WO2021143713A1 - Method for preparing intermediate of l-glufosinate-ammonium - Google Patents

Method for preparing intermediate of l-glufosinate-ammonium Download PDF

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WO2021143713A1
WO2021143713A1 PCT/CN2021/071426 CN2021071426W WO2021143713A1 WO 2021143713 A1 WO2021143713 A1 WO 2021143713A1 CN 2021071426 W CN2021071426 W CN 2021071426W WO 2021143713 A1 WO2021143713 A1 WO 2021143713A1
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group
alkyl
formula
compound
alkyl group
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刘永江
周磊
曾伟
徐敏
程柯
尹英遂
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利尔化学股份有限公司
广安利尔化学有限公司
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Priority to CN202180006003.4A priority Critical patent/CN114585631A/en
Publication of WO2021143713A1 publication Critical patent/WO2021143713A1/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/28—Phosphorus compounds with one or more P—C bonds
    • C07F9/30—Phosphinic acids [R2P(=O)(OH)]; Thiophosphinic acids ; [R2P(=X1)(X2H) (X1, X2 are each independently O, S or Se)]
    • C07F9/32—Esters thereof
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Definitions

  • the present invention relates to a method for preparing L-glufosinate-ammonium intermediate.
  • Glufosinate-ammonium is an important herbicide.
  • the present invention provides a method for preparing enantiomerically pure compounds of formula (I) and salts thereof,
  • the method includes the following steps:
  • Hal is halogen
  • PG is hydrogen or an amino protecting group
  • Z is OX or OY
  • R 1 is a C 1 -C 16 alkyl, cyclohexyl, cyclopentyl or phenyl group, wherein each group can be hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or dioxane Amino substitution;
  • R 2 is a C 1 -C 8 alkyl group, a C 1 -C 8 ether group or a phenyl group;
  • X and Y are each independently an alkyl group, an alkenyl group or an aryl group
  • R 2 is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
  • the aforementioned base is an organic base or an inorganic base, preferably an organic base.
  • the aforementioned organic base is selected from organic amines, pyridines or pyridine derivatives having 1 to 3 substituents attached to one or more carbon atoms of the heterocyclic ring, piperidines or having 1 to 3 attached to the A piperidine derivative with a substituent on one or more carbon atoms of a heterocyclic ring.
  • the aforementioned organic amine is selected from aliphatic amines, alcohol amines, amides, alicyclic amines, aromatic amines or naphthylamines, preferably aliphatic amines; the aforementioned substituents are each independently selected from lower alkyl groups, lower alkoxy groups, and hydroxy lower alkyl groups. Group, amino group, lower alkylamino group and lower alkylamino lower alkyl group, lower alkyl group and lower alkoxy group are preferred.
  • the aforementioned inorganic base is selected from alkali metal hydroxides, alkali metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen carbonates or alkaline earth metal hydrogen carbonates.
  • R 1 is a phenyl group or a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, more preferably a methyl group.
  • X and Y are each independently a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
  • R 1 is methyl
  • X is ethyl
  • Y is ethyl
  • the aforementioned enantiomer ratio is (L):(D)-enantiomer or (D):(L)-enantiomer from 50.5:49.5 to 99.5:0.5.
  • the aforementioned enantiomer ratio is (L):(D)-enantiomers ranging from 50.5:49.5 to 99.5:0.5.
  • the reaction can occur at room temperature, and the temperature of the reaction may be 20 to 200°C. Taking the efficiency of the reaction into consideration, it is preferably 90 to 140°C. If the temperature is too low, the reaction rate is too slow, and if the temperature is too high, by-products will be formed.
  • the aforementioned reaction can be carried out in a solvent-free condition or in an inert solvent. Adding solvent can reduce the generation of impurities and increase the reaction time.
  • the inert solvent may be selected from any one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or ester solvents.
  • the inert solvent can be selected from chlorobenzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, nitromethylpyrrolidone, N,N-dimethyl Any one or more of methyl formamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate.
  • the solvent has a certain influence on the reaction effect, preferably benzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, nitrogen methyl pyrrolidone, N, N-dimethyl methyl Amide.
  • the foregoing reaction can adopt a variety of feeding methods.
  • the compound of formula (II) and the compound of formula (III) can be mixed first, and the base is added to it; the compound of formula (II) and the base are first mixed, and the compound of formula (III) is added to it.
  • the molar ratio of the aforementioned base to the compound of formula (II) is 1:(1-100), preferably 1:(2-10).
  • the molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(1-10), preferably 1:(1.3-2).
  • the reaction time can be varied within a wide range, depending on the temperature, operating conditions and batch size, it can be 0.5 to 48 hours.
  • the present invention also provides a method for preparing L- glufosinate-ammonium, which includes the following steps:
  • PG, Z and R 2 are as defined above.
  • the present invention also provides a compound of formula (I) or a salt, enantiomer or a mixture of enantiomers in all ratios,
  • PG, Z, R 1 and R 2 are as defined above;
  • the method of the present invention can effectively maintain the ee value of the raw materials by adding alkali, and the organic alkali has the better effect.
  • amino protecting group refers to a group that can be attached to a nitrogen atom on an amino group so as to protect the amino group from participating in the reaction and which can be easily removed in a subsequent reaction.
  • Suitable amino protecting groups include, but are not limited to the following protecting groups:
  • alkyl refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 18 carbon atoms. Preferred are alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like.
  • the alkyl group may be substituted or unsubstituted. When substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.
  • alkenyl refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like.
  • the alkenyl group may be substituted or unsubstituted. When substituted, the substituent may be a halogen, a nitro group, a sulfonyl group, an etheroxy group, an etherthio group, an ester group, a thioester group, or a cyano group.
  • aromatic group refers to a group having at least one aromatic ring structure.
  • the aromatic group is preferably phenyl or benzyl.
  • the phenyl and benzyl groups may be substituted or unsubstituted.
  • the C 1 -C 4 alkyl group is straight or branched and contains a saturated hydrocarbon chain of 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.
  • the temperature of the system was maintained at 10°C, and the reaction was stirred for 30 minutes. The temperature was gradually increased to 35°C, and the reaction was stirred for 20 hours. During the process, bubbles continued to be generated. The progress of the reaction was monitored by LC-MS and the reaction was terminated. Among them, the intermediate product (chlorohomoserine ethyl ester hydrochloride), ester impurities, and ether impurities are all LC detection values. The temperature of the system was lowered to room temperature, and the remaining thionyl chloride and ethanol were removed by distillation under reduced pressure.
  • the chlorohomoserine ethyl ester hydrochloride solid was reacted with saturated sodium carbonate solution, the pH of the system was adjusted to 7-8, and ethyl acetate was added for extraction, and the total extraction was 3 times.
  • the amount of ethyl acetate for the 3 extraction processes was 30 mL. , 10mL and 10mL.
  • the organic phase was collected and concentrated to obtain 10.30g of the target oily compound chlorohomoserine ethyl ester (165.62g/mol, 0.0591mol), HPLC purity 95%, ee value 99%, based on the intermediate product chlorohomoserine ethyl ester hydrochloric acid
  • the salt yield is 90%.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Biochemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Molecular Biology (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

The present invention relates to a method for preparing an intermediate of L-glufosinate-ammonium.

Description

制备L-草铵膦中间体的方法Method for preparing L-glufosinate-ammonium intermediate 技术领域Technical field
本发明涉及一种制备L-草铵膦中间体的方法。The present invention relates to a method for preparing L-glufosinate-ammonium intermediate.
背景技术Background technique
草铵膦是一种重要的除草剂。Glufosinate-ammonium is an important herbicide.
发明内容Summary of the invention
本发明提供了一种制备对映体纯的式(I)化合物及其盐的方法，The present invention provides a method for preparing enantiomerically pure compounds of formula (I) and salts thereof,
Figure PCTCN2021071426-appb-000001
Figure PCTCN2021071426-appb-000001
所述方法包括以下步骤：The method includes the following steps:
使对映体纯的式(II)化合物Enantiomerically pure compound of formula (II)
Figure PCTCN2021071426-appb-000002
Figure PCTCN2021071426-appb-000002
与式(III)化合物在碱的存在下反应，React with the compound of formula (III) in the presence of a base,
Figure PCTCN2021071426-appb-000003
Figure PCTCN2021071426-appb-000003
其中：in:
Hal为卤素；Hal is halogen;
PG为氢或氨基保护基；PG is hydrogen or an amino protecting group;
Z为OX或OY；Z is OX or OY;
R 1为C 1-C 16的烷基、环己基、环戊基或苯基，其中每个基团可被氢、C 1-C 6烷基、C 1-C 6烷氧基或二烷基氨基取代； R 1 is a C 1 -C 16 alkyl, cyclohexyl, cyclopentyl or phenyl group, wherein each group can be hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or dioxane Amino substitution;
R 2为C 1-C 8烷基、C 1-C 8醚基或苯基； R 2 is a C 1 -C 8 alkyl group, a C 1 -C 8 ether group or a phenyl group;
X和Y各自独立地为烷基、烯基或芳香基；X and Y are each independently an alkyl group, an alkenyl group or an aryl group;
手性碳原子标有*。Chiral carbon atoms are marked with *.
进一步地，前述R 2为C 1-C 6烷基，优选C 1-C 4烷基。 Further, the aforementioned R 2 is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
进一步地，前述碱为有机碱或无机碱，优选有机碱。Furthermore, the aforementioned base is an organic base or an inorganic base, preferably an organic base.
进一步地，前述有机碱选自有机胺、吡啶或具有1～3个连接到该杂环的一个或多个碳原子上的取代基的吡啶衍生物、哌啶或具有1～3个连接到该杂环的一个或多个碳原子上的取代基的哌啶衍生物。Further, the aforementioned organic base is selected from organic amines, pyridines or pyridine derivatives having 1 to 3 substituents attached to one or more carbon atoms of the heterocyclic ring, piperidines or having 1 to 3 attached to the A piperidine derivative with a substituent on one or more carbon atoms of a heterocyclic ring.
进一步地，前述有机胺选自脂肪胺、醇胺、酰胺、脂环胺、芳香胺或萘胺，优选脂肪胺；前述取代基各自独立地选自低级烷基、低级烷氧基、羟基低级烷基、氨基、低级烷基氨基和低级烷基氨基低级烷基，优选低级烷基和低级烷氧基。Further, the aforementioned organic amine is selected from aliphatic amines, alcohol amines, amides, alicyclic amines, aromatic amines or naphthylamines, preferably aliphatic amines; the aforementioned substituents are each independently selected from lower alkyl groups, lower alkoxy groups, and hydroxy lower alkyl groups. Group, amino group, lower alkylamino group and lower alkylamino lower alkyl group, lower alkyl group and lower alkoxy group are preferred.
进一步地，前述无机碱选自碱金属氢氧化物、碱金属氢氧化物、碱金属碳酸盐、碱土金属碳酸盐、碱金属碳酸氢盐或碱土金属碳酸氢盐。Further, the aforementioned inorganic base is selected from alkali metal hydroxides, alkali metal hydroxides, alkali metal carbonates, alkaline earth metal carbonates, alkali metal hydrogen carbonates or alkaline earth metal hydrogen carbonates.
进一步地，前述R 1为苯基或C 1-C 6烷基，优选C 1-C 4烷基，更优选甲基。 Further, the aforementioned R 1 is a phenyl group or a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, more preferably a methyl group.
进一步地，前述X和Y各自独立的为C 1-C 6烷基，优选C 1-C 4烷基。 Further, the aforementioned X and Y are each independently a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
进一步地，前述R 1为甲基，X为乙基，Y为乙基。 Further, the aforementioned R 1 is methyl, X is ethyl, and Y is ethyl.
进一步地，前述对映体比值是50.5∶49.5至99.5∶0.5的(L)∶(D)-对映体或(D)∶(L)-对映体。Further, the aforementioned enantiomer ratio is (L):(D)-enantiomer or (D):(L)-enantiomer from 50.5:49.5 to 99.5:0.5.
进一步地，前述对映体比值是50.5∶49.5至99.5∶0.5的(L)∶(D)-对映体。Further, the aforementioned enantiomer ratio is (L):(D)-enantiomers ranging from 50.5:49.5 to 99.5:0.5.
反应在室温下即可发生，反应的温度可以是20～200℃，考虑到反应的效率，优选90～140℃。温度过低反应速率过慢，温度过高会有副产物生成。The reaction can occur at room temperature, and the temperature of the reaction may be 20 to 200°C. Taking the efficiency of the reaction into consideration, it is preferably 90 to 140°C. If the temperature is too low, the reaction rate is too slow, and if the temperature is too high, by-products will be formed.
前述反应可以在无溶剂条件下或惰性溶剂中进行。加入溶剂可以减少杂质的产生，增长反应时间。惰性溶剂可选自苯类溶剂、酰胺类溶剂、卤代烃类溶剂、醚类溶剂或酯类溶剂中的任一种或一种以上。The aforementioned reaction can be carried out in a solvent-free condition or in an inert solvent. Adding solvent can reduce the generation of impurities and increase the reaction time. The inert solvent may be selected from any one or more of benzene solvents, amide solvents, halogenated hydrocarbon solvents, ether solvents or ester solvents.
作为具体实施方式，惰性溶剂可选自氯苯、三甲苯、1，4-二氧六环、1，2-二氯乙烷、二甲亚砜、氮甲基吡咯烷酮、N，N-二甲基甲酰胺、石油醚、正庚烷、四氢呋喃、甲基四氢呋喃、苯、甲苯、乙酸乙酯、乙酸丁酯中的任一种或一种以上。溶剂对反应效果有一定影响，优选苯、三甲苯、1，4-二氧六环、1，2-二氯乙烷、二甲亚砜、氮甲基吡咯烷酮、N，N-二甲基甲酰胺。As a specific embodiment, the inert solvent can be selected from chlorobenzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, nitromethylpyrrolidone, N,N-dimethyl Any one or more of methyl formamide, petroleum ether, n-heptane, tetrahydrofuran, methyltetrahydrofuran, benzene, toluene, ethyl acetate, and butyl acetate. The solvent has a certain influence on the reaction effect, preferably benzene, trimethylbenzene, 1,4-dioxane, 1,2-dichloroethane, dimethyl sulfoxide, nitrogen methyl pyrrolidone, N, N-dimethyl methyl Amide.
前述反应可采取多种投料方式，可以先将式(II)化合物与式(III)化合物混合，向其中加入碱；先将式(II)化合物与碱混合，向其中加入式(III)化合物。The foregoing reaction can adopt a variety of feeding methods. The compound of formula (II) and the compound of formula (III) can be mixed first, and the base is added to it; the compound of formula (II) and the base are first mixed, and the compound of formula (III) is added to it.
进一步地，前述碱与式(II)化合物的摩尔比为1∶(1～100)，优选1∶(2～10)。Further, the molar ratio of the aforementioned base to the compound of formula (II) is 1:(1-100), preferably 1:(2-10).
前述式(II)化合物与式(III)化合物的摩尔比为1∶(1～10)，优选1∶(1.3～2)。The molar ratio of the compound of formula (II) to the compound of formula (III) is 1:(1-10), preferably 1:(1.3-2).
反应时间可在较宽范围内变化，根据温度、操作条件和批次的大小，可以是0.5～48小时。The reaction time can be varied within a wide range, depending on the temperature, operating conditions and batch size, it can be 0.5 to 48 hours.
本发明还提供了一种制备L-草铵膦的方法，该方法包括以下步骤：The present invention also provides a method for preparing L- glufosinate-ammonium, which includes the following steps:
按照前述的方法制备得到式(Ia)化合物，Prepare the compound of formula (Ia) according to the aforementioned method,
Figure PCTCN2021071426-appb-000004
Figure PCTCN2021071426-appb-000004
使所得式(Ia)化合物在酸性条件下水解，得到L-草铵膦；Hydrolyze the obtained compound of formula (Ia) under acidic conditions to obtain L-glufosinate-ammonium;
其中，PG、Z和R 2如前述所定义。 Wherein, PG, Z and R 2 are as defined above.
本发明还提供了式(I)化合物或其盐、对映异构体或所有比例的对映异构体的混合物，The present invention also provides a compound of formula (I) or a salt, enantiomer or a mixture of enantiomers in all ratios,
Figure PCTCN2021071426-appb-000005
Figure PCTCN2021071426-appb-000005
其中，PG、Z、R 1和R 2如前述定义； Wherein, PG, Z, R 1 and R 2 are as defined above;
手性碳原子标有*。Chiral carbon atoms are marked with *.
本发明方法通过加入碱，可以有效保持原料的ee值，其中有机碱效果较佳。The method of the present invention can effectively maintain the ee value of the raw materials by adding alkali, and the organic alkali has the better effect.
除非有相反陈述，下列用在说明书和权利要求书中的术语具有下述含义。Unless stated to the contrary, the following terms used in the specification and claims have the following meanings.
术语“氨基保护基”指可连接至氨基上的氮原子从而保护所述氨基不参与反应并且其可在后面的反应中容易地除去的基团。合适的氨基保护基包括，但不限于下述保护基：The term "amino protecting group" refers to a group that can be attached to a nitrogen atom on an amino group so as to protect the amino group from participating in the reaction and which can be easily removed in a subsequent reaction. Suitable amino protecting groups include, but are not limited to the following protecting groups:
式-C(O)O-R的氨基甲酸酯基团，其中R例如甲基、乙基、叔丁基、苄基、苯乙基、CH 2＝CH-CH 2-，等等；式-C(O)-R′的酰胺基团，其中R′例如甲基、乙基、苯基、三氟甲基，等等；式-SO 2-R″的N-磺酰基衍生物-基团，其中R″例如甲苯基、苯基、三氟甲基、2，2，5，7，8-五甲基色满-6-基-、2，3，6-三甲基-4-甲氧基苯，等等。 A carbamate group of formula -C(O)OR, where R is for example methyl, ethyl, tert-butyl, benzyl, phenethyl, CH 2 =CH-CH 2 -, etc.; formula -C (O) An amide group of -R', where R'is such as methyl, ethyl, phenyl, trifluoromethyl, etc.; an N-sulfonyl derivative-group of the formula -SO 2 -R", Wherein R" such as tolyl, phenyl, trifluoromethyl, 2,2,5,7,8-pentamethylchroman-6-yl-, 2,3,6-trimethyl-4-methoxy Benzene, etc.
术语“烷基”指饱和的脂族烃基团，包括1至18个碳原子的直链和支链基团。优选含有1至6个碳原子的烷基，例如甲基、乙基、丙基、2-丙基、正丁基、异丁基、叔丁基、戊基等。烷基可以是取代的或未取代的，当被取代时，取代基可以为卤素、硝基、磺酰基、醚氧基、醚硫基、酯基、硫代酯基或氰基。The term "alkyl" refers to saturated aliphatic hydrocarbon groups, including straight and branched chain groups of 1 to 18 carbon atoms. Preferred are alkyl groups containing 1 to 6 carbon atoms, such as methyl, ethyl, propyl, 2-propyl, n-butyl, isobutyl, tert-butyl, pentyl and the like. The alkyl group may be substituted or unsubstituted. When substituted, the substituent may be halogen, nitro, sulfonyl, etheroxy, etherthio, ester, thioester, or cyano.
术语“烯基”指由至少两个碳原子和至少一个碳-碳双键组成的如上述定义的烷基。例 如乙烯基、1-丙烯基、2-丙烯基、1-，2-或3-丁烯基等。烯基可以是取代的或未取代的，当被取代时，取代基可以为卤素、硝基、磺酰基、醚氧基、醚硫基、酯基、硫代酯基或氰基。The term "alkenyl" refers to an alkyl group as defined above composed of at least two carbon atoms and at least one carbon-carbon double bond. For example, vinyl, 1-propenyl, 2-propenyl, 1-, 2- or 3-butenyl and the like. The alkenyl group may be substituted or unsubstituted. When substituted, the substituent may be a halogen, a nitro group, a sulfonyl group, an etheroxy group, an etherthio group, an ester group, a thioester group, or a cyano group.
术语“芳香基”指具有至少一个芳环结构的基团。芳香基优选苯基或苄基。苯基和苄基可以是取代的或未取代的。The term "aromatic group" refers to a group having at least one aromatic ring structure. The aromatic group is preferably phenyl or benzyl. The phenyl and benzyl groups may be substituted or unsubstituted.
C 1-C 4烷基是直链的或支链的，包含1至4个碳原子的饱和烃链。它可以是甲基、乙基、丙基、异丙基、丁基、异丁基、仲丁基或叔丁基基团。 The C 1 -C 4 alkyl group is straight or branched and contains a saturated hydrocarbon chain of 1 to 4 carbon atoms. It can be a methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl or tert-butyl group.
具体实施方式Detailed ways
实施例2-12中，ee值为水解完全后，反应液ee值，通过重结晶分离后L-草铵膦ee值95％-97％In Examples 2-12, the ee value of the reaction solution after the hydrolysis is complete, the ee value of L-glufosinate-ammonium after separation by recrystallization is 95%-97%
实施例1Example 1
Figure PCTCN2021071426-appb-000006
Figure PCTCN2021071426-appb-000006
称量式(I)化合物盐酸盐(L-高丝氨酸内酯盐酸盐，ee值99％，137.56g/mol，0.073mol)10g到反应容器中，加入乙醇(46.07g/mol，0.886mol，0.816g/mL)50mL，高丝氨酸内酯盐酸盐与乙醇的摩尔比为1∶12.1。将体系温度降至10℃，开始缓慢滴加二氯亚砜(118.97g/mol，0.182mol)21.7g，L-高丝氨酸内酯盐酸盐与二氯亚砜的摩尔比为1∶2.5。维持体系温度10℃，搅拌反应30min。逐渐升温至35℃，搅拌反应20h，过程中持续有气泡产生，利用LC-MS监测反应的进程，终止反应。其中，中间产物(氯代高丝氨酸乙酯盐酸盐)、酯杂质、醚杂质均为LC检测值。将体系温度降至室温，减压蒸馏除去剩余的二氯亚砜和乙醇，固体残渣用30mL正己烷/乙酸乙酯混合溶剂打浆(正己烷和乙酸乙酯的体积比为2∶1)，过滤并烘干，得氯代高丝氨酸乙酯盐酸盐(202.08g/mol，0.0657mol)13.69g，HPLC纯度97％，基于反应物L-高丝氨酸内酯盐酸盐的量计算的收率为90％。Weigh 10g of compound of formula (I) hydrochloride (L-homoserine lactone hydrochloride, ee value 99%, 137.56g/mol, 0.073mol) into the reaction vessel, add ethanol (46.07g/mol, 0.886mol) , 0.816g/mL) 50mL, the molar ratio of homoserine lactone hydrochloride to ethanol is 1:12.1. The temperature of the system was lowered to 10°C, and 21.7 g of thionyl chloride (118.97 g/mol, 0.182 mol) was slowly added dropwise, and the molar ratio of L-homoserine lactone hydrochloride to thionyl chloride was 1:2.5. The temperature of the system was maintained at 10°C, and the reaction was stirred for 30 minutes. The temperature was gradually increased to 35°C, and the reaction was stirred for 20 hours. During the process, bubbles continued to be generated. The progress of the reaction was monitored by LC-MS and the reaction was terminated. Among them, the intermediate product (chlorohomoserine ethyl ester hydrochloride), ester impurities, and ether impurities are all LC detection values. The temperature of the system was lowered to room temperature, and the remaining thionyl chloride and ethanol were removed by distillation under reduced pressure. The solid residue was slurried with 30 mL of n-hexane/ethyl acetate mixed solvent (the volume ratio of n-hexane and ethyl acetate was 2:1), and filtered And dried to obtain 13.69g of chlorohomoserine ethyl ester hydrochloride (202.08g/mol, 0.0657mol), HPLC purity 97%, the yield calculated based on the amount of reactant L-homoserine lactone hydrochloride 90%.
将氯代高丝氨酸乙酯盐酸盐固体与饱和碳酸钠溶液反应，体系pH调节至7-8，加入乙酸乙酯萃取，总计萃取3次，3次萃取过程的乙酸乙酯的用量分别为30mL、10mL和10mL。收集有机相并浓缩，得油状目标产品化合物氯代高丝氨酸乙酯(165.62g/mol，0.0591mol)10.30g，HPLC纯度95％，ee值99％，基于中间产物氯代高丝氨酸乙酯盐酸盐的收率90％。The chlorohomoserine ethyl ester hydrochloride solid was reacted with saturated sodium carbonate solution, the pH of the system was adjusted to 7-8, and ethyl acetate was added for extraction, and the total extraction was 3 times. The amount of ethyl acetate for the 3 extraction processes was 30 mL. , 10mL and 10mL. The organic phase was collected and concentrated to obtain 10.30g of the target oily compound chlorohomoserine ethyl ester (165.62g/mol, 0.0591mol), HPLC purity 95%, ee value 99%, based on the intermediate product chlorohomoserine ethyl ester hydrochloric acid The salt yield is 90%.
MS(ESI)：m/z[M+H] +C6H13ClNO2计算值：166.06；实测值：166.0. MS(ESI): m/z[M+H] + C6H13ClNO2 calculated value: 166.06; found value: 166.0.
1H NMR(CDCl 3，400MHz)δ：4.04(q，J＝7.1Hz，2H)，3.65-3.50(m，2H)，3.48(dd，J＝9.0，4.7Hz，1H)，2.05(dddd，J＝14.7，8.5，6.4，4.6Hz，1H)，1.87-1.64(m，3H)，1.13(t，J＝7.2Hz，3H). 1 H NMR (CDCl 3 , 400MHz) δ: 4.04 (q, J = 7.1 Hz, 2H), 3.65-3.50 (m, 2H), 3.48 (dd, J = 9.0, 4.7 Hz, 1H), 2.05 (dddd, J = 14.7, 8.5, 6.4, 4.6 Hz, 1H), 1.87-1.64 (m, 3H), 1.13 (t, J = 7.2 Hz, 3H).
13C NMR(CDCl 3，100MHz)δ：175.3，61.0，51.6，41.5，37.0，14.1. 13 C NMR (CDCl 3 , 100MHz) δ: 175.3, 61.0, 51.6, 41.5, 37.0, 14.1.
实施例2Example 2
Figure PCTCN2021071426-appb-000007
Figure PCTCN2021071426-appb-000007
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯(33.0g，242.4mmol，2.0eq)，化合物1-a(20.0g，121.2mmol，1.0eq)和氯苯(41g，363.6mmol，3.0eq)，滴加三乙胺(1.1g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至120℃，反应18h，减压蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-a，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite (33.0g, 242.4mmol, 2.0eq), compound 1-a (20.0g, 121.2mmol, 1.0eq) and chlorobenzene (41g, 363.6mmol, 3.0eq), triethylamine (1.1g, 12.1mmol, 0.1eq) was added dropwise, stirred at room temperature for 30min, heated to 120℃, reacted for 18h, the solvent and excess methylphosphonite were distilled off under reduced pressure Diethyl ester gives compound 2-a, which is directly proceeded to the next step.
Figure PCTCN2021071426-appb-000008
Figure PCTCN2021071426-appb-000008
在三口瓶中分别加入上步产物2-a(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦(白色晶体，16.4g，两步的分离收率75％，95％ee)。Add the product 2-a of the previous step (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled and crystallized, filtered, and dried to obtain L- glufosinate-ammonium (white crystals, 16.4 g, two-step separation yield 75%, 95% ee).
实施例3Example 3
Figure PCTCN2021071426-appb-000009
Figure PCTCN2021071426-appb-000009
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯(33.0g，242.4mmol，2.0eq)，化合物l-a(20.0g，121.2mmol，1.0eq)和三甲苯(43.7g，363.6mmol，3.0eq)，滴加三乙胺(1.1g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至120℃，反应20h， 减压蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-a，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite (33.0g, 242.4mmol, 2.0eq), compound la (20.0g, 121.2mmol, 1.0eq) and trimethylbenzene (43.7g, 363.6 mmol, 3.0eq), triethylamine (1.1g, 12.1mmol, 0.1eq) was added dropwise, stirred at room temperature for 30min, heated to 120°C, reacted for 20h, the solvent and excess methylphosphonite were distilled off under reduced pressure Ethyl esters give compound 2-a and proceed directly to the next step.
Figure PCTCN2021071426-appb-000010
Figure PCTCN2021071426-appb-000010
在三口瓶中分别加入上步产物2-a(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦，(白色晶体，14.4g，两步的分离收率66％，97％ee)。Add the product 2-a of the previous step (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled and crystallized, filtered, and dried to obtain L-glufosinate-ammonium (white crystals, 14.4 g, two-step separation yield 66%, 97% ee).
实施例4Example 4
Figure PCTCN2021071426-appb-000011
Figure PCTCN2021071426-appb-000011
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯(33.0g，242.4mmol，2.0eq)，化合物1-a(20.0g，121.2mmol，1.0eq)和氯苯(41g，363.6mmol，3.0eq)，滴加吡啶(1.0g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至120℃，反应18h，减压蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-a，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite (33.0g, 242.4mmol, 2.0eq), compound 1-a (20.0g, 121.2mmol, 1.0eq) and chlorobenzene (41g, 363.6mmol, 3.0eq), pyridine (1.0g, 12.1mmol, 0.1eq) was added dropwise, stirred at room temperature for 30min, heated to 120℃, reacted for 18h, and distilled off the solvent and excess methylphosphonite under reduced pressure The ester yields compound 2-a, which is directly proceeded to the next step.
Figure PCTCN2021071426-appb-000012
Figure PCTCN2021071426-appb-000012
在三口瓶中分别加入上步产物2-a(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦(白色晶体，17.5g，两步的分离收率80％，94.7％ee)。Add the product 2-a of the previous step (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled and crystallized, filtered, and dried to obtain L-glufosinate-ammonium (white crystals, 17.5 g, two-step separation yield 80%, 94.7% ee).
实施例5Example 5
Figure PCTCN2021071426-appb-000013
Figure PCTCN2021071426-appb-000013
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯((33.0g，242.4mmol，2.0eq)，化合物1-a(20.0g，121.2mmol，1.0eq)和三甲苯(43.7g，363.6mmol，3.0eq)，滴加哌啶(1.0g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至120℃，反应20h，减压蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-a，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite ((33.0g, 242.4mmol, 2.0eq), compound 1-a (20.0g, 121.2mmol, 1.0eq) and trimethylbenzene (43.7 g, 363.6mmol, 3.0eq), add piperidine (1.0g, 12.1mmol, 0.1eq) dropwise, stir at room temperature for 30min, warm up to 120℃, react for 20h, distill off the solvent and excess methylphosphinite under reduced pressure Diethyl acid to obtain compound 2-a, proceed directly to the next step.
Figure PCTCN2021071426-appb-000014
Figure PCTCN2021071426-appb-000014
在三口瓶中分别加入上步产物2-a(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦，(白色晶体，14.0g，两步的分离收率64％，91％ee)。Add the product 2-a of the previous step (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled to crystallize, filtered, and dried to obtain L-glufosinate-ammonium (white crystals, 14.0 g, two-step separation yield 64%, 91% ee).
实施例6Example 6
Figure PCTCN2021071426-appb-000015
Figure PCTCN2021071426-appb-000015
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯(33.0g，242.4mmol，2.0eq)，化合物1-a(20.0g，121.2mmol，1.0eq)和氯苯(41g，363.6mmol，3.0eq)，加入氢氧化钠(0.5g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至120℃，反应18h，减压蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-a，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite (33.0g, 242.4mmol, 2.0eq), compound 1-a (20.0g, 121.2mmol, 1.0eq) and chlorobenzene (41g, 363.6mmol, 3.0eq), sodium hydroxide (0.5g, 12.1mmol, 0.1eq) was added, stirred at room temperature for 30 minutes, heated to 120°C, reacted for 18 hours, and distilled off the solvent and excess methylphosphonite under reduced pressure Ethyl esters give compound 2-a and proceed directly to the next step.
Figure PCTCN2021071426-appb-000016
Figure PCTCN2021071426-appb-000016
在三口瓶中分别加入上步产物2-a(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回 流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦(白色晶体，9.8g，两步的分离收率49％，87％ee)。Add the product 2-a of the previous step (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled and crystallized, filtered, and dried to obtain L-glufosinate-ammonium (white crystals, 9.8 g, two-step separation yield 49%, 87% ee).
实施例7Example 7
Figure PCTCN2021071426-appb-000017
Figure PCTCN2021071426-appb-000017
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯((33.0g，242.4mmol，2.0eq)，化合物1-a(20.0g，121.2mmol，1.0eq)和氯苯(41g，363.6mmol，3.0eq)，加入碳酸氢钠(1.0g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至120℃，反应20h，减压蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-a，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite ((33.0g, 242.4mmol, 2.0eq), compound 1-a (20.0g, 121.2mmol, 1.0eq) and chlorobenzene (41g , 363.6mmol, 3.0eq), add sodium bicarbonate (1.0g, 12.1mmol, 0.1eq), stir at room temperature for 30min, warm up to 120℃, react for 20h, distill off the solvent and excess methylphosphonite under reduced pressure Diethyl ester gives compound 2-a, which is directly proceeded to the next step.
Figure PCTCN2021071426-appb-000018
Figure PCTCN2021071426-appb-000018
在三口瓶中分别加入上步产物2-a(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦，(白色晶体，9.6g，两步的分离收率44％，79％ee)。Add the product 2-a of the previous step (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled to crystallize, filtered, and dried to obtain L-glufosinate-ammonium (white crystals, 9.6 g, two-step separation yield 44%, 79% ee).
实施例8Example 8
Figure PCTCN2021071426-appb-000019
Figure PCTCN2021071426-appb-000019
在氮气氛围下，往三口瓶中分别加入甲基亚膦酸二乙酯((66.0g，484.8mmol，4.0eq)，化合物l-c(43.3g，121.2mmol，1.0eq)和氯苯(41g，363.6mmol，3.0eq)，加入吡啶(1.0g，12.1mmol，0.1eq)，室温下搅拌30min后，升温至140℃，反应36h，减压 蒸馏出溶剂和多余的甲基亚膦酸二乙酯得到化合物2-c，直接进行下一步。Under a nitrogen atmosphere, add diethyl methylphosphonite ((66.0g, 484.8mmol, 4.0eq), compound lc (43.3g, 121.2mmol, 1.0eq) and chlorobenzene (41g, 363.6 mmol, 3.0eq), add pyridine (1.0g, 12.1mmol, 0.1eq), stir at room temperature for 30min, raise the temperature to 140°C, react for 36h, distill off the solvent and excess diethyl methylphosphonite under reduced pressure to obtain Compound 2-c, proceed directly to the next step.
Figure PCTCN2021071426-appb-000020
Figure PCTCN2021071426-appb-000020
在三口瓶中分别加入上步产物2-c(1.0eq，按照100％计算)和36％HCl(147.5ml，1212mmol，10.0eq)加热回流至原料反应完全，蒸干溶剂后，加入95％乙醇的水溶液回流直至产物完全溶解，冷却结晶，过滤，干燥得到L-草铵膦，(白色晶体，34.5g，两步的分离收率79％，95％ee)。Add the product of the previous step 2-c (1.0eq, calculated as 100%) and 36% HCl (147.5ml, 1212mmol, 10.0eq) into a three-necked flask and heat to reflux until the reaction of the raw materials is complete. After evaporating the solvent, add 95% ethanol The aqueous solution was refluxed until the product was completely dissolved, cooled and crystallized, filtered, and dried to obtain L-glufosinate-ammonium (white crystals, 34.5 g, two-step separation yield 79%, 95% ee).

Claims (12)

  1. 制备对映体纯的式(I)化合物及其盐的方法，A method for preparing enantiomerically pure compounds of formula (I) and their salts,
    Figure PCTCN2021071426-appb-100001
    Figure PCTCN2021071426-appb-100001
    其特征在于，所述方法包括以下步骤：It is characterized in that the method includes the following steps:
    使对映体纯的式(II)化合物Enantiomerically pure compound of formula (II)
    Figure PCTCN2021071426-appb-100002
    Figure PCTCN2021071426-appb-100002
    与式(III)化合物在碱的存在下反应，React with the compound of formula (III) in the presence of a base,
    Figure PCTCN2021071426-appb-100003
    Figure PCTCN2021071426-appb-100003
    其中：in:
    Hal为卤素；Hal is halogen;
    PG为氢或氨基保护基；PG is hydrogen or an amino protecting group;
    Z为OX或OY；Z is OX or OY;
    R 1为C 1-C 16的烷基、环己基、环戊基或苯基，其中每个基团可被氢、C 1-C 6烷基、C 1-C 6烷氧基或二烷基氨基取代； R 1 is a C 1 -C 16 alkyl, cyclohexyl, cyclopentyl or phenyl group, wherein each group can be hydrogen, C 1 -C 6 alkyl, C 1 -C 6 alkoxy or dioxane Amino substitution;
    R 2为C 1-C 8烷基、C 1-C 8醚基或苯基； R 2 is a C 1 -C 8 alkyl group, a C 1 -C 8 ether group or a phenyl group;
    X和Y各自独立地为烷基、烯基或芳香基；X and Y are each independently an alkyl group, an alkenyl group or an aryl group;
    手性碳原子标有*。Chiral carbon atoms are marked with *.
  2. 根据权利要求1所述的方法，其特征在于：所述R 2为C 1-C 6烷基，优选C 1-C 4烷基。 The method according to claim 1, wherein the R 2 is a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
  3. 根据权利要求1或2所述的方法，其特征在于：所述碱为有机碱或无机碱，优选有机碱。The method according to claim 1 or 2, wherein the base is an organic base or an inorganic base, preferably an organic base.
  4. 根据权利要求3所述的方法，其特征在于：所述有机碱选自有机胺、吡啶或具有1～3个连接到该杂环的一个或多个碳原子上的取代基的吡啶衍生物、哌啶或具有1～3个连 接到该杂环的一个或多个碳原子上的取代基的哌啶衍生物。The method according to claim 3, wherein the organic base is selected from organic amines, pyridines, or pyridine derivatives having 1 to 3 substituents connected to one or more carbon atoms of the heterocyclic ring, Piperidine or a piperidine derivative having 1 to 3 substituents attached to one or more carbon atoms of the heterocyclic ring.
  5. 根据权利要求4所述的方法，其特征在于：所述有机胺选自脂肪胺、醇胺、酰胺、脂环胺、芳香胺或萘胺，优选脂肪胺；所述取代基各自独立地选自C 1-C 4烷基、C 1-C 4烷氧基、羟基C 1-C 4烷基、C 1-C 4烷基氨基，优选C 1-C 4烷基和C 1-C 4烷氧基。 The method according to claim 4, wherein the organic amine is selected from aliphatic amines, alcohol amines, amides, alicyclic amines, aromatic amines or naphthylamines, preferably fatty amines; each of the substituents is independently selected from C 1 -C 4 alkyl, C 1 -C 4 alkoxy, hydroxy C 1 -C 4 alkyl, C 1 -C 4 alkylamino, preferably C 1 -C 4 alkyl and C 1 -C 4 alkane Oxy.
  6. 根据权利要求1-5任一项所述的方法，其特征在于：所述R 1为苯基或C 1-C 6烷基，优选C 1-C 4烷基，更优选甲基。 The method according to any one of claims 1 to 5, wherein the R 1 is a phenyl group or a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group, more preferably a methyl group.
  7. 根据权利要求1-6任一项所述的方法，其特征在于：所述X和Y各自独立的为C 1-C 6烷基，优选C 1-C 4烷基。 The method according to any one of claims 1 to 6, characterized in that: the X and Y are each independently a C 1 -C 6 alkyl group, preferably a C 1 -C 4 alkyl group.
  8. 根据权利要求7所述的方法，其特征在于：所述R 1为甲基，X为乙基，Y为乙基。 The method according to claim 7, wherein the R 1 is methyl, X is ethyl, and Y is ethyl.
  9. 根据权利要求1-8任一项所述的方法，其特征在于：所述反应的温度为20～200℃，优选90～140℃。The method according to any one of claims 1-8, wherein the temperature of the reaction is 20-200°C, preferably 90-140°C.
  10. 根据权利要求1-9任一项所述的方法，其特征在于：所述反应在无溶剂条件下或惰性溶剂中进行。The method according to any one of claims 1-9, wherein the reaction is carried out under solvent-free conditions or in an inert solvent.
  11. 根据权利要求1-10任一项所述的方法，其特征在于：所述碱与式(II)化合物的摩尔比为1∶(1～100)，优选1∶(2～10)。The method according to any one of claims 1-10, wherein the molar ratio of the base to the compound of formula (II) is 1:(1-100), preferably 1:(2-10).
  12. 一种制备L-草铵膦的方法，其特征在于：所述方法包括以下步骤：A method for preparing L-glufosinate-ammonium, characterized in that: the method comprises the following steps:
    按照权利要求1-11任一项所述的方法制备得到式(Ia)化合物，The compound of formula (Ia) is prepared according to the method of any one of claims 1-11,
    Figure PCTCN2021071426-appb-100004
    Figure PCTCN2021071426-appb-100004
    使所得式(Ia)化合物在酸性条件下水解，得到L-草铵膦；Hydrolyze the obtained compound of formula (Ia) under acidic conditions to obtain L-glufosinate-ammonium;
    其中，PG、Z和R 2如权利要求1-11任一项中所定义。 Wherein, PG, Z and R 2 are as defined in any one of claims 1-11.
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