WO2019000910A1 - 一种2-氟丙烯酸酯的制备方法 - Google Patents

一种2-氟丙烯酸酯的制备方法 Download PDF

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WO2019000910A1
WO2019000910A1 PCT/CN2018/072199 CN2018072199W WO2019000910A1 WO 2019000910 A1 WO2019000910 A1 WO 2019000910A1 CN 2018072199 W CN2018072199 W CN 2018072199W WO 2019000910 A1 WO2019000910 A1 WO 2019000910A1
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formula
acid
structure shown
process according
chloride
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PCT/CN2018/072199
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English (en)
French (fr)
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仇昆伦
王文博
於钱杰
李波涛
练雄东
李功勇
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临海天宇药业有限公司
上海新埠医药科技有限公司
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Priority to KR1020197037267A priority Critical patent/KR20200020712A/ko
Priority to JP2019571235A priority patent/JP6880249B2/ja
Priority to US16/626,211 priority patent/US10844000B2/en
Priority to EP18825404.9A priority patent/EP3647304B1/en
Priority to ES18825404T priority patent/ES2901485T3/es
Publication of WO2019000910A1 publication Critical patent/WO2019000910A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/01—Preparation of ethers
    • C07C41/18—Preparation of ethers by reactions not forming ether-oxygen bonds
    • C07C41/30—Preparation of ethers by reactions not forming ether-oxygen bonds by increasing the number of carbon atoms, e.g. by oligomerisation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/39—Preparation of carboxylic acid esters by oxidation of groups which are precursors for the acid moiety of the ester
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C41/00—Preparation of ethers; Preparation of compounds having groups, groups or groups
    • C07C41/48—Preparation of compounds having groups
    • C07C41/50—Preparation of compounds having groups by reactions producing groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C45/00—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds
    • C07C45/51—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition
    • C07C45/511—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups
    • C07C45/515—Preparation of compounds having >C = O groups bound only to carbon or hydrogen atoms; Preparation of chelates of such compounds by pyrolysis, rearrangement or decomposition involving transformation of singly bound oxygen functional groups to >C = O groups the singly bound functional group being an acetalised, ketalised hemi-acetalised, or hemi-ketalised hydroxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/16—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation
    • C07C51/285—Preparation of carboxylic acids or their salts, halides or anhydrides by oxidation with peroxy-compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/08—Preparation of carboxylic acid esters by reacting carboxylic acids or symmetrical anhydrides with the hydroxy or O-metal group of organic compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/14—Preparation of carboxylic acid esters from carboxylic acid halides

Definitions

  • the invention relates to the field of chemical synthesis, in particular to a preparation method of 2-fluoroacrylate.
  • 2-fluoroacrylate is a very important intermediate in medicines and pesticides.
  • Veltassa a high molecular polymer drug prepared from 2-fluoroacrylate developed by Relysa Corporation of the United States, is used to treat hyperkalemia in patients with CKD.
  • 2-fluoroacrylate is also a key polymerizable monomer for fluorofiber materials. Fluorinated fiber materials have high glass transition temperatures, low surface energy, and resistance to aging.
  • 2-fluoroacrylate can be used to make high-strength structural materials, such as supersonic aircraft driving windshields, which have been used to manipulate microcrystalline etching integrated circuits and electronic circuit board materials.
  • 2-fluoroacetic acid ethyl ester is highly toxic and requires low temperature control and relatively expensive alkali reagents in the addition reaction with formaldehyde.
  • 2-chloropropionate is fluorinated, NBS brominated and eliminated to give the desired product. This method often requires stoichiometric NBS and DBU.
  • 2-fluoromalonate is added to the base under conditions of formaldehyde and then dehydrated and decarboxylated to give the desired product.
  • the cost of raw materials in this method is relatively large, and the use of atoms is not economical.
  • the present invention aims to provide a novel process for the preparation of 2-fluoroacrylate.
  • the present invention provides a process for preparing a 2-fluoroacrylate having the structure shown in Formula F, which comprises the steps of: (1) mixing a vinyl ether having a structure such as Formula A with monofluoromethylene chloride; Obtaining a substituted cyclopropane compound having the structure shown in Formula B;
  • R 1 , R 2 and R 3 are each independently selected from a substituent of a fatty or aromatic structure of 1 to 20 carbon atoms.
  • a phase transfer catalyst is added to the addition reaction occurring after the mixing of the step (1); the phase transfer catalyst is selected from one or more of the following: tetramethylammonium chloride, tetrabutyl Ammonium chloride, tetraoctyl ammonium chloride, methyl trioctyl ammonium chloride, tetraoctyl ammonium bromide, tetrahexylammonium chloride, tetrabutylammonium iodide, tetrabutylammonium bromide, and three - Dodecylmethyl ammonium iodide.
  • the mixing temperature of the substituted cyclopropane compound and R 2 OH having the structure shown in Formula B in the step (2) is from 80 to 150 ° C; more preferably from 80 to 115 ° C; most preferably from 110 to 115 °C.
  • the substituted cyclopropane compound of the formula B and the R 2 OH are mixed in the step (2) to obtain an acetal product having the structure shown in formula C, which is hydrolyzed under acidic conditions to give a structure such as formula D. 2-Fluoropropenal shown.
  • the acidic condition is that the reactant used is selected from the group consisting of aqueous solutions of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, acetic acid, more preferably aqueous hydrochloric acid.
  • the oxidizing agent used in the oxidation in the step (3) is selected from the group consisting of sodium chlorite, sodium hypochlorite, 30% hydrogen peroxide, peracetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, sodium persulfate. And t-butanol peroxide; more preferably 30% hydrogen peroxide, peroxybenzoic acid or oxygen and air.
  • the catalyst used in the oxidation in the step (3) is selected from the group consisting of iron salts, phosphonium salts, tungstate salts, molybdenum salts, or double salts thereof; more preferably, the catalyst is selected from the group consisting of three Ferric chloride, ferrous sulfate, ferrous chloride, tungstic acid, sodium tungstate, iron triacetylacetonate or cobalt diacetylacetonate.
  • the mixing temperature in the step (4) is from 10 to 50 ° C; more preferably from 30 to 40 ° C.
  • the R1, R2 and R3 are each selected from the group consisting of a substituent of a fatty or aromatic structure of from 1 to 10 carbon atoms; preferably from a methyl group, an ethyl group, a propyl group or a butyl group, respectively.
  • the present invention provides a method for preparing 2-fluoroacrylate which is environmentally friendly, has good product selectivity, high product purity, high atomic economy and low cost.
  • the inventors have conducted extensive and intensive research and found that a stable and readily available vinyl monoether is used as a starting material, and a 2-fluoroacrylate is obtained by cyclization, acetalization, oxidation and esterification.
  • the intermediates in each step of the process have good stability, and effective quality control can be achieved by refining the intermediates to ensure high quality target products.
  • the present invention has been completed.
  • the preparation method of the 2-fluoroacrylate provided by the invention comprises the steps of:
  • R 1 , R 2 and R 3 are each independently selected from the group consisting of a substituent of a fatty or aromatic structure of 1 to 20 carbon atoms, preferably a substituent of a fatty or aromatic structure of 1 to 10 carbon atoms, more preferably a methyl group or a Base, propyl or butyl.
  • the substituted cyclopropane compound having the structure shown in Formula B is first reacted with a monohydric alcohol under basic conditions to obtain an acetal product having the structure shown in Formula C, and then hydrolyzed under acidic conditions to obtain a structure as shown in Formula D.
  • 2-fluoroacrolein; or a substituted cyclopropane compound of the formula B as shown in Formula B is reacted with water under heating to obtain 2-fluoroacrolein having the structure shown in Formula D;
  • the 2-fluoroacrolein having the structure shown in Formula D is oxidized to obtain 2-fluoroacrylic acid having the structure shown in Formula E;
  • the reaction temperature of the addition reaction is 0 to 50 ° C, preferably 10 to 30 ° C;
  • the addition substrate added in the addition reaction is a vinyl ether, preferably a vinyl group. Methyl ether, vinyl ethyl ether or vinyl butyl ether; the addition reaction is carried out under basic conditions, the base added is selected from sodium hydroxide, potassium hydroxide, or lithium hydroxide, preferably sodium hydroxide;
  • the solvent for the addition reaction is an organic solvent selected from the group consisting of dichloromethane, toluene, chlorobenzene, n-heptane, ethyl acetate, or methyl tert-butyl ether;
  • the phase transfer catalyst to be added is selected from one or more of the following: tetramethylammonium chloride, tetrabutylammonium chloride, tetraoctyl ammonium chloride, methyltrioctyl ammonium chloride,
  • the reaction temperature with the monohydric alcohol is 80-150 ° C, preferably 110-115 ° C; the base added in the reaction with the monohydric alcohol is selected from the group consisting of sodium hydroxide, potassium hydroxide, and carbonic acid.
  • the base added in the reaction with the monohydric alcohol is selected from the group consisting of sodium hydroxide, potassium hydroxide, and carbonic acid.
  • Sodium, potassium carbonate, lithium hydroxide, triethylamine, tri-n-propylamine, tri-n-butylamine, diisopropylethylamine or pyridine preferably pyridine, sodium carbonate, triethylamine, tri-n-propylamine or diisopropyl Ethylamine.
  • the ring-opening step of the acetal intermediate having the structure shown in Formula C is thermally cleaved in the presence of a base and an alcohol to obtain a 2-fluoroprop acetal, and the R 2 included in the added monohydric alcohol is not limited to include
  • a fat having 1 to 20 carbon atoms or a substituent having an aromatic structure is preferably methanol, ethanol, propanol or n-butanol.
  • Compounds of the formula C as shown in Formula C can be subjected to extensive purification to ensure high quality of the final product; including, but not limited to, distillation purification.
  • the reaction temperature in the hydrolysis reaction under acidic conditions referred to in the above second step is 50-90 ° C, preferably 65-75 ° C; the acidic condition is that the reactant used is selected from the group consisting of hydrochloric acid, sulfuric acid, phosphoric acid, formic acid, and acetic acid.
  • An aqueous solution preferably an aqueous hydrochloric acid solution.
  • the second step described above is cleaved in the presence of water to give 2-fluoroacrolein of the formula D.
  • the reaction temperature in the oxidation reaction is 0-60 ° C, preferably 15-25 ° C;
  • the oxidizing agent used in the oxidation reaction is selected from the group consisting of sodium chlorite, sodium hypochlorite, 30% hydrogen peroxide, Peracetic acid, peroxybenzoic acid, m-chloroperoxybenzoic acid, sodium persulfate, t-butanol peroxide, preferably 30% hydrogen peroxide, peroxybenzoic acid or oxygen and air;
  • the catalyst for the oxidation reaction may be iron salt , strontium salt, tungstate, molybdenum salt, or a double salt derived therefrom, such as, but not limited to, ferric chloride, ferrous sulfate, ferrous chloride, tungstic acid, sodium tungstate, iron triacetylacetonate, and Cobalt diacetylacetonate;
  • the reaction solvent for the oxidation reaction is selected from one or more of the following: tol
  • the structure obtained in the third step is purified by crystallization of 2-fluoroacrylic acid represented by Formula E, and then subjected to the fourth step reaction.
  • the reaction temperature in the esterification reaction is 10 to 50 ° C, preferably 30 to 40 ° C; and R 3 in the monohydric alcohol to be added includes, without limitation, including 1 to 20 carbon atoms.
  • a substituent of a fatty or aromatic structure preferably methanol, ethanol, propanol or n-butanol;
  • the esterification reagent added by the esterification reaction is concentrated sulfuric acid, ion exchange resin, immobilized acid, dichlorosulfoxide, grass Acid chloride, phosphorus oxychloride, phosgene, etc.;
  • the esterification reaction does not require a solvent, or one or more selected from the group consisting of toluene, n-heptane, n-hexane, dichloromethane, ethyl acetate, and Isopropyl acetate.
  • the preparation method provided by the invention is simple in operation, mild in reaction condition, and suitable for industrial production.
  • the starting material of the preparation method provided by the invention is stable and easy to obtain, and can be purchased in large quantities, and the intermediates of each step also have good stability.
  • the preparation method provided by the present invention can perform good quality control, and obtain a stable intermediate (structure such as an acetal intermediate represented by Formula C) and a solid intermediate (structure of 2-fluoroacrylic acid represented by Formula E). Thereby, a high quality target product (structure of 2-fluoroacrylate as shown in Formula F) is obtained.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • Engineering & Computer Science (AREA)
  • Oil, Petroleum & Natural Gas (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Low-Molecular Organic Synthesis Reactions Using Catalysts (AREA)

Abstract

2-氟丙烯酸酯的制备方法，采用如下步骤：(1)将结构如式A所示的乙烯基醚和一氟二氯甲烷混合，得到结构如式B所示的取代环丙烷化合物；(2)将结构如式B所示的取代环丙烷化合物和R2OH混合得到结构如式C所示的缩醛产物后水解得到结构如式D所示的2-氟丙烯醛；或将结构如式B所示的取代环丙烷化合物和水反应裂解得到结构如式D所示的2-氟丙烯醛；(3)使结构如式D所示的2-氟丙烯醛经氧化得到结构如式E所示的2-氟丙烯酸；和(4)结构如式E所示的2-氟丙烯酸和R3OH混合得到如式F所示的2-氟丙烯酸酯。

Description

一种2-氟丙烯酸酯的制备方法 技术领域
本发明涉及化学合成领域，具体地涉及一种2-氟丙烯酸酯的制备方法。
背景技术
2-氟丙烯酸酯是医药和农药中非常重要的中间体，例如美国Relysa公司开发的由2-氟丙烯酸酯制备的高分子聚合物药物Veltassa(patiromer)，用于治疗CKD患者的高血钾症。同时，2-氟丙烯酸酯也是含氟光纤材料的关键聚合单体。含氟光纤材料玻璃化温度高，表面能低，而且耐老化。同时，2-氟丙烯酸酯可以用于制作高强度结构材料，如超音速飞机驾驶挡风玻璃，已经用于操作微晶蚀刻的集成电路和电子线路板的材料。
现在，对2-氟丙烯酸酯的合成主要有这样几种工艺：
从2-氟代乙酸酯和甲醛反应，再脱水反应得到。2-氟乙酸乙酯具有高毒性，而且和甲醛的加成反应中需要低温控制和较昂贵的碱试剂。
从2-氯丙酸酯出发的合成：2-氯丙酸酯经氟代、NBS溴化和消除反应得到目标产物。这个方法往往需要化学计量的NBS和DBU。
从2-氟丙二酸酯出发的合成：2-氟丙二酸酯经过碱性条件下和甲醛加成然后脱水、脱羧，得到目标产物。这个方法中原料的成本相对较大，而且原子利用上不够经济。
因此，本领域迫切需要一种环境友好，产品选择性好，产物纯度高，原子经济性高且成本低的2-氟丙烯酸酯制备方法。
发明内容
本发明旨在提供一种新的2-氟丙烯酸酯的制备方法。
本发明提供了一种结构如式F所示的2-氟丙烯酸酯的制备方法，所述方法包括步骤：(1)将结构如式A所示的乙烯基醚和一氟二氯甲烷混合，得到结构如式B所示的取代环丙烷化合物；
(2)将结构如式B所示的取代环丙烷化合物和R 2OH混合得到结构如式C所示的缩醛产物后水解得到结构如式D所示的2-氟丙烯醛；或
将结构如式B所示的取代环丙烷化合物和水反应裂解得到结构如式D所示的2-氟丙烯醛；
(3)使结构如式D所示的2-氟丙烯醛经氧化得到结构如式E所示的2-氟丙烯酸；和
(4)结构如式E所示的2-氟丙烯酸和R 3OH混合得到结构如式F所示的2-氟丙烯酸酯；
Figure PCTCN2018072199-appb-000001
其中，R 1、R 2和R 3分别选自1至20个碳原子的脂肪或芳香结构的取代基。
在另一优选例中，步骤(1)混合后发生的加成反应中添加相转移催化剂；所述相转移催化剂选自下述的一种或两种以上：四甲基氯化铵、四丁基氯化铵、四辛基氯化铵、甲基三辛基氯化铵、四辛基溴化铵、四己基氯化铵、四丁基碘化铵、四丁基溴化铵、和三-十二烷基甲基碘化铵。
在另一优选例中，步骤(2)中结构如式B所示的取代环丙烷化合物和R 2OH的混合温度为80-150℃；更优选为80-115℃；最优选为110-115℃。
在另一优选例中，步骤(2)中将结构如式B所示的取代环丙烷化合物和R 2OH混合得到结构如式C所示的缩醛产物在酸性条件下水解得到结构如式D所示的2-氟丙烯醛。
在另一优选例中，所述酸性条件为所用反应物选自盐酸、硫酸、磷酸、甲酸、乙酸的水溶液，更优选为盐酸水溶液。
在另一优选例中，步骤(3)中的氧化所使用的氧化剂选自亚氯酸钠、次氯酸钠、30％双氧水、过氧乙酸、过氧苯甲酸、间氯过氧苯甲酸，过硫酸钠、过氧化叔丁醇；更优选为30％双氧水、过氧苯甲酸或氧气及空气。
在另一优选例中，步骤(3)中的氧化所使用的催化剂选自铁盐，矾盐，钨酸盐，钼盐，或者它们衍生的复盐；更优选地，所述催化剂选自三氯化铁、硫酸亚铁、氯化亚铁、钨酸、钨酸钠、三乙酰丙酮铁或二乙酰丙酮钴。
在另一优选例中，步骤(4)中的混合温度为10-50℃；更优选为30-40℃。
在另一优选例中，所述R1、R2和R3分别选自1至10个碳原子的脂肪或芳香结构的取代基；分别优选自甲基、乙基、丙基或丁基。
据此，本发明提供了一种环境友好，产品选择性好，产物纯度高，原子经济性高且成本低的2-氟丙烯酸酯制备方法。
具体实施方式
发明人经过广泛深入的研究，发现可以稳定方便易得的乙烯基单醚为起始原料，通过环化、缩醛、氧化和酯化得到2-氟丙烯酸酯。这样的工艺流程中各步的中间体有良好的稳定性，并且可以通过对中间体的精制实现有效的品质控制，从而保证得到高品质的目标产物。在此基础上，完成了本发明。
本发明提供的2-氟丙烯酸酯的制备方法包括步骤：
Figure PCTCN2018072199-appb-000002
其中，R 1、R 2和R 3分别选自1至20个碳原子的脂肪或芳香结构的取代基，优选1至10个碳原子的脂肪或芳香结构的取代基，更优选甲基、乙基、丙基或丁基。
具体为：
第一步，使结构如式A所示的乙烯基醚与一氟二氯甲烷发生加成反应，得到结构如式B所示的取代环丙烷化合物；
第二步，结构如式B所示的取代环丙烷化合物在碱性条件下先与一元醇反应得到结构如式C所示的缩醛产物，再在酸性条件下水解得到结构如式D所示的2-氟丙烯醛；或者使结构如式B所示的取代环丙烷化合物在加热条件下和水反应裂解得到结构如式D所示的2-氟丙烯醛；
第三步，使结构如式D所示的2-氟丙烯醛经氧化得到结构如式E所示的2-氟丙烯酸；
第四步，结构如式E所示的2-氟丙烯酸和一元醇反应得到结构如式F所 示的2-氟丙烯酸酯。
在本发明的上述第一步中，加成反应的反应温度为0-50℃，优选为10-30℃；所述加成反应中所添加的加成底物为乙烯基醚，优选乙烯基甲醚、乙烯基乙醚或乙烯基丁醚；所述加成反应在碱性条件下进行，所添加的碱选自氢氧化钠、氢氧化钾、或氢氧化锂，优选氢氧化钠；所述加成反应的溶剂为有机溶剂和水，所述有机溶剂选自二氯甲烷、甲苯、氯代苯，正庚烷、乙酸乙酯、或甲基叔丁基醚；所述加成反应中所添加的相转移催化剂选自下述的一种或两种以上：四甲基氯化铵、四丁基氯化铵、四辛基氯化铵、甲基三辛基氯化铵、四辛基溴化铵、四己基氯化铵、四丁基碘化铵、四丁基溴化铵、和三-十二烷基甲基碘化铵。
在本发明的上述第二步中，与一元醇的反应温度为80-150℃，优选为110-115℃；与一元醇的反应中所添加的碱选自氢氧化钠、氢氧化钾、碳酸钠，碳酸钾，氢氧化锂、三乙胺、三正丙胺、三正丁胺、二异丙基乙基胺或吡啶，优选吡啶、碳酸钠、三乙胺、三正丙胺或二异丙基乙基胺。
上述第二步中经过结构如式C所示的缩醛中间体的开环步骤在碱和醇存在下加热裂解得到2-氟丙烯缩醛，所添加的一元醇中R 2包括并不限于包括含1至20个碳原子的脂肪或含芳香结构的取代基，优选甲醇、乙醇、丙醇或正丁醇。结构如式C所示的化合物可进行深度的纯化，从而保证最终产品的高品质；所述纯化方式包括但不限于，蒸馏纯化。
上述第二步中涉及的酸性条件下的水解反应中的反应温度为50-90℃，优选为65-75℃；所述酸性条件为所用反应物选自盐酸、硫酸、磷酸、甲酸、乙酸的水溶液，优选盐酸水溶液。
上述第二步中在水存在下裂解得到结构如式D所示的2-氟丙烯醛。
在本发明的上述第三步中，氧化反应中的反应温度为0-60℃，优选为15-25℃；所述氧化反应所使用的氧化剂选自亚氯酸钠、次氯酸钠、30％双氧水、过氧乙酸、过氧苯甲酸、间氯过氧苯甲酸，过硫酸钠、过氧化叔丁醇，优选30％双氧水、过氧苯甲酸或氧气及空气；所述氧化反应的催化剂可以是铁盐，矾盐，钨酸盐，钼盐，或者它们衍生的复盐，例如但不限于，三氯化铁、硫酸亚铁、氯化亚铁、钨酸、钨酸钠、三乙酰丙酮铁、和二乙酰丙酮钴；所述氧化反应的反应溶剂选自下述的一种或两种以上：甲苯、甲醇、乙醇、正庚烷、正己烷、和二氯甲烷。
在本发明的一种优选实施方式中，第三步得到的结构如式E所示的2-氟丙烯酸经结晶纯化后进行第四步反应。
在本发明的上述第四步中，酯化反应中的反应温度为10-50℃，优选为30-40℃；所添加的一元醇中R 3包括并不限于包括含1至20个碳原子的脂肪或芳香结构的取代基，优选甲醇、乙醇、丙醇或正丁醇；所述酯化反应所添加的酯化试剂为浓硫酸、离子交换树脂，固载酸，二氯亚砜、草酰氯、三氯氧磷、光气等；所述酯化反应无需溶剂，或从以下溶剂中选择一种或两种以上：甲苯、正庚烷、正己烷、二氯甲烷、乙酸乙酯、和乙酸异丙酯。
本发明提到的上述特征，或实施例提到的特征可以任意组合。本案说明书所揭示的所有特征可与任何组合物形式并用，说明书中所揭示的各个特征，可以任何可提供相同、均等或相似目的的替代性特征取代。因此除有特别说明，所揭示的特征仅为均等或相似特征的一般性例子。
本发明的主要优点在于：
1、本发明提供的制备方法操作简便，反应条件温和，适合工业化生产。
2、本发明提供的制备方法的起始原料乙烯基单醚稳定方便易得，可以大量采购，各步的中间体也有不错的稳定性。
3、本发明提供的制备方法可以进行良好的品质控制，得到稳定的中间体(结构如式C所示的缩醛中间体)以及固体中间体(结构如式E所示的2-氟丙烯酸)，从而保证得到高品质的目标产物(结构如式F所示的2-氟丙烯酸酯)。
下面结合具体实施例，进一步阐述本发明。应理解，这些实施例仅用于说明本发明而不用于限制本发明的范围。下列实施例中未注明具体条件的实验方法，通常按照常规条件或按照制造厂商所建议的条件。除非另外说明，否则所有的百分数、比率、比例、或份数按重量计。本发明中的重量体积百分比中的单位是本领域技术人员所熟知的，例如是指在100毫升的溶液中溶质的重量。除非另行定义，文中所使用的所有专业与科学用语与本领域熟练人员所熟悉的意义相同。此外，任何与所记载内容相似或均等的方法及材料皆可应用于本发明方法中。文中所述的较佳实施方法与材料仅作示范之用。
实施例1
2-丁氧基-1-氯-1-氟环丙烷的制备
在500ml四口瓶中依次加入水42.8g(2.38mol)，氢氧化钠42.8g(1.07mol)，乙烯基丁醚20g(0.2mol)，甲苯49.2g(0.58mol)，氮气保护，升温至40℃，开始滴加二氯一氟甲烷27.79g(0.27mol)，保温反应12h，分层，有机相减压蒸馏，回收溶剂，继续升温蒸馏，得到2-丁氧基-1-氯-1-氟环丙烷。纯度98％，收率96％。
1H NMR(400MHz，CDCl 3)：3.74-3.39(m，3H)，1.75-1.49(m，3H)，1.49-1.22(m，3H)，1.04-0.82(m，3H).
19F NMR(400MHz，CDCl 3)：-158.76--159.38(m，1F)(43％，trans-isomer)，-137.11--138.48(m，1F)(57％，cis-isomer).
实施例2
1-((1-丁氧基-2-氟丙烯基)氧基)丁烷的制备
在250ml四口瓶中加入吡啶15.3g(0.19mol)，正丁醇15.5g(0.21mol)，2-丁氧基-1-氯-1-氟环丙烷30.0g(0.18mol)，回流反应16h，蒸馏得到1-((1-丁氧基-2-氟丙烯基)氧基)丁烷。收率98％。
1H NMR(400MHz，CDCl 3)：1.00-0.69(m，6H)，1.42-1.20(m，4H)，1.62-1.42(m，4H)，3.68-3.22(m，4H)，4.79-4.55(m，2H)，4.90-4.79(s，1H).
19F NMR(400MHz，CDCl 3)：-137.46--138.52(m，1F).
实施例3
2-氟丙烯醛的制备
向1-((1-丁氧基-2-氟丙烯基)氧基)丁烷中滴加10％盐酸73g(0.2mol)，70℃反应2小时，反应完毕后精馏，得到2-氟丙烯醛。收率90％。
1H NMR(400MHz，CDCl 3)：5.63-5.38(m，1H)，5.87-5.65(m，1H)，9.47-9.03(d，1H).
19F NMR(400MHz，CDCl 3)：-121.28--125.09(m，1F).
实施例4
2-氟丙烯醛的制备
将1-((1-丁氧基-2-氟丙烯基)氧基)丁烷和水蒸汽按1∶1混合，氮气作为载气，通过250℃裂解反应器，尾气降温后精馏得到2-氟丙烯醛产品。收率70％。
1H NMR(400MHz，CDCl 3)：5.63-5.38(m，1H)，5.87-5.65(m，1H)，9.47-9.03(d，1H).
19F NMR(400MHz，CDCl 3)：-121.28--125.09(m，1F).
实施例5
2-氟丙烯酸的制备
在250ml四口瓶四口瓶中混合2-氟丙烯醛8.89g(0.12mol)，三氯化铁0.89g(5.5mmol)，保温30℃，滴加30％双氧水40.8g(0.36mol)，保温搅拌2h，加入乙酸乙酯20g萃取，有机相水洗，浓缩至干，得到2-氟丙烯酸粗品，用10g正庚烷结晶得到2-氟丙烯酸成品。收率90％。
1H NMR(400MHz，CDCl 3)：5.62-5.17(m，1H)，6.07-5.62(m，1H)，7.45-7.20(s，1H).
19F NMR(400MHz，CDCl 3)：-118.55(dd，1F).
实施例6
2-氟丙烯酸的制备
在250ml四口瓶中混合2-氟丙烯醛8.89g(0.12mol)，m-cpba 26g(0.15mol)，二氯甲烷30g，保温20℃搅拌2h，降温至0℃左右，过滤，滤液浓缩至干，得到2-氟丙烯酸粗品，用10g正庚烷结晶得到2-氟丙烯酸成品。收率92％。
1H NMR(400MHz，CDCl 3)：5.62-5.17(m，1H)，6.07-5.62(m，1H)，7.45-7.20(s，1H).
19F NMR(400MHz，CDCl 3)：-118.55(dd，1F).
实施例7
2-氟丙烯酸甲酯的制备
在100ml三口瓶中混合甲醇6.4g(0.2mol)和2-氟丙烯酸8.64g(0.096mol)，升温至30℃，滴加浓硫酸4.9g(0.05mol)，保温30-35℃反应2h，加入饱和NaHCO 3中和体系至中性，加入甲基叔丁基醚20g(0.23mol)萃取，有机相精馏得到2-氟丙烯酸甲酯。收率89％。
1H NMR(400MHz，CDCl 3)：3.89-3.78(s，3H)，5.35-5.25(m，1H)，5.74-5.55(m，1H).
19F NMR(400MHz，CDCl 3)：-117.72(dd，1F).
实施例8
2-氟丙烯酸甲酯的制备
在100ml三口瓶中于5-10℃混合2-氟丙烯酸8.64g(0.096mol)和二氯亚砜13.1g(0.11mol)，升温至30℃，滴加甲醇6.4g(0.2mol)，保温30-35℃反应2h，加入NaHCO 3水溶液中和体系至中性，加入甲基叔丁基醚20g(0.23mol)萃取，有机相精馏得到2-氟丙烯酸甲酯。收率93％。
1H NMR(400MHz，CDCl 3)：3.89-3.78(s，3H)，5.35-5.25(m，1H)，5.74-5.55(m，1H).
19F NMR(400MHz，CDCl 3)：-117.72(dd，1F).
实施例7和8得到的2-氟丙烯酸甲酯品质：
测试方法 结果
外观 目测 无色至浅黄色透明液体
纯度 GC-FID ＞99.5％
水份 KF ＜500ppm
R21 GC-FID ND.
2-氯丙烯酸甲酯 GC-FID ＜1ppm
2-溴丙烯酸甲酯 GC-FID ND.
一氯甲烷 GC-FID ND.
2-氟乙酸甲酯 GC-FID ND.
实施例9
2-氟丙烯酸丁酯的制备
在100ml三口瓶中混合丁醇14.8g(0.2mol)和2-氟丙烯酸8.64g(0.096mol)，升温至30℃，滴加浓硫酸4.9g(0.05mol)，保温30-35℃反应2h，加入饱和NaHCO 3中和体系至中性，加入甲基叔丁基醚20g(0.23mol)萃取，有机相精馏得到2-氟丙烯酸丁酯。收率90％。
1H NMR(400MHz，CDCl 3)：1.03-0.81(t，3H)，1.50-1.30(m，2H)，1.78-1.60(m，2H)，4.34-4.10(m，2H)，5.90-5.18(m，2H).
19F NMR(400MHz，CDCl 3)：-117.52(dd，1F).
实施例9得到的2-氟丙烯酸丁酯品质：
测试方法 结果
外观 目测 无色至浅黄色透明液体
纯度 GC-FID ＞99.5％
水份 KF ＜500ppm
R21 GC-FID ND.
2-氯丙烯酸丁酯 GC-FID ＜1ppm
2-溴丙烯酸丁酯 GC-FID ND.
一氯丁烷 GC-FID ND.
2-氟乙酸丁酯 GC-FID ND.
以上所述仅为本发明的较佳实施例而已，并非用以限定本发明的实质技术内容范围，本发明的实质技术内容是广义地定义于申请的权利要求范围中，任何他人完成的技术实体或方法，若是与申请的权利要求范围所定义的完全相同，也或是一种等效的变更，均将被视为涵盖于该权利要求范围之中。

Claims (12)

  1. 一种结构如式F所示的2-氟丙烯酸酯的制备方法，其特征在于，所述方法包括步骤：(1)将结构如式A所示的乙烯基醚和一氟二氯甲烷混合，得到结构如式B所示的取代环丙烷化合物；
    (2)将结构如式B所示的取代环丙烷化合物和R 2OH混合得到结构如式C所示的缩醛产物后水解得到结构如式D所示的2-氟丙烯醛；或
    将结构如式B所示的取代环丙烷化合物和水反应裂解得到结构如式D所示的2-氟丙烯醛；
    (3)使结构如式D所示的2-氟丙烯醛经氧化得到结构如式E所示的2-氟丙烯酸；
    (4)结构如式E所示的2-氟丙烯酸和R 3OH混合得到结构如式F所示的2-氟丙烯酸酯；
    Figure PCTCN2018072199-appb-100001
    Figure PCTCN2018072199-appb-100002
    其中，R 1、R 2和R 3分别选自1至20个碳原子的脂肪或芳香结构的取代基。
  2. 如权利要求1所述的制备方法，其特征在于，步骤(1)混合后发生的加成反应中添加相转移催化剂；所述相转移催化剂选自下述的一种或两种以上：四甲基氯化铵、四丁基氯化铵、四辛基氯化铵、甲基三辛基氯化铵、四辛基溴化铵、四己基氯化铵、四丁基碘化铵、四丁基溴化铵、和三-十二烷基甲基碘化铵。
  3. 如权利要求1所述的制备方法，其特征在于，步骤(2)中结构如式B所示的取代环丙烷化合物和R 2OH的混合温度为80-150℃。
  4. 如权利要求3所述的制备方法，其特征在于，步骤(2)中结构如式B所示的取代环丙烷化合物和R 2OH的混合温度为80-115℃。
  5. 如权利要求3所述的制备方法，其特征在于，步骤(2)中结构如式B所示的取代环丙烷化合物和R 2OH的混合温度为110-115℃。
  6. 如权利要求1所述的制备方法，其特征在于，步骤(2)中将结构如式B所示的取代环丙烷化合物和R 2OH混合得到结构如式C所示的缩醛产物在酸性条件下水解得到结构如式D所示的2-氟丙烯醛。
  7. 如权利要求6所述的制备方法，其特征在于，所述酸性条件为所用反应物选自盐酸、硫酸、磷酸、甲酸、乙酸的水溶液，优选盐酸水溶液。
  8. 如权利要求1所述的制备方法，其特征在于，步骤(3)中的氧化所使用的氧化剂选自亚氯酸钠、次氯酸钠、30％双氧水、过氧乙酸、过氧苯甲酸、 间氯过氧苯甲酸，过硫酸钠、过氧化叔丁醇，优选30％双氧水、过氧苯甲酸或氧气及空气。
  9. 如权利要求1所述的制备方法，其特征在于，步骤(3)中的氧化所使用的催化剂选自铁盐，矾盐，钨酸盐，钼盐，或者它们衍生的复盐。
  10. 如权利要求9所述的制备方法，其特征在于，所述催化剂选自三氯化铁、硫酸亚铁、氯化亚铁、钨酸、钨酸钠、三乙酰丙酮铁或二乙酰丙酮钴。
  11. 如权利要求1所述的制备方法，其特征在于，步骤(4)中的混合温度为10-50℃，优选为30-40℃。
  12. 如权利要求1-11任一项所述的制备方法，其特征在于，所述R1、R2和R3分别选自1至10个碳原子的脂肪或芳香结构的取代基；分别优选自甲基、乙基、丙基或丁基。
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