioxolinyl, pyrrolidinyl, pyrrolidone, imidazolidinyl, pyrazolidinyl, pyrroline, tetrahydropyranyl, piperidinyl, morpholinyl, dithianyl, thiomorpholinyl, piperazinyl or trithianyl.

[0085] As used herein, the term "aryl" refers to a monocyclic or fused polycyclic aromatic group of all carbon atoms having a conjugated π-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 is optionally substituted by 1 or more (such as 1 to 3) suitable substituents (such as halogen, -OH, -CN, -NO2, C 1-6 alkyl, etc.).

[0086] As used herein, the term "aralkyl" preferably refers to an aryl-substituted alkyl, wherein the aryl and the alkyl are as defined herein. Generally, the aryl may have 6 to 10 carbon atoms, and the alkyl may have 1 to 6 carbon atoms. Exemplary aralkyls include, but are not limited to, benzyl, phenylethyl, phenylpropyl, phenylbutyl.

[0087] As used herein, the term "heteroaryl" refers to a monovalent monocyclic, bicyclic or tricyclic aromatic ring system having 5, 6, 8, 9, 10, 11, 12, 13 or 14 ring atoms, particularly 1 or 2 or 3 or 4 or 5 or 6 or 9 or 10 carbon atoms, and containing at least one heteroatom (the heteroatom being, for example, oxygen, nitrogen or sulfur) which may be the same or different, and which may additionally be benzo-fused in each case. In particular, heteroaryl is selected from thienyl, furyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl, thiadiazolyl, etc., and their benzo derivatives; or pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, etc., and their benzo derivatives.

[0088] As used herein, the term "substituted" means that one or more (such as one, two, three or four) hydrogens on the designated atom are replaced by a selection from the indicated groups, provided that the normal valence of the designated atom in the current case is not exceeded and the substitution forms a stable compound. Combinations of substituents and / or variables are only permitted if such combinations form a stable compound.

[0089] As used herein, the term "base without active hydrogen" refers to a base that does not contain groups such as NH, OH, SH, and PH in its molecule.

[0090] As used herein, "mixture of enantiomers in all ratios" has the same meaning as "mixture of enantiomers in any ratio". Detailed implementation mode

[0091] Example 1

[0092]

[0093] Add a solution of ethyl chlorohomoserinate (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) to a 1 L four-necked flask. After addition, replace the air with nitrogen, and cool down to 0 °C in an ice-water bath. Add a solution of MDP (1 eq, 55 g, 0.47 mol) in chlorobenzene (127.4 g) to a constant-pressure dropping funnel, start dropping while controlling the temperature at 0 - 5 °C, and complete the dropping in 1.5 h.

[0094] Heat the obtained reaction solution to 90 °C in an oil bath, react for 2 h, naturally cool down to 30 °C after the reaction is completed, filter by suction, and wash the filter cake with chlorobenzene (200 g).

[0095] Add water (300 g) to the filtrate, stir at 50 °C for 1 h, then add 25% ammonia water (40 g) to adjust the pH to 7. After neutralization, separate the phases, and extract the lower organic phase with water (100 g) for a second time. Combine the aqueous phases and concentrate under reduced pressure to a viscous state. Add 500 g of hydrochloric acid, heat up to 100 °C and hydrolyze for 8 h. Take a sample to determine the absolute content of glufosinate acid and the ee value in the reaction solution. Calculated based on the theoretical yield of glufosinate acid (85.1 g) of the MDP feed amount, the yield of glufosinate acid is 92.6%, and the ee value is 98%.

[0096] Example 2:

[0097]

[0098] Add 255 g of a chlorobenzene solution of ethyl chlorohomoserinate (concentration 30% w / w, 2.1 eq, 0.46 mol, ee: 99%) and 46.7 g of triethylamine (2.1 eq) to a 1 L four-necked flask. Cool the mixture to 0 °C in an ice-water bath and displace the air with nitrogen three times. Add 60.5 g of a chlorobenzene solution of MDP (concentration 43.17% w / w, 1 eq, 0.22 mol) to a constant-pressure dropping funnel. Add MDP dropwise under nitrogen protection, controlling the temperature at 0 - 5 °C during the addition, which takes about 1.5 h. After the addition is complete, carry out a stepwise temperature-raising reaction. First, raise the temperature to 60 °C and react for 1 h, then raise the temperature to 80 °C and react for 0.5 h, and then naturally cool to 20 - 30 °C. Filter by suction, wash the filter cake with 110 g of chlorobenzene, and leave the filtrate for the next reaction.

[0099] Add the above filtrate to a 1 L four-necked flask, add 160 g of water, and raise the temperature to 50 °C. Stir mechanically for 1 h. Then, add 20 g of ammonia water (concentration 25% w / w, 1.33 eq, 0.29 mol) at 50 °C, adjust the pH to 7 - 8, stir for 5 min, and separate the phases after neutralization. The product is in the aqueous phase. Extract the lower organic phase with water (60 g × 2), combine the aqueous phases, and back-extract the ethyl chlorohomoserinate in the aqueous phase with 100 g of chlorobenzene. Finally, the aqueous phase is used for the next hydrolysis, and the organic phase is reserved for the recovery of the raw material ethyl chlorohomoserinate.

[0100] Distill the above final aqueous phase under reduced pressure to remove most of the water and concentrate it to a viscous state. Add 250 g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 2.1 mol), raise the temperature to 100 °C, and hydrolyze for 8 h. Then, take a sample to determine the absolute content of glufosinate acid (by LC determination) and the ee value. Calculated based on the theoretical yield of glufosinate acid with the MDP feed amount, the yield of glufosinate acid is 93.05%, and the ee value is 96.85%.

[0101] Take a sample to determine the absolute content of ethyl chlorohomoserinate (by LC determination) and the ee value in the above organic phase, and calculate that the recovery rate of the excess ethyl chlorohomoserinate (1.1 eq) is 95%, and the ee value is 96%.

[0102] Example 3:

[0103]

[0104] Add 375 g of a chlorobenzene solution of ethyl 2-chloro-3-hydroxypropionate (concentration 40% w / w, 4.1 eq, 0.91 mol, ee: 96.3%) to a 1 L four-necked flask, cool it to 0 °C in an ice-water bath, and displace the air with nitrogen three times. Add 60.5 g of a chlorobenzene solution of MDP (concentration 43.17% w / w, 1 eq, 0.22 mol) to a constant-pressure dropping funnel, and add MDP dropwise under nitrogen protection. During the addition, control the temperature at 0 - 5 °C, which takes about 1.5 h. After the addition, carry out a stepwise temperature-raising reaction. First, raise the temperature to 60 °C and react for 1 h, then raise the temperature to 80 °C and react for 0.5 h, and then cool naturally.

[0105] When the internal temperature drops to 60 °C, add 160 g of water, adjust the temperature to 50 °C, stir mechanically for 1 h, add 50 g of ammonia water (concentration 25% w / w, 3.3 eq, 0.74 mol) at 50 °C, adjust the pH to 7 - 8, stir for 5 min, and separate the phases after neutralization. The product is in the aqueous phase. Extract the lower organic phase with water (60 g × 2), combine the aqueous phases, and back-extract the ethyl 2-chloro-3-hydroxypropionate in the aqueous phase with 100 g of chlorobenzene. Finally, the aqueous phase is used for the next hydrolysis step, and the organic phase is retained for the recovery of the raw material ethyl 2-chloro-3-hydroxypropionate.

[0106] Distill the above final aqueous phase under reduced pressure to remove most of the water, concentrate it to a viscous state, add 250 g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 2.1 mol), raise the temperature to 100 °C and hydrolyze for 8 h, then take a sample to determine the absolute content of glufosinate acid (by LC) and the ee value. Calculated based on the theoretical yield of glufosinate acid with the MDP feed amount, the yield of glufosinate acid is 92.8%, and the ee value is 93.8%.

[0107] Take a sample to determine the absolute content of ethyl 2-chloro-3-hydroxypropionate (by LC) and the ee value in the above organic phase, and calculate the recovery rate of the excess ethyl 2-chloro-3-hydroxypropionate (3.1 eq) to be 98%, and the ee value is 94%.

[0108] Example 4:

[0109]

[0110] Add 375 g of a chlorobenzene solution of ethyl chloro-homoserinate (concentration 40% w / w, 2.75 eq, 0.91 mol, ee: 96.3%) to a 1 L four-necked flask, cool it to 0 °C in an ice-water bath, and displace the air with nitrogen three times. Add 53 g of a chlorobenzene solution of MDP (concentration 49% w / w, 2 / 3 eq, 0.22 mol) to a constant-pressure dropping funnel, and add MDP dropwise under nitrogen protection. During the dropping process, control the temperature at 0 - 5 °C, which takes about 1.5 h. After the dropping is completed, stir for 30 min, and introduce ammonia gas at a rate of 200 mL / min for 45 min until gas overflows, then stop introducing ammonia. The total amount of ammonia used is 7.5 g (1.33 eq, 0.44 mol). Then raise the temperature to 15 - 20 °C, and carry out ammonia removal under vacuum at -0.095 MPa for 30 min, and then fill with nitrogen. Cool to 0 - 10 °C, and then add 13.2 g of a chlorobenzene solution of MDP (concentration 49% w / w, 1 / 3 eq, 0.11 mol) dropwise. After the dropping is completed, carry out a stepwise temperature-rising reaction. First, raise the temperature to 60 °C and react for 1 h, then raise the temperature to 80 °C and react for 0.5 h, and then cool naturally.

[0111] When the internal temperature drops to 60 °C, add 200 g of water, adjust the internal temperature to 50 °C, and carry out mechanical stirring reaction for 1 h. Add 50 g of ammonia water (concentration 25% w / w, 2.3 eq, 0.75 mol) at 50 °C, adjust the pH to 7 - 8, stir for 5 min, and after neutralization, separate the phases. The product is in the aqueous phase, and the lower organic phase is extracted with water (60 g × 2). Combine the aqueous phases, and back-extract the ethyl chloro-homoserinate in the aqueous phase with 100 g of chlorobenzene. Finally, the aqueous phase is used for the next hydrolysis step, and the organic phase is retained for the recovery of the raw material ethyl chloro-homoserinate.

[0112] The above-mentioned final aqueous phase is subjected to vacuum distillation to remove most of the water, concentrated to a viscous state, add 373 g of hydrochloric acid (concentration 30% w / w, 9.3 eq, 3.07 mol), raise the temperature to 100 °C and hydrolyze for 8 h, then take a sample to measure the absolute content of glufosinate acid (by LC determination) and the ee value. Calculated based on the theoretical yield of glufosinate acid with the MDP feeding amount, the yield of glufosinate acid is 90.77%, and the ee value is 92.3%.

[0113] Take a sample to measure the absolute content of ethyl chloro-homoserinate (by LC determination) and the ee value in the above-mentioned organic phase, and calculate that the recovery rate of the excessive ethyl chloro-homoserinate (1.75 eq) is 95.2%, and the ee value is 93.5%.

[0114] Example 5:

[0115]

[0116] Add 163.4 g of a xylene solution of butyl 2-chloro-homoserinate (concentration 41.5% w / w, 2.1 eq, 0.35 mol, ee: 99%) and 35.4 g of triethylamine (2.1 eq) to a 1 L four-necked flask. Cool the mixture to 0 °C in an ice-water bath and displace the air with nitrogen three times. Add 38.7 g of a xylene solution of MDP (concentration 50% w / w, 1 eq, 0.165 mol) to a constant-pressure dropping funnel. Add MDP dropwise under nitrogen protection, controlling the temperature at 0 - 5 °C during the addition, which takes about 1.5 h. After the addition is complete, carry out a stepwise temperature-raising reaction. First, raise the temperature to 60 °C and react for 1 h, then raise the temperature to 80 °C and react for 0.5 h, and then naturally cool to 20 - 30 °C. Filter by suction, wash the filter cake with 150 g of xylene, and leave the filtrate for the next reaction.

[0117] Add the above filtrate to a 1 L four-necked flask, add 180 g of water, heat up to 50 °C, and stir mechanically for 1 h. Add 20 g of ammonia water (concentration 25% w / w, 1.78 eq, 0.29 mol) at 50 °C, adjust the pH to 7 - 8, stir for 5 min, separate the phases after neutralization. The product is in the aqueous phase. Extract the upper organic phase with water (60 g × 2). Combine the aqueous phases, and back-extract the butyl 2-chloro-homoserinate in the aqueous phase with 100 g of xylene. Finally, the aqueous phase is used for the next hydrolysis, and the organic phase is reserved for the recovery of the raw material butyl 2-chloro-homoserinate.

[0118] Carry out vacuum distillation on the above final aqueous phase to remove most of the water, concentrate it to a viscous state, add 255 g of hydrochloric acid (concentration 30% w / w, 12.7 eq, 2.1 mol), heat up to 100 °C and hydrolyze for 8 h, then take a sample to determine the absolute content of glufosinate acid (by LC determination) and the ee value. Calculated based on the theoretical yield of glufosinate acid with the MDP feed amount, the yield of glufosinate acid is 87.5%, and the ee value is 97.10%.

[0119] Take a sample to determine the absolute content of butyl 2-chloro-homoserinate (by LC determination) and the ee value in the above organic phase, and calculate the recovery rate of the excess butyl 2-chloro-homoserinate (1.1 eq) to be 95%, and the ee value is 98.25%.

[0120] Example 6:

[0121]

[0122] Add 470.5 g of xylene solution of butyl 2-chloro-L-homoserinate (concentration 38.54% w / w, 4.1 eq, 0.935 mol, ee: 99.6%) to a 1 L four-necked flask, cool it to 0 - 5 °C in an ice-water bath, and displace the air with nitrogen three times. Add 53.35 g of xylene solution of MDP (concentration 50% w / w, 1 eq, 0.228 mol) to a constant pressure dropping funnel, and add MDP dropwise under nitrogen protection. During the dropping process, control the temperature at 0 - 5 °C, which takes about 1.5 h. After the dropping is completed, raise the temperature to 80 °C and react for 2 h, then cool it naturally.

[0123] When the internal temperature drops to 70 °C, add 160 g of water, adjust the temperature to 70 °C, stir mechanically for 1 h, add 50 g of ammonia water (concentration 25% w / w, 3.2 eq, 0.74 mol) at 25 - 30 °C to adjust the pH to 7 - 8, stir for 5 min, separate the phases after neutralization. The product is in the aqueous phase. Extract the upper organic phase with water (60 g × 2), combine the aqueous phases, and back-extract the butyl 2-chloro-L-homoserinate in the aqueous phase with 100 g of xylene. Finally, the aqueous phase is used for the next hydrolysis, and the organic phase is reserved for the recovery of the raw material butyl 2-chloro-L-homoserinate.

[0124] Distill the above final aqueous phase under reduced pressure to remove most of the water, concentrate it to a viscous state, add 250 g of hydrochloric acid (concentration 30% w / w, 9.2 eq, 2.1 mol), raise the temperature to 100 °C and hydrolyze for 8 h, then take samples to determine the absolute content of glufosinate acid (by LC) and the ee value. Calculated based on the theoretical yield of glufosinate acid with the MDP feed amount, the yield of glufosinate acid is 88%, and the ee value is 97.29%.

[0125] Take samples to determine the absolute content of butyl 2-chloro-L-homoserinate (by LC) and the ee value in the above organic phase, and calculate the recovery rate of the excess butyl 2-chloro-L-homoserinate (3.1 eq) to be 95.73%, and the ee value is 95.68%.

[0126] Example 7:

[0127]

[0128] Add 370.9 g of xylene solution of butyl 2-chlorohomoserinate (concentration 38.54% w / w, 2.75 eq, 0.69 mol, ee: 99.6%) to a 1 L four-necked flask, cool it to 0 °C in an ice-water bath, and displace with nitrogen three times; add 39.2 g of xylene solution of MDP (concentration 50% w / w, 2 / 3 eq) to a constant-pressure dropping funnel, and dropwise add MDP under nitrogen protection. During the dropping process, control the temperature at 0 - 5 °C, which takes about 1.5 h. After the dropping is completed, stir for 10 - 30 min, and introduce ammonia gas at a rate of 200 mL / min for 30 min until gas overflows, then stop introducing ammonia. The total amount of ammonia used is 5.7 g (1.33 eq, 0.33 mol); then raise the temperature to 15 - 20 °C, and carry out ammonia removal under vacuum at -0.095 MPa for 20 - 30 min, and then fill with nitrogen. Cool to 0 - 10 °C, and then dropwise add 19.5 g of xylene solution of MDP (concentration 50% w / w, 1 / 3 eq), raise the temperature to 80 °C and react for 2 h, and then cool naturally.

[0129] When the internal temperature drops to 70 °C, add 180 g of water, adjust the temperature to 70 °C, stir mechanically for 1 h, add 50 g of ammonia water (concentration 25% w / w, 2.96 eq, 0.74 mol) at 25 - 30 °C, adjust the pH to 7 - 8, stir for 5 min, after neutralization, separate the phases. The product is in the aqueous phase, and the upper organic phase is extracted with water (60 g × 2). Combine the aqueous phases, and back-extract the butyl 2-chlorohomoserinate in the aqueous phase with 100 g of xylene. Finally, the aqueous phase is used for the next hydrolysis, and the organic phase is reserved for the recovery of the raw material butyl 2-chlorohomoserinate.

[0130] The above final aqueous phase is distilled under reduced pressure to remove most of the water, concentrated to a viscous state, add 250 g of hydrochloric acid (concentration 30% w / w, 8.4 eq, 2.1 mol), raise the temperature to 100 °C and hydrolyze for 8 h, then take a sample to measure the absolute content of glufosinate acid (LC determination) and ee value. Calculated based on the theoretical yield of glufosinate acid with the feeding amount of MDP, the yield of glufosinate acid is 85.2%, and the ee value is 97.61%.

[0131] Take a sample to measure the absolute content of butyl 2-chlorohomoserinate (LC determination) and ee value in the above organic phase, and calculate that the recovery rate of the excessive butyl 2-chlorohomoserinate (1.75 eq) is 95.68%, and the ee value is 96.15%.

[0132] Example 8

[0133]

[0134] Add 375 g of a chlorobenzene solution of ethyl chlorohomoserinate (concentration 40% w / w, 2.75 eq, 0.91 mol, ee: 96.3%) to a 1 L four-necked flask, cool it to 0 °C in an ice-water bath, and displace the air with nitrogen three times; add 53 g of a chlorobenzene solution of MDP (concentration 49% w / w, 2 / 3 eq, 0.22 mol) to a constant-pressure dropping funnel, and dropwise add MDP under nitrogen protection. During the dropping process, control the temperature at 0 - 5 °C, which takes about 1.5 h. After the dropping is completed, stir for 30 min, then pass ammonia gas at a rate of 200 mL / min for 45 min until gas overflows, and stop passing ammonia. The total amount of ammonia used is 7.5 g (1.33 eq, 0.44 mol); then raise the temperature to 15 - 20 °C and carry out ammonia removal under vacuum at -0.095 MPa for 30 min, and then fill with nitrogen. Cool to 0 - 10 °C, and then dropwise add 13.2 g of a chlorobenzene solution of MDP (concentration 49% w / w, 1 / 3 eq, 0.11 mol). After dropping, carry out a stepwise temperature-rising reaction. First, raise the temperature to 60 °C and react for 1 h, then raise the temperature to 80 °C and react for 0.5 h, and then cool naturally.

[0135] When the internal temperature drops to 60 °C, add 200 g of water, adjust the internal temperature to 50 °C, and carry out mechanical stirring reaction for 1 h. Add 50 g of ammonia water (concentration 25% w / w, 2.3 eq, 0.75 mol) at 50 °C, adjust the pH to 7 - 8, stir for 5 min, and after neutralization, separate the phases. The product is in the aqueous phase, and the lower organic phase is extracted with water (60 g × 2), and the aqueous phases are combined; extract ethyl chlorohomoserinate in the aqueous phase with 100 g of chlorobenzene, and retain the organic phase for the recovery of the raw material ethyl chlorohomoserinate.

[0136] Take a sample to measure the absolute content of MPN in the above aqueous phase (determined by LC), and calculate the MPN yield of 77.5% based on the theoretical yield of MPN with the feeding amount of MDP.

[0137] Take a sample to measure the absolute content (determined by LC) and ee value of ethyl chlorohomoserinate in the above organic phase, and calculate the recovery rate of the excessive ethyl chlorohomoserinate (1.75 eq) to be 97.8% and the ee value to be 95.3%.

[0138] Except for those described herein, various modifications of the present invention will be apparent to those skilled in the art based on the foregoing description. Such modifications are also intended to fall within the scope of the appended claims. All references cited in this application (including all patents, patent applications, journal articles, books, and any other publications) are incorporated herein by reference in their entirety.

Claims

1. A process for 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: a) Reacting a compound of formula (II) or a salt, enantiomer or mixture of enantiomers in any ratio thereof with a compound of formula (III); b-1) Whether or not the intermediate is isolated, reacting in the presence of R8OH to obtain a compound of formula (I)-1 or a salt, enantiomer or mixture of enantiomers in any ratio thereof; When PG is an amino protecting group, it may further include the step of removing the amino protecting group; Wherein: X is halogen, -OAc, -OTs, -OMs or Hal Hal, Hal 1 and Hal 2 each independently represents a halogen, such as fluorine, chlorine, bromine or iodine; Y is -OR1, -NH2, -NHR2 or -N(R2)(R3); PG is hydrogen or an 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 aralkyl, 5-14-membered heteroaryl, 3-10-membered heterocyclic group, 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 aralkyl, 5-14-membered heteroaryl, and 3-10-membered heterocyclic group; 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 aralkyl, 5-14-membered heteroaryl, or 3-10-membered heterocyclic group; R8 is H, C1-C6 alkyl, C 3-10 cycloalkyl, C 6-10 aryl, C 6-12 aralkyl, 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 above-mentioned alkyl, alkenyl, alkynyl, cycloalkyl, aryl, aralkyl, heteroaryl and heterocyclic group are each optionally substituted by one or more substituents independently selected from the following: 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 aralkyl, 5-14 membered heteroaryl and 3-10 membered heterocyclic group; The chiral carbon atoms are marked with *.

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

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

5.

4. The method according to any one of claims 1-3, wherein the molar ratio of the compound of formula (II) to the compound of formula (III) ≥ 2:

1.

5. The method according to any one of claims 1-4, wherein the compound of formula (III) or its solution is added to the compound of formula (II) or its solution; Alternatively, adding the compound of formula (II) or its solution to the compound of formula (III) or its solution; Preferably, adding the compound of formula (III) or its solution in batches or at once to the compound of formula (II) or its solution; Alternatively, adding the compound of formula (II) or its solution in batches or at once to the compound of formula (III) or its solution.

6. The method according to any one of claims 1-5, wherein X is chlorine, bromine, iodine, -OAc, -OTs, -OMs or Preferably, X is chlorine.

7. The method according to any one of claims 1-6, wherein R1, R2 and R3 are each independently hydrogen, C1-C6 alkyl, C 6-10 aryl or C 6-12 aralkyl; 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.

8. The method according to any one of claims 1-7, wherein Y is -NHCH2CH2CH2CH3, -N(CH3)2, -OCH3, -OCH2CH3, -OCH2CH2CH3, -OCH(CH3)2, -OCH2CH2CH2CH3, -OCH2CH(CH3)2 or -OBn.

9. The method according to any one of claims 1-8, wherein Y is -OR1, and R1 is preferably ethyl or n-butyl.

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