Preparation method of refined glufosinate-ammonium

Abstract

The invention relates to the technical field of pesticides and herbicides, and discloses a preparation method of refined glufosinate-ammonium. Feeding the feed liquid of the compound shown in the formula (II) and the feed liquid of the compound shown in the formula (V) into a first continuous flow reaction device, and reacting at 70-150 DEG C to obtain a first reaction product; enabling the first reaction product to enter a second continuous flow reaction device for hydrolysis reaction to obtain refined glufosinate-ammonium; wherein Y is-OR3, and R3 is selected from a C1-C6 alkyl group or a C3-C6 cycloalkyl group; r1 and R2 are respectively and independently selected from hydrogen, C1-C6 alkyl and C3-C6 cycloalkyl, or R1 and R2 and N atoms connected with R1 and R2 form three-membered to six-membered heterocycloalkyl. According to the present invention, the compound represented by the formula (II) and the compound represented by the formula (V) are subjected to the reaction through the continuous flow reactor at the high temperature to obtain the pre-hydrolysis reaction liquid, such that the operation of the low-temperature reaction before the hydrolysis step and the high-temperature reaction after the hydrolysis step in the prior art is avoided, the reaction is simplified, the two-step reaction is completed in one step, and the product yield is improved. # imgabs0 #

Description

Technical Field

[0001] The invention relates to the technical field of pesticide herbicides, and in particular to a method for preparing refined glufosinate ammonium. Background Art

[0002] Glufosinate has the characteristics of broad weed control spectrum, high activity, low toxicity, easy degradation in soil, safety to crops, small drift, good environmental compatibility and rapid weed control. It can prevent and quickly kill more than 100 annual and perennial broad-leaved weeds and grass weeds such as crabgrass and ryegrass.

[0003] Ordinary glufosinate is a mixture of two enantiomers, but only the L-enantiomer, i.e. refined glufosinate, is active. Refined glufosinate is easier to decompose in the soil and is less toxic to humans and animals, which can significantly reduce environmental pressure. Although the D / L mixture is still the main form of glufosinate technical on the market, with the innovation and progress of related technologies in recent years, the trend of refined glufosinate entering the mainstream market and replacing ordinary glufosinate is irreversible.

[0004] The existing methods for synthesizing refined glufosinate ammonium mainly include chemical method and biological method. The chemical method includes asymmetric hydrogenation, chemical resolution method and semi-synthesis method.

[0005] The asymmetric hydrogenation method uses the intermediate keto acid PPO as a raw material, and in the presence of a chiral catalyst and a ligand, undergoes a reduction amination reaction with an amine, followed by deprotection to obtain refined glufosinate ammonium. This route is the earliest method used in the industrial production of refined glufosinate ammonium at home and abroad. It was developed and industrialized by Yongnong Biotechnology and Meiji Seika. This method has the advantages of mild reaction and high yield, but its further promotion and application are limited by defects such as the instability of the intermediate PPO and the high process cost.

[0006] The chemical resolution method is to resolve racemic D / L-phosphinothricin or its derivatives by a chiral resolution agent, thereby obtaining optically pure glufosinate. The patent application specification with publication number WO1995023805A1 discloses a method for obtaining L- or D-homoalanine-4-yl-(methyl)phosphonic acid and its salt by racemic resolution of D,L-homoalanine-4-yl-(methyl)phosphonic acid using a chiral base such as quinine and cinchonine to precipitate one of the diastereoisomer salts. This method requires the use of expensive chiral resolution agents, has a low yield, and has no obvious industrial advantages.

[0007] The semi-synthetic method uses fermented amino acids, such as methionine and homoserine, as raw materials to prepare refined glufosinate ammonium through multi-step reactions.

[0008] The patent application specification with publication number US5442088A discloses a method of obtaining refined glufosinate hydrochloride by ring-opening chlorination, esterification, Michaelis-Arbuzov reaction with methylphosphite diester, and finally hydrolysis and purification using L-homoserine lactone derivative as raw material. The reaction route is as follows:

[0009]

[0010] The multi-step reaction process unit is easy to operate, but the activity of the raw material chlorinated substrate of the Michaelis-Arbuzov reaction is limited, and it usually needs to be carried out at a higher temperature (130-140°C or higher). At the same time, due to the high temperature, the chlorinated alkane by-product further reacts with the methyl phosphite diester, which greatly increases its unit consumption. In addition, at this temperature, the reaction decreases in the L-type enantiomeric excess due to the racemization of some raw materials or products.

[0011] The patent specification with publication number CN113490671A discloses that an amino-protected or unprotected halogenated homoserine ester is used as a raw material, condensed with methylphosphonous acid monochloroester to obtain an intermediate, and then hydrolyzed to obtain refined glufosinate. The reaction route is as follows:

[0012]

[0013] This method uses homoserine as the raw material and undergoes multiple steps of synthesis, such as cyclization, chlorination, esterification, and protective group protection, and the reaction steps are relatively long. In addition, the Michaelis-Arbuzov reaction inevitably produces halogenated alkanes, which are small molecule halogenated alkanes that are Class 3 carcinogens and have a destructive effect on ozone in the atmosphere.

[0014] The patent specification with the announcement number CN116041387A discloses that glufosinate ammonium is prepared by using chlorohomoserine ester as raw material through condensation cyclization, hydrolysis and refining and purification. The reaction route is as follows:

[0015]

[0016] Due to the different reaction mechanism, the reaction temperature of this novel process route is milder than that of the Michaelis-Arbuzov reaction, and the reaction temperature can be reduced by 30-80°C compared with the former. Thanks to this, the racemization of the L-enantiomer or raw material at high temperature can also be reduced when preparing refined glufosinate ammonium, thereby increasing the ee value of the product L-enantiomer. Similarly, this process can avoid the by-product of halogenated hydrocarbons in the Michaelis-Arbuzov reaction, eliminating the equipment and engineering investment for the separation, purification and collection of the above-mentioned by-products, and also avoiding the potential environmental and safety risks brought by the above-mentioned by-products. However, this process route has problems such as violent reaction and high reaction heat in the preparation of phosphorus-containing intermediates, and it is difficult to achieve the continuity and automation of this multi-step process.

[0017] In recent years, with the growing demand for refined glufosinate ammonium, there is an urgent need to develop a method for synthesizing refined glufosinate ammonium with mild reaction conditions, higher yield, lower cost and simple operation, which is of great significance for reducing the amount of herbicides used and increasing their efficiency. Summary of the invention

[0018] The purpose of the present invention is to overcome the problems existing in the prior art and to provide a method for preparing refined glufosinate-ammonium.

[0019] The endpoints and any values ​​of the ranges disclosed in this article are not limited to the precise ranges or values, and these ranges or values ​​should be understood to include values ​​close to these ranges or values. For numerical ranges, the endpoint values ​​of each range, the endpoint values ​​of each range and the individual point values, and the individual point values ​​can be combined with each other to obtain one or more new numerical ranges, which should be considered as specifically disclosed in this article.

[0020] For the sake of simplicity, the "compound of formula (N) (such as the compound of formula (III))" mentioned below may also include any optical isomer, geometric isomer, tautomer or isomer mixture, or agriculturally acceptable salt of the compound of formula (N).

[0021] Unless otherwise indicated, the reference herein to "compounds of formula (N) (e.g., compounds of formula (III)") also encompasses isotope-labeled compounds obtained by replacing any atom in the compound with an isotope atom thereof. That is, the present invention includes all agriculturally acceptable isotope-labeled compounds of compounds of formula (N), wherein one or more atoms are replaced by atoms having the same atomic number as the atoms usually found in nature but with a different atomic mass or mass number.

[0022] Examples of suitable isotopes for inclusion in the compounds of the present invention include isotopes of hydrogen such as 2 H(D) and 3 H(T), isotopes of carbon, such as 11 C.13 C and 14 C, isotopes of chlorine, such as 37 Cl, isotopes of fluorine, such as 18 F, isotopes of iodine, such as 123 I and 125 I, isotopes of nitrogen, such as 13 N and 15 N, isotopes of oxygen, such as 15 O. 17 O and 18 O, and isotopes of sulfur such as 35 S.

[0023] Isotopically labeled compounds of formula (N) can generally be prepared by conventional techniques known to those skilled in the art or by using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously used in an analogous manner to those described in the Examples and Preparations appended herein.

[0024] The compound of formula (N) may exist in the form of an agriculturally acceptable salt, for example, an acid addition salt and / or a base addition salt of the compound of formula (N). Unless otherwise indicated, "agriculturally acceptable salt" as used herein includes acid addition salts or base addition salts that may occur in the compound of formula (N).

[0025] Agriculturally acceptable salts of the compound of formula (N) include acid addition salts and base addition salts thereof. Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include, but are not limited to, hydrochloride, acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate / carbonate, bisulfate / sulfate, borate, camphorsulfonate, citrate, cyclaminate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2-(4-hydroxybenzyl)benzoate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, 2-hydroxyethanesulfonate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthoate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate / hydrogenphosphate / dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, toluenesulfonate, and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to, ammonium, aluminum, arginine, calcium, choline, diethylamine, diethanolamine, glycine, lysine, magnesium, meglumine, ethanolamine, potassium, sodium, lithium, tromethamine, and zinc salts. Hemisalts of acids and bases, such as hemisulphate and hemicalcium salts, can also be formed. Methods for preparing agriculturally acceptable salts of the compounds described herein are known to those skilled in the art.

[0026] Certain compounds of the present invention may exist in unsolvated forms as well as solvated forms (including hydrated forms). In general, compounds of formula (N) are encompassed within the scope of the present invention regardless of whether they exist in solvated or unsolvated forms.

[0027] Certain compounds of the present invention may exist in different crystalline or amorphous forms. Regardless of the form in which they exist, the compounds of formula (N) are included within the scope of the present invention.

[0028] To avoid ambiguity, the following definitions are given for the terms used in this article. Unless otherwise specified, the meanings of the terms used in this article are as follows.

[0029] As used herein, the term "substituted" means that one or more (preferably 1 to 5, more preferably 1 to 3) hydrogen atoms in the group are independently replaced by a corresponding number of substituents.

[0030] As used herein, the term "independently" means that when there are more than one substituent, the substituents may be the same or different.

[0031] As used herein, the term "optional" or "optionally" means that the event it describes can or cannot occur. For example, a group "optionally substituted" means that the group can be unsubstituted or substituted.

[0032] As used herein, the term "alkyl" refers to a saturated aliphatic hydrocarbon, including straight and branched chains. In some embodiments, the alkyl group has, for example, 1-6 or 1-3 carbon atoms. For example, the term "C 1 -C 6 "Alkyl" refers to a straight or branched chain radical having 1 to 6 carbon atoms. 1 -C 6 The term "alkyl" includes in its definition the term "C 1-6 Alkyl", "C 1 -C 3 Alkyl" and "C 1 -C 4 Alkyl". Examples of alkyl include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, 3-pentyl, isopentyl, neopentyl, (R)-2-methylbutyl, (S)-2-methylbutyl, 3-methylbutyl, 2,3-dimethylpropyl, 2,3-dimethylbutyl, hexyl, and the like.

[0033] As used in this article, the term “C 3 -C 6 "Cycloalkyl" refers to a cycloalkyl group having 3 to 6 carbon atoms forming the ring. For example, C 3 -C6 Cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

[0034] As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group having m carbon atoms forming a ring and (nm) heteroatoms forming a ring, wherein the heteroatoms are selected from at least one of N, O and S. For example, three-membered to six-membered heterocycloalkyl groups include, but are not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine.

[0035] In order to achieve the above object, the first aspect of the present invention provides a method for preparing refined glufosinate-ammonium or a salt thereof represented by formula (I), wherein the method comprises the following steps:

[0036]

[0037] (1) allowing a liquid of the compound of formula (II) and a liquid of the compound of formula (V) to enter a first continuous flow reaction device and react at 70-150° C. to obtain a first reaction product;

[0038]

[0039] (2) allowing the first reaction product obtained in step (1) to enter a second continuous flow reaction device for hydrolysis reaction to obtain a compound of formula (I);

[0040] Where Y is -OR 3 , R 3 Selected from C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;

[0041] R 1 and R 2 are each independently selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a three- to six-membered heterocycloalkyl group.

[0042] In the present invention, the compound of formula (I) prepared by the method can be a pure L-enantiomer, or it can exist in the form of a mixture of L and D-enantiomers, preferably the L-enantiomer exists in a larger proportion in the mixture of enantiomers. For example, in one embodiment, the ee value of the compound of formula (I) can be 75% or more (e.g., 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 98.5% or more, 99% or more, 99.3% or more, 99.5% or more, 99.7% or more, 99.8% or more, 99.9% or more).

[0043] After extensive research, the inventors of the present invention surprisingly found that by reacting the compound of formula (II) with the compound of formula (V) in a continuous flow reactor at a fixed higher temperature, they can be directly converted into an intermediate compound for the next reaction, thereby combining the two-step reaction disclosed in CN116041387A into a one-step reaction, eliminating the need for segmented control of the reaction temperature and shortening the reaction time.

[0044] In the present invention, during continuous feeding, the feed liquid of the compound of formula (II) and the feed liquid of the compound of formula (V) can be fed into the first continuous flow reaction device at the same time, or the feed liquid of the compound of formula (II) and / or the feed liquid of the compound of formula (V) can be fed into the first continuous flow reaction device in portions at different time points and / or at different feeding points. Preferably, the combination of the two conditions can achieve a higher conversion rate in the first continuous flow reaction device.

[0045] In the present invention, the feed solution of the compound may be a solution obtained by dissolving the compound in a solvent, or may be a reaction product containing the compound obtained by a method for preparing the compound.

[0046] In the present invention, the first reaction product may be directly fed into the second continuous flow reaction device, or may be fed into the second continuous flow reaction device after one or more operations of desolventizing, adding solvent, solid-liquid separation, and extraction and separation. The desolventizing and adding solvent specifically refer to reducing or increasing the solvent (changing the concentration of reactants), or switching to different solvents; the solid-liquid separation specifically refers to removing the by-product salts of step (1), such as R, by common methods such as suction filtration, centrifugation, and filter pressing. 1 and R 2 When both are ethyl, the byproduct salt is diethylamine hydrochloride, and the obtained filtrate is then subjected to the reaction of step (2); the extraction and liquid separation specifically refers to adding acid water after the optional solid-liquid separation, separating the aqueous phase and then conducting the reaction of step (2). The above-mentioned various optional operation processes can be carried out intermittently, or continuously using appropriate equipment. For example, the continuous liquid separation process can be achieved using a liquid separation device; the desolventizing process can also be achieved using a continuous desolventizing device, etc.

[0047] In the present invention, the compound of formula (I) is obtained from the hydrolysis reaction product by conventional post-treatment. The first reaction product and the hydrolysis reaction product refer to the entire stream flowing out of the first continuous flow reaction device and the second continuous flow reaction device, respectively, including the reaction product, unreacted raw materials, by-products, solvents and salts.

[0048] In some embodiments of the present invention, R 3 C 1 -C 3 alkyl.

[0049] In some embodiments of the present invention, R 3 It is methyl (Me).

[0050] In some embodiments of the present invention, R 3 It is ethyl (Et).

[0051] In some embodiments of the present invention, R 3 It is n-propyl (n-Pr).

[0052] In some embodiments of the present invention, R 3 It is isopropyl (i-Pr).

[0053] In some embodiments of the present invention, the compound of formula (II) is selected from the following compounds:

[0054]

[0055] In some embodiments of the present invention, R 1 and R 2 Both C 1 -C 3 alkyl.

[0056] In some embodiments of the present invention, R 1 and R 2 All are methyl.

[0057] In some embodiments of the present invention, R 1 and R 2 All are ethyl.

[0058] In some embodiments of the present invention, R 1 and R 2 All are n-propyl.

[0059] In some embodiments of the present invention, R 1 and R 2 All are isopropyl.

[0060] In some embodiments of the present invention, the compound of formula (V) is selected from the following compounds:

[0061]

[0062] In some embodiments of the present invention, in step (1), the molar ratio of the compound of formula (II) to the compound of formula (V) is 1:0.9-5, for example 1:0.9, 1:0.95, 1:1, 1:1.01, 1:1.02, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:2, 1:3, 1:4, 1:5, and any value within the range of any two of the above values, preferably 1:0.9-1.2, and more preferably 1:0.98-1.02.

[0063] In some embodiments of the present invention, the reaction temperature in step (1) is, for example, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, and any value within the range of any two of the above values, preferably 80-140°C, more preferably 90-105°C, and more preferably 95-100°C. Optionally, before the compound of formula (II) and the compound of formula (V) enter the reaction device, they may be preheated to reach or approach the reaction temperature. The preheating device may be any cooling or heating device known in the art.

[0064] In some embodiments of the present invention, the reaction time in step (1) is 1 minute to 4 hours, which can be adjusted according to parameters such as reaction temperature, reactant molar ratio, feed flow rate, etc., for example, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1 hour and 5 minutes, 1 hour and 10 minutes, 1 hour and 15 minutes, 1 hour and 20 minutes, 1 hour and 25 minutes, 1 hour and 30 minutes, 1 hour and 35 minutes, 1 hour and 40 minutes, 1 hour and 45 minutes, 1 hour and 50 minutes, 1 hour 55 minutes, 2 hours, 2 hours 5 minutes, 2 hours 10 minutes, 2 hours 15 minutes, 2 hours 20 minutes, 2 hours 25 minutes, 2 hours 30 minutes, 2 hours 35 minutes, 2 hours 40 minutes, 2 hours 45 minutes, 2 hours 50 minutes, 2 hours 55 minutes, 3 hours, 3 hours 5 minutes, 3 hours 10 minutes, 3 hours 15 minutes, 3 hours 20 minutes, 3 hours 25 minutes, 3 hours 30 minutes, 3 hours 35 minutes, 3 hours 40 minutes, 3 hours 45 minutes, 3 hours 50 minutes, 3 hours 55 minutes, 4 hours, and any value within the range of any two of the above values, preferably 2 hours 15 seconds to 3 hours 15 seconds. The reaction time can be the residence time in the case of a continuous flow reaction device.

[0065] In some embodiments of the present invention, the solvent for the reaction in step (1) is selected from at least one of aromatic hydrocarbon solvents (e.g., benzene, xylene, trimethylolbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halogenated benzene or dihalogenated benzene), alkane solvents (e.g., n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane), ether solvents (e.g., tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, dioxane or diethylene glycol dimethyl ether), or ester solvents (e.g., ethyl acetate, isopropyl acetate or butyl acetate), preferably toluene and / or chlorobenzene.

[0066] In some embodiments of the present invention, the method further comprises: before step (1), allowing the feed solution of the compound of formula (VII) and the feed solution of the compound of formula (VIII) to enter a third continuous flow reaction device for reaction to obtain a feed solution of the compound of formula (V);

[0067]

[0068] Among them, R 1 and R 2 As defined before.

[0069] Wherein, in some embodiments of the present invention, the molar ratio of the compound of formula (VII) to the compound of formula (VIII) is 1:3-5, for example 1:3, 1:3.1, 1:3.2, 1:3.3, 1:3.4, 1:3.5, 1:3.6, 1:3.7, 1:3.8, 1:3.9, 1:4.0, 1:4.1, 1:4.2, 1:4.3, 1:4.4, 1:4.5, 1:4.6, 1:4.7, 1:4.8, 1:4.9, 1:5, and any value within the range composed of any two of the above values, preferably 1:4-4.5, more preferably 1:4.01, or 1:4.04, or 1:4.05, or 1:4.07, or 1:4.08, or 1:4.12.

[0070] Wherein, in some embodiments of the present invention, the molar ratio of the compound of formula (VII) to the compound of formula (II) is 0.9-5:1, for example 0.9:1, 0.95:1, 0.99:1, 1:1, 1.01:1, 1.02:1, 1.05:1, 1.1:1, 1.15:1, 1.2:1, 1.25:1, 1.3:1, 1.35:1, 1.4:1, 1.45:1, 1.5:1, 2:1, 3:1, 4:1, 5:1, and any value within the range composed of any two of the above values, preferably 0.9-1.2:1, and more preferably 0.98-1.02:1.

[0071] Wherein, in some embodiments of the present invention, the temperature of the reaction of the compound of formula (VII) and the compound of formula (VIII) is 10-100°C, for example, 10°C, 15°C, 20°C, 25°C, 30°C, 35°C, 40°C, 45°C, 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, and any value within the range of any two of the above values, preferably 40-70°C, more preferably 50-60°C. Optionally, before the compound of formula (VII) and the compound of formula (VIII) enter the third continuous flow reaction device, they can be preheated to reach or approach the reaction temperature. The preheating device can adopt any cooling or heating device known in the art.

[0072] Wherein, in some embodiments of the present invention, the reaction time can be adjusted according to parameters such as reaction temperature, reactant molar ratio, feed flow rate, etc. The reaction time can be 8 seconds to 15 minutes, for example, 8 seconds, 9 seconds, 10 seconds, 11 seconds, 12 seconds, 13 seconds, 14 seconds, 15 seconds, 16 seconds, 17 seconds, 18 seconds, 19 seconds, 20 seconds, 21 seconds, 22 seconds, 23 seconds, 24 seconds, 25 seconds, 26 seconds, 27 seconds, 28 seconds, 29 seconds, 30 seconds, 31 seconds, 32 seconds, 33 seconds, 34 seconds, 35 seconds, 36 seconds, 37 seconds, 38 seconds, 39 seconds, 40 seconds, 41 seconds, 42 seconds, 43 seconds, 44 seconds, 45 seconds, 46 seconds, 47 seconds, 48 ​​seconds, 49 seconds, 50 seconds, 51 seconds, 52 seconds, 53 seconds, 54 seconds, 55 seconds, 56 seconds, 57 seconds, 58 seconds, 30 seconds, 15 minutes, 18 minutes, 19 minutes, 20 seconds, 30 seconds, 7 minutes, 7 minutes, 30 seconds, 10 minutes, 18 minutes, 20 seconds, 30 seconds, 15 minutes, 18 minutes, 20 seconds, 30 seconds, 8 minutes, 30 seconds, 10 minutes, 18 minutes, 20 seconds, 30 seconds, 15 minutes, 18 minutes, 20 seconds, 30 seconds, 8 minutes, 30 seconds, 10 minutes, 18 minutes, 20 seconds, 30 seconds, 8 minutes, 30 seconds, 10 minutes, 18 minutes, 20 seconds, 30 seconds, 8 minutes, 30 seconds, 10 minutes, 18 minutes, 20 seconds, 30 seconds, 8 minutes, 30 seconds, 10 minutes, 18 minutes, 20 seconds, 30 seconds, 8 minutes

[0073] Among them, in some embodiments of the present invention, the solvent used in the reaction is selected from at least one of aromatic hydrocarbon solvents (such as benzene, xylene, trimethylolbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halogenated benzene or dihalogenated benzene), alkane solvents (such as n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane), ether solvents (such as tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, dioxane or diethylene glycol dimethyl ether) or ester solvents (such as ethyl acetate, isopropyl acetate or butyl acetate), preferably toluene and / or chlorobenzene.

[0074] In some embodiments of the present invention, during continuous feeding, the feed liquid of the compound of formula (VII) and the feed liquid of the compound of formula (VIII) can be fed into the third continuous flow reaction device at the same time, or the feed liquid of the compound of formula (VII) and / or the feed liquid of the compound of formula (VIII) can be fed into the third continuous flow reaction device in portions at different time points and / or at different feeding points. Preferably, the combination of the two conditions achieves a higher conversion rate in the third continuous flow reaction device.

[0075] In some embodiments of the present invention, the liquid feed of the compound of formula (V) can directly enter the first continuous flow reaction device, or can enter after desolventizing, adding solvent, solid-liquid separation, distillation and other operations.

[0076] In some embodiments of the present invention, the feed liquid of the compound of formula (V) refers to the entire feed stream flowing out of the third continuous flow reaction device, including reaction products, unreacted raw materials, by-products, solvents and salts.

[0077] In some embodiments of the present invention, the first continuous flow reaction device, the second continuous flow reaction device and the third continuous flow reaction device respectively include a first continuous flow reactor, a second continuous flow reactor and a third continuous flow reactor. Specifically, the continuous flow reaction device includes a conveying device, a mixer, a preheater, a continuous flow reactor, a liquid separation device, a heat exchanger and a continuous desolventizing device, etc., and one or more of them can be selected according to the process parameters for free combination. In addition, the number and combination order of various forms of reactors can also be freely adjusted according to needs.

[0078] In some embodiments of the present invention, in the first continuous flow reaction device, the second continuous flow reaction device and the third continuous flow reaction device, when different process parameters and device combinations are selected, the reaction can be carried out under non-pressurized or pressurized conditions, and the reaction pressure can be 1-20atm, preferably 1-5atm.

[0079] The conveying device can be composed of one or more conveying pumps connected in parallel or in series. Accordingly, the mixer (or preheater) directly connected thereto can also be composed of one or more mixers (or preheaters) connected in parallel or in series, and the number is the same as the conveying pumps directly connected thereto. It is also possible to not use a mixer and a preheater according to production needs, and the reactants can directly enter the continuous flow reactor from the conveying device for reaction.

[0080] In some embodiments of the present invention, the first continuous flow reactor, the second continuous flow reactor and the third continuous flow reactor are each independently selected from at least one of a continuous tank reactor, a microchannel plate reactor and a tubular reactor, preferably a microchannel plate reactor and / or a tubular reactor. It can be optionally composed of one or more, identical or different reactors connected in parallel or in series. There is no particular restriction on the type of reactor, as long as the requirement for continuous production is met.

[0081] In the present invention, there is no particular restriction on the number of continuous flow reactors, which can be selected according to actual production requirements.

[0082] In some embodiments of the present invention, the number of the first continuous flow reactors is 1-4, preferably 1-2.

[0083] In some embodiments of the present invention, the number of the second continuous flow reactors is 1-6, preferably 2-4.

[0084] In some embodiments of the present invention, the number of the third continuous flow reactors is 1-6, preferably 2-4.

[0085] In some embodiments of the present invention, the hydrolysis can be carried out directly under neutral conditions, that is, the hydrolysis reaction can be carried out directly in the presence of water. In addition, the hydrolysis can also be preferably carried out in the presence of an acid. More specifically, the acid can be selected from at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid and acetic acid, preferably hydrochloric acid or sulfuric acid, more preferably hydrochloric acid. The concentration of hydrochloric acid can be selected from 15-35%, preferably 18-20%.

[0086] In some embodiments of the present invention, the molar ratio of the acid used for hydrolysis to the compound of formula (II) is 1.5-10:1, preferably 1.5-4:1, and more preferably 1.7-2.6:1.

[0087] In some embodiments of the present invention, the temperature of the hydrolysis reaction is 60-150°C, for example 60°C, 65°C, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, and any value within the range of any two of the above values, preferably 80-130°C, and more preferably 100°C-105°C.

[0088] In some embodiments of the present invention, the time of the hydrolysis reaction can be adjusted according to parameters such as reaction temperature, reactant molar ratio, feed flow rate, etc., and can be selected from 1 minute to 10 hours, for example, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1 hour and 5 minutes, 1 hour and 10 minutes, 1 hour and 15 minutes, 1 hour and 20 minutes, 1 hour and 25 minutes, 1 hour and 30 minutes, 1 hour and 35 minutes, 1 hour and 40 minutes, 1 hour and 45 minutes, 1 hour and 50 minutes, 1 hour and 55 minutes, 2 hours, 2 hours and 5 minutes, 2 hours and 10 minutes, 2 hours and 15 minutes, 2 hours and 20 minutes, 2 hours and 25 minutes, 2 hours and 30 minutes The present invention relates to a method for carrying out the present invention to a plurality of embodiments of the present invention. The method comprises the following steps: the method of carrying out the present invention comprises the following steps: (a) the method of carrying out the present invention and the plurality of embodiments of the present invention; b) the method of carrying out the present invention comprises the following steps: (a) the method of carrying out the present invention and the plurality of embodiments of the present invention; c) the method of carrying out the present invention and the plurality of embodiments of the present invention; and e) the method of carrying out the present invention comprises the following steps:

[0089] In some embodiments of the present invention, the first reaction product is allowed to enter the second continuous flow reaction device for hydrolysis reaction, and a hydrolyzate is obtained after the hydrolysis. It can be further treated with reference to the method disclosed in CN116041387A, for example: the hydrochloride of formula (I) is obtained through the steps of liquid separation, decompression precipitation, crystallization and drying, and the indexes such as content and ee value are further tested to calculate the separation yield. In addition, when carrying out condition screening and process optimization, the hydrolyzate can also be directly quantified by external standard method, so as to more easily obtain the indexes such as content, quantitative yield and ee value of the compound of formula (I) in the hydrolyzate.

[0090] In some embodiments of the present invention, the first reaction product and the acid can be fed into the second continuous flow reaction device at the same time, or the first reaction product and / or the acid can be divided into several portions and fed into the second continuous flow reaction device at different time points and / or at different feeding points.

[0091] In some embodiments of the present invention, the product of the hydrolysis reaction can be directly subjected to continuous deacidification, or can be subjected to one or more operations of desolventization, solid-liquid separation, and extraction and liquid separation. The above post-treatment operation process can be optionally carried out intermittently or continuously using suitable equipment.

[0092] A second aspect of the present invention provides a method for preparing a compound of formula (III), wherein the method comprises:

[0093]

[0094] The feed liquid of the compound of formula (II) and the feed liquid of the compound of formula (V) enter into a first continuous flow reaction device, and react at 70-150° C. to obtain the compound of formula (III);

[0095]

[0096] Where Y is -OR 3 , R 3 Selected from C 1 -C 6 Alkyl or C 3 -C 6 Cycloalkyl;

[0097] R 1 and R 2 are each independently selected from hydrogen, C 1 -C 6 Alkyl, C 3 -C 6 Cycloalkyl, or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a three- to six-membered heterocycloalkyl group.

[0098] In the preparation of the compound of formula (III), the inventors of the present invention surprisingly found after extensive research that the compound of formula (II) can be directly converted into the compound of formula (III) by reacting the compound of formula (V) in a continuous flow reactor at a fixed higher temperature, thereby combining the two-step reaction disclosed in CN116041387A into a one-step reaction, eliminating the need for staged control of the reaction temperature and shortening the reaction time.

[0099] In some embodiments of the present invention, during continuous feeding, the feed liquid of the compound of formula (II) and the feed liquid of the compound of formula (V) can be fed into the continuous flow reaction device at the same time, or the feed liquid of the compound of formula (II) and / or the feed liquid of the compound of formula (V) can be fed into the continuous flow reaction device in portions at different time points and / or at different feeding points. Preferably, the combination of the two conditions can achieve a higher conversion rate in the continuous flow reaction device.

[0100] In some embodiments of the present invention, the obtained reaction product can be directly fed into the subsequent reactor, or it can be fed into the subsequent reactor after one or more operations of desolventizing, adding solvent, solid-liquid separation, and extraction and separation. The desolventizing and adding solvent specifically refer to reducing or increasing the solvent (changing the concentration of the reactants), or switching to a different solvent; the solid-liquid separation specifically refers to removing the by-product salts of step (1), such as R, by common methods such as suction filtration, centrifugation, and filter pressing. 1 and R 2 When both are ethyl, the byproduct salt is diethylamine hydrochloride, and the obtained filtrate is further subjected to subsequent reactions; the extraction and liquid separation specifically refers to adding acid water after optional solid-liquid separation, separating the aqueous phase and then conducting subsequent reactions. The above-mentioned various optional operation processes can be carried out intermittently, or continuously using appropriate equipment. For example, the continuous liquid separation process can be achieved using a liquid separation device.

[0101] In the present invention, the compound of formula (III) prepared by the method can be a pure L-enantiomer, or it can exist in the form of a mixture of L and D-enantiomers, preferably the L-enantiomer is preferably present in a larger proportion in the mixture of enantiomers. For example, in one embodiment, the ee value of the compound of formula (III) can be 75% or more (e.g., 80% or more, 85% or more, 90% or more, 95% or more, 97% or more, 98% or more, 98.5% or more, 99% or more, 99.3% or more, 99.5% or more, 99.7% or more, 99.8% or more, 99.9% or more).

[0102] In the present invention, the compound of formula (III) is obtained from the reaction product through conventional post-treatment.

[0103] In some embodiments of the present invention, R 3 C 1 -C 3 alkyl.

[0104] In some embodiments of the present invention, R 3 It is methyl.

[0105] In some embodiments of the present invention, R 3 It is ethyl.

[0106] In some embodiments of the present invention, R 3 It is n-propyl.

[0107] In some embodiments of the present invention, R 3 It is isopropyl.

[0108] In some embodiments of the present invention, the compound of formula (II) is selected from the following compounds:

[0109]

[0110] In some embodiments of the present invention, R 1 and R 2 Both C 1 -C 3 alkyl.

[0111] In some embodiments of the present invention, R 1 and R 2 All are methyl.

[0112] In some embodiments of the present invention, R 1 and R 2 All are ethyl.

[0113] In some embodiments of the present invention, R 1 and R 2 All are n-propyl.

[0114] In some embodiments of the present invention, R 1 and R 2 All are isopropyl.

[0115] In some embodiments of the present invention, the compound of formula (V) is selected from the following compounds:

[0116]

[0117] In some embodiments of the present invention, the compound of formula (III) is selected from the following compounds:

[0118]

[0119]

[0120] In some embodiments of the present invention, the molar ratio of the compound of formula (II) to the compound of formula (V) is 1:0.9-5, for example 1:0.9, 1:0.95, 1:1, 1:1.01, 1:1.02, 1:1.05, 1:1.1, 1:1.15, 1:1.2, 1:1.25, 1:1.3, 1:1.35, 1:1.4, 1:1.45, 1:1.5, 1:2, 1:3, 1:4, 1:5, and any value within the range of any two of the above values, preferably 1:0.9-1.2, and more preferably 1:0.98-1.02.

[0121] In some embodiments of the present invention, the reaction temperature is, for example, 70°C, 75°C, 80°C, 85°C, 90°C, 95°C, 100°C, 105°C, 110°C, 115°C, 120°C, 125°C, 130°C, 135°C, 140°C, 145°C, 150°C, and any value within the range of any two of the above values, preferably 80-140°C, more preferably 90-105°C, more preferably 95-100°C. Optionally, before the compound of formula (II) and the compound of formula (V) enter the first reactor group, they may be preheated to reach or approach the reaction temperature. The preheating device may be any cooling or heating device known in the art.

[0122] In some embodiments of the present invention, the reaction time is 1 minute to 4 hours, which can be adjusted according to parameters such as reaction temperature, reactant molar ratio, feed flow rate, etc., for example, 1 minute, 2 minutes, 3 minutes, 4 minutes, 5 minutes, 6 minutes, 7 minutes, 8 minutes, 9 minutes, 10 minutes, 15 minutes, 20 minutes, 25 minutes, 30 minutes, 35 minutes, 40 minutes, 45 minutes, 50 minutes, 55 minutes, 1 hour, 1 hour and 5 minutes, 1 hour and 10 minutes, 1 hour and 15 minutes, 1 hour and 20 minutes, 1 hour and 25 minutes, 1 hour and 30 minutes, 1 hour and 35 minutes, 1 hour and 40 minutes, 1 hour and 45 minutes, 1 hour and 50 minutes, 1 hour 15 seconds to 3 hours 15 seconds. The reaction time may be a residence time in the case of a continuous flow reaction device.

[0123] In some embodiments of the present invention, the solvent of the reaction is selected from at least one of aromatic solvents (such as benzene, xylene, trimethylolbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halogenated benzene or dihalogenated benzene), alkane solvents (such as n-hexane, cyclohexane, n-heptane, methylcyclohexane, ethylcyclohexane), ether solvents (such as tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methyl cyclopentyl ether, ethylene glycol dimethyl ether, dioxane or diethylene glycol dimethyl ether) or ester solvents (such as ethyl acetate, isopropyl acetate or butyl acetate), preferably toluene and / or chlorobenzene.

[0124] In some embodiments of the present invention, the first continuous flow reaction device includes a first continuous flow reactor. Specifically, the continuous flow reaction device includes a conveying device, a mixer, a preheater, a continuous flow reactor, a liquid separation device, a heat exchanger and a continuous desolventizing device, etc., and one or more of them can be selected according to the process parameters to be freely combined. In addition, the number and combination order of various forms of reactors can also be freely adjusted according to needs.

[0125] The conveying device can be composed of one or more conveying pumps connected in parallel or in series. Accordingly, the mixer (or preheater) directly connected thereto can also be composed of one or more mixers (or preheaters) connected in parallel or in series, and the number is the same as the conveying pumps directly connected thereto. It is also possible to not use a mixer and a preheater according to production needs, and the reactants can directly enter the continuous flow reactor from the conveying device for reaction.

[0126] In some embodiments of the present invention, the continuous flow reactor is selected from at least one of a continuous tank reactor, a microchannel plate reactor and a tubular reactor, preferably a microchannel plate reactor and / or a tubular reactor. It can be optionally composed of one or more, identical or different reactors connected in parallel or in series. There is no particular restriction on the type of reactor, as long as it meets the requirements for achieving continuous production.

[0127] In some embodiments of the present invention, the number of the first continuous flow reactors is 1-4, preferably 1-2.

[0128] Through the above technical solution, the beneficial technical effects achieved by the present invention are as follows:

[0129] (1) The present invention realizes a continuous flow reaction for preparing refined glufosinate ammonium through multi-step reactions, and the multi-step reaction time is greatly shortened. For example, the synthesis of the compound of formula (V) can be completed within a few seconds, and the reaction time for preparing refined glufosinate ammonium from the compound of formula (II) and the compound of formula (V) is shortened from more than ten hours to 2-3 hours.

[0130] (2) The present invention realizes the reaction of the compound of formula (II) and the compound of formula (V) at a relatively high temperature by a continuous flow reactor to obtain a pre-hydrolysis reaction liquid, thereby avoiding the operation of first low-temperature reaction before the hydrolysis step and then high-temperature reaction in the prior art, simplifying the reaction, achieving the completion of two-step reaction in one step, and also improving the product yield. The separation yield of refined glufosinate-ammonium is increased from the highest 85% in the original process to more than 90%, with a maximum of 96%.

[0131] (3) In conventional kettle reactions, the compound of formula (V) or the compound of formula (VII) needs to be in excess of the molar amount of formula (II) by 5-20% or more in order to obtain a higher yield. However, the present invention benefits from the improvement of the process flow and the reactor, so that a higher conversion rate can still be obtained when the two reactants are close to equal proportions, thereby stabilizing and slightly improving the product content, greatly shortening the reaction time, and thus achieving a stable increase in the ee value by about 1-2%, while also reducing the generation of the three wastes to a certain extent.

[0132] (4) The amount of acid used in the hydrolysis process is greatly reduced from 7 eq. in the original process to 1.7-2.6 eq., which greatly reduces the amount of waste acid to be treated after the reaction and also helps to alleviate the racemization problem during the acid hydrolysis process. BRIEF DESCRIPTION OF THE DRAWINGS

[0133] Figure 1 is a synthesis flow chart of the third group of reactors and the compound of formula (V-1);

[0134] Figure 2 It is the synthesis process of the compound of formula (I) and the whole set of reactor diagram. DETAILED DESCRIPTION

[0135] The present invention will be described in detail below through examples.

[0136] In the following examples and comparative examples, if no specific conditions are specified, the experiments were carried out under conventional conditions or conditions recommended by the manufacturer. The reagents or instruments used, if no manufacturer is specified, are conventional products that can be obtained through commercial channels.

[0137] Example 1

[0138] This example is used to illustrate the synthesis of the compound of formula (V-1).

[0139]

[0140] The compound of formula (VII) was added into chlorobenzene to prepare a solution with a concentration of 20% w / w. The compound of formula (VIII-1) was added into chlorobenzene to prepare a solution with a concentration of 24% w / w.

[0141] The above-mentioned solution of the compound of formula (VII) and the solution of the compound of formula (VIII-1) were respectively fed into the third group of reactors (i.e., the third continuous flow reaction device) at a flow rate of 41.9 mL / min and 64.9 mL / min (molar ratio of 1:4.05), which consisted of a mixer and two microchannel plate reactors. The reactor temperature was controlled to be 55±1°C and the reaction was allowed to stand for 8 seconds to obtain the third group of reaction products, the feed solution of the compound of formula (V-1). The samples were taken and weighed for external standard quantitative analysis, and the yield was 99.1%. m / z (ESI) 135.09 ([M+1] + ,100%);31 P NMR (33 MHz) δ: 87.63.

[0142] The feed liquid can be used directly to react with the compound of formula (II), or it can be used to obtain a filtrate of the third group of reaction products, compounds of formula (V-1), for reaction with the compound of formula (II) after solid-liquid separation under nitrogen protection, and the filtrate concentration is 11.2% w / w.

[0143] Reactor and process Figure 1 shown.

[0144] Example 2

[0145] This example is used to illustrate the synthesis of the compound of formula (V-2).

[0146]

[0147] The compound of formula (VII) was added to chlorobenzene to prepare a solution with a concentration of 20% w / w. The compound of formula (VIII-2) was added to chlorobenzene to prepare a solution with a concentration of 30% w / w.

[0148] The above-mentioned solution of the compound of formula (VII) and the solution of the compound of formula (VIII-2) were respectively fed into the third group of reactors (i.e., the third continuous flow reaction device) at a flow rate of 41.9 mL / min and 83.8 mL / min (molar ratio of 1:4.07), which consisted of a mixer and two microchannel plate reactors. The reactor temperature was controlled to be 55±1°C and the reaction was allowed to stand for 8 seconds to obtain the third group of reaction products of the compound of formula (V-2). The sample was taken and weighed for external standard quantitative analysis, and the yield was 99.5%. m / z (ESI) 191.17 ([M+1] + ,100%); 31 P NMR (33 MHz) δ: 79.29.

[0149] The feed liquid can be used directly to react with the compound of formula (II), or it can be used to obtain a filtrate of the third group of reaction products, compounds of formula (V-2), for reaction with the compound of formula (II) after solid-liquid separation under nitrogen protection, and the filtrate concentration is 13.9% w / w.

[0150] Example 3

[0151] This example is used to illustrate the synthesis of the compound of formula (V-3).

[0152]

[0153] The compound of formula (VII) was added to chlorobenzene to prepare a solution with a concentration of 20% w / w. The compound of formula (VIII-2) was added to chlorobenzene to prepare a solution with a concentration of 32% w / w.

[0154] The above-mentioned solution of the compound of formula (VII) and the solution of the compound of formula (VIII-3) were respectively fed into the third group of reactors (i.e., the third continuous flow reaction device) at a flow rate of 41.9 mL / min and 104.6 mL / min (molar ratio of 1:4.08), which consisted of a mixer and two microchannel plate reactors. The reactor temperature was controlled to be 55±1°C and the reaction was allowed to stand for 8 seconds to obtain the third group of reaction products of the compound of formula (V-3). The sample was taken and weighed for external standard quantitative analysis, and the yield was 99.3%. m / z (ESI) 247.12 ([M+1] + ,100%); 31 P NMR (33 MHz) δ: 47.80.

[0155] The feed liquid can be used directly to react with the compound of formula (II), or it can be used to obtain a filtrate of the third group of reaction products, compounds of formula (V-3), for reaction with the compound of formula (II) after solid-liquid separation under nitrogen protection, and the filtrate concentration is 15.4% w / w.

[0156] Example 4

[0157] This example is used to illustrate the synthesis of the compound of formula (V-4).

[0158]

[0159] The compound of formula (VII) was added to chlorobenzene to prepare a solution with a concentration of 20% w / w. The compound of formula (VIII-2) was added to chlorobenzene to prepare a solution with a concentration of 31% w / w.

[0160] The above-mentioned solution of the compound of formula (VII) and the solution of the compound of formula (VIII-4) were respectively fed into the third group of reactors (i.e., the third continuous flow reaction device) at a flow rate of 41.9 mL / min and 107.4 mL / min (molar ratio of 1:4.08), which consisted of a mixer and two microchannel plate reactors. The reactor temperature was controlled to be 55±1°C and the reaction was allowed to stand for 8 seconds to obtain the third group of reaction products of the compound of formula (V-4). The sample was taken and weighed for external standard quantitative analysis, and the yield was 99.0%. m / z (ESI) 247.22 ([M+1] + ,100%); 31 P NMR (33 MHz) δ: 39.78.

[0161] The feed liquid can be used directly to react with the compound of formula (II), or it can be used to obtain a filtrate of the third group of reaction products, compounds of formula (V-4), for reaction with the compound of formula (II) after solid-liquid separation under nitrogen protection, and the filtrate concentration is 14.8% w / w.

[0162] Example 5-12

[0163] Examples 5-12 are used to illustrate the synthesis of compounds of formula (I).

[0164] A. Preparation of the feed solution of formula (II-1) and the feed solution of formula (II-2)

[0165]

[0166] The compound of formula (II-1) was added to chlorobenzene, stirred at high speed for 1 hour at 60-80°C, and mixed thoroughly to obtain a 20% w / w solution of the compound of formula (II-1). The ee value was measured to be 99.9%.

[0167] The compound of formula (II-2) was added to chlorobenzene, stirred at high speed for 1 hour at 60-80°C, and mixed thoroughly to obtain a 22.4% w / w solution of the compound of formula (II-2). The ee value was measured to be 99.7%.

[0168] B. Synthesis of compounds of formula (I)

[0169] The compound of formula (VII) and the compound of formula (VIII) are respectively introduced into a third continuous flow reaction device, which is composed of a mixer and two microchannel plate reactors, at the flow rate shown in Table 1 below, and the reactor temperature is controlled to be 55±1°C, and the reaction mixture is kept for 8 seconds to obtain a third group of reaction products, the compound of formula (V). After the feed liquid is subjected to solid-liquid separation under nitrogen protection, the filtrate of the third group of reaction products, the compound of formula (V), is obtained for reaction with the compound of formula (II).

[0170] The filtrate of the third group of reaction products, the compound of formula (V) and the feed liquid of the compound of formula (II), enter the first continuous flow reaction device at the flow rate shown in Table 1 below, which is composed of a mixer, a microchannel plate reactor and a tubular reactor. The temperature of the microchannel plate reactor and the tubular reactor is controlled to be stable at T 1 The residence time in the microchannel plate reactor and tubular reactor is t 1 and t 2 , and obtain the first group of reaction products.

[0171] The first group of reaction products and 20% hydrochloric acid enter the first continuous flow reaction device at the flow rate shown in Table 1, which is composed of a mixer, a continuous liquid separation device and a tubular reactor. The hydrolysis temperature is controlled to be T 2 , the residence time is t 3 , and obtain a hydrolyzate, i.e., a feed solution of the compound of formula (I).

[0172] The hydrolyzate can be further post-processed with reference to the method described in Example 1 of CN116041387A, and the hydrochloride of formula (I) can be obtained through the steps of liquid separation, decompression desolventization, crystallization and drying, and the content, ee value and other indicators can be further tested to calculate the separation yield. The hydrolyzate can also be directly quantified by external standard method to more easily obtain the content, yield and ee value of the compound of formula (I) in the hydrolyzate.

[0173] The experimental conditions and results of Examples 5-12 are shown in Table 1 below.

[0174] The synthesis process and reactor diagram of the compound of formula (I) are as follows Figure 2 shown.

[0175] Table 1: Experimental conditions and results of Examples 5-12

[0176]

[0177] Note: a. The third group of reaction products obtained by reacting the compound of formula (VII) with the compound of formula (VIII) are subjected to solid-liquid separation under nitrogen protection to obtain the third group of reaction product filtrate for reaction with the compound of formula (II).

[0178] Examples 13-21

[0179] Examples 13-21 are used to illustrate the synthesis of compounds of formula (I).

[0180] A. Preparation of the feed solution of formula (II-1) and the feed solution of formula (II-2)

[0181] Same as Part A in Example 5-12.

[0182] B. Synthesis of compounds of formula (I)

[0183] The experimental conditions and results of Examples 13-21 are shown in Table 2. The synthesis process and reactor diagram of the compound of formula (I) are shown in Table 2. Figure 2 shown.

[0184] Table 2: Experimental conditions and results of Examples 13-21

[0185]

[0186] Note:

[0187] a. The acid solution obtained by the reaction of Example 6 was post-treated, and the hydrochloride of formula (I) was obtained by separation, desolventization under reduced pressure, crystallization and drying;

[0188] b. The acid hydrolyzate is post-treated to obtain the solid hydrochloride of formula (I) by steps of separation, decompression desolventizing, crystallization and drying, etc., in terms of formula (II).

[0189] It can be seen from the results of Table 1 and Table 2 that the present invention allows the compound of formula (II) and the compound of formula (V) to enter a continuous flow reactor for a one-step reaction at a relatively high reaction temperature, and can prepare refined glufosinate-ammonium at a lower cost and simpler operation under milder reaction conditions. The present invention also optimizes the process parameters of the entire preparation process to obtain a yield significantly higher than that of the prior art, which can be as high as 96%. The present invention also has the advantages of short reaction time, less raw material consumption, and less waste liquid.

[0190] Comparative Example 1-2

[0191] Comparative Examples 1-2 are used to illustrate the synthesis of the compound of formula (I) under different conditions.

[0192] A. Preparation of the liquid of formula (II-1a) (i.e., the free state of formula (II-1))

[0193]

[0194] First, prepare the liquid of formula (II-1) according to the method in Part A of Example 5-12.

[0195] Preparation of the liquid of formula (II-1a):

[0196] The compound of formula (II-1) was added to chlorobenzene, and an equivalent amount of diethylamine was added. The mixture was stirred at a high speed for 1 hour at 60-80°C and mixed thoroughly to obtain a 21% w / w solution of the compound of formula (II-1a). The ee value was measured to be 97.1%.

[0197] B. Synthesis of compounds of formula (I)

[0198] The experimental conditions and results of Comparative Example 1-2 are shown in Table 3. The synthesis process and reactor diagram of the compound of formula (I) are shown in Table 3. Figure 2 shown.

[0199] Table 3: Comparative Example 1-2 Experimental conditions and results

[0200]

[0201] Note:

[0202] a. The acid hydrolyzate is post-treated to obtain the solid hydrochloride of formula (I) by steps of separation, decompression desolventizing, crystallization and drying, etc., in terms of formula (II).

[0203] It can be seen from the results in Table 3 that when the compound of formula (II-1a) (i.e., the free state of formula (II-1)) is used as the reaction raw material, the separation yield, content and ee value of the prepared compound of formula (I) are all reduced.

[0204] The preferred embodiments of the present invention are described in detail above, but the present invention is not limited thereto. Within the technical concept of the present invention, the technical solution of the present invention can be subjected to a variety of simple modifications, including the combination of various technical features in any other suitable manner, and these simple modifications and combinations should also be regarded as the contents disclosed by the present invention and belong to the protection scope of the present invention.

Claims

1. A method for preparing refined glufosinate-ammonium or a salt thereof represented by formula (I), characterized in that: The method comprises the following steps: (1) allowing a liquid of the compound of formula (II) and a liquid of the compound of formula (V) to enter a first continuous flow reaction device and react at 70-150° C. to obtain a first reaction product; (2) allowing the first reaction product obtained in step (1) to enter a second continuous flow reaction device for hydrolysis reaction to obtain a compound of formula (I); Where Y is -OR 3 , R 3 Selected from C1-C6 alkyl or C3-C6 cycloalkyl; R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a three- to six-membered heterocycloalkyl group.

2. The method according to claim 1, wherein: R 3 is a C1-C3 alkyl group; Preferably, R 3 is methyl; Preferably, R 3 is ethyl; Preferably, R 3 is n-propyl; Preferably, R 3 is isopropyl; Preferably, the compound of formula (II) is selected from the following compounds:

3. The method according to claim 1 or 2, wherein: R 1 and R 2 All are C1-C3 alkyl; Preferably, R 1 and R 2 All are methyl; Preferably, R 1 and R 2 All are ethyl; Preferably, R 1 and R 2 All are n-propyl; Preferably, R 1 and R 2 All are isopropyl; Preferably, the compound of formula (V) is selected from the following compounds:

4. The method according to any one of claims 1 to 3, wherein: In the step (1), the molar ratio of the compound of formula (II) to the compound of formula (V) is 1:0.9-5, preferably 1:0.9-1.2, and more preferably 1:0.98-1.02; Preferably, the reaction temperature in step (1) is 80-140°C, preferably 90-105°C, and more preferably 95-100°C; Preferably, the reaction time in step (1) is 1 minute to 4 hours, preferably 2 hours 15 seconds to 3 hours 15 seconds; Preferably, the solvent for the reaction in step (1) is selected from at least one of aromatic hydrocarbon solvents, alkane solvents, ether solvents or ester solvents, preferably toluene and / or chlorobenzene.

5. The method according to any one of claims 1 to 4, wherein: The hydrolysis reaction in step (2) is carried out in the presence of an acid; Preferably, the acid is selected from at least one of hydrochloric acid, sulfuric acid, hydrobromic acid, hydroiodic acid, phosphoric acid, nitric acid, formic acid and acetic acid, preferably hydrochloric acid or sulfuric acid; Preferably, the molar ratio of the acid to the compound of formula (II) is 1.5-10:1, preferably 1.5-4:1, and more preferably 1.7-2.6:1; Preferably, the temperature of the hydrolysis reaction in step (2) is 60-150°C, preferably 80-130°C, and more preferably 100°C-105°C; Preferably, the hydrolysis reaction time in step (2) is 1 minute to 10 hours, preferably 30 minutes.

6. The method according to any one of claims 1 to 5, wherein: The method further comprises: before step (1), allowing the feed solution of the compound of formula (VII) and the feed solution of the compound of formula (VIII) to enter a third continuous flow reaction device for reaction to obtain a feed solution of the compound of formula (V); Among them, R 1 and R 2 As defined in claim 1 or 3; Preferably, the molar ratio of the compound of formula (VII) to the compound of formula (VIII) is 1:3-5, preferably 1:4-4.5, further preferably 1:4.01, or 1:4.04, or 1:4.05, or 1:4.07, or 1:4.08, or 1:4.12; Preferably, the molar ratio of the compound of formula (VII) to the compound of formula (II) is 0.9-5:1, preferably 0.9-1.2:1, and more preferably 0.98-1.02:1; Preferably, the reaction temperature is 10-100°C, preferably 40-70°C, and more preferably 50-60°C; Preferably, the reaction time is 8 seconds to 15 minutes, preferably 10 seconds to 15 minutes, and more preferably 30 seconds to 1 minute; Preferably, the solvent of the reaction is selected from at least one of aromatic hydrocarbon solvents, alkane solvents, ether solvents or ester solvents, preferably toluene and / or chlorobenzene.

7. The method according to any one of claims 1 to 6, wherein: The first continuous flow reaction device, the second continuous flow reaction device and the third continuous flow reaction device respectively include a first continuous flow reactor, a second continuous flow reactor and a third continuous flow reactor; Preferably, the first continuous flow reactor, the second continuous flow reactor and the third continuous flow reactor are each independently selected from at least one of a continuous tank reactor, a microchannel plate reactor and a tubular reactor, preferably a microchannel plate reactor and / or a tubular reactor; Preferably, the number of the first continuous flow reactors is 1-4, preferably 1-2; Preferably, the number of the second continuous flow reactors is 1-6, preferably 2-4; Preferably, the number of the third continuous flow reactors is 1-6, preferably 2-4.

8. A method for preparing a compound of formula (III), characterized in that: The method comprises: The feed liquid of the compound of formula (II) and the feed liquid of the compound of formula (V) enter into a first continuous flow reaction device, and react at 70-150° C. to obtain the compound of formula (III); Where Y is -OR 3 , R 3 Selected from C1-C6 alkyl or C3-C6 cycloalkyl; R 1 and R 2 are each independently selected from hydrogen, C1-C6 alkyl, C3-C6 cycloalkyl, or R 1 and R 2 Together with the nitrogen atom to which it is attached, it forms a three- to six-membered heterocycloalkyl group.

9. The method according to claim 8, wherein: R 3 is a C1-C3 alkyl group; Preferably, R 3 is methyl; Preferably, R 3 is ethyl; Preferably, R 3 is n-propyl; Preferably, R 3 is isopropyl; Preferably, the compound of formula (II) is selected from the following compounds: Preferably, R 1 and R 2 All are C1-C3 alkyl; Preferably, R 1 and R 2 All are methyl; Preferably, R 1 and R 2 All are ethyl; Preferably, R 1 and R 2 All are n-propyl; Preferably, R 1 and R 2 All are isopropyl; Preferably, the compound of formula (V) is selected from the following compounds: Preferably, the compound of formula (III) is selected from the following compounds:

10. The method according to claim 8 or 9, wherein: The molar ratio of the compound of formula (II) to the compound of formula (V) is 1:0.9-5, preferably 1:0.9-1.2, and more preferably 1:0.98-1.02; Preferably, the reaction temperature is 80-140°C, preferably 90-105°C, and more preferably 95-100°C; Preferably, the reaction time is 1 minute to 4 hours, preferably 2 hours 15 seconds to 3 hours 15 seconds; Preferably, the solvent of the reaction is selected from at least one of an aromatic hydrocarbon solvent, an alkane solvent, an ether solvent or an ester solvent, preferably toluene and / or chlorobenzene; Preferably, the first continuous flow reaction device comprises a first continuous flow reactor; Preferably, the first continuous flow reactor is selected from at least one of a continuous tank reactor, a microchannel plate reactor and a tubular reactor, preferably a microchannel plate reactor and / or a tubular reactor; Preferably, the number of the first continuous flow reactors is 1-4, preferably 1-2.

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