WO2021057945A1 - 制备草铵膦海因中间体及类似物的方法 - Google Patents

制备草铵膦海因中间体及类似物的方法 Download PDF

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WO2021057945A1
WO2021057945A1 PCT/CN2020/118013 CN2020118013W WO2021057945A1 WO 2021057945 A1 WO2021057945 A1 WO 2021057945A1 CN 2020118013 W CN2020118013 W CN 2020118013W WO 2021057945 A1 WO2021057945 A1 WO 2021057945A1
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enantiomers
mixture
formula
compound
reaction
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French (fr)
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刘永江
曾伟
周磊
左翔
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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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/66—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D233/72—Two oxygen atoms, e.g. hydantoin
    • C07D233/76—Two oxygen atoms, e.g. hydantoin with substituted hydrocarbon radicals attached to the third ring carbon atom
    • 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)]
    • C07F9/301—Acyclic saturated acids which can have further substituents on alkyl
    • 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
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/645—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom having two nitrogen atoms as the only ring hetero atoms
    • C07F9/6503—Five-membered rings
    • C07F9/6506—Five-membered rings having the nitrogen atoms in positions 1 and 3
    • 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 invention relates to a method for preparing glufosinate-ammonium hydantoin intermediates and analogs.
  • Glufosinate-ammonium is a broad-spectrum organophosphorus contact herbicide developed by Hurst in the 1980s.
  • Glufosinate-ammonium is a glutamine synthesis inhibitor. Its systemic effect is not strong. Glyphosate kills roots differently.
  • Glufosinate ammonium kills leaves first, and then conducts transmission in the xylem of plants through plant transpiration. Its quick-acting effect is between paraquat and glyphosate. It is a non-selective contact herbicide.
  • the preparation method of glufosinate generally has the problems of complicated reaction, low efficiency and high production cost.
  • the present invention provides a method for preparing a glufosinate-ammonium hydantoin intermediate of formula (I) and its analogues:
  • the method comprises the following steps:
  • Hal is a halogen atom
  • X is O or S
  • Y is O or S
  • R 1 is hydrogen or an amino protecting group
  • R 2 is hydrogen, C 1 -C 4 alkyl or benzyl.
  • the present invention further provides a method for preparing the glufosinate-ammonium hydantoin intermediate of formula (VI) and its analogues:
  • the method comprises the following step:
  • Hal is a halogen atom
  • Y is O or S
  • R 1 is hydrogen or an amino protecting group
  • R 2 is hydrogen, C 1 -C 4 alkyl or benzyl
  • R 3 is R 6 or R 7 ;
  • R 4 is an alkyl group or an aromatic group
  • R 5 is hydrogen or R 1 ;
  • R 6 and R 7 are each independently hydrogen, alkyl, alkenyl, or aryl.
  • X is O
  • R 1 is hydrogen
  • Y is O and R 2 is hydrogen.
  • R 4 is a C 1 -C 6 alkyl group.
  • R 4 is a methyl group.
  • R 6 and R 7 are each independently a C 1 -C 6 alkyl group.
  • R 4 is an ethyl group
  • R 6 is an ethyl group
  • R 7 is an ethyl group.
  • Hal is chlorine, bromine or iodine, preferably chlorine or bromine.
  • step (a) the temperature of the reaction is 80-120°C, preferably 90-110°C.
  • step (a) the reaction time is between 1 to 30 hours, 3 to 30 hours, 5 to 30 hours, 5 to 20 hours or 5 to 10 hours.
  • step (a) the reaction is carried out in a solvent, and the solvent is selected from water or a polar organic solvent.
  • the acid is any one of hydrochloric acid, nitric acid, sulfuric acid, and acetic acid or a mixture thereof.
  • step (b) is carried out at 60-120°C.
  • step (b) is carried out in water or an organic solvent.
  • steps (a) and (b) are a one-pot method, that is, the compound of formula (IV) prepared by step (a) does not need to be separated from the reaction medium and directly participates in step (b).
  • step (c) of the present invention is carried out by reacting a compound of formula (V) with a halogenating agent such as hydrogen halide or with a compound capable of producing hydrogen halide with a protic solvent, especially with an alcohol or carboxylic acid.
  • a halogenating agent such as hydrogen halide or with a compound capable of producing hydrogen halide with a protic solvent, especially with an alcohol or carboxylic acid.
  • the aforementioned halogenating agent includes, for example, acid halides, especially compounds of formula (VIII) (group A):
  • R 8 is an alkyl group, a cycloalkyl group, an aryl group, an arylalkyl group or a heterocyclylalkyl group
  • the group may be optionally substituted in each case.
  • R 8 is preferably C 1 -C 10 -alkyl, C 3 -C 10 -cycloalkyl, aryl-C 1 -C 4 -alkyl, especially phenyl-C 1 -C 4 -alkyl, each
  • the group may be optionally monosubstituted or polysubstituted, wherein suitable substituents are OH, SH, halogen, C 1 -C 6 -alkoxy, C 1 -C 6 -alkylthio, C 1 -C 6 -Alkyl and aryl, especially phenyl, or heterocyclylmethyl
  • the heterocyclyl is a heterocyclic group having 1 or 2 (preferably 1) selected from nitrogen, oxygen, and sulfur Unsaturated or saturated
  • the aforementioned halogen (atom) is preferably F, Cl, Br, I, especially F, Cl, Br, especially F, Cl.
  • R 3 is particularly preferably C 1 -C 4 -alkyl, C 3 -C 6 -cycloalkyl, benzyl or phenylethyl, in each case the group can be optionally taken from 1 to 5 (preferably 1-3 substitution, particularly preferably mono- or di-substituted), wherein suitable substituents are OH, Cl, Br, F, C 1 -C 4 -alkoxy, C 1 -C 4 -alkylthio, C 1 -C 4 -Alkyl and aryl, especially phenyl; or heterocyclylmethyl, wherein said heterocyclyl is especially furyl, tetrahydrofuryl, thienyl or pyridyl.
  • the compound of formula (VIII) is known, and is either commercially available or easily prepared by known methods.
  • the aforementioned halogenating agent also includes (Group B): reactive non-metal halides and reactive non-metal oxyhalides.
  • Group B reactive non-metal halides and reactive non-metal oxyhalides.
  • Hal is chlorine
  • oxalyl chloride, phosphorus trichloride, phosphorus pentachloride, phosphorus oxychloride, sulfur dichloride, thionyl chloride, and sulfonyl chloride are preferred, and phosphorus trichloride and phosphorus pentachloride are particularly preferred.
  • Phosphorus oxychloride, thionyl chloride, sulfonyl chloride and oxalyl chloride very particularly preferred are thionyl chloride, sulfonyl chloride, phosphorus oxychloride and oxalyl chloride.
  • Hal is bromine
  • phosphorus tribromide, phosphorus pentabromide, and phosphorus oxybromide are preferred.
  • Compounds of group B are known compounds, which themselves are commercially available or prepared by known methods.
  • Step (c) can optionally be carried out in the presence of a diluent.
  • suitable diluents are organic solvents, polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol or isobutanol, and polar aprotic solvents , Such as acetone, acetonitrile and acetate (such as ethyl acetate), ethers and cyclic ethers such as diethyl ether, diisobutyl ether, THF, dioxane, or non-polar aprotic solvents such as hydrocarbons , Such as benzene, toluene or xylene, halogenated hydrocarbons such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene or o-dichlorobenzene.
  • polar protic solvents such as methanol, ethanol, n-propanol, isopropanol, n-butanol or is
  • suitable diluents are polar protic solvents such as alcohols or carboxylic acids. Particularly suitable are alcohols, especially methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol.
  • Suitable diluents are ethers, such as dibutyl ether, THF, dioxane, ethylene glycol dimethyl ether or diglyme, and hydrocarbons, such as benzene, toluene or xylene, halogenated hydrocarbons , Such as dichloromethane, chloroform, carbon tetrachloride, chlorobenzene or o-dichlorobenzene, nitriles such as acetonitrile, carboxylic acid esters such as ethyl acetate or ketones such as acetone or methyl isopropyl ketone.
  • Mixtures of said diluents can also be used.
  • Step (c) is usually carried out at a temperature of 0°C to 200°C, preferably 50°C to 150°C, more preferably 80 to 110°C.
  • the reaction time is between 1 to 30 hours, 3 to 30 hours, 8 to 30 hours, 8 to 20 hours or 8 to 15 hours.
  • Step (c) is preferably carried out under atmospheric pressure, especially for low-boiling diluents, optionally under elevated pressure.
  • the molar ratio of hydrogen halide or compound of formula (VIII) or compound of group B to the starting compound of formula (V) is usually 0.5:1 to 10:1, preferably 1:1 to 5:1.
  • the reaction is generally carried out by heating the starting material of formula (V) with hydrogen halide or a compound of formula (VIII) or a compound of group B, optionally in a diluent and optionally in a solvent, to the desired temperature. It is also possible to continuously meter in the hydrogen halide or the compound of formula (VIII) or the compound of group B during the reaction.
  • water or alkali is optionally added to adjust the pH value, and the mixture is optionally evaporated and concentrated, and the final product is separated by, for example, filtration or extraction.
  • This step is preferably carried out in a diluent.
  • a diluent is alcohols, especially methanol, ethanol, propanol, isopropanol, isobutanol, n-butanol, sec-butanol.
  • the reaction mixture can also be subjected to anhydrous post-treatment by the following method: when the reaction is complete, the diluent and, if appropriate, the solvent are distilled, and the remaining residue is extracted with a suitable extractant.
  • suitable extractants are in principle all solvents in which the final product is inert and the final product is sufficiently soluble in it.
  • Examples thereof include aliphatic hydrocarbons such as n-pentane, n-hexane, cyclohexane, halogenated aliphatic hydrocarbons such as methylene chloride or chloroform, aromatic hydrocarbons such as benzene, toluene or xylene, halogenated aromatic hydrocarbons, For example, chlorobenzene or o-dichlorobenzene, or ethers, such as methyl tert-butyl ether.
  • the resulting product crystallizes, optionally after evaporating and concentrating the extractant, and can be separated by filtration, or the extractant is completely or substantially completely removed, and if necessary, the residue is purified, for example, by recrystallization.
  • step (d) the rearrangement reaction is Arbuzov rearrangement reaction.
  • This reaction is also called the Michaelis-Arbuzov reaction.
  • the method for realizing this rearrangement reaction is well known to those skilled in the art, for example, it can be realized by adding iodine.
  • the reaction temperature is 60-200°C, preferably 80-150°C.
  • the reaction is carried out under the catalysis of Lewis acid.
  • the reaction temperature is 20-200°C.
  • the present invention further provides a method for preparing glufosinate-ammonium.
  • the compound of formula (I) is prepared according to the aforementioned method.
  • the compound of formula (I) and diethyl methyl phosphite undergo an Arbuzov rearrangement reaction, and then undergo a hydrolysis reaction to obtain grass.
  • the aforementioned hydrolysis reaction is carried out in the presence of an acid or a base.
  • the invention provides a preparation method for preparing hydantoin intermediates and their analogs.
  • the hydantoin intermediates and their analogs are used in the synthesis of glufosinate-ammonium, which can solve the problem of high cost and low efficiency in the prior art.
  • the problem is a method with a greater cost advantage.
  • 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.
  • amino protecting group refers to a group that can be attached to a nitrogen atom on an amino group 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:
  • 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 ee value of the raw material L-homoserine is 95% or more.
  • the product structure analysis data is as follows:
  • the product structure analysis data is as follows:
  • the product structure analysis data is as follows:
  • Method 1 Add diethyl methylphosphonite (20.5g, 150.1mmol), 5-(2-chloroethyl)imidazolidine-2,4-dione (20.3g, 125mmol), chlorine into a 250mL three-necked flask Benzene was 20mL, replaced with argon three times, stirred, heated to 140°C and reacted for 20h. After the solvent and unreacted raw materials were removed under reduced pressure, 23.1g of pale yellow viscous liquid was obtained, the yield was 79%, and the HPLC purity was 96%.
  • Method 2 Add diethyl methylphosphonite (20.5g, 150.1mmol), 5-(2-chloroethyl)imidazolidine-2,4-dione 3 (20.3g, 125mmol), Tetrabutylammonium bromide (2.1g, 6.25mmol), chlorobenzene 20mL, argon replacement three times, stirring, warming to 140°C and reacting for 8h, removing solvent and unreacted raw materials under reduced pressure to obtain a pale yellow viscous liquid 24.0g, yield 82%, HPLC purity 96.5%.
  • Example 8 The product obtained in Example 8 (24g, 102.5mmol), 36% HCl (40mL) was added to the sealed tube, and the temperature was raised to 130°C to react for 40h. The solvent was removed under reduced pressure to obtain a pale yellow viscous liquid, and ethanol (20mL) was added at room temperature. After stirring for 3 hours, a large amount of white solid appeared, filtered with suction, washed with ethanol (20 mL x 3), and dried to obtain 17.6 g of glufosinate-ammonium with a yield of 95% and an HPLC purity of 98.7%.
  • Example 9 Add the product obtained in Example 9 (24 g, 102.5 mmol), 100 mL of water, and Ba(OH) 2 ⁇ 8H 2 O (31.6 g, 100 mmol) into a 250 mL three-necked flask, and heat to reflux for 30 h. Add H 2 SO 4 to adjust the pH value to 5-6, filter, adjust the pH value of the filtrate to 12 with ammonia water, and add methanol to recrystallize the filtrate. After drying, 17.8 g of glufosinate-ammonium was obtained, the yield was 96%, and the HPLC purity was 98.5%.
  • the present invention is not limited to the foregoing specific embodiments.
  • the present invention extends to any new feature or any new combination disclosed in this specification, and any new method or process step or any new combination disclosed.

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Abstract

本发明涉及制备草铵膦海因中间体及其类似物的方法，使用式（II）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与式（III）化合物反应，得到式（IV）化合物；式（IV）化合物分子内缩合得到式（V）化合物；式（V）化合物与卤化剂反应，得到式（I）化合物。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与式（VII）化合物经重排反应，转化为式（VI）化合物。将本发明涉及的海因中间体及其类似物用于草铵膦的合成，可解决现有技术中成本较高、效率较低等问题，是一种具备较大成本优势的方法。

Description

制备草铵膦海因中间体及类似物的方法 技术领域
本发明涉及制备草铵膦海因中间体及类似物的方法。
背景技术
草铵膦是由赫斯特公司于80年代开发成功的一种广谱有机磷触杀型除草剂，草铵膦是一种谷氨酰胺合成抑制剂，其内吸作用不强，与早期的草甘膦杀根不同，草铵膦先杀叶，再通过植物蒸腾作用可以在植物木质部进行传导，其速效性间于百草枯和草甘膦之间，是一种非选择性触杀除草剂。现有技术中，草铵膦的制备方法，普遍存在反应繁琐、效率较低和生产成本偏高的问题。
发明内容
本发明提供了一种制备式(I)草铵膦海因中间体及其类似物的方法：
Figure PCTCN2020118013-appb-000001
或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物，所述方法包括以下步骤：
(a)使式(II)化合物
Figure PCTCN2020118013-appb-000002
或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其L-构型的对映异构体，与式(III)化合物
Figure PCTCN2020118013-appb-000003
反应得到式(IV)化合物
Figure PCTCN2020118013-appb-000004
或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物；
(b)使所得式(IV)化合物分子内缩合得到式(V)化合物
Figure PCTCN2020118013-appb-000005
或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物；
(c)使所得(V)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与卤化剂反应，得到式(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；
其中：
Hal为卤素原子；
X为O或S；
Y为O或S；
R 1为氢或氨基保护基；
R 2为氢、C 1-C 4烷基或苄基。
本发明进一步提供了一种制备式(VI)草铵膦海因中间体及其类似物的方法：
Figure PCTCN2020118013-appb-000006
或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物，其特征在于：所述方法包括以下步骤：
前述方法得到式(I)化合物
Figure PCTCN2020118013-appb-000007
或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物
(d)使所得(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，脱去氨基保护基或不脱去氨基保护，与式(VII)化合物
Figure PCTCN2020118013-appb-000008
经重排反应，转化为式(VI)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；
其中：
Hal为卤素原子；
Y为O或S；
R 1为氢或氨基保护基；
R 2为氢、C 1-C 4烷基或苄基；
R 3为R 6或R 7；
R 4为烷基或芳香基；
R 5为氢或R 1；
R 6和R 7各自独立地为氢、烷基、烯基或芳香基。
进一步地，所述X为O，R 1为氢。
进一步地，所述Y为O，R 2为氢。
进一步地，所述R 4为C 1-C 6烷基。
进一步地，所述R 4为甲基。
进一步地，所述R 6和R 7各自独立的为C 1-C 6烷基。
进一步地，所述R 4为乙基，R 6为乙基，R 7为乙基。
进一步地，Hal为氯、溴或碘，优选氯或溴。
进一步地，步骤(a)中，所述反应的温度为80～120℃，优选90～110℃。步骤(a)中，反应时间在1至30小时、3至30小时、5至30小时、5至20小时或5至10小时之间进行。通过在该温度范围和时间范围内进行步骤(a)反应，可以更容易地制备式(IV)化合物。
进一步地，步骤(a)中，所述反应在溶剂中进行，所述溶剂选自水或极性有机溶剂。
进一步地，步骤(b)中，所述酸为盐酸、硝酸、硫酸、乙酸中的任一种或它们的混合物。
进一步地，所述步骤(b)在60～120℃下进行。
进一步地，所述步骤(b)在水或有机溶剂中进行。
进一步地，所述步骤(a)和步骤(b)是一锅法，即通过步骤(a)制备得到的式(IV)化合物无需从反应介质中分离而直接参与步骤(b)。
本发明步骤(c)的方法是通过将式(V)化合物与卤化剂例如卤化氢或者与能和质子溶剂、特别是和醇或羧酸产生卤化氢的化合物反应来进行的。
尤其当Hal为氯或溴时，前述卤化剂包括例如酰卤，特别是式(VIII)化合物(A组)：
Figure PCTCN2020118013-appb-000009
其中R 8是烷基、环烷基、芳基、芳基烷基或杂环基烷基，每种情况下所述基团可以任选地被取代。R 8优选为C 1-C 10-烷基、C 3-C 10-环烷基、芳基-C 1-C 4-烷基，特别是苯基-C 1-C 4-烷基，每种情况下所述基团可以任选地单取代或多取代，其中合适的取代基是OH、SH、卤素、C 1-C 6-烷氧基、C 1-C 6-烷硫基、C 1-C 6-烷基和芳基、特别是苯基，或者是杂环基甲基，其中所述杂环基是具有1或2个(优选1个)选自氮、氧、硫的杂原子的不饱和或饱和5-元或6-元杂环，特别是呋喃基、四氢呋喃基、噻吩基或吡啶基。
前述卤素(原子)优选为F、Cl、Br、I，特别是F、Cl、Br，尤其是F、Cl。R 3特别优选为C 1-C 4-烷基、C 3-C 6-环烷基、苄基或苯基乙基，每种情况下所述基团可以任选地1-5取(优选1-3取代，特别优选单取代或二取代)，其中合适的取代基是OH、Cl、Br、F、C 1-C 4-烷氧基、C 1-C 4-烷硫基、C 1-C 4-烷基和芳基、特别是苯基；或者是杂环基甲基，其中所述杂环基特别是呋喃基、四氢呋喃基、噻吩基或吡啶基。
式(VIII)化合物是已知的，并且可商购获得或者易于通过已知方法制得。
前述卤化剂还包括(B组)：反应性非金属卤化物以及反应性非金属卤氧化物。例如，当Hal为氯时，优选草酰氯、三氯化磷、五氯化磷、三氯氧磷、二氯化硫、亚硫酰氯和磺酰氯，特别优选三氯化磷、五氯化磷、三氯氧磷、亚硫酰氯、磺酰氯和草酰氯，非常特别优选亚硫酰氯、磺酰氯、三氯氧磷和草酰氯。例如，当Hal为溴时，优选三溴化磷、五溴化磷和三溴氧磷。
B组化合物是已知化合物，其本身可商购获得或者通过已知方法制得。
步骤(c)可任选在稀释剂存在下进行。
当使用卤化氢，尤其是氯化氢时，合适的稀释剂是有机溶剂，极性质子溶剂，例如甲醇、乙醇、正丙醇、异丙醇、正丁醇或异丁醇，以及极性非质子溶剂，例如丙酮、乙腈和乙酸酯(例如乙酸乙酯)，醚和环状醚，例如乙醚、二异丁基醚、THF、二氧杂环己烷，或非极性非质子溶剂，例如烃，如苯、甲苯或二甲苯，卤代烃，例如二氯甲烷、氯仿、四氯化碳、氯苯或邻二氯苯。
当使用(A)或(B)组化合物时，合适的稀释剂是极性质子溶剂，例如醇或羧酸。特别合适的是醇，特别是甲醇、乙醇、正丙醇、异丙醇、正丁醇、异丁醇。
向反应混合物中加入另一稀释剂可能是有利的。合适的稀释剂是醚，例如二丁基醚、THF、二氧杂环己烷、乙二醇二甲醚或二甘醇二甲醚，和烃，例如苯、甲苯或二甲苯，卤代烃，例如二氯甲烷、氯仿、四氯化碳、氯苯或邻二氯苯，腈，例如乙腈，羧酸酯，例如乙酸乙酯或酮，例如丙酮或甲基异丙基酮。
还可以使用所述稀释剂的混合物。
步骤(c)通常在0℃-200℃温度下进行，优选50℃-150℃，更优选80～110℃。步骤(c)中，反应时间在1至30小时、3至30小时、8至30小时、8至20小时或8至15小时之间进行。通过在该温度范围和时间范围内进行步骤(c)反应，可以更容易地制备式(I)化合物。
步骤(c)优选在大气压下进行，特别是对于低沸点稀释剂，还可任选在升压下进行。
在使用时，卤化氢或式(VIII)化合物或B组化合物与式(V)原料化合物的摩尔比通常为0.5∶1至10∶1、优选1∶1至5∶1。
该反应一般通过将式(V)原料与卤化氢或式(VIII)化合物或B组化合物，任选在稀释剂以及任选在溶剂中加热至所需温度来进行。在反应期间还可以连续地计量加入卤化氢或式(VIII)化合物或B组化合物。
为了进行后处理，冷却后，任选加入水或碱调pH值，任选将混合物蒸发浓缩后，通过例如过滤或萃取分离出终产物。
该步骤优选在稀释剂中进行，当将该反应混合物冷却时，可直接将终产物结晶，并以简单方法分离，例如通过过滤分离。对于此，合适的稀释剂是醇，特别是甲醇、乙醇、丙醇、异丙醇、异丁醇、正丁醇、仲丁醇。
还可以通过下述方法对反应混合物进行无水后处理：当反应完时，适当的话将稀释剂和适当的话将溶剂蒸馏，并用合适的萃取剂萃取剩余的残余物。合适的萃取剂原则上是对于终产物呈惰性、并且终产物足以溶于其中的所有溶剂。
其实例包括脂族烃，例如正戊烷、正己烷、环己烷，卤代脂族烃，例如二氯甲烷或氯仿，芳族烃，例如苯、甲苯或二甲苯，卤代芳族烃，例如氯苯或邻二氯苯，或醚，例如甲基叔丁基醚。
所得产物结晶出来，任选在将萃取剂蒸发浓缩后结晶出来，并可以通过过滤分离，或者将萃取剂完全或基本上完全除去，并且如果需要的话，纯化残余物，例如通过重结晶纯化。
步骤(d)中，所述重排反应为Arbuzov重排反应。该反应也称Michaelis-Arbuzov反应。该重排反应的实现方法对于本领域技术人员是公知的，例如可以通过加入碘单质而实现。
进一步的，所述步骤(d)中，反应的温度为60～200℃，优选80～150℃。
进一步的，所述步骤(d)中，反应在路易斯酸的催化下进行。
进一步的，所述步骤(d)中，反应的温度为20～200℃。
本发明进一步提供了一种草铵膦的制备方法，按照前述方法制备得到式(I)化合物，式(I)化合物与甲基亚磷酸二乙酯发生Arbuzov重排反应，再经过水解反应得草铵膦。
前述水解反应在酸或碱的存在下进行。
本发明提供了制备海因中间体及其类似物的制备方法，所涉及的海因中间体及其类似物用于草铵膦的合成，可解决现有技术中成本较高、效率较低等问题，是一种具备较大成本优势的方法。
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。
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。
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。
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。
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：
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。
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。
具体实施方式
本说明书中公开的所有特征，或公开的所有方法或过程中的步骤，除了互相排斥的特征和/或步骤以外，均可以以任何方式组合。
本说明书中公开的任一特征，除非特别叙述，均可被其他等效或具有类似目的的替代特征加以替换。即除非特别叙述，每个特征只是一系列等效或类似特征中的一个例子而已。
下面结合实施例对本发明绿草定丁氧基乙酯？？？的制备方法作进一步的说明。
原料L-高丝氨酸的ee值为95％以上。
实施例1
Figure PCTCN2020118013-appb-000010
在500mL三口瓶中，加入L-高丝氨酸(140g，1.18mol)，尿素(106g，1.76mol)，水(250mL)，加热升至内温100℃反应8h，冷却至室温，将水旋干后，用甲醇(100mL)打浆，甲醇洗三次(50mL x 3)，烘干，得到白色晶体4-羟基-2-脲基丁酸181.7g，收率95％，HPLC纯度96％，检测其为外消旋混合物。
产物结构分析数据如下：MS(ESI)：m/z[M+H] +calcd for C 5H 11N 2O 4：163.06；found：163.1.
实施例2
Figure PCTCN2020118013-appb-000011
在250mL三口瓶中，加入实施例1制备得到的4-羟基-2-脲基丁酸(28g，172.7mmol)，18％HCl(57.6mL，345.4mmol)，加热搅拌升温至内温90℃反应6h，冷却至室温，将水旋干后得到白色固体，用乙醇(100mL x 3)洗白色固体，烘干，得到白色固体5-(2-羟基乙基)咪唑烷-2，4-二酮24g，收率97％，HPLC纯度97％，检测其为外消旋混合物。
产物结构分析数据如下：
MS(ESI)：m/z[M+H] +calcd for C 5H 9N 2O 3：145.06；found：146.3.
1H NMR(D 2O，400MHz)δ：4.22(dd，J＝8.0，4.0Hz，1H)，3.72-3.50(m，2H)，1.97(dtd，J＝14.4，6.0，4.8Hz，1H)，1.87(dtd，J＝14.4，7.2，6.0Hz，1H).
13C NMR(D 2O，100MHz)δ：179.0，159.3，57.4，56.2，32.7.
实施例3
Figure PCTCN2020118013-appb-000012
在250mL三口瓶中，加入实施例1制备得到的4-羟基-2-脲基丁酸(28g，172.7mmol)，18％H 2SO 4(57.6mL，345.4mmol)，加热搅拌升温至内温100℃反应4h，冷却至室温，旋掉一部分水后，降至0℃下冷却结晶，用乙醇(50mL x 3)洗白色固体，烘干，得到白色固体5-(2-羟基乙基)咪唑烷-2，4-二酮23.6g，收率95％，HPLC纯度99％，检测其为外消旋混合物。
实施例4
Figure PCTCN2020118013-appb-000013
在250mL三口瓶中，加入实施例1制备得到的4-羟基-2-脲基丁酸(28g，172.7mmol)，CH 3COOH(50mL)，加热搅拌升温至内温80℃反应8h，冷却至室温，旋干CH 3COOH后得白色固体，用乙醇(50mL x 3)洗白色固体，烘干，得到白色固体5-(2-羟基乙基) 咪唑烷-2，4-二酮22.4g，收率90％，HPLC纯度95％，检测其为外消旋混合物。
实施例5
Figure PCTCN2020118013-appb-000014
在500mL三口瓶中，加入L-高丝氨酸(140g，1.18mol)，尿素(85.5g，1.42mol)，水(250mL)，加热升至内温100℃反应8h，MS检测原料消失，冷却至室温下，滴加36％HCl(200mL，2.36mol)，加热搅拌升温至内温90℃反应6h，冷却至室温，将水旋干后得到白色固体，用乙醇(150mL x 3)洗白色固体，烘干，得到白色固体5-(2-羟基乙基)咪唑烷-2，4-二酮163.2g，收率96％，HPLC纯度97.5％，检测其为外消旋混合物。
实施例6
Figure PCTCN2020118013-appb-000015
在250mL封管中，加入5-(2-羟基乙基)咪唑烷-2，4-二酮(12g，83.2mmol)，48％氢溴酸乙酸溶液(34mL，50g，300mmol)，密闭封压，90℃下反应10h，自然冷却至室温，将反应体系中的溶剂旋干后，用乙酸乙酯重结晶抽滤，烘干，得到白色固体产物5-(2-溴乙基)咪唑烷-2，4-二酮14.6g，收率85％，HPLC纯度96.5％。
实施例7
Figure PCTCN2020118013-appb-000016
在250mL封管中，加入5-(2-羟基乙基)咪唑烷-2，4-二酮(20g，138.8mmol)，36％盐酸(56.3g，555mmol)，密闭封压，100℃下反应10h，自然冷却至室温，将反应体系中的溶剂旋干后，用乙酸乙酯重结晶，抽滤，烘干，得到白色固体产物5-(2-氯乙基)咪唑烷-2，4-二酮20.3g，收率90％，HPLC纯度98％。
产物结构分析数据如下：
1H NMR(DMSO-d6，400MHz)δ：10.69(s，1H)，8.05(s，1H)，4.19-4.11(m，1H)，3.92-3.65(m，2H)，2.16(dtd，J＝14.8，7.6，4.8Hz，1H)，2.01(ddt，J＝14.4，8.4，6.0Hz，1H).
实施例8
Figure PCTCN2020118013-appb-000017
在250mL三口瓶加入甲基亚膦酸二乙酯(20.5g，150.1mmol)、5-(2-溴乙基)咪唑烷-2，4-二酮(25.7g，125mmol)、甲苯20mL，氩气置换三次，搅拌，升温至100℃反应5h，减压脱溶除去溶剂及未反应完原料后得淡黄色黏稠状液体25.2g，收率86.0％，HPLC纯度97％。
产物结构分析数据如下：
1H NMR(DMSO-d6，400MHz)δ：1.20(t，J＝7.0Hz，3H)，1.40(d，J＝13.7Hz，3H)，1.64(dq，J＝15.2，7.6Hz，4H)，3.93-3.89(m，2H)，4.07(t，J＝5.6Hz，1H)，8.05(s，1H)，10.75(s，1H).
实施例9
Figure PCTCN2020118013-appb-000018
方法一：在250mL三口瓶加入甲基亚膦酸二乙酯(20.5g，150.1mmol)、5-(2-氯乙基)咪唑烷-2，4-二酮(20.3g，125mmol)、氯苯20mL，氩气置换三次，搅拌，升温至140℃反应20h，减压脱溶除去溶剂及未反应完原料后得淡黄色黏稠状液体23.1g，收率79％，HPLC纯度96％。
方法二：在250mL三口瓶加入甲基亚膦酸二乙酯(20.5g，150.1mmol)、5-(2-氯乙基)咪唑烷-2，4-二酮3(20.3g，125mmol)、四丁基溴化铵(2.1g，6.25mmol)，氯苯20mL，氩气置换三次，搅拌，升温至140℃反应8h，减压脱溶除去溶剂及未反应完原料后得淡黄色黏稠状液体24.0g，收率82％，HPLC纯度96.5％。
实施例10
Figure PCTCN2020118013-appb-000019
在封管中加入实施例8所得产物(24g，102.5mmol)，36％HCl(40mL)，升温至130℃下反应40h，减压脱溶得到淡黄色粘稠液体，加入乙醇(20mL)室温下搅拌3h，出现大量白色固体，抽滤，用乙醇洗涤(20mL x 3)，烘干，得到草铵膦17.6g，收率95％，HPLC纯度98.7％。
实施例11
Figure PCTCN2020118013-appb-000020
在250mL三口瓶中加入实施例9所得产物(24g，102.5mmol)，水100mL，Ba(OH) 2·8H 2O(31.6g，100mmol)，加热回流30h。加入H 2SO 4调节pH值至5～6，过滤，滤液用氨水调节pH值至12，旋蒸脱溶后加入甲醇重结晶。烘干，得到草铵膦17.8g，收率96％，HPLC纯度98.5％。
本发明并不局限于前述的具体实施方式。本发明扩展到任何在本说明书中披露的新特征或任何新的组合，以及披露的任一新的方法或过程的步骤或任何新的组合。

Claims (11)

  1. 一种制备式(I)草铵膦海因中间体及其类似物的方法：
    Figure PCTCN2020118013-appb-100001
    或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物，其特征在于：所述方法包括以下步骤：
    (a)使式(II)化合物
    Figure PCTCN2020118013-appb-100002
    或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其L-构型的对映异构体，与式(III)化合物
    Figure PCTCN2020118013-appb-100003
    反应得到式(IV)化合物
    Figure PCTCN2020118013-appb-100004
    或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物；
    (b)使所得式(IV)化合物分子内缩合得到式(V)化合物
    Figure PCTCN2020118013-appb-100005
    或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物；
    (c)使所得(V)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与卤化剂反应，得到式(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；
    其中：
    Hal为卤素原子；
    X为O或S；
    Y为O或S；
    R 1为氢或氨基保护基；
    R 2为氢、C 1-C 4烷基或苄基。
  2. 一种制备式(VI)草铵膦海因中间体及其类似物的方法：
    Figure PCTCN2020118013-appb-100006
    或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物，其特征在于：所述方法包括以下步骤：
    按照权利要求1所述方法得到式(I)化合物
    Figure PCTCN2020118013-appb-100007
    或其盐、对映异构体或所有比例的对映异构体的混合物，特别是其对映异构体的混合物，特别尤其是其外消旋混合物
    (d)使所得(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，脱去氨基保护基或不脱去氨基保护，与式(VII)化合物
    Figure PCTCN2020118013-appb-100008
    经重排反应，转化为式(VI)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；
    其中：
    Hal为卤素原子；
    Y为O或S；
    R 1为氢或氨基保护基；
    R 2为氢、C 1-C 4烷基或苄基；
    R 3为R 6或R 7；
    R 4为烷基或芳香基；
    R 5为氢或R 1；
    R 6和R 7各自独立地为氢、烷基、烯基或芳香基。
  3. 根据权利要求1或2所述的方法，其特征在于：所述X为O，R 1为氢，Y为O，R 2为氢。
  4. 根据权利要求2所述的方法，其特征在于：
    所述R 4为C 1-C 6烷基，优选甲基；和/或，
    所述R 6为C 1-C 6烷基，优选乙基；和/或，
    所述R 7为为C 1-C 6烷基，优选乙基。
  5. 根据权利要求1或2所述的方法，其特征在于：Hal为氯、溴或碘。
  6. 根据权利要求1或2所述的方法，其特征在于：所述步骤(a)中，
    反应的温度为80～120℃；和/或，
    反应在溶剂中进行，所述溶剂选自水或极性有机溶剂。
  7. 根据权利要求1或2所述的方法，其特征在于：所述步骤(b)中，在下列任一条件或下列条件的任何组合下进行：
    酸为盐酸、硝酸、硫酸、乙酸中的任一种或它们的混合物；和，
    步骤(b)在60～120℃下进行；和，
    步骤(b)在水或有机溶剂中进行。
  8. 根据权利要求1或2所述的方法，其特征在于：所述步骤(a)和步骤(b)是一锅法。
  9. 根据权利要求1或2所述的方法，其特征在于：所述步骤(c)中，
    卤化剂为氢卤酸；和/或，
    反应在50～150℃下进行。
  10. 根据权利要求2所述的方法，其特征在于：所述步骤(d)中，在下列任一条件或下列条件的任何组合下进行：
    重排反应为Arbuzov重排反应；和，
    反应的温度为60～200℃；和，
    反应在路易斯酸的催化下进行。
  11. 根据权利要求10所述的方法，其特征在于：所述步骤(d)中，反应在路易斯酸 的催化下进行，反应的温度为20～200℃。
PCT/CN2020/118013 2019-09-29 2020-09-27 制备草铵膦海因中间体及类似物的方法 WO2021057945A1 (zh)

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