WO2024051121A1 - 一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法 - Google Patents

一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法 Download PDF

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WO2024051121A1
WO2024051121A1 PCT/CN2023/079816 CN2023079816W WO2024051121A1 WO 2024051121 A1 WO2024051121 A1 WO 2024051121A1 CN 2023079816 W CN2023079816 W CN 2023079816W WO 2024051121 A1 WO2024051121 A1 WO 2024051121A1
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preparation
acid
reaction
solvent
chloride
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PCT/CN2023/079816
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French (fr)
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周曙光
杨立荣
秦龙
周海胜
余神銮
吴坚平
王林林
詹波
王萍
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浙江新安化工集团股份有限公司
浙江大学
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Publication of WO2024051121A1 publication Critical patent/WO2024051121A1/zh

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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)]
    • 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
    • C07F9/28—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)]

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  • the present invention relates to the technical field of fine chemicals, and more specifically, to a preparation method of a pesticide intermediate 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.
  • PPO 4-(Hydroxymethylphosphono)-2-carbonylbutyric acid
  • PPO 4-(Hydroxymethylphosphono)-2-carbonylbutyric acid
  • the Chinese patent with publication number CN103665032A discloses a method for preparing glufosinate-ammonium.
  • the patent uses oxygen- and phosphorus-containing five-membered heterocyclic phosphonic acid anhydride and cyanide as raw materials, and a cyanation reaction occurs in an organic solvent to generate ketonitriles. compound; and then undergo hydrolysis in an acidic solution to obtain the ketoacid substance 4-(hydroxy Methylphosphono)-2-carbonylbutyric acid.
  • the cyclic phosphonic acid anhydride used in this method is difficult to prepare, has high cost, and is difficult to purify.
  • the object of the present invention is to provide a preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which has a simple process, mild conditions, easy control, low cost, and high yield. .
  • the invention provides a preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which includes the following steps:
  • step b) Mix the acryloyl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, perform a hydrolysis reaction, and then undergo purification to obtain crude 2-carbonyl-3-butenoic acid;
  • step b) Mix the crude 2-carbonyl-3-butenoic acid obtained in step b) with the second solvent, methylphosphine dichloride, and perform an addition reaction to obtain a solution containing bisacyl chloride;
  • step d) Mix the bisyl chloride-containing solution obtained in step c) with water, perform a hydrolysis reaction, and obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid after purification.
  • the first solvent in step a) is selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran and phenylacetonitrile.
  • the polymerization inhibitor in step a) is selected from one or more of p-hydroxyanisole, 2,6-di-tert-butyl-p-cresol, tert-butylhydroquinone and methylhydroquinone. kind; the mass ratio of the polymerization inhibitor and acryloyl chloride is (0.001 ⁇ 0.05):1.
  • the catalyst in step a) is cuprous cyanide; the molar ratio of the catalyst, potassium ferrocyanide and acryloyl chloride is (0.01 ⁇ 0.1): (0.3 ⁇ 3):1.
  • the temperature of the substitution reaction in step a) is 0°C to 100°C, and the time is 0.5h to 48h.
  • the temperature of the vacuum distillation in step a) is 10°C to 60°C.
  • the temperature of the hydrolysis reaction in step b) is 50°C to 130°C, and the time is 1h to 24h.
  • the second solvent in step c) is selected from one or more of dichloromethane, dichloroethane, chloroform, hexane, heptane, benzene, toluene and xylene.
  • the temperature of the addition reaction in step c) is 0°C to 100°C, and the time is 1h to 24h.
  • the temperature of the hydrolysis reaction in step d) is 0°C to 100°C, and the time is 0.1h to 24h.
  • the invention provides a preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which includes the following steps: a) combining acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst and potassium ferrocyanide Mix, perform a substitution reaction, and obtain an acryl cyanide intermediate after distillation under reduced pressure; b) Mix the acryl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, perform a hydrolysis reaction, and then purify to obtain 2- Crude carbonyl-3-butenoic acid; c) Mix the crude 2-carbonyl-3-butenoic acid obtained in step b) with the second solvent, methylphosphine dichloride, and perform an addition reaction to obtain bisacyl chloride-containing Solution; d) Mix the bisyl chloride-containing solution obtained in step c) with water, perform a hydrolysis reaction, and obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid after purification.
  • the preparation method provided by the present invention uses acryloyl chloride as raw material, adds a polymerization inhibitor at the same time, carries out a substitution reaction with potassium ferrocyanide in the presence of a catalyst to obtain acryloyl cyanide, and then hydrolyzes it under acidic conditions.
  • 2-Carbonyl-3-butenoic acid, 2-carbonyl-3-butenoic acid and methylphosphine dichloride are added to each other to obtain bisacyl chloride, which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)- 2-Carbonylbutyric acid; the preparation method has simple process, mild conditions, easy control, low cost, and high yield.
  • Figure 1 is the GC spectrum of acryloyl cyanide in Example 1 of the present invention.
  • Figure 2 is the HPLC spectrum of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid obtained in Example 1 of the present invention
  • Figure 3 is the HPLC spectrum of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid standard.
  • the invention provides a preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which includes the following step:
  • step b) Mix the acryloyl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, perform a hydrolysis reaction, and then undergo purification to obtain crude 2-carbonyl-3-butenoic acid;
  • step b) Mix the crude 2-carbonyl-3-butenoic acid obtained in step b) with the second solvent, methylphosphine dichloride, and perform an addition reaction to obtain a solution containing bisacyl chloride;
  • step d) Mix the bisyl chloride-containing solution obtained in step c) with water, perform a hydrolysis reaction, and obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid after purification.
  • the invention provides a preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.
  • Acryloyl chloride (formula I below) is used as raw material, while a small amount of polymerization inhibitor is added, and ferrous iron is mixed with ferrous iron in the presence of a catalyst.
  • Potassium cyanide undergoes a substitution reaction to obtain acryloyl cyanide (formula II below), which is then hydrolyzed under acidic conditions to obtain 2-carbonyl-3-butenoic acid (formula III below), 2-carbonyl-3-butenoic acid and methyl
  • the addition reaction of phosphine dichloride yields bisacyl chloride (formula IV below), which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid (formula V below);
  • acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst and potassium ferrocyanide are first mixed, a substitution reaction is performed, and an acryl cyanide intermediate is obtained after distillation under reduced pressure.
  • the present invention has no special restrictions on the sources of acryloyl chloride and potassium ferrocyanide, and commercially available products well known to those skilled in the art can be used.
  • the first solvent is preferably selected from one or more of acetonitrile, ethyl acetate, tetrahydrofuran and phenylacetonitrile, and is more preferably acetonitrile or ethyl acetate.
  • the present invention has no special restrictions on the source of the first solvent, and commercially available products well known to those skilled in the art can be used.
  • the polymerization inhibitor is preferably selected from p-hydroxyanisole (MEHQ), 2,6-di-tert-butyl-p-cresol (BHT), tert-butylhydroquinone (MTBHQ) and methyl One or more hydroquinones (THQ), more preferably p-hydroxyanisole (MEHQ).
  • MEHQ p-hydroxyanisole
  • BHT 2,6-di-tert-butyl-p-cresol
  • MTBHQ tert-butylhydroquinone
  • THQ methyl One or more hydroquinones
  • MEHQ methyl One or more hydroquinones
  • the mass ratio of the polymerization inhibitor and acryloyl chloride is preferably (0.001-0.05):1, and more preferably (0.002-0.02):1.
  • the catalyst is preferably cuprous cyanide.
  • the present invention has no special restrictions on the source of the catalyst, and commercially available products well known to those skilled in the art can be used.
  • the molar ratio of the catalyst, potassium ferrocyanide and acryloyl chloride is preferably (0.01 ⁇ 0.1): (0.3 ⁇ 3):1, more preferably (0.02 ⁇ 0.05): (0.5 ⁇ 1.5): 1.
  • the process of mixing acryloyl chloride, first solvent, polymerization inhibitor, catalyst and potassium ferrocyanide is preferably as follows:
  • the temperature is raised to react for a period of time, and after the temperature is lowered, a feed liquid containing acryl cyanide is obtained, and then the acryl cyanide intermediate is separated by distillation under reduced pressure at a certain temperature.
  • the temperature of the substitution reaction is preferably 0°C to 100°C, more preferably 50°C to 80°C; the time of the substitution reaction is preferably 0.5h to 48h, more preferably 6h to 12h.
  • the temperature of the vacuum distillation is preferably 10°C to 60°C, and more preferably 30°C to 50°C.
  • the present invention mixes the obtained acryl cyanide intermediate with hydrochloric acid and a polymerization inhibitor, performs a hydrolysis reaction, and then undergoes purification treatment to obtain crude 2-carbonyl-3-butenoic acid.
  • the mass concentration of the hydrochloric acid is preferably 20% to 36%; the present invention has no special restrictions on the source of the hydrochloric acid, and commercially available products well known to those skilled in the art can be used.
  • the molar ratio of hydrochloric acid to acryloyl cyanide is preferably (1-15):1, more preferably (2-5):1.
  • the polymerization inhibitor is preferably selected from p-hydroxyanisole (MEHQ), 2,6-di-tert-butyl-p-cresol (BHT), tert-butylhydroquinone (MTBHQ) and methyl One or more hydroquinones (THQ), more preferably p-hydroxyanisole (MEHQ).
  • MEHQ p-hydroxyanisole
  • BHT 2,6-di-tert-butyl-p-cresol
  • MTBHQ tert-butylhydroquinone
  • THQ methyl One or more hydroquinones
  • MEHQ methyl One or more hydroquinones
  • the mass ratio of the polymerization inhibitor and acrylic cyanide is preferably (0.001 ⁇ 0.05):1, More preferably, it is (0.005-0.02): 1.
  • the process of mixing the obtained acryloyl cyanide intermediate with hydrochloric acid and polymerization inhibitor is preferably as follows:
  • the temperature of the hydrolysis reaction is preferably 50°C to 130°C, more preferably 80°C to 110°C; the time of the hydrolysis reaction is preferably 1h to 24h, more preferably 3h to 6h.
  • the purification process is preferably as follows:
  • the present invention mixes the obtained crude 2-carbonyl-3-butenoic acid with a second solvent and methylphosphine dichloride, and performs an addition reaction to obtain a mixture containing Solution of bisacyl chloride.
  • the second solvent is preferably selected from one or more of dichloromethane, dichloroethane, chloroform, hexane, heptane, benzene, toluene and xylene, more preferably dichloromethane , hexane or toluene.
  • the present invention has no special restrictions on the source of the second solvent, and commercially available products well known to those skilled in the art can be used.
  • the second solvent is preferably subjected to anhydrous treatment to obtain a solvent after anhydrous treatment.
  • the present invention has no special restrictions on the source of the methylphosphine dichloride, and commercially available products well known to those skilled in the art can be used.
  • the molar ratio of methylphosphine dichloride to acryloyl cyanide is preferably (0.95-1.2):1, more preferably (1-1.05):1.
  • the process of mixing the obtained crude 2-carbonyl-3-butenoic acid with the second solvent and methylphosphine dichloride is preferably as follows:
  • the temperature of the addition reaction is preferably 0°C to 100°C, more preferably 30°C to 70°C; the time of the addition reaction is preferably 1h to 24h, more preferably 3h to 8h.
  • the present invention mixes the obtained solution containing bisacyl chloride with water, performs a hydrolysis reaction, and obtains 4-(hydroxymethylphosphono)-2-carbonylbutyric acid after purification.
  • the mass ratio of the water to the second solvent is preferably (0.1-5):1, more preferably (0.5-2):1; water is added slowly for reaction.
  • the temperature of the hydrolysis reaction is preferably 0°C to 100°C, more preferably 10°C to 40°C; the time of the hydrolysis reaction is preferably 0.1h to 24h, more preferably 0.5h to 3h.
  • the purification process is preferably as follows:
  • the second solvent is removed by layering, and the aqueous layer is separated by vacuum distillation to obtain the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid.
  • the invention provides a preparation method of 4-(hydroxymethylphosphono)-2-carbonylbutyric acid, which includes the following steps: a) combining acryloyl chloride, a first solvent, a polymerization inhibitor, a catalyst and potassium ferrocyanide Mix, perform a substitution reaction, and obtain an acryl cyanide intermediate after distillation under reduced pressure; b) Mix the acryl cyanide intermediate obtained in step a) with hydrochloric acid and a polymerization inhibitor, perform a hydrolysis reaction, and then purify to obtain 2- Crude carbonyl-3-butenoic acid; c) Mix the crude 2-carbonyl-3-butenoic acid obtained in step b) with the second solvent, methylphosphine dichloride, and perform an addition reaction to obtain bisacyl chloride-containing Solution; d) Mix the bisyl chloride-containing solution obtained in step c) with water, perform a hydrolysis reaction, and obtain 4-(hydroxymethylphosphono)-2-carbonylbutyric acid after purification.
  • the preparation method provided by the present invention uses acryloyl chloride as raw material, adds a polymerization inhibitor at the same time, carries out a substitution reaction with potassium ferrocyanide in the presence of a catalyst to obtain acryloyl cyanide, and then hydrolyzes it under acidic conditions.
  • 2-Carbonyl-3-butenoic acid, 2-carbonyl-3-butenoic acid and methylphosphine dichloride are added to each other to obtain bisacyl chloride, which is further hydrolyzed and purified to obtain the target product 4-(hydroxymethylphosphono)- 2-Carbonylbutyric acid; the preparation method has simple process, mild conditions, easy control, low cost, and high yield.
  • Example 1 The preparation method provided in Example 1 is adopted, with the difference that: the polymerization inhibitor p-hydroxyanisole is not added in the substitution reaction stage, the solvent in the addition step is hexane (replacing dichloromethane), and other steps are the same as in Example 1. 49.5g of 95% acryloyl cyanide intermediate was obtained with a yield of 58%; 103.3g of the product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained with a purity of 88% and a yield of 87%.
  • Example 1 The preparation method provided in Example 1 is adopted, with the difference that: the solvent in the substitution reaction stage is ethyl acetate (replacing acetonitrile), the solvent in the addition step is toluene (replacing dichloromethane), and other steps are the same as in Example 1. 68.3g of 95% acryloyl cyanide intermediate was obtained with a yield of 80%; 142.5g of product 4-(hydroxymethylphosphono)-2-carbonylbutyric acid was obtained with a purity of 89% and a yield of 88%.
  • the solvent in the substitution reaction stage is ethyl acetate (replacing acetonitrile)
  • the solvent in the addition step is toluene (replacing dichloromethane)
  • other steps are the same as in Example 1. 68.3g of 95% acryloyl cyanide intermediate was obtained with a yield of 80%; 142.5g of product 4-(hydroxymethylphosphono)-2-carbony

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Abstract

本发明提供了一种4-（羟基甲基膦酰基）-2-羰基丁酸的制备方法，包括以下步骤：a）将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体；b）将步骤a）得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品；c）将步骤b）得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液；d）将步骤c）得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-（羟基甲基膦酰基）-2-羰基丁酸。本发明提供的制备方法工艺简单，条件温和、易控，成本低，并且具有较高的收率。

Description

一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法
本申请要求于2022年9月8日提交中国专利局、申请号为202211096537.3、发明名称为“一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及精细化工技术领域，更具体地说，是涉及一种农药中间体4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法。
背景技术
4-(羟基甲基膦酰基)-2-羰基丁酸，简称PPO或酮酸，是草铵膦合成过程的重要中间体，该化合物通过氨化还原等步骤即可得到草铵膦，通过生物酶法转化即可得到L-草铵膦。
1980年，FBC公司首先申请了制备酮酸中间体的专利US4399287A，3-(乙氧基甲基膦酰基)丙酸酯经克莱森缩合反应延伸碳链得到酮酸中间体4-(羟基甲基膦酰基)-2-羰基丁酸，4-(羟基甲基膦酰基)-2-羰基丁酸的分离收率约为30％。
1991年，Hoechst公司报道了4-(羟基甲基膦酰基)-2-羰基丁酸的化学合成法，利用甲基亚膦酸单乙酯与丙烯酸乙酯在乙醇钠的作用下发生迈克尔加成反应制备得到3-(乙氧基甲基膦酰基)-丙酸乙酯，然后在-50℃与草酸二乙酯在乙醇钠作用下发生克莱森酯缩合反应，再利用盐酸水解脱羧后制得4-(羟基甲基膦酰基)-2-羰基丁酸。但是该方法需要在-50℃下进行反应，且整体收率较低，有大量的废水产生，同时产物析晶时间长达48h(J.Org.Chem.,1991,56,1783-1788)，反应式如下所示：
公开号为CN103665032A的中国专利公开了一种草铵膦的制备方法，该专利以含氧、磷的五元杂环环膦酸酐与氰化物为原料，在有机溶剂中发生氰化反应生成酮腈化合物；然后再在酸性溶液中经过水解过程得到酮酸物质4-(羟基 甲基膦酰基)-2-羰基丁酸。该法所使用的环膦酸酐制备不易，成本高，且纯化困难。
因此，如何提供一种收率高、纯化简单，并且原料易得的4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，成为目前亟待解决的问题。
发明内容
有鉴于此，本发明的目的在于提供一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，工艺简单，条件温和、易控，成本低，并且具有较高的收率。
本发明提供了一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，包括以下步骤：
a)将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体；
b)将步骤a)得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品；
c)将步骤b)得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液；
d)将步骤c)得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-(羟基甲基膦酰基)-2-羰基丁酸。
优选的，步骤a)中所述第一溶剂选自乙腈、乙酸乙酯、四氢呋喃和苯乙腈中的一种或多种。
优选的，步骤a)中所述阻聚剂选自对羟基苯甲醚、2,6-二叔丁基对甲酚、特丁基对苯二酚和甲基氢醌中的一种或多种；所述阻聚剂和丙烯酰氯的质量比为(0.001～0.05)：1。
优选的，步骤a)中所述催化剂为氰化亚铜；所述催化剂、亚铁氰化钾和丙烯酰氯摩尔比为(0.01～0.1)：(0.3～3)：1。
优选的，步骤a)中所述取代反应的温度为0℃～100℃，时间为0.5h～48h。
优选的，步骤a)中所述减压蒸馏的温度为10℃～60℃。
优选的，步骤b)中所述水解反应的温度为50℃～130℃，时间为1h～24h。
优选的，步骤c)中所述第二溶剂选自二氯甲烷、二氯乙烷、氯仿、己烷、庚烷、苯、甲苯和二甲苯中的一种或多种。
优选的，步骤c)中所述加成反应的温度为0℃～100℃，时间为1h～24h。
优选的，步骤d)中所述水解反应的温度为0℃～100℃，时间为0.1h～24h。
本发明提供了一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，包括以下步骤：a)将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体；b)将步骤a)得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品；c)将步骤b)得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液；d)将步骤c)得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-(羟基甲基膦酰基)-2-羰基丁酸。与现有技术相比，本发明提供的制备方法以丙烯酰氯为原料，同时加入阻聚剂，在催化剂存在下与亚铁氰化钾进行取代反应得到丙烯酰氰，再于酸性条件下水解得到2-羰基-3-丁烯酸，2-羰基-3-丁烯酸与甲基二氯化膦加成反应得到双酰氯，进一步水解、纯化得到目标产物4-(羟基甲基膦酰基)-2-羰基丁酸；该制备方法工艺简单，条件温和、易控，成本低，并且具有较高的收率。
附图说明
图1为本发明实施例1中丙烯酰氰的GC谱图；
图2为本发明实施例1得到的4-(羟基甲基膦酰基)-2-羰基丁酸的HPLC谱图；
图3为4-(羟基甲基膦酰基)-2-羰基丁酸标样的HPLC谱图。
具体实施方式
下面将结合本发明实施例，对本发明的技术方案进行清楚、完整地描述，显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。基于本发明中的实施例，本领域普通技术人员在没有做出创造性劳动前提下所获得的所有其他实施例，都属于本发明保护的范围。
本发明提供了一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，包括以下 步骤：
a)将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体；
b)将步骤a)得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品；
c)将步骤b)得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液；
d)将步骤c)得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-(羟基甲基膦酰基)-2-羰基丁酸。
本发明提供了一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，以丙烯酰氯(下式I)为原料，同时加入少量阻聚剂，在催化剂存在下与亚铁氰化钾进行取代反应得到丙烯酰氰(下式II)，再于酸性条件下水解得到2-羰基-3-丁烯酸(下式III)，2-羰基-3-丁烯酸与甲基二氯化膦加成反应得到双酰氯(下式IV)，进一步水解、纯化得到目标产物4-(羟基甲基膦酰基)-2-羰基丁酸(下式V)；
本发明提供的4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法反应式如下：
本发明首先将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体。本发明对所述丙烯酰氯和亚铁氰化钾的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述第一溶剂优选选自乙腈、乙酸乙酯、四氢呋喃和苯乙腈中的一种或多种，更优选为乙腈或乙酸乙酯。本发明对所述第一溶剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述阻聚剂优选选自对羟基苯甲醚(MEHQ)、2,6-二叔丁基对甲酚(BHT)、特丁基对苯二酚(MTBHQ)和甲基氢醌(THQ)中的一种或多种，更优选为对羟基苯甲醚(MEHQ)。本发明对所述阻聚剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述阻聚剂和丙烯酰氯的质量比优选为(0.001～0.05)：1，更优选为(0.002～0.02)：1。
在本发明中，所述催化剂优选为氰化亚铜。本发明对所述催化剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述催化剂、亚铁氰化钾和丙烯酰氯摩尔比优选为(0.01～0.1)：(0.3～3)：1，更优选为(0.02～0.05)：(0.5～1.5)：1。
在本发明中，所述将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合的过程优选具体为：
将丙烯酰氯置于第一溶剂中，再加入阻聚剂、催化剂和亚铁氰化钾。
之后，升温反应一段时间，降温后得到含有丙烯酰氰的料液，再在一定温度下减压蒸馏分离得到丙烯酰氰中间体。
在本发明中，所述取代反应的温度优选为0℃～100℃，更优选为50℃～80℃；所述取代反应的时间优选为0.5h～48h，更优选为6h～12h。
在本发明中，所述减压蒸馏的温度优选为10℃～60℃，更优选为30℃～50℃。
得到所述丙烯酰氰中间体后，本发明将得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品。
在本发明中，所述盐酸的质量浓度优选为20％～36％；本发明对所述盐酸的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述盐酸与丙烯酰氰的摩尔比优选为(1～15)：1，更优选为(2～5)：1。
在本发明中，所述阻聚剂优选选自对羟基苯甲醚(MEHQ)、2,6-二叔丁基对甲酚(BHT)、特丁基对苯二酚(MTBHQ)和甲基氢醌(THQ)中的一种或多种，更优选为对羟基苯甲醚(MEHQ)。本发明对所述阻聚剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述阻聚剂和丙烯酰氰的质量比优选为(0.001～0.05)：1， 更优选为(0.005～0.02)：1。
在本发明中，所述将得到的丙烯酰氰中间体与盐酸、阻聚剂混合的过程优选具体为：
将丙烯酰氰中间体加入一定量的盐酸中，再加入少量阻聚剂。
之后，升温水解反应一段时间，再经纯化处理，得到2-羰基-3-丁烯酸粗品。
在本发明中，所述水解反应的温度优选为50℃～130℃，更优选为80℃～110℃；所述水解反应的时间优选为1h～24h，更优选为3h～6h。
在本发明中，所述纯化处理的过程优选具体为：
水解反应后，继续减压除去酸水，得到含有2-羰基-3-丁烯酸与氯化铵的混合物，再加入丙酮溶解，过滤除去不溶性盐，滤液减压蒸馏，得到产物2-羰基-3-丁烯酸粗品，直接用于下一步反应。
得到所述2-羰基-3-丁烯酸粗品后，本发明将得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液。
在本发明中，所述第二溶剂优选选自二氯甲烷、二氯乙烷、氯仿、己烷、庚烷、苯、甲苯和二甲苯中的一种或多种，更优选为二氯甲烷、己烷或甲苯。本发明对所述第二溶剂的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。在本发明中，所述第二溶剂优选进行无水处理，得到无水处理后的溶剂。
本发明对所述甲基二氯化膦的来源没有特殊限制，采用本领域技术人员熟知的市售商品即可。
在本发明中，所述甲基二氯化膦与丙烯酰氰摩尔比优选为(0.95～1.2)：1，更优选为(1～1.05)：1。
在本发明中，所述将得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合的过程优选具体为：
将得到的2-羰基-3-丁烯酸粗品分散于第二溶剂中，在氮气保护下缓慢滴加甲基二氯化膦。
之后，保温反应一定时间，降温得到含有双酰氯的溶液。
在本发明中，所述加成反应的温度优选为0℃～100℃，更优选为30℃～70℃；所述加成反应的时间优选为1h～24h，更优选为3h～8h。
得到所述含有双酰氯的溶液后，本发明将得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-(羟基甲基膦酰基)-2-羰基丁酸。
在本发明中，所述水与第二溶剂的质量比优选为(0.1～5)：1，更优选为(0.5～2)：1；缓慢加水反应。
在本发明中，所述水解反应的温度优选为0℃～100℃，更优选为10℃～40℃；所述水解反应的时间优选为0.1h～24h，更优选为0.5h～3h。
在本发明中，所述纯化的过程优选具体为：
水解反应完成后，分层除去第二溶剂，水层减压蒸馏分离得到产品4-(羟基甲基膦酰基)-2-羰基丁酸。
本发明提供的制备方法具有如下有益效果：
(1)选择廉价丙烯酰氯为原料，反应条件温和，操作简便，生产成本低，易于实现工业化；(2)通过取代、水解、加成等简单工艺步骤及较温和条件下高效获得最终产物4-(羟基甲基膦酰基)-2-羰基丁酸。
本发明提供了一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，包括以下步骤：a)将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体；b)将步骤a)得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品；c)将步骤b)得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液；d)将步骤c)得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-(羟基甲基膦酰基)-2-羰基丁酸。与现有技术相比，本发明提供的制备方法以丙烯酰氯为原料，同时加入阻聚剂，在催化剂存在下与亚铁氰化钾进行取代反应得到丙烯酰氰，再于酸性条件下水解得到2-羰基-3-丁烯酸，2-羰基-3-丁烯酸与甲基二氯化膦加成反应得到双酰氯，进一步水解、纯化得到目标产物4-(羟基甲基膦酰基)-2-羰基丁酸；该制备方法工艺简单，条件温和、易控，成本低，并且具有较高的收率。
为了进一步说明本发明，下面通过以下实施例进行详细说明。本发明以下实施例中所用的原料均为市售商品。
实施例1
(1)于1000mL四口烧瓶中加入94.3g 96％丙烯酰氯及300mL乙腈，再加入 0.2g对羟基苯甲醚，4.5g 99％氰化亚铜及376g亚铁氰化钾，升温至70～80℃，回流反应12h，降温后得到含有丙烯酰氰的料液，控制40～50℃下减压蒸馏，分离得到71.2g 97％丙烯酰氰中间体(GC谱图参见图1所示)，收率85％。
(2)将上述得到的丙烯酰氰加入装有210g 30％盐酸的500mL四口烧瓶中，添加0.2g对羟基苯甲醚，升温至100～110℃进行水解反应，3h后减压除去酸水，得到含有2-羰基-3-丁烯酸与氯化铵的混合物，加入100mL丙酮溶解，过滤除去不溶性盐，滤液减压蒸馏，得到产物2-羰基-3-丁烯酸粗品。
(3)上述得到的2-羰基-3-丁烯酸粗品分散于经无水处理的200g二氯甲烷中，在氮气保护下缓慢滴加102g 97％甲基二氯化膦，控制温度为40～50℃保温反应5h，降温得到含有双酰氯的溶液。
(4)上述得到的含有双酰氯的溶液中，缓慢加入100g水，控制温度为20～30℃下进行反应1h，反应完成后分层除去溶剂，水层减压蒸馏分离得到156.4g产品4-(羟基甲基膦酰基)-2-羰基丁酸(HPLC谱图参见图2所示，标样为图3)，纯度为92％，收率为94％。
实施例2
(1)于1000mL四口烧瓶中加入94.3g 96％丙烯酰氯及300mL乙腈，再加入1.0g 2,6-二叔丁基对甲酚，1.8g 99％氰化亚铜及113g亚铁氰化钾，升温至50～60℃，保温反应6h，降温后得到含有丙烯酰氰的料液，控制30～40℃下减压蒸馏，分离得到61.6g 96％丙烯酰氰中间体，收率73％。
(2)将上述得到的丙烯酰氰加入装有440g 30％盐酸的1000mL四口烧瓶中，添加0.2g对羟基苯甲醚，升温至80～90℃进行水解反应，6h后减压除去酸水，得到含有2-羰基-3-丁烯酸与氯化铵的混合物，加入100mL丙酮溶解，过滤除去不溶性盐，滤液减压蒸馏，得到产物2-羰基-3-丁烯酸粗品。
(3)上述得到的2-羰基-3-丁烯酸粗品分散于经无水处理的200g二氯甲烷中，在氮气保护下缓慢滴加93g 97％甲基二氯化膦，控制温度为30～40℃保温反应8h，降温得到含有双酰氯的溶液。
(4)上述得到的含有双酰氯的溶液中，缓慢加入200g水，控制温度为10～20℃下进行反应3h，反应完成后分层除去溶剂，水层减压蒸馏分离得到132.9g产品4-(羟基甲基膦酰基)-2-羰基丁酸，纯度为91％，收率为92％。
实施例3
(1)于1000mL四口烧瓶中加入94.3g 96％丙烯酰氯及300mL乙腈，再加入1.0g甲基氢醌，4.5g 99％氰化亚铜及188g亚铁氰化钾，升温至70～80℃，回流反应10h，降温后得到含有丙烯酰氰的料液，控制40～50℃下减压蒸馏，分离得到68.1g 94％丙烯酰氰中间体，收率79％。
(2)将上述得到的丙烯酰氰加入装有290g 20％盐酸的500mL四口烧瓶中，添加0.2g对羟基苯甲醚，升温至90～100℃进行水解反应，5h后减压除去酸水，得到含有2-羰基-3-丁烯酸与氯化铵的混合物，加入100mL丙酮溶解，过滤除去不溶性盐，滤液减压蒸馏，得到产物2-羰基-3-丁烯酸粗品。
(3)上述得到的2-羰基-3-丁烯酸粗品分散于经无水处理的150g二氯甲烷中，在氮气保护下缓慢滴加95g 97％甲基二氯化膦，控制温度为60～70℃保温反应3h，降温得到含有双酰氯的溶液。
(4)上述得到的含有双酰氯的溶液中，缓慢加入300g水，控制温度为30～40℃下进行反应0.5h，反应完成后分层除去溶剂，水层减压蒸馏分离得到143.9g产品4-(羟基甲基膦酰基)-2-羰基丁酸，纯度为90％，收率为91％。
实施例4
(1)于1000mL四口烧瓶中加入94.3g 96％丙烯酰氯及250mL乙腈，再加入0.2g对羟基苯甲醚，4.5g 99％氰化亚铜及188g亚铁氰化钾，升温至70～80℃，回流反应10h，降温后得到含有丙烯酰氰的料液，控制40～50℃下减压蒸馏，分离得到68.4g 96％丙烯酰氰中间体，收率81％。
(2)将上述得到的丙烯酰氰加入装有295g 30％盐酸的500mL四口烧瓶中，添加0.2g对羟基苯甲醚，升温至100～110℃进行水解反应，3h后减压除去酸水，得到含有2-羰基-3-丁烯酸与氯化铵的混合物，加入100mL丙酮溶解，过滤除去不溶性盐，滤液减压蒸馏，得到产物2-羰基-3-丁烯酸粗品。
(3)上述得到的2-羰基-3-丁烯酸粗品分散于经无水处理的200g二氯甲烷中，在氮气保护下缓慢滴加100g 97％甲基二氯化膦，控制温度为40～50℃保温反应5h，降温得到含有双酰氯的溶液。
(4)上述得到的含有双酰氯的溶液中，缓慢加入100g水，控制温度为20～30℃下进行反应2h，反应完成后分层除去溶剂，水层减压蒸馏分离得到150.7g产品4-(羟基甲基膦酰基)-2-羰基丁酸，纯度为90％，收率为93％。
实施例5
采用实施例1提供的制备方法，区别在于：取代反应阶段不添加阻聚剂对羟基苯甲醚，加成步骤溶剂为己烷(替换二氯甲烷)，其它步骤同实施例1。得到49.5g 95％丙烯酰氰中间体，收率58％；得到103.3g产物4-(羟基甲基膦酰基)-2-羰基丁酸，纯度为88％，收率87％。
实施例6
采用实施例1提供的制备方法，区别在于：取代反应阶段溶剂为乙酸乙酯(替换乙腈)，加成步骤溶剂为甲苯(替换二氯甲烷)，其它步骤同实施例1。得到68.3g 95％丙烯酰氰中间体，收率80％；得到142.5g产物4-(羟基甲基膦酰基)-2-羰基丁酸，纯度为89％，收率88％。
以上所述仅是本发明的优选实施方式，应当指出，对于本技术领域的普通技术人员来说，在不脱离本发明原理的前提下，还可以做出若干改进和润饰，这些改进和润饰也应视为本发明的保护范围。

Claims (10)

  1. 一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法，包括以下步骤：
    a)将丙烯酰氯、第一溶剂、阻聚剂、催化剂和亚铁氰化钾混合，进行取代反应，减压蒸馏后得到丙烯酰氰中间体；
    b)将步骤a)得到的丙烯酰氰中间体与盐酸、阻聚剂混合，进行水解反应，再经纯化处理，得到2-羰基-3-丁烯酸粗品；
    c)将步骤b)得到的2-羰基-3-丁烯酸粗品与第二溶剂、甲基二氯化膦混合，进行加成反应，得到含有双酰氯的溶液；
    d)将步骤c)得到的含有双酰氯的溶液与水混合，进行水解反应，纯化后得到4-(羟基甲基膦酰基)-2-羰基丁酸。
  2. 根据权利要求1所述的制备方法，其特征在于，步骤a)中所述第一溶剂选自乙腈、乙酸乙酯、四氢呋喃和苯乙腈中的一种或多种。
  3. 根据权利要求1所述的制备方法，其特征在于，步骤a)中所述阻聚剂选自对羟基苯甲醚、2,6-二叔丁基对甲酚、特丁基对苯二酚和甲基氢醌中的一种或多种；所述阻聚剂和丙烯酰氯的质量比为(0.001～0.05)：1。
  4. 根据权利要求1所述的制备方法，其特征在于，步骤a)中所述催化剂为氰化亚铜；所述催化剂、亚铁氰化钾和丙烯酰氯摩尔比为(0.01～0.1)：(0.3～3)：1。
  5. 根据权利要求1所述的制备方法，其特征在于，步骤a)中所述取代反应的温度为0℃～100℃，时间为0.5h～48h。
  6. 根据权利要求1所述的制备方法，其特征在于，步骤a)中所述减压蒸馏的温度为10℃～60℃。
  7. 根据权利要求1所述的制备方法，其特征在于，步骤b)中所述水解反应的温度为50℃～130℃，时间为1h～24h。
  8. 根据权利要求1所述的制备方法，其特征在于，步骤c)中所述第二溶剂选自二氯甲烷、二氯乙烷、氯仿、己烷、庚烷、苯、甲苯和二甲苯中的一种或多种。
  9. 根据权利要求1所述的制备方法，其特征在于，步骤c)中所述加成反应的温度为0℃～100℃，时间为1h～24h。
  10. 根据权利要求1所述的制备方法，其特征在于，步骤d)中所述水解反应的温度为0℃～100℃，时间为0.1h～24h。
PCT/CN2023/079816 2022-09-08 2023-03-06 一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法 WO2024051121A1 (zh)

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US4399287A (en) * 1979-12-08 1983-08-16 Fbc Limited Phosphinic acid derivatives
CN101641363A (zh) * 2007-03-23 2010-02-03 明治制果株式会社 含磷的α-酮酸的制造方法
CN103665032A (zh) * 2013-12-09 2014-03-26 江苏七洲绿色化工股份有限公司 一种草铵膦的制备方法
CN106459110A (zh) * 2014-05-13 2017-02-22 拜耳作物科学股份公司 制备含磷羟腈的方法
CN111004277A (zh) * 2019-10-29 2020-04-14 南京红太阳生物化学有限责任公司 一种新的草铵膦的制备方法
CN114085244A (zh) * 2021-11-26 2022-02-25 浙江新安化工集团股份有限公司 一种4-(羟基甲基膦酰基)-2-羰基丁酸的制备方法

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* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4399287A (en) * 1979-12-08 1983-08-16 Fbc Limited Phosphinic acid derivatives
CN101641363A (zh) * 2007-03-23 2010-02-03 明治制果株式会社 含磷的α-酮酸的制造方法
CN103665032A (zh) * 2013-12-09 2014-03-26 江苏七洲绿色化工股份有限公司 一种草铵膦的制备方法
CN106459110A (zh) * 2014-05-13 2017-02-22 拜耳作物科学股份公司 制备含磷羟腈的方法
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