WO2022188627A1 - 制备次膦酸酯的方法以及装置系统 - Google Patents

制备次膦酸酯的方法以及装置系统 Download PDF

Info

Publication number
WO2022188627A1
WO2022188627A1 PCT/CN2022/077305 CN2022077305W WO2022188627A1 WO 2022188627 A1 WO2022188627 A1 WO 2022188627A1 CN 2022077305 W CN2022077305 W CN 2022077305W WO 2022188627 A1 WO2022188627 A1 WO 2022188627A1
Authority
WO
WIPO (PCT)
Prior art keywords
formula
substituted
reactor
unsubstituted
reaction
Prior art date
Application number
PCT/CN2022/077305
Other languages
English (en)
French (fr)
Inventor
王欣
徐敏
左翔
程柯
Original Assignee
利尔化学股份有限公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 利尔化学股份有限公司 filed Critical 利尔化学股份有限公司
Priority to CN202280015949.1A priority Critical patent/CN116867794A/zh
Publication of WO2022188627A1 publication Critical patent/WO2022188627A1/zh

Links

Classifications

    • 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

Definitions

  • the present invention relates to methods and apparatus systems for preparing phosphinates.
  • Phosphinate is an important pharmaceutical and pesticide intermediate.
  • the preparation of phosphinate is usually carried out by reacting 1 mol of hydrocarbyl phosphine dichloride with more than 2 mol of alcohol, referring to the following reaction equation:
  • the inventors have surprisingly found that, by introducing water into the above reaction system, not only the desired product phosphinate can be prepared, but also the amount of alcohol used can be reduced, and the amount of by-product chlorinated hydrocarbons can be reduced or even eliminated by-products
  • the product is chlorinated hydrocarbon, which reduces the complexity of separation and purification steps and is environmentally friendly.
  • a method for the preparation of a phosphinate of formula (I) comprising the steps in the following sequence:
  • R 1 and R 2 are each independently selected from substituted or unsubstituted hydrocarbon groups, for example, substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl and substituted or unsubstituted aralkyl.
  • a device system for preparing the phosphinate of formula (I) characterized in that the device system comprises a storage tank of the compound of formula (II), a storage tank of the compound of formula (III) an alcohol storage tank, a water storage tank, a first reactor, a second reactor and an optional collection tank for the phosphinate of formula (I);
  • the definitions of groups R 1 and R 2 are the same as in the first aspect; the first reactor is used for the reaction of the compound of formula (II) with water, and the second reactor is used in the first reactor
  • the discharged reaction mixture is reacted with the alcohol of the formula (III); the storage tank of the compound of the formula (II) and the water storage tank are respectively fluidly connected to the first reactor through pipelines; the formula (III)
  • the storage tank of the alcohol of ) is fluidly connected to the second reactor by a pipeline, and the collection tank of the phosphinate of formula (I) is fluidly connected to the outlet of the second reactor.
  • the amount of alcohol used in the preparation of phosphinate can be reduced, the by-product chlorinated hydrocarbons can be reduced or eliminated, and the complexity of the process can be reduced, high yield and high product purity can be achieved, and the Environment friendly.
  • the verification and determination of target products and/or by-products can be performed according to conventional methods in the art, for example, gas chromatography, gas mass spectrometry, liquid mass spectrometry and the like can be used.
  • the target product refers to a phosphinate having the structure of formula (I).
  • a method for the preparation of a phosphinate of formula (I) comprising the steps of the following sequence:
  • the groups R 1 and R 2 are not particularly limited, as long as the reaction of the present invention can be carried out, specific groups of R 1 and R 2 can be selected as required, such as substituted or unsubstituted hydrocarbon groups, preferably, the said Hydrocarbyl groups do not contain ethylenic unsaturation.
  • the groups R1 and R2 are each independently selected from substituted or unsubstituted alkyl, substituted or unsubstituted aryl, substituted or unsubstituted cycloalkyl, substituted or unsubstituted alkaryl, and substituted or unsubstituted Unsubstituted aralkyl.
  • R 1 and R 2 are each independently selected from substituted or unsubstituted C 1 -C 6 alkyl (eg C 1 -C 5 alkyl, C 1 -C 4 alkyl, C 1 -C 3 alkyl ), substituted or unsubstituted C 6 -C 12 aryl (eg C 6 -C 11 aryl, C 6 -C 10 aryl, C 6 -C 9 aryl, C 6 -C 8 aryl), substituted or unsubstituted C 3 -C 10 cycloalkyl (e.g.
  • C 7 -C 12 alkaryl eg C 7 -C 11 alkaryl, C 7 -C 10 alkaryl
  • R 1 and R 2 are each independently selected from methyl, ethyl, propyl, butyl, pentyl, hexyl, phenyl, benzyl, phenethyl, phenylpropyl, methylphenyl , ethyl phenyl, propyl phenyl.
  • R 1 is selected from methyl and ethyl and R 2 is selected from methyl, ethyl, propyl and butyl.
  • R1 is methyl and R2 is methyl, ethyl, propyl or butyl.
  • the amounts of the three reactants can be selected such that the final product can be obtained in the desired yield.
  • the molar ratio of the compound of formula (II) to water is greater than 1:2, preferably greater than or equal to 1:1, for example, can be 1:(0.01-1.5), 1:1: (0.1-1), 1:(0.2-1), 1:(0.3-1), 1:(0.4-1), 1:(0.5-1), 1:(0.6-1), 1:(0.7 -1), 1:(0.8-1), 1:(0.9-1), preferably 1:0.8, 1:0.9 and 1:1, most preferably 1:1.
  • step (a) the mixing manner and order of the compound of formula (II) and water are not particularly limited.
  • Conventional mixing methods in the art, such as stirring, can be used.
  • the mixing sequence can be, for example, adding water to the compound of formula (II), or adding the compound of formula (II) to water, as long as the final mixing ratio of the two falls within the above-mentioned range. Water is preferably added to the compound of formula (II).
  • the molar ratio of the amount of alcohol of formula (III) to the amount of compound of formula (II) in step (a) is greater than or equal to 1:1, for example, (1-10) :1, (1-8):1, (1-6):1, (1-5):1, (1-4):1, (1-3):1, (1-2):1 , (1-1.5):1, (1-1.2):1, (1-1.1):1, 1:1, preferably, 1.9:1, 1.8:1, 1.7:1, 1.6:1, 1.4:1, 1.3:1, 1.2:1, 1.1:1, 1:1, most preferably 1:1.
  • step (b) the mixing manner and order of the reaction mixture obtained in step (a) and the alcohol of formula (III) are not particularly limited. Conventional mixing methods in the art, such as stirring, can be used.
  • the mixing sequence for example, the reaction mixture obtained in step (a) may be added to the alcohol of formula (III), or the alcohol of formula (III) may be added to the reaction mixture obtained in step (a), as long as the final mixing ratio falls within the above-mentioned range.
  • the "reaction mixture obtained in step (a)” refers to the total amount of all substances remaining in the reactor after the reaction, and the hydrogen chloride that has been discharged from the reactor in the form of gas is not included in the within the range of the reaction mixture.
  • the hydrogen chloride produced is not removed.
  • Do not remove the generated hydrogen chloride means that no technical means are artificially applied to remove the generated hydrogen chloride in step (a), but there may be gaseous hydrogen chloride that escapes naturally.
  • the reaction can be carried out at a temperature of -20°C to 100°C
  • the reaction of step (a) can be carried out at a temperature of -20°C to 100°C
  • step (b) ) can be carried out at a temperature of -20°C to 100°C
  • step (a) can be carried out at -15°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C
  • step (b) can be performed at -15°C, -10°C, 0°C, 10°C, 20°C, 30°C, 40°C, 50°C, 60°C , 70°C, 80°C, and 90°C.
  • reaction pressure there is no special requirement for the reaction pressure, and the reaction can be carried out under a pressure that naturally occurs during the reaction, such as atmospheric pressure, a slight negative pressure or a slight increase in pressure.
  • the reaction can be carried out in a solvent-free condition or in an inert solvent, preferably, the inert solvent is selected from one or more of benzene-based solvents, halogenated hydrocarbon-based solvents and ether-based solvents.
  • the benzene-based solvent can be selected from toluene, xylene, trimethylbenzene, o-dichlorobenzene, p-dichlorobenzene, m-dichlorobenzene, trichloro-substituted benzene, trimethyl-substituted benzene;
  • the halogenated hydrocarbon solvent Can be selected from chlorohexane, chloroheptane, chlorooctane, dichlorohexane, dichloroheptane, dichlorooctane, trichloroethylene, tetrachloroethylene, tribromopropane, trichloropropane; the ethers
  • the generated hydrogen chloride when carried out under solvent-free conditions, is not removed after the reaction is completed in step (a); when an inert solvent is used, the generated hydrogen chloride can be removed after the reaction is completed in step (a), or not The hydrogen chloride produced is removed.
  • the reaction can be carried out in any suitable reactor, such as a conventionally used column reactor, especially a packed column; a continuous flow reactor with an intermediate feeding point .
  • a conventionally used column reactor especially a packed column
  • a continuous flow reactor with an intermediate feeding point .
  • continuous flow reactor has the usual meaning in the art, specifically, as long as the reactor can achieve continuous entry of reactants and continuous discharge of reactants, it belongs to the continuous flow reactor within the scope of the present application.
  • step (a) the reaction of step (a) can be carried out in one reactor, and then the mixture reacted in step (a) is discharged and conveyed to the next reactor to react with formula (III) ) to react with alcohol.
  • step (a) can be reacted by feeding the compound of formula (II) with water in a specified ratio to a module of a continuous flow reactor, and then passing out the module
  • the reaction mixture of step (a) and the alcohol of formula (III) are fed into another module of the continuous reactor according to the prescribed ratio for reaction.
  • the method may further comprise the step of adding a base for neutralization, preferably, the base is selected from ammonia, aliphatic amines and aromatic amines, for example, three Ethylamine, ethylenediamine and aniline.
  • a base for neutralization preferably, the base is selected from ammonia, aliphatic amines and aromatic amines, for example, three Ethylamine, ethylenediamine and aniline.
  • the method of the present invention may also include other conventional phosphinate separation steps in the phosphinate preparation method, such as filtration, vacuum distillation, condensation, and the like.
  • the present invention also provides an apparatus system for preparing a phosphinate of formula (I), the apparatus system comprising a storage tank of a compound of formula (II), a compound of formula (III) an alcohol storage tank, a water storage tank, a first reactor, a second reactor and an optional collection tank for the phosphinate of formula (I);
  • the definitions of groups R 1 and R 2 are the same as in the first aspect; the first reactor is used for the reaction of the compound of formula (II) with water, and the second reactor is used in the first reactor
  • the discharged reaction mixture is reacted with the alcohol of the formula (III); the storage tank of the compound of the formula (II) and the water storage tank are respectively fluidly connected to the first reactor through pipelines, the formula (III)
  • the storage tank of the alcohol of ) is fluidly connected to the second reactor by a pipeline, and the collection tank of the phosphinate of formula (I) is fluidly connected to the outlet of the second reactor.
  • the first reactor and the second reactor are understood as containers that respectively contain reactants for the reaction in the order of reaction, and can be physically two different reactors or the same reactor. a reactor.
  • the first reactor and the second reactor are fluidly connected to each other by piping.
  • the reaction mixture of step (a) can be discharged to another vessel for temporary storage, and then added to the The reaction of step (b) is carried out in the reactor.
  • reaction mixture discharged from the first reactor has the same meaning as the aforementioned "reaction mixture obtained in step (a)".
  • the plant system may also include an alkali storage tank.
  • the connection point of the alkali storage tank in the device system is such that the alkali is connected into the device system through pipelines (for example, connected to a reactor or other container or pipeline) to neutralize the hydrogen chloride produced by the reaction and not affect the normal operation of the reaction. conduct.
  • pipelines for example, connected to a reactor or other container or pipeline
  • Fluidically connected means that fluid can flow from a vessel at one end of a pipeline to a vessel at the other end of the pipeline, where other devices such as flow meters, preheaters, pumps, condensers, etc. may be provided.
  • water storage tank can be understood as a container for storing water, and can also be understood as a water supply device connected to a water source.
  • the water source can be from municipal water supply, water purification equipment, etc.
  • the device system may further comprise filters, evaporators, condensers, vacuum pumps, etc. arranged downstream of the reactor for separating and purifying the phosphinate of formula (I).
  • the apparatus system of the present invention comprises a storage tank for the compound of formula (II), a storage tank for the alcohol of formula (III), a water storage tank, a first reactor and a second reactor.
  • the plant system of the present invention comprises a storage tank for the compound of formula (II), a storage tank for the alcohol of formula (III), a water storage tank, a first reactor, a second reactor, and a base storage tank Can.
  • the apparatus system of the present invention comprises a storage tank for the compound of formula (II), a storage tank for an alcohol of formula (III), a water storage tank, a first reactor, a second reactor, an alkali storage tank Tanks, filters, evaporators, condensers and vacuum pumps.
  • the apparatus system of the present invention comprises a storage tank for the compound of formula (II), a storage tank for the alcohol of formula (III), a water storage tank, a first reactor, a second reactor, a filter , evaporator, condenser and vacuum pump.
  • Heating gradient 80°C (0min), 20°C/min, 300°C (6min)
  • Needle washing solution A-ethanol, B-dichloromethane; B three times before injection, A and B three times after injection
  • sample content is calculated as 100%, take 100 ⁇ L sample, dissolve in 1.0mL dichloromethane
  • VWD Ultraviolet Detector
  • Detection wavelength 205nm, 215nm dual wavelength
  • Atomizing gas pressure 35psig
  • the content of the sample is calculated as 100%. First, the sample is prepared into a 1.0 mg/mL solution, and then 100 ⁇ L of the sample is diluted to 1.0 mL. Both the sample preparation solvent and the diluent (10% ACN ⁇ H 2 O) are used.
  • reaction mixture A1 In a 50mL three-necked flask, add 20g (0.169mol) of methyl phosphine dichloride (MDP), then cool down to -5°C, under stirring, dropwise add 3g (0.169mol) of H 2 O, while controlling the internal temperature At 0 °C, the dropwise addition was completed for 10 min, and then the mixture was kept at 0 °C and stirred for 1 h to stop the reaction to obtain a reaction mixture A1.
  • MDP methyl phosphine dichloride
  • Post-processing add triethylamine to the crude product B1, adjust the pH value to about 8, filter, remove the hydrochloride of triethylamine, wash the filter cake with dichloroethane, combine the organic phases, and concentrate to obtain a liquid,
  • the relative content of the product in the liquid after the post-treatment was detected by gas chromatography to be 96%, and the product yield was calculated to be 92% by multiplying it by the mass of the liquid. The results are shown in Table 1 below.
  • Example 1 change the process parameters according to the following table 1, carry out Examples 1a-1f, obtain the relative content of n-butyl methylphosphite in each crude product, the yield after the above-mentioned post-treatment And the relative content of n-butyl methylphosphinate in the processed product is shown in Table 1 (where eq is equivalent, and the following meanings are the same).
  • the reaction mixture A1 was obtained in the same method steps as in Example 1.
  • the reaction mixture A1 was cooled to -5°C, and under stirring, 12.5g (0.169mol) n-butanol was added dropwise to the reaction mixture A1, and the internal temperature was controlled within the range of 0-5°C, and the dropwise addition was completed for 20 min. , continue to stir for 1h to stop the reaction.
  • the crude product B2 was obtained. Sampling was detected by the above gas chromatography and liquid mass spectrometry, and the relative content of n-butyl methyl hypophosphite in the crude product B2 was 93%, and no chlorobutane was detected.
  • Example 3 change the process parameters according to the following table 2, carry out Examples 3a and 3b, obtain the relative content of n-butyl methylphosphite in each product crude product, the yield after the above-mentioned post-treatment And the relative content of n-butyl methylphosphite in the treated product is shown in Table 2.
  • Post-processing the temperature is raised slowly, and under the condition of maintaining the negative pressure, the temperature is raised to about 100° C., the product is collected, and the yield is 91%.
  • the relative content of n-butyl methylphosphinate in the treated product was detected by gas chromatography, and the results were shown in Table 3 below.
  • Example 4a to 4g obtain the relative content of n-butyl methylphosphite in each product crude product, the yield after the above-mentioned post-treatment And the relative content of n-butyl methylphosphite in the treated product is shown in Table 3.
  • the relative content of n-butyl methylphosphinate in the reaction solution was compared after removing the solvent peak.
  • the relative content of n-butyl methylphosphinate in the reaction solution was compared after removing the solvent peak and removing the butanol peak.
  • Example 4 change the process parameters according to the following table 4, carry out Example 4h to 4j, obtain the relative content of the product in each product crude product, the yield after the above-mentioned post-treatment and the product in the processed product The relative content is shown in Table 4.
  • the three-necked flask was cooled to -5°C, and n-butanol (12.5 g, 0.169 mol) was slowly added dropwise. During the dropwise addition, a large amount of solid was generated, and the solid was a by-product of hypophosphorous acid polymerization. Reactions are mixed. Response failed.

Landscapes

  • Chemical & Material Sciences (AREA)
  • 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

提供了制备次膦酸酯的方法以及装置系统，具体地，所述方法包括如下顺序的步骤： (a)使式(II)的化合物与水以大于1:2的摩尔比进行反应， (b)使步骤(a)所得的反应混合物与式(III)的醇进行反应，其中，R 1和R 2各自独立地选自取代或未取代的烃基。

Description

制备次膦酸酯的方法以及装置系统 技术领域
本发明涉及制备次膦酸酯的方法以及装置系统。
背景技术
次膦酸酯是一种重要的医药、农药中间体。在现有技术中，例如参见CN106674275B，次膦酸酯的制备通常采用1mol的烃基二氯化膦与2mol以上的醇反应来进行，参见如下反应方程式：
Figure PCTCN2022077305-appb-000001
在该反应中产生大量的氯代烃等副产物以及存在过量的醇，产品后处理方式复杂。此外，在上述反应中，现有技术的方法都采用无水的反应体系。
在本领域中存在减少副产物和/或减少工艺复杂性的需求。
发明内容
本发明人出人意料地发现，通过在上述反应体系中引入水，不仅可以制备所需的产物次膦酸酯，同时还可以减少醇的使用量，并且降低副产物氯代烃的量或者甚至消除副产物氯代烃，从而减少了分离提纯步骤的复杂性，而且对环境友好。
因此，在本发明的第一方面，提供了一种制备式(I)的次膦酸酯的方法，该方法包括如下顺序的步骤：
(a)使式(II)的化合物与水以大于1:2的摩尔比进行反应，
(b)使步骤(a)所得的反应混合物与式(III)的醇进行反应，
Figure PCTCN2022077305-appb-000002
其中，R 1和R 2各自独立地选自取代或未取代的烃基，例如，取代或未取代的烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的烷芳基和取代或未取代的芳烷基。
在本发明的第二方面，提供了一种制备式(I)的次膦酸酯的装置系统，其特征在于，所述装置系统包括式(II)的化合物的储罐、式(III)的醇的储罐、水储罐、第一反应器、第二反应器和任选存在的式(I)的次膦酸酯的收集罐；
Figure PCTCN2022077305-appb-000003
其中，基团R 1和R 2的定义与第一方面中相同；所述第一反应器用于式(II)的化合物与水进行反应，所述第二反应器用于所述第一反应器中排出的反应混合物与式(III)的醇进行反应；所述式(II)的化合物的储罐和所述水储罐分别通过管路与所述第一反应器流体连接；所述式(III)的醇的储罐通过管路与所述第二反应器流体连接，所述式(I)的次膦酸酯的收集罐与所述第二反应器的出口流体连接。
通过本发明的方法和装置系统，可以减少次膦酸酯制备过程中醇的使用量，减少或消除副产物氯代烃并且减少工艺复杂性，可以实现高收率以及产品的高纯度，而且对环境友好。
具体实施方式
除非另外说明，本发明提到的所有的出版物、专利申请、专利和其它参考文献都以引用的方式全文结合入本文中，相当于全文呈现于本文。
除非另外定义，本文中使用的所有技术和科学术语具有本发明所属领域普通技术人员通常所理解的同样含义。在抵触的情况下，以本说明书包括 定义为准。
除非另外说明，所有的百分数、份数、比例等都以重量计。
当以范围、优选范围、或者优选或示例的数值的形式表述某个量、浓度或其它值或参数的时候,应当理解相当于具体揭示了通过将任意一对范围上限或下限或优选或示例数值结合起来的任何范围。除非另外指出，本文所列出的数值范围旨在包括范围的端点，和该范围之内的所有整数和分数。
除非有另外的说明，本发明的材料、方法和实施例仅仅是示例性的，而非限制性的。
当使用术语“约”描述值或范围的端点时，应当被理解为包括具体的值或所涉及的端点的±5％，优选±3％，更优选±1％范围内。在本发明中，除非另有说明，提到的数值都应当被视为用“约”修饰。
在本发明中，对于目标产物和/或副产物的验证和测定可以根据本领域常规方法进行，例如，可以采用气相色谱法、气相质谱联用法、液相质谱联用法等等。在本文中，目标产物是指具有式(I)结构的次膦酸酯。
在下文中将对本发明的两个方面进行具体的描述。
第一方面的方法
在本发明的第一方面中，提供了一种制备式(I)的次膦酸酯的方法，该方法包括如下顺序的步骤：
(a)使式(II)的化合物与水以大于1:2的摩尔比进行反应，
(b)使步骤(a)所得的反应混合物与式(III)的醇进行反应，
Figure PCTCN2022077305-appb-000004
其中，基团R 1和R 2没有特别的限制，只要该本发明的反应可以进行，可以根据需要选择R 1和R 2的具体基团，例如取代或未取代的烃基，优选地，所述烃基不含烯属不饱和键。
例如，基团R 1和R 2各自独立地选自取代或未取代的烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的烷芳基和取代或未取代的芳烷基。
优选地，R 1和R 2各自独立地选自取代或未取代的C 1-C 6烷基(例如C 1-C 5烷基，C 1-C 4烷基，C 1-C 3烷基)、取代或未取代的C 6-C 12芳基(例如C 6-C 11芳基，C 6-C 10芳基，C 6-C 9芳基，C 6-C 8芳基)、取代或未取代的C 3-C 10环烷基(例如C 3-C 9环烷基，C 3-C 8环烷基，C 3-C 7环烷基，C 3-C 6环烷基，C 3-C 5环烷基，C 3-C 4环烷基)、取代或未取代的C 7-C 12烷芳基(例如C 7-C 11烷芳基，C 7-C 10烷芳基，C 7-C 9烷芳基，C 7-C 8烷芳基)和取代或未取代的C 7-C 12芳烷基(例如C 7-C 11芳烷基，C 7-C 10芳烷基，C 7-C 9芳烷基，C 7-C 8芳烷基)。
更优选地，R 1和R 2各自独立地选自甲基、乙基、丙基、丁基、戊基、己基、苯基、苯甲基、苯乙基、苯丙基、甲基苯基、乙基苯基、丙基苯基。
还更优选地，R 1选自甲基和乙基，R 2选自甲基、乙基、丙基和丁基。例如，R 1为甲基，R 2为甲基、乙基、丙基或丁基。
可以选择三种反应物的量，使得能够以希望的产率获得最终产物。
在本发明的方法的步骤(a)中，式(II)的化合物与水的摩尔比为大于1:2，优选大于等于1:1，例如，可以为1:(0.01-1.5)，1:(0.1-1)、1:(0.2-1)、1:(0.3-1)、1:(0.4-1)、1:(0.5-1)、1:(0.6-1)、1:(0.7-1)、1:(0.8-1)、1:(0.9-1)，优选1:0.8、1:0.9和1:1，最优选1:1。
在步骤(a)中，式(II)的化合物与水的混合方式和顺序没有特别的限制。可以采用本领域常规的混合方式，例如搅拌。混合顺序例如可以将水加入式(II)的化合物中，也可以把式(II)的化合物加入水中，只要二者最终混合比例落入上述的范围内。优选将水加入式(II)的化合物中。
在本发明的方法的步骤(b)中，式(III)的醇的用量与步骤(a)中式(II)的化合物的用量的摩尔比为大于等于1:1，例如，(1-10):1，(1-8):1，(1-6):1，(1-5):1，(1-4):1，(1-3):1，(1-2):1，(1-1.5):1，(1-1.2):1，(1-1.1):1，1:1，优选地，可以选择1.9:1、1.8:1、1.7:1、1.6:1、1.4:1、1.3:1、1.2:1、1.1:1、1:1，最优 选1:1。
在步骤(b)中，步骤(a)所得的反应混合物与式(III)的醇的混合方式和顺序没有特别的限制。可以采用本领域常规的混合方式，例如搅拌。混合顺序例如可以将步骤(a)所得的反应混合物加入式(III)的醇中，也可以式(III)的醇加入步骤(a)所得的反应混合物中，只要最终混合比例落入上述的范围内。
在本发明的方法中，所述“步骤(a)所得的反应混合物”是指反应之后在反应器中所保留的所有物质的总量，以气体形式从反应器中已经排出的氯化氢不包括在所述反应混合物的范围内。在步骤(a)中，不去除产生的氯化氢。“不去除产生的氯化氢”是指在步骤(a)中不人为施加技术手段来去除产生的氯化氢，但是可以有自然溢出的气体氯化氢。
在第一方面的方法中，所述反应可以在-20℃至100℃的温度下进行，具体而言，步骤(a)的反应可以在-20℃至100℃的温度下进行，步骤(b)的反应可以在-20℃至100℃的温度下进行，例如，步骤(a)可以在-15℃、-10℃、0℃、10℃、20℃、30℃、40℃、50℃、60℃、70℃、80℃、90℃的温度下进行，步骤(b)可以在-15℃、-10℃、0℃、10℃、20℃、30℃、40℃、50℃、60℃、70℃、80℃、90℃的温度下进行。
在第一方面的方法中，对于反应压力没有特别的要求，可以在反应进行过程中自然发生的压力下进行，例如大气压下、稍微的负压或稍微的加压下进行。
所述反应可以在无溶剂条件下或者惰性溶剂中进行，优选地，所述惰性溶剂选自苯类溶剂、卤代烃类溶剂和醚类溶剂的一种或多种。例如苯类溶剂可以选自甲苯、二甲苯、三甲苯，邻二氯苯，对二氯苯、间二氯苯、三氯取代的苯、三甲基取代的苯；所述卤代烃类溶剂可以选自氯己烷、氯庚烷、氯辛烷、二氯己烷、二氯庚烷、二氯辛烷、三氯乙烯、四氯乙烯、三溴丙烷、三氯丙烷；所述醚类溶剂可以选自苯醚、苯甲醚、苯乙醚。优选地，在无溶剂条件下进行时，在步骤(a)中反应结束后不去除产生的氯化氢；当使用惰性溶剂时，在步骤(a)中反应结束后可以去除产生的氯化氢，也可以不去除产生的氯化氢。
在本发明的方法中，对反应器没有特别的要求，反应可以在任何适合的反应器中进行，例如常规使用的塔式反应器，特别是填料塔；具有中间加料位点的连续流反应器。术语“连续流反应器”具有本领域通常的含义，具体地，只要能实现反应物料的连续进入并且反应物的连续排出的反应器，都属于本申请范围内的连续流反应器。
本发明方法以批式反应进行的情况下，例如，可以在一个反应器中进行步骤(a)的反应，然后，将步骤(a)反应的混合物排出输送到下一个反应器中与式(III)的醇进行反应。
本发明方法以连续方式进行的情况下，例如，步骤(a)可以通过将式(II)的化合物与水按照规定的比例进料到连续流反应器的一个模块进行反应，然后将流出该模块的步骤(a)的反应混合物与式(III)的醇按照规定的比例进料到连续反应器的另一个模块中进行反应。
在步骤(a)和(b)反应完成后，如果需要，所述方法还可以包括加入碱进行中和的步骤，优选地，所述碱选自氨气、脂肪胺和芳香胺，例如，三乙胺、乙二胺和苯胺。
此外，本发明的方法还可以包括次膦酸酯制备方法中其它的常规的次膦酸酯分离步骤，例如，过滤、真空蒸馏、冷凝等。
第二方面的装置系统
相应于本发明的第一方面的方法，本发明还提供了制备式(I)的次膦酸酯的装置系统，所述装置系统包括式(II)的化合物的储罐、式(III)的醇的储罐、水储罐、第一反应器、第二反应器和任选存在的式(I)的次膦酸酯的收集罐；
Figure PCTCN2022077305-appb-000005
其中，基团R 1和R 2的定义与第一方面中相同；所述第一反应器用于式(II)的化合物与水进行反应，所述第二反应器用于所述第一反应器中排出的反应混合物与式(III)的醇进行反应；所述式(II)的化合物的储罐和所述水储 罐分别通过管路与所述第一反应器流体连接，所述式(III)的醇的储罐通过管路与所述第二反应器流体连接，所述式(I)的次膦酸酯的收集罐与所述第二反应器的出口流体连接。
所述第一反应器和所述第二反应器在本发明中理解为在反应发生顺序上分别容纳反应物进行反应的容器，在实体上既可以为两个不同的反应器，也可以为同一个反应器。当在实体上为两个不同的反应器时，所述第一反应器与所述第二反应器通过管路彼此流体连接。当在实体上为同一个反应器时，步骤(a)的反应混合物可以排出到另一个容器用于暂存，然后在清洗该反应器后再按规定的比例与式(III)的醇加入该反应器中进行步骤(b)的反应。
所述第一反应器中排出的反应混合物与前述“步骤(a)所得的反应混合物”具有相同的含义。
此外，所述装置系统还可以包括碱储罐。所述碱储罐在装置系统中的连接位点为使得碱通过管路连接入装置系统中(例如连接到反应器或者其它容器或者管路)以中和反应产生的氯化氢并且不影响反应的正常进行。本领域技术人员可以根据实际需要进行位点的选择。
本文所述的“流体连接”是指流体从管路一端的容器能够流动至管路另一端的容器，在管路上可以设置其它的装置例如流量计、预热器、泵、冷凝器等。
上述“水储罐”可以理解为存储水的容器，也可以理解为连接到水源的供水装置。水源可以是来自市政供水、水纯化设备等。
此外，所述装置系统还可以包括设置在反应器下游的过滤器、蒸发器、冷凝器、真空泵等，用于分离纯化式(I)的次膦酸酯。
在一个具体实施方式中，本发明的装置系统包括式(II)的化合物的储罐、式(III)的醇的储罐、水储罐、第一反应器和第二反应器。
在另一个具体实施方式中，本发明的装置系统包括式(II)的化合物的储罐、式(III)的醇的储罐、水储罐、第一反应器、第二反应器和碱储罐。
在另一个具体实施方式中，本发明的装置系统包括式(II)的化合物的储 罐、式(III)的醇的储罐、水储罐、第一反应器、第二反应器、碱储罐、过滤器、蒸发器、冷凝器和真空泵。
在另一个具体实施方式中，本发明的装置系统包括式(II)的化合物的储罐、式(III)的醇的储罐、水储罐、第一反应器、第二反应器、过滤器、蒸发器、冷凝器和真空泵。
实施例
下面结合具体实施例对本发明的技术方案进一步描述，但是本发明不仅限于以下的实施例。实施例中所采用的条件可以根据具体要求做进一步调整，未注明的实施条件为常规实验条件。
所用的检测方法
1.气相色谱法
1.1仪器设备
气相色谱仪：Agillent 7820A或与之相当的GC系统；
检测器：氢火焰离子化检测器(FID)
色谱柱：Agillent Rtx-440 30m×320μm×0.25μm
1.2色谱条件
升温梯度：80℃(0min)，20℃/min，300℃(6min)
进样口温度：280℃
检测器温度：300℃
载气：N 2
空气：氢气：尾吹气(N 2)→400:30:25
柱流量(恒流)：2.0mL/min
分流比：10:1
洗针液：A-乙醇，B-二氯甲烷；进样前B三次，进样后A、B各三次
进样量：0.2μL
1.3样品配制
样品含量以100％计，取100μL样品，溶于1.0mL二氯甲烷
2.液相质谱联用法
2.1仪器设备
液相色谱-质谱连用仪：Agillent G6125B
检测器：紫外检测器(VWD)
电离源：API-ES
色谱柱：Agillent Poroshell 120 EC-C183.0×150mm×2.7μm
2.2色谱条件
2.2.1液相参数
检测波长：205nm、215nm双波长
柱温：30℃
流速：0.4mL/min
运行时间：18.0min
后运行时间：关闭
流动相A：0.1％HCOOH水溶液
流动相B：色谱乙腈
进样量：2.0μL
洗脱梯度：
时间(min) A(％) B(％) 流速(mL/min)
0.0 30.0 700 0.4
2.0 30.0 70.0 0.4
8.0 90.0 90.0 0.4
10.0 90.0 90.0 0.4
12.0 30.0 70.0 0.4
18.0 30.0 70.0 0.4
2.2.2雾化室参数
气体温度：350℃
干燥气：12.0L/min
雾化气压力：35psig
VCap(Positive)：3000V
VCap(Negative)：3000V
2.2.3扫描参数
时间(min) 质量范围 碰撞诱导解离 增益 步径
0.00 50-700 70 1.0 0.1
2.3样品配制
样品含量以100％计，先将样品配成1.0mg/mL的溶液，再取100μL样品稀释到1.0mL，配样溶剂和稀释液均用(10％ACN·H 2O)。
实施例1和1a至1f
在50mL的三口烧瓶中加入20g(0.169mol)的甲基二氯化膦(MDP)，然后降温到-5℃，搅拌状态下，滴加3g(0.169mol)的H 2O，同时控制内部温度为0℃，10min滴加完毕，之后，保温0℃搅拌1h，停止反应，获得反应混合物A1。
在另一个50mL的三口烧瓶中加入12.5g(0.169mol)的正丁醇，将内部温度降低到0℃，搅拌状态下，将上述反应混合物A1滴加到包含正丁醇的三口烧瓶中，控制内部温度在0-5℃范围内，20min滴加完毕，之后，继续搅拌1h，停止反应，获得产物粗品B1。取样通过上述气相色谱法和液相质谱法检测，产物粗品B1中的甲基次磷酸正丁酯的相对含量95％，未检测到氯丁烷。
后处理：在产物粗品B1中加入三乙胺，将pH值调节至约8，过滤，除去三乙胺的盐酸盐，滤饼用二氯乙烷洗，合并有机相，浓缩，得液体，气相色谱检测后处理后液体中产物相对含量96％，乘以液体质量计算得产物收率为92％。结果示于下表1。
此外，采用实施例1的工艺步骤，根据下表1改变工艺参数，进行实施例1a-1f，获得各个产物粗品中的甲基次磷酸正丁酯的相对含量、经过上述后处理后的收率以及处理后产品中甲基次磷酸正丁酯的相对含量示于表1中(其中eq为当量，以下含义相同)。
表1
Figure PCTCN2022077305-appb-000006
实施例2
以与实施例1相同的方法步骤获得反应混合物A1。
将反应混合物A1降温到-5℃，在搅拌状态下，将12.5g(0.169mol)正丁醇滴加到反应混合物A1中，控制内部温度在0-5℃范围内，20min滴加完毕，之后，继续搅拌1h，停止反应。获得产物粗品B2。取样通过上述气相色谱法和液相质谱法检测，产物粗品B2中的甲基次磷酸正丁酯的相对含量93％，未检测到氯丁烷。
实施例3和3a至3b
在100mL的三口瓶中加入(20g，0.169mol)的MDP和邻二氯苯(60g)，然后降温到-5℃，搅拌状态下，缓慢滴加H 2O(3g，0.169mol)，控制内温在0℃左右，大约在10min滴加完毕，滴加完毕后，升温到室温搅拌1h，并在负压(水泵)下，除去HCl,除氯化氢的时间为2h。获得反应液C。
准备250mL的三口瓶，加入正丁醇(12.5g，0.169mol)，将内温控制在0℃，将上述反应液C转移到恒温恒压滴液漏斗中，缓慢将反应液C滴加入丁醇的反应瓶中，控制内温在0℃，滴加完毕后，继续搅拌1h，停止反应。取样通过上述气相色谱法和液相质谱法检测，反应液中甲基次磷酸正丁酯相对含量为95％。
后处理：向反应液中滴加三乙胺，调节pH值至约8，过滤，除去三乙胺的盐酸盐，滤饼用溶剂(即邻二氯苯)洗涤，收集有机相的产品，蒸馏出 产品，收率为92％。用气相色谱法检测处理后产品中甲基次磷酸正丁酯的相对含量，结果示于下表2。
此外，采用实施例3的工艺步骤，根据下表2改变工艺参数，进行实施例3a和3b，获得各个产物粗品中的甲基次磷酸正丁酯的相对含量、经过上述后处理后的收率以及处理后产品中甲基次磷酸正丁酯的相对含量示于表2中。
表2
Figure PCTCN2022077305-appb-000007
实施例4和4i至4j
在100mL的三口瓶中加入(20g，0.169mol)的MDP和邻二氯苯(60g)，然后降温到-5℃，搅拌状态下，缓慢滴加H 2O(3g，0.169mol)，控制内温在0℃左右，大约在10min滴加完毕，滴加完毕后，升温到室温搅拌1h，并在负压(水泵)下，除去HCl,除氯化氢的时间为2h。获得反应液D。
准备250mL的三口瓶，加入正丁醇(12.5g，0.169mol)，将内温控制在25℃，保持在负压(-0.095MPa)条件下(水泵)，将上述反应液D转移到恒温恒压滴液漏斗中，缓慢将反应液D滴加入丁醇的反应瓶中，控制内温在25-30℃，滴加完毕后，继续搅拌1h，停止反应。取样通过上述气相色谱法和液相质谱法检测，反应液中甲基次磷酸正丁酯相对含量为96％。
后处理：缓慢升温，并保持该负压的条件下，升温到100℃左右，收集产品，收率为91％。用气相色谱法检测处理后产品中甲基次磷酸正丁酯的相对含量，结果示于下表3。
此外，采用实施例4的工艺步骤，根据下表3改变工艺参数，进行实施例4a至4g，获得各个产物粗品中的甲基次磷酸正丁酯的相对含量、经过 上述后处理后的收率以及处理后产品中甲基次磷酸正丁酯的相对含量示于表3中。在实施例4和4a和4b中，反应液中甲基次磷酸正丁酯相对含量是在除去溶剂峰后进行比较。在实施例4c至4g中，反应液中甲基次磷酸正丁酯相对含量是在除去溶剂峰并除去丁醇峰后进行比较。
表3：
Figure PCTCN2022077305-appb-000008
此外，采用实施例4的工艺步骤，根据下表4改变工艺参数，进行实施例4h至4j，获得各个产物粗品中的产物的相对含量、经过上述后处理后的收率以及处理后产品中产物的相对含量示于表4中。
表4：
Figure PCTCN2022077305-appb-000009
对比例1
在50mL的三口烧瓶中加入20g(0.169mol)的甲基二氯化膦，然后降温到-5℃，搅拌状态下，滴加3g(0.169mol)的H 2O，同时控制内部温度为0℃，10min滴加完毕，之后，升温到室温搅拌1h，并在水泵负压下除去HCl,除氯化氢的时间为2h，获得反应混合物A2，此时反应混合物A2 粘稠并有恶臭味。将上述反应混合物A2转移到恒温恒压滴液漏斗中。
在另一个50mL的三口烧瓶中加入12.5g(0.169mol)的正丁醇，将内部温度降低到0℃，搅拌状态下，将反应混合物A2从滴液漏斗中滴加到正丁醇中，控制内部温度在0-5℃范围内，在滴加过程中，有大量的固体生成，该固体经检测为次磷酸聚合副产物。反应失败。
对比例2
在50ml的三口瓶中加入(20g，0.169mol)的甲基二氯化膦，然后降温到-5℃，搅拌状态下，缓慢滴加H 2O(3g，0.169mol)，控制内温在0℃左右，大约在10min滴加完毕，滴加完毕后，升温到室温搅拌1h，并在负压(水泵)下，除去HCl,除氯化氢的时间为2h。
将三口瓶降温到-5℃，开始缓慢滴加正丁醇(12.5g，0.169mol)，在滴加过程中，有大量的固体生成，该固体为次磷酸聚合副产物。反应很杂。反应失败。

Claims (10)

  1. 制备式(I)的次膦酸酯的方法，其特征在于，所述方法包括如下顺序的步骤：
    (a)使式(II)的化合物与水以大于1:2的摩尔比进行反应，
    (b)使步骤(a)所得的反应混合物与式(III)的醇进行反应，
    Figure PCTCN2022077305-appb-100001
    其中，R 1和R 2各自独立地选自取代或未取代的烃基，例如，取代或未取代的烷基、取代或未取代的芳基、取代或未取代的环烷基、取代或未取代的烷芳基和取代或未取代的芳烷基；
    优选地，R 1和R 2各自独立地选自取代或未取代的C 1-C 6烷基、取代或未取代的C 6-C 12芳基、取代或未取代的C 3-C 10环烷基、取代或未取代的C 7-C 12烷芳基和取代或未取代的C 7-C 12芳烷基；更优选地，R 1和R 2各自独立地选自甲基、乙基、丙基、丁基、戊基、己基、苯基、苯甲基、苯乙基、苯丙基、甲基苯基、乙基苯基、丙基苯基；更优选地，R 1选自甲基和乙基，R 2选自甲基、乙基、丙基和丁基。
  2. 权利要求1所述的方法，其特征在于，在步骤(a)中，式(II)的化合物与水的摩尔比为1:(0.1-1.5)，例如1:(0.2-1)、1:(0.5-1)、1:(0.7-1)、1:(0.9-1)。
  3. 权利要求1或2所述的方法，其特征在于，在步骤(b)中，式(III)的醇的用量与步骤(a)中式(II)的化合物的用量的摩尔比为小于等于1:1，例如，(1-10):1、(1-6):1、(1-4):1、(1-2):1、(1-1.5):1、(1-1.1):1。
  4. 权利要求1-3任一项所述的方法，其特征在于，步骤(a)的反应在-20℃至100℃的温度下进行，例如-15℃、0℃、10℃、20℃、30℃、40℃、50℃、60℃、70℃、80℃、90℃。
  5. 权利要求1-4任一项所述的方法，其特征在于，步骤(b)的反应在-20℃至100℃的温度下进行，例如-15℃、0℃、10℃、20℃、30℃、40℃、50℃、60℃、70℃、80℃、90℃。
  6. 权利要求1-5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者惰性溶剂中进行，优选地，所述惰性溶剂选自苯类溶剂、卤代烃类溶剂和醚类溶剂中的一种或多种。
  7. 权利要求6所述的方法，其特征在于，当反应在无溶剂条件下进行时，不除去步骤(a)中产生的氯化氢。
  8. 权利要求6所述的方法，其特征在于，当反应在惰性溶剂条件下进行时，不除去步骤(a)中产生的氯化氢或者除去步骤(a)中产生的氯化氢。
  9. 权利要求6或8所述的方法，其特征在于，所述苯类溶剂可以选自甲苯、二甲苯、三甲苯，邻二氯苯，对二氯苯、间二氯苯、三氯取代的苯、三甲基取代的苯；所述卤代烃类溶剂可以选自氯己烷、氯庚烷、氯辛烷、二氯己烷、二氯庚烷、二氯辛烷、三氯乙烯、四氯乙烯、三溴丙烷、三氯丙烷；所述醚类溶剂可以选自苯醚、苯甲醚、苯乙醚。
  10. 制备式(I)的次膦酸酯的装置系统，其特征在于，所述装置系统包括式(II)的化合物的储罐、式(III)的醇的储罐、水储罐、第一反应器、第二反应器和任选存在的式(I)的次膦酸酯的收集罐；
    Figure PCTCN2022077305-appb-100002
    其中，基团R 1和R 2的定义与权利要求1中相同，
    所述第一反应器用于式(II)的化合物与水进行反应，所述第二反应器用于所述第一反应器中排出的反应混合物与式(III)的醇进行反应，
    所述式(II)的化合物的储罐和所述水储罐分别通过管路与所述第一反应器流体连接，所述式(III)的醇的储罐通过管路与所述第二反应器流体连接，所述式(I)的次膦酸酯的收集罐与所述第二反应器的出口流体连接。
PCT/CN2022/077305 2021-03-10 2022-02-22 制备次膦酸酯的方法以及装置系统 WO2022188627A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202280015949.1A CN116867794A (zh) 2021-03-10 2022-02-22 制备次膦酸酯的方法以及装置系统

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202110259639.1 2021-03-10
CN202110259639 2021-03-10

Publications (1)

Publication Number Publication Date
WO2022188627A1 true WO2022188627A1 (zh) 2022-09-15

Family

ID=83227380

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2022/077305 WO2022188627A1 (zh) 2021-03-10 2022-02-22 制备次膦酸酯的方法以及装置系统

Country Status (2)

Country Link
CN (1) CN116867794A (zh)
WO (1) WO2022188627A1 (zh)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102351900A (zh) * 2011-08-18 2012-02-15 江苏优士化学有限公司 一种单烷基次膦酸酯的合成方法
CN106674275A (zh) * 2015-11-11 2017-05-17 利尔化学股份有限公司 甲基次磷酸酯的制备工艺、制备装置以及制备方法
CN107021981A (zh) * 2017-04-11 2017-08-08 四川福思达生物技术开发有限责任公司 一种甲基乙基次磷酸铝的制备方法
CN111793086A (zh) * 2020-06-30 2020-10-20 江苏七洲绿色化工股份有限公司 一种甲基次磷酸酯的合成方法

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN102351900A (zh) * 2011-08-18 2012-02-15 江苏优士化学有限公司 一种单烷基次膦酸酯的合成方法
CN106674275A (zh) * 2015-11-11 2017-05-17 利尔化学股份有限公司 甲基次磷酸酯的制备工艺、制备装置以及制备方法
CN107021981A (zh) * 2017-04-11 2017-08-08 四川福思达生物技术开发有限责任公司 一种甲基乙基次磷酸铝的制备方法
CN111793086A (zh) * 2020-06-30 2020-10-20 江苏七洲绿色化工股份有限公司 一种甲基次磷酸酯的合成方法

Also Published As

Publication number Publication date
CN116867794A (zh) 2023-10-10

Similar Documents

Publication Publication Date Title
JP5449082B2 (ja) メチレンジアニリンおよびメチレンビス（フェニルイソシアナート）の製造方法
US20200299224A1 (en) Ketamine flow synthesis
US9868699B2 (en) Process for removing cations from an isophoronenitrile product mixture
EP2820027B1 (en) Metathesis catalysts containing onium groups
US11220520B2 (en) Method for preparing phosphorus-containing α-aminonitriles
US20040138491A1 (en) Process for the production and purification of bis(tertiary-butylamino)silane
CN114835126A (zh) 一种二碘硅烷的制备方法及装置
WO2022188627A1 (zh) 制备次膦酸酯的方法以及装置系统
WO2022188626A1 (zh) 制备次膦酸酯的方法以及装置系统
Li et al. Continuous flow aminolysis under high temperature and pressure
CN101500981A (zh) 四烷基卤化铵的制备方法
JP5982400B2 (ja) ２，２−ジフルオロ−１−クロロエタンとアンモニアから２，２−ジフルオロエチルアミンを製造する方法
CN113717103A (zh) 一种酮化合物的制备方法
CN111548248A (zh) 一种生产1,3,3,3-四氯丙烯的方法
CN110818581A (zh) 一种沙库巴曲缬沙坦钠中间体的后处理方法
KR100250415B1 (ko) 고순도 1,3-디알킬-2-이미다졸리디논의 제조방법
WO2019131855A1 (ja) 有機アミンの回収方法
KR20220020949A (ko) 프로펠레인계 화합물의 연속 합성 방법
CN114369070B (zh) 一种卢非酰胺的制备工艺
CN109046367A (zh) 五氧化二铌负载铜催化剂及其制备方法与应用
RU2092478C1 (ru) Способ получения м-хлордифенилметилмочевины
US20240067609A1 (en) Laurolactam preparation method, synthesizing device therefor, laurolactam composition prepared thereby, and polylaurolactam preparation method using same
KR102560093B1 (ko) 라우로락탐의 제조방법, 이의 합성장치, 이에 의해 제조된 라우로락탐 조성물, 이를 이용한 폴리라우로락탐의 제조방법
JP2023553095A (ja) エチレンシアノヒドリンの精製方法
CN1084728C (zh) 偶氮甲碱化合物和α－卤代N－乙酰苯胺的制备方法

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 22766153

Country of ref document: EP

Kind code of ref document: A1

WWE Wipo information: entry into national phase

Ref document number: 202280015949.1

Country of ref document: CN

NENP Non-entry into the national phase

Ref country code: DE

122 Ep: pct application non-entry in european phase

Ref document number: 22766153

Country of ref document: EP

Kind code of ref document: A1