CN115873033A - Preparation method of glufosinate-ammonium - Google Patents

Abstract

The application relates to a preparation method of glufosinate-ammonium. Specifically, the invention relates to a method for preparing glufosinate-ammonium represented by formula (I) or salts, enantiomers or mixtures of enantiomers in any ratio, which comprises the following steps: (IV) hydrolyzing the compound of formula (IV) to obtain the compound of formula (I). Due to different reaction mechanisms, the method can avoid or reduce the halogenated hydrocarbon by-product in the Michaelis-Arbuzov reaction, prevent the halogenated hydrocarbon by-product from damaging ozone in the atmosphere, correspondingly, save equipment and engineering investment for separating, purifying, collecting and the like of the by-product, and avoid potential environmental and safety risks brought by the by-product.

Description

Preparation method of glufosinate-ammonium

Technical Field

The application relates to the field of pesticide herbicides, in particular to a preparation method of glufosinate-ammonium.

Background

Glufosinate, a chemical name of 4- [ hydroxy (methyl) phosphono ] -DL-homoalanine ammonium salt, developed and marketed by hester, germany in 1986, is a glutamine synthesis inhibitor, and acts by inhibiting glutamine synthetase activity in plants, resulting in glutamine synthesis inhibition, nitrogen metabolism disorder, and ammonium ion accumulation, thereby interfering with plant metabolism and causing plant death.

Glufosinate has the characteristics of high herbicidal activity, wide herbicidal spectrum and good environmental compatibility, and is very suitable for developing herbicide resistance genes, wherein the glufosinate resistance genes are introduced into more than 20 crops such as rice, wheat, corn, beet, tobacco, soybean, cotton, potato, tomato, rape, sugarcane, and the like, and the transgenic crops are popularized and planted in agricultural countries in the areas such as America, asia, europe, australia in recent years [ Yang Yijun, zhang Bo. [ J ]. World pesticides, 2021,43 (4): 19-34 ].

The common glufosinate-ammonium is a mixture of two enantiomers, but only the L-isomer has activity, is easier to decompose in soil, has low toxicity to human and animals, can greatly reduce environmental stress, and has better activity and control effect on resistant weeds than the common glufosinate-ammonium. Although most of the glufosinate-ammonium commodities sold in the market at present still are racemes, with technical innovation and progress, the L-isomer is unlikely to enter the mainstream market.

The existing method for synthesizing chiral pure L-glufosinate-ammonium mainly comprises a chemical method and a biological method. Wherein the chemical method comprises a chemical resolution method and a chemical synthesis method.

The chemical resolution method is to resolve racemic D, L-glufosinate-ammonium or the derivative thereof synthesized by a chemical method through a chiral resolution reagent, thereby obtaining the optically pure L-glufosinate-ammonium. Patent specification WO1995023805A1 discloses a process for obtaining single [ L ] -or [ D ] -homoalanin-4-yl- (methyl) phosphonic acid and salts thereof by racemic resolution of D, L-homoalanin-4-yl- (methyl) phosphonic acid by precipitation as a salt with one of the diastereomeric salts with a chiral base such as quinine and cinchonine. The method needs expensive chiral resolution reagent, has low yield and has no obvious industrial advantage.

The chemical synthesis method takes natural chiral amino acid as a raw material or synthesizes the L-glufosinate-ammonium by an asymmetric method.

The patent specification with publication number US5442088a discloses a method for obtaining L-glufosinate-ammonium hydrochloride by using L-homoserine lactone derivative as a raw material, performing ring-opening chlorination and esterification, performing Arbuzov reaction with methyl phosphorous acid diester, and finally performing hydrolysis and refining.

The multi-step reaction process unit is convenient to operate, but the activity of the chlorinated substrate of the Arbuzov reaction raw material is low, the reaction can be carried out only at a high temperature, meanwhile, the unit consumption is greatly increased because the chlorinated alkane byproduct further generates a side reaction with the methyl phosphite diester at a high temperature, and in addition, the L-type enantiomer excess value is reduced because of racemization of partial raw materials or products in the reaction at the temperature.

Patent specification publication No. CN113490671B discloses: halogenated homoserine ester with or without amino protection is taken as a raw material, and condensed with methyl phosphonite monochloro ester to obtain an intermediate, and L-glufosinate-ammonium is obtained after hydrolysis.

The method takes homoserine as a raw material, and adopts multi-step reaction synthesis through cyclization, chlorination, esterification, protecting group protection and the like, and the reaction steps are long. In addition, the Arbuzov reaction inevitably produces halogenated alkanes, and the small-molecule halogenated hydrocarbons are 3 kinds of carcinogens and have a destructive effect on ozone in the atmosphere.

In recent years, with the increasing demand of glufosinate-ammonium, the development of a glufosinate-ammonium synthesis method which is mild in reaction conditions, higher in yield, lower in cost and simple to operate has an extremely important significance for reducing and enhancing the use amount of the herbicide.

Disclosure of Invention

For the sake of simplicity, the "compound of formula (N)", hereinafter described as a compound of formula (III) "may also encompass any optical isomer, geometric isomer, tautomer or mixture of isomers of the compound of formula (N), or agriculturally acceptable salt.

The term "optical isomer" means that, when a compound has one or more chiral centers, each chiral center may exist in an R configuration or an S configuration, and thus the respective isomers composed thereof are optical isomers. Optical isomers include all diastereoisomers, enantiomers, meso-isomers, racemic forms or mixtures thereof. For example, optical isomers may be separated by chiral chromatography columns or by chiral synthesis.

The term "geometric isomer" means that when a double bond is present in a compound, the compound may exist as cis, trans, E and Z isomers. The geometric isomers include cis-isomer, trans-isomer, E-isomer, Z-isomer or mixtures thereof.

The term "tautomer" refers to an isomer resulting from the rapid movement of an atom in a molecule at two positions. Those skilled in the art will understand that: tautomers can be mutually converted, and in a certain state, an equilibrium state can be reached to coexist.

Unless otherwise indicated, reference herein to "a compound of formula (N) (e.g. a compound of formula (III)") also encompasses isotopically-labelled compounds in which any atom of the compound is replaced by an isotopic atom thereof. That is, the present invention includes all agriculturally acceptable isotopically labeled compounds of the compounds of formula (N) wherein one or more atoms are replaced by an atom having the same atomic number, but a different atomic mass or mass number than the atom normally found in nature.

Examples of isotopes suitable for inclusion in compounds of the 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 isotopes of C, 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 isotopes of N, oxygen, such as ¹⁵ O、 ¹⁷ O and ¹⁸ o, and isotopes of sulfur, such as ³⁵ S。

Isotopically-labelled compounds of formula (N) can generally be prepared by conventional techniques known to those skilled in the art or by using a suitable isotopically-labelled reagent in place of the non-labelled reagent previously used in a manner analogous to that described in the examples and preparations appended hereto.

The compounds of formula (N) may be present in the form of agriculturally acceptable salts, for example, acid addition salts and/or base addition salts of the compounds of formula (N). As used herein, unless otherwise indicated, "agriculturally acceptable salts" include acid addition salts or base addition salts that may be present within compounds of formula (N).

Agriculturally acceptable salts of the compounds 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 thereof include, but are not limited to: acetate, adipate, aspartate, benzoate, benzenesulfonate, bicarbonate/carbonate, bisulfate/sulfate, borate, camphorsulfonate, citrate, cyclohexylamine sulfonate, edisylate, formate, fumarate, glucoheptonate, gluconate, glucuronate, hexafluorophosphate, 2- (4-hydroxybenzyl) benzoate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, 2-isethionate, lactate, malate, maleate, malonate, methanesulfonate, methylsulfate, naphthenate, 2-naphthalenesulfonate, nicotinate, nitrate, orotate, oxalate, hexadecanoate, phosphate/hydrogenphosphate/dihydrogenphosphate, pyroglutamate, glucarate, stearate, salicylate, tannate, tartrate, tosylate and trifluoroacetate. Suitable base addition salts are formed from bases which form non-toxic salts. Examples include, but are not limited to: ammonium salts, 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 hemisulfate and hemicalcium salts, may also be formed. Methods for preparing agriculturally acceptable salts of the compounds described herein are known to those skilled in the art.

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), whether present in solvated or unsolvated forms, are included within the scope of the present invention.

Certain compounds of the present invention may exist in different or amorphous forms, and the compounds of formula (N) are included within the scope of the present invention regardless of the form in which they exist.

For the avoidance of doubt, definitions are given below for terms used herein. Unless otherwise indicated, the terms used herein have the following meanings.

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

As used herein, the term "independently" means that when the number of substituents is more than one, the substituents may be the same or different.

As used herein, the term "optional" or "optionally" means that the event it describes may or may not occur. For example, a group "optionally substituted" means: the group may be unsubstituted or substituted.

As used herein, the term "heteroatom" represents oxygen (O), nitrogen (N), or S (O) _m (wherein m may be 0, 1 or 2, i.e. the sulfur atom S, or the sulfoxide group SO, or the sulfonyl group S (O)) ₂ )。

As used herein, the term "alkyl" refers to saturated aliphatic hydrocarbons, including straight and branched chains. In a1In some embodiments, the alkyl group has, for example, 1 to 6 or 1 to 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. The term "C ₁ -C ₆ Alkyl "includes in its definition the term" C _1-6 Alkyl group "," C ₁ -C ₃ Alkyl "and" C ₁ -C ₄ Alkyl groups ". Examples of alkyl groups 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.

As used herein, the term "C ₃ -C ₆ Cycloalkyl "refers to cycloalkyl having 3 to 6 carbon atoms forming a ring. E.g. C ₃ -C ₆ Cycloalkyl includes cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl.

As used herein, the term "n-membered heterocycloalkyl" refers to a cycloalkyl group having m ring-forming carbon atoms and (n-m) ring-forming heteroatoms selected from at least one of N, O and S. For example, a tri-to hexa-heterocycloalkyl group includes, but is not limited to, oxetane, thietane, azetidine, tetrahydrofuran, tetrahydrothiophene, pyrrolidine, tetrahydropyran, tetrahydrothiopyran, piperidine, morpholine, piperazine.

As used herein, the term "C ₆ -C ₁₀ Aryl "means an aryl group having an aromatic ring containing 6 to 10 carbon atoms, preferably a phenyl group.

As used herein, the term "n-membered heteroaryl" refers to a heteroaryl group having m aromatic ring-forming carbon atoms and (n-m) aromatic ring-forming heteroatoms selected from at least one of N, O and S. For example, five-to ten-membered heteroaryl groups include, but are not limited to, pyrazine, pyrazole, pyrrole, furan, thiophene, thiazole, pyridine.

As used herein, the term "haloalkyl" refers to an alkyl group having one or more halogen substituents (up to perhaloalkyl, i.e., an alkyl group)Each hydrogen atom of (a) is substituted with a halogen atom). For example, the term "C ₁ -C ₆ Haloalkyl "refers to C having one or more halogen substituents ₁ -C ₆ An alkyl group (up to perhaloalkyl, i.e., an alkyl group in which each hydrogen atom is replaced by a halogen atom). As another example, the term "C ₁ Haloalkyl "refers to a methyl group having 1, 2, or 3 halogen substituents. Examples of haloalkyl groups include: CF (compact flash) ₃ 、C ₂ F ₅ 、CHF ₂ 、CH ₂ F、CH ₂ CF ₃ 、CH ₂ Cl, and the like.

As used herein, the recitation of numerical ranges by numbers in relation to numbers of substituents, carbon atoms, and ring atoms is meant to be a shorthand recitation of all integers subsumed within that range, and ranges are intended to be a shorthand representation. For example: "1-4 substituents" means 1, 2,3 or 4 substituents; "3 to 8 carbon atoms" means 3, 4, 5, 6, 7 or 8 carbon atoms. Thus, any numerical range relating to the number of substituents, the number of carbon atoms, the number of ring atoms also encompasses any subrange thereof, and each subrange is also considered disclosed herein.

In a first aspect, the present application provides a process for the preparation of glufosinate-ammonium represented by formula (I) or a salt, enantiomer or mixture of enantiomers in any ratio thereof, comprising the steps of:

(ii) hydrolyzing the compound of formula (IV) to obtain a compound of formula (I),

wherein, the first and the second end of the pipe are connected with each other,

x is halogen;

y is-OR ³ or-N (R) ⁴ )(R ⁵ )；

Z is an amino protecting group;

R ¹ and R ² Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ¹ And R ² Form a three-to six-membered heterocycloalkyl group together with the N atom to which it is attached, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution;

R ³ 、R ⁴ and R ⁵ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ⁴ And R ⁵ Form a three-to six-membered heterocycloalkyl group together with the N atom to which it is attached, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution;

R ⁶ and R ⁷ Each independently selected from hydrogen, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ⁷ And R ⁸ Form a three-to six-membered heterocycloalkyl group together with the N atom to which it is attached, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution; and is

* For identifying chiral carbon atoms.

As used herein, "amino protecting group" refers to a protecting group applied to an amino group before a reaction when a multifunctional group organic compound is subjected to the reaction, in order to allow the reaction to occur only at a desired group while avoiding the influence of the amino group, and may be selected from various amino protecting groups known in the art, and it is within the ability of those skilled in the art to adjust and select according to actual needs. In one embodiment of the invention, the amino protecting group may be selected from one or more of the following: -C (O) R ⁸ 、-C(O)OR ⁹ 、-CH ₂ R ¹⁰ and-SO ₂ R ¹¹ Wherein R is ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Each independently selected from C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₆ -C ₁₀ Aryl or five to ten membered heteroaryl. Preferably, the amino protecting group may be an ethoxycarbonyl group.

According to the invention, the compounds of formula (I) may exist as a single enantiomer, for example, in one embodiment of the invention, the compounds of formula (I) may be pure L-glufosinate-ammonium or D-glufosinate-ammonium. In addition, the compounds of formula (I) may also be present in the form of a mixture of enantiomers, and the enantiomers may each be present in any ratio in the mixture of enantiomers, for example, in one embodiment of the invention, a mixture of enantiomers in any ratio of the compound of formula (I) comprises 0.1:99.9 to 99.9:0.1 of L-glufosinate-ammonium and D-glufosinate-ammonium. However, since only L-glufosinate-ammonium is active, the L-enantiomer of the compound of formula (I) of the present invention may also preferably be present in a larger proportion in the enantiomeric mixture, e.g., in one embodiment, a mixture of any proportion of enantiomers of the compound of formula (I) comprises 50:50 to 99.9:0.1 (e.g., 60.

In the production method of the first aspect of the present invention, the hydrolysis of the compound of the formula (IV) may be carried out directly under neutral conditions, that is, the hydrolysis reaction may be carried out directly in the presence of water. In addition, the hydrolysis may also preferably be carried out in the presence of an acid or a base. More specifically, the acid may 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; the base may be selected from the group consisting of alkali or alkaline earth metal hydroxides, carbonates, bicarbonates or hydroxycarbonates, ammonia, organic bases, organic ammonia, preferably sodium hydroxide or triethylamine. In one embodiment of the present invention, the hydrolysis may be carried out at a temperature of, for example, 30 to 140 ℃ (e.g., 40 ℃, 50 ℃, 60 ℃, 70 ℃, 80 ℃, 90 ℃, 100 ℃, 110 ℃, 120 ℃, 130 ℃, etc.), preferably 60 to 110 ℃.

As a preferred embodiment of the compounds of formula (IV), R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Can be independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl, preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl. In addition, in a preferred embodiment, as used hereinWhen used, halogen may be selected from fluorine, chlorine or bromine; c ₁ -C ₆ The alkyl group may be selected from methyl, ethyl, propyl or isopropyl; c ₂ -C ₆ Alkenyl may be selected from ethenyl, propenyl, 1-butenyl, 2-butenyl or isobutenyl; c ₂ -C ₆ Alkynyl may be selected from ethynyl, propynyl, 1-butynyl or 2-butynyl; c ₃ -C ₆ Cycloalkyl groups may be selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl; a tri-to six-membered heterocycloalkyl group can be selected from cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl containing at least one heteroatom of N, O and S; c ₆ -C ₁₀ Aryl may be selected from phenyl or naphthyl; and/or five to ten membered heteroaryl may be selected from pyrazinyl, pyrazolyl, pyrrolyl, furanyl, thienyl, thiazolyl or pyridyl.

As an alternative to the compounds of the formula (IV), R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Or each may be independently selected from-Si (R) ¹⁵ )(R ¹⁶ )(R ¹⁷ ) Wherein R is ¹⁵ 、R ¹⁶ And R ¹⁷ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution.

Further, the production method of the first aspect of the present invention may further comprise a step of producing the compound of formula (IV).

In one embodiment of the invention, the compound of formula (IV) may be prepared by reacting a compound of formula (II)

With compounds of the formula (III)

The preparation method comprises the steps of reacting to prepare the compound,

wherein R is ¹ 、R ² X, Y, Z, A and as defined above.

Preferably, the molar ratio of the compound of formula (II) to the compound of formula (III) may be 1:0.9 to 5, preferably 1:1.05-1.5.

In addition, the compound of formula (III) may further comprise a compound of formula (V) and a compound of formula (VI) and/or (VII); or a combination of a compound of formula (VIII) and a compound of formula (VI) and/or (VII),

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X and X are as defined in claim 1.

In the step of preparing the compound of formula (III) as described above, the compound of formula (V-VIII) used may be added to the reaction system as an initial reactant, or may be further obtained by in situ reaction of other compounds. For example, the compound of formula (VIII) may be obtained by reacting the compound of formula (V) with the compound of formula (VI) and/or the compound of formula (VII) in situ. Further, in the above-mentioned various steps for producing the compound of the formula (III), there is no limitation on the order of charging the respective raw materials, that is, the respective raw materials may be charged into the reaction system in an arbitrary order.

According to the invention, the procedure described above for the preparation of the compound of formula (III) may be advantageousOptionally in the presence of an acid-binding agent. In particular, the acid scavenger may be selected from NR ¹² R ¹³ R ¹⁴ Wherein R is ¹² 、R ¹³ And R ¹⁴ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ¹² 、R ¹³ And R ¹⁴ Any two of which form together with the N atom to which they are attached a three-to six-membered heterocycloalkyl group, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution. It is to be noted that, since the compounds of formula (VI) and formula (VII) conform to the above acid-binding agent general formulas, i.e., also conform to the requirements as an acid-binding agent, in the case where the compound of formula (VI) and/or the compound of formula (VII) has been added to the reaction system, it may be preferable to add an excess of the compound of formula (VI) and/or the compound of formula (VII) as an acid-binding agent present in the reaction. In a preferred embodiment of the present invention, the acid scavenger may be selected from an excess of at least one of the compound of formula (VI) and/or the compound of formula (VII), ammonia, triethylamine, morpholine, and piperidine.

Further, the step of preparing the compound of formula (IV) as described above may be carried out in the absence of a solvent or an organic solvent. In one embodiment of the present invention, the organic solvent is selected from an aromatic hydrocarbon solvent (e.g., benzene, xylene, trimethylbenzene, ethylbenzene, diethylbenzene, isopropylbenzene, diisopropylbenzene, halogenated benzene, or dihalobenzene), an alkane solvent (e.g., N-hexane, cyclohexane, N-heptane, methylcyclohexane, ethylcyclohexane), a halogenated hydrocarbon solvent (e.g., methylene chloride, dichloroethane, chloroform, or carbon tetrachloride), an ether solvent (e.g., tetrahydrofuran, methyltetrahydrofuran, methyl tert-butyl ether, diisopropyl ether, methylcyclopentyl ether, ethylene glycol dimethyl ether, dioxane, or diethylene glycol dimethyl ether), an ester solvent (e.g., ethyl acetate, isopropyl acetate, or butyl acetate), an amide solvent (e.g., N-dimethylformamide, N-dimethylacetamide, hexamethylphosphoric triamide, N-methylpyrrolidone, or 1,3-dimethyl-2-imidazolidinone), or a sulfur-containing solvent (e.g., dimethyl sulfoxide or sulfolane), preferably, the organic solvent is selected from at least one of toluene and chlorobenzene.

The amounts of the reactants and the reaction conditions in the step of preparing the compound of formula (IV) as described above can be adjusted according to practical needs and the knowledge of those skilled in the art. In one embodiment of the invention, the molar ratio of the composition to the acid scavenger may be 1:0.01 to 5, preferably 1:0.1-1.5. In another embodiment of the invention, the reaction may be carried out at a temperature of-10 to 130 ℃ (e.g., -5 ℃,0 ℃, 5 ℃, 10 ℃,20 ℃, 40 ℃, 60 ℃, 80 ℃, 100 ℃, or 120 ℃, etc.) for 1 to 25 hours (e.g., 2 hours, 4 hours, 6 hours, 12 hours, 18 hours, or 24 hours, etc.).

In a second aspect, the present application provides a compound of formula (IV) or a salt, enantiomer or a mixture of enantiomers in any proportion thereof,

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X, Y, Z and as previously defined.

Preferably, the compound of formula (IV) may be prepared with reference to the first aspect of the invention.

In a third aspect, the present application provides a process for the preparation of a compound of formula (IV) or a salt, enantiomer or mixture of enantiomers in any ratio thereof, comprising the steps of:

reacting a compound of formula (II)

With compounds of the formula (III)

The reaction is carried out in the presence of a catalyst,

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X, Y, Z and as defined above.

In a fourth aspect, the present application provides a composition comprising a compound of formula (V), a compound of formula (VI), and a compound of formula (VII); or a compound of formula (VIII), a compound of formula (VI) and a compound of formula (VII),

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X and X are as previously defined.

In a fifth aspect, the present application provides the use of a composition of the fourth aspect for the preparation of glufosinate-ammonium represented by formula (I) or a salt, enantiomer or mixture of enantiomers in any ratio thereof

It will be understood by those skilled in the art that the definitions and preferences described in one aspect of the application apply equally to the other aspect. It will be clear to a person skilled in the art that embodiments of the various aspects of the present application can be combined in various ways without departing from the subject-matter and the idea of the application, and that such combinations are also included within the scope of the application.

The research shows that compared with the prior art, the invention at least comprises the following beneficial effects:

1. due to different reaction mechanisms, halogenated hydrocarbon by-products in the Michaelis-Arbuzov reaction can be avoided or reduced, the halogenated hydrocarbon by-products are usually chloroethane and chloromethane, are 3 kinds of carcinogens and have a destructive effect on ozone in the atmosphere, accordingly, equipment and engineering investment for separating, purifying, collecting and the like of the by-products are omitted, and potential environment and safety risks brought by the by-products are avoided;

2. the substrate has higher reaction activity, so that the construction condition of a P-C bond is milder, the reaction temperature can be reduced by 30-70 ℃ compared with the former reaction temperature, the racemization of the L-configuration at high temperature can be reduced during the preparation of the L-glufosinate-ammonium, and the purity of the L-configuration of the product is improved; and

3. the raw materials can be prepared and used in situ, and the processes of synthesis, rectification and purification of the methyl diphosphorous acid diester are omitted. Meanwhile, the raw materials are simple and convenient to prepare, the parameter selection space is large when the preparation process of the dichlorophosphorus and the amine is selected, and the fault tolerance rate is high.

Detailed Description

The invention is further illustrated with reference to the following examples; these examples do not limit the scope of the present invention. All reactants used in the examples were obtained commercially unless otherwise stated; instruments and equipment used in synthesis experiments and product analysis and detection are all conventional instruments and equipment commonly used in organic synthesis.

Example 1: synthesis of L-glufosinate-ammonium hydrochloride (I-1)

1) Synthesis of Compound (III-1)

Diethylamine (76.95g, 1.052mol, 4.1eq.) was added to 150g of toluene, the temperature was reduced to-5 ℃ under nitrogen protection, and methyl phosphorus dichloride (30g, 0.257mol, 1.0eq.) was added dropwise while maintaining the system temperature at-5 ℃. After the dripping is finished, the reaction is carried out for 0.5 hour under the condition of heat preservation to obtain the compound (III-1), the salt is removed by filtration, and the filtrate is directly used for the next reaction.

m/z(ESI)154.08([M+1] ⁺ ,100％)； ³¹ P NMR(33MHz)δ:79.29。

2) Synthesis of Compound (IV-1)

Under the protection of nitrogen, the compound (II-1) (57.94g, 0.244mol, 0.95eq.) is added into the filtrate of the compound (III-1), the temperature is slowly raised to 90-95 ℃, the reaction is kept for 15 hours, and the solution of the compound (IV-1) is obtained and can be directly used for the next reaction after desolventization.

m/z(ESI)392.21([M-Cl] ⁺ ,100％)； ³¹ P NMR(33MHz)δ:64.68。

3) Synthesis of Compound (I-1)

To the feed solution of the above-mentioned compound (IV-1), 180g of 30% hydrochloric acid was added, and the mixture was heated to reflux reaction. After the reaction is finished, reduced pressure distillation is carried out for removing, 150g of absolute ethyl alcohol is added, heating reflux is carried out, cooling crystallization is carried out, suction filtration and drying are carried out, and white solid, namely the target product (I-1), is obtained, wherein the yield is 85.5 percent, the content is 98.5 percent, and the ee value is 97.1 percent.

m/z(ESI)182.07([M+1] ⁺ ,100％)；

³¹ P NMR(243MHz,D ₂ O)δ:53.67；

¹ H NMR(600MHz,D ₂ O)δ:4.10(t,J＝6.1Hz,1H),2.25–2.05(m,2H),1.99–1.75(m,2H),1.47(d,J＝14.1Hz,3H)；

¹³ C NMR(151MHz,D ₂ O)δ:171.29,52.96(d,J＝16.6Hz),25.25(d,J＝93.0Hz),22.72(d,J＝2.6Hz),13.61(d,J＝92.5Hz)。

Example 2: synthesis of L-glufosinate-ammonium hydrochloride (I-1)

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1) Synthesis of Compound (III-2)

The temperature is reduced to-5 to 5 ℃ under the protection of nitrogen, dimethylamine (37.95g, 0.842mol, 4.1eq.) is slowly introduced into 150g of toluene, and methyl phosphorus dichloride (24g, 0.205mol, 1.0eq.) is added dropwise while the system temperature is kept at-5 to 5 ℃. After dropping, the reaction was carried out for 0.5 hour under heat to obtain compound (V-2), which was then filtered to remove salts and the filtrate was used directly in the next reaction.

m/z(ESI)135.09([M+1] ⁺ ,100％)； ³¹ P NMR(33MHz)δ:87.63。

2) Synthesis of Compound (IV-2)

Adding the compound (II-1) (46.35g, 0.195mol, 0.95eq.) into the filtrate of the compound (III-2) under the protection of nitrogen, slowly heating to 90-95 ℃, keeping the temperature and reacting for 12 hours to obtain a compound (IV-2) solution, and directly using the solution for the next reaction after desolventizing.

m/z(ESI)336.13([M-Cl] ⁺ ,100％)； ³¹ P NMR(33MHz)δ:70.12。

3) Synthesis of Compound (I-1)

To the feed solution of the above-mentioned compound (IV-1), 180g of 30% hydrochloric acid was added, and the mixture was heated to reflux reaction. After the reaction is finished, reduced pressure distillation is carried out for removing, 150g of absolute ethyl alcohol is added, heating reflux is carried out, cooling crystallization is carried out, suction filtration and drying are carried out, and white solid, namely the target product (I-1), is obtained, wherein the yield is 33.4g, the content is 97.1%, and the ee value is 96.5%.

Example 3: synthesis of DL-glufosinate-ammonium hydrochloride (I-2)

1) Synthesis of Compound (III-1)

Diethylamine (66.47g, 0.909mol, 4.25eq.) was added into 150g of toluene, the temperature was reduced to-5 ℃ under the protection of nitrogen, and methyl phosphorus dichloride (25.0 g,0.214mol, 1.0eq.) was added dropwise while the system temperature was kept at-5 ℃. After the dripping is finished, the reaction is carried out for 0.5 hour under the condition of heat preservation to obtain the compound (III-1), the salt is removed by filtration, and the filtrate is directly used for the next reaction.

2) Synthesis of Compound (IV-3)

Under the protection of nitrogen, adding the compound (II-2) (49.81g, 0.210mol, 0.98eq.) into the filtrate of the compound (III-1), slowly heating to 90-95 ℃, keeping the temperature and reacting for 15 hours to obtain a compound (IV-3) solution, and directly using the compound (IV-3) solution for the next reaction after desolventization.

3) Synthesis of Compound (I-2)

To the feed solution of the above-mentioned compound (IV-3), 180g of 30% hydrochloric acid was added, and the mixture was heated to reflux reaction. After the reaction is finished, reduced pressure distillation is carried out for removing, 150g of absolute ethyl alcohol is added, heating reflux is carried out, cooling crystallization is carried out, suction filtration and drying are carried out, and white solid, namely 37.9g of the target product (I-2), is obtained, the yield is 81.5 percent, and the content is 98.1 percent.

The preferred embodiments of the present invention have been described in detail, however, the present invention is not limited to the specific details of the above embodiments, and various simple modifications may be made to the technical solution of the present invention within the technical idea of the present invention, and these simple modifications are within the protective scope of the present invention.

It should be noted that, in the above embodiments, the various features described in the above embodiments may be combined in any suitable manner, and in order to avoid unnecessary repetition, the present invention does not separately describe various possible combinations.

In addition, any combination of the various embodiments of the present invention is also possible, and the same should be considered as the disclosure of the present invention as long as it does not depart from the spirit of the present invention.

Claims (24)

1. A process for the preparation of glufosinate-ammonium represented by formula (I) or a salt, enantiomer or mixture of enantiomers in any ratio thereof, comprising the steps of:

(ii) hydrolyzing the compound of formula (IV) to obtain a compound of formula (I),

wherein the content of the first and second substances,

x is halogen;

y is-OR ³ or-N (R) ⁴ )(R ⁵ )；

Z is an amino protecting group;

R ¹ and R ² Each independently selected from hydrogen, C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ¹ And R ² Form a three-to six-membered heterocycloalkyl group together with the N atom to which it is attached, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution;

R ³ 、R ⁴ and R ⁵ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ⁴ And R ⁵ Form a three-to six-membered heterocycloalkyl group together with the N atom to which it is attached, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution;

R ⁶ and R ⁷ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ⁷ And R ⁸ Form a three-to six-membered heterocycloalkyl group together with the N atom to which it is attached, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution; and is

* For identifying chiral carbon atoms.

2. The process according to claim 1, wherein the amino protecting group is selected from one or more of: -C (O) R ⁸ 、-C(O)OR ⁹ 、-CH ₂ R ¹⁰ and-SO ₂ R ¹¹ Wherein R is ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Each independently selected from C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl radical, C ₆ -C ₁₀ Aryl or five to ten membered heteroaryl, preferably ethoxycarbonyl.

3. The process of claim 1, wherein the hydrolysis is carried out in the presence of an acid or a base.

4. The method according to claim 3, wherein 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.

5. A process according to claim 3, wherein the base is selected from the group consisting of alkali or alkaline earth metal hydroxides, carbonates, bicarbonates or hydroxycarbonates, aqueous ammonia, organic bases or organic amines, preferably sodium hydroxide or triethylamine.

6. The process according to claim 1, wherein the hydrolysis is carried out at a temperature of 30-140 ℃, preferably 60-110 ℃, for 0.5-36 hours.

7. The method of claim 1, wherein the enantiomer of glufosinate-ammonium is L-glufosinate-ammonium or D-glufosinate-ammonium.

8. The method of claim 1, wherein the mixture of enantiomers of glufosinate in any proportion comprises 0.1:99.9 to 99.9:0.1 of L-glufosinate-ammonium and D-glufosinate-ammonium, preferably 50:50 to 99.9:0.1 of L-glufosinate-ammonium and D-glufosinate-ammonium.

9. The method of claim 1 or 2,

halogen is selected from fluorine, chlorine or bromine;

C ₁ -C ₆ the alkyl is selected from methyl, ethyl, propyl or isopropyl;

C ₂ -C ₆ alkenyl is selected from ethenyl, propenyl, 1-butenyl, 2-butenyl or isobutenyl;

C ₂ -C ₆ alkynyl is selected from ethynyl, propynyl, 1-butynyl or 2-butynyl;

C ₃ -C ₆ cycloalkyl is selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl;

a tri-to six-membered heterocycloalkyl selected from cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl containing at least one heteroatom of N, O and S;

C ₆ -C ₁₀ aryl is selected from phenyl or naphthyl; and/or

Five-to ten-membered heteroaryl is selected from pyrazinyl, pyrazolyl, pyrrolyl, furanyl, thienyl, thiazolyl or pyridyl.

10. The method of claim 1 or 2, wherein R ¹ 、R ² 、R ³ 、R ⁴ 、R ⁵ 、R ⁶ 、R ⁷ 、R ⁸ 、R ⁹ 、R ¹⁰ And R ¹¹ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl, preferably hydrogen, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, hexyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or phenyl.

11. The method of claim 1, wherein the compound of formula (IV) is prepared by reacting a compound of formula (II)

With compounds of the formula (III)

The preparation method comprises the steps of reacting to prepare the compound,

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X, Y, Z and as defined in claim 1.

12. The process of claim 11, wherein the molar ratio of compound of formula (II) to compound of formula (III) is 1:0.9 to 5, preferably 1:1.05-1.5.

13. The method of claim 11, wherein the compound of formula (III) is prepared from a mixture comprising a compound of formula (V), a compound of formula (VI), and a compound of formula (VII); or a combination of a compound of formula (VIII), a compound of formula (VI) and a compound of formula (VII),

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X, Y, Z and as defined in claim 1.

14. The process of claim 13, wherein the reaction is carried out in the presence of an acid scavenger.

15. The method of claim 14, wherein said acid scavenger is selected from NR ¹² R ¹³ R ¹⁴ Wherein R is ¹² 、R ¹³ And R ¹⁴ Each independently selected from hydrogen and C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl, or R ¹² 、R ¹³ And R ¹⁴ Any two of which form together with the N atom to which they are attached a three-to six-membered heterocycloalkyl group, wherein said C ₁ -C ₆ Alkyl radical, C ₂ -C ₆ Alkenyl radical, C ₂ -C ₆ Alkynyl, C ₃ -C ₆ Cycloalkyl, tri-to hexa-membered heterocycloalkyl, C ₆ -C ₁₀ Aryl or five-to ten-membered heteroaryl optionally substituted by halogen, carboxy, hydroxy, cyano, amino, nitro, C ₁ -C ₃ Alkyl radical, C ₁ -C ₃ Haloalkyl, C ₁ -C ₃ Alkoxy radical, C ₃ -C ₆ Cycloalkyl or C ₆ -C ₁₀ Aryl substitution.

16. The method of claim 14, wherein the molar ratio of the composition to the acid scavenger is 1:0.01 to 5, preferably 1:0.1-1.5.

17. The process according to claim 11, wherein the reaction is carried out in the absence of a solvent or an organic solvent.

18. The method according to claim 11, wherein the organic solvent is selected from an aromatic hydrocarbon solvent, an alkane solvent, a halogenated hydrocarbon solvent, an ether solvent, an ester solvent, an amide solvent, or a sulfur-containing solvent, preferably, the organic solvent is selected from at least one of toluene and chlorobenzene.

19. The process according to claim 11, wherein the reaction is carried out at a temperature of-10-130 ℃, preferably 30-95 ℃ for 1-25 hours.

20. A compound of formula (IV) or a salt, enantiomer or mixture of enantiomers in any proportion thereof,

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X, Y, Z and as defined in claim 1.

21. A compound of formula (IV) according to claim 20, or a salt, an enantiomer, or a mixture of enantiomers in any proportion thereof, prepared by a step in a process according to any one of claims 11-19.

22. A process for the preparation of a compound of formula (IV) or a salt, enantiomer or mixture of enantiomers in any ratio thereof, comprising the steps of:

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reacting a compound of formula (II)

With compounds of the formula (III)

The reaction is carried out in the presence of a catalyst,

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X, Y, Z and as defined in claim 1.

23. A composition, comprising: compounds of formula (V), compounds of formula (VI) and compounds of formula (VII); or a compound of formula (VIII), a compound of formula (VI) and a compound of formula (VII),

wherein R is ¹ 、R ² 、R ⁶ 、R ⁷ X and X are as defined in claim 1.

24. Use of a composition according to claim 23 for the preparation of glufosinate-ammonium represented by formula (I) or a salt, an enantiomer or a mixture of enantiomers in any ratio thereof

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