Synthetic method of perfluorocarboxylate vinyl ether monomer and intermediate thereof

Abstract

The invention discloses a synthetic method of a perfluorocarboxylate vinyl ether monomer and an intermediate thereof. Specifically, the invention provides a preparation method of a compound as shown in a formula II and application of the compound in preparation of a perfluorocarboxylate vinyl ether monomer, and the preparation method of the compound as shown in the formula II comprises the following steps: S1, in an organic solvent, under the action of zinc, carrying out a coupling reaction as shown in the following formula on a compound as shown in a formula I to obtain a compound as shown in the formula II; the compound shown in the formula II is obtained. The route has one or more of the following advantages: high safety, low cost and environmental friendliness.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, and discloses a self-coupling method for fluoroalkyl halides, and further applies it to the efficient synthesis of perfluorocarboxylic acid ester vinyl ether monomers. Background Technology

[0002] Perfluorocarboxylate vinyl ethers, as important fluorinated vinyl ether monomers, occupy a pivotal position in high-tech fields and demonstrate broad application prospects due to their excellent physicochemical properties. Therefore, their synthesis methods and application areas have attracted much attention. Perfluorocarboxylate vinyl ethers play a crucial role in the preparation of fluoropolymers, especially in the synthesis of perfluorinated ion exchange membranes. Perfluorinated ion exchange membranes are special fluorinated polymer materials widely used in hydrogen-oxygen fuel cells, ion-selective permeation membranes in chlor-alkali industrial electrolyzers, and various water treatment and electrolysis equipment, playing a significant role in promoting green chemistry and environmental protection. Furthermore, perfluorocarboxylate vinyl ethers can also participate in polymerization reactions as comonomers or modifying monomers to improve various properties of fluoropolymers and fluoroelastomers. Therefore, developing efficient synthesis methods for perfluorocarboxylate vinyl ethers has significant academic value and application prospects.

[0003] In the 1960s, DuPont first reported a synthetic route for perfluorocarboxylic acid ester vinyl ethers. This method uses tetrafluorosuccinyl difluoride as the starting material, which undergoes an addition reaction with hexafluoropropylene oxide, followed by alkaline thermal cracking and acidification esterification steps to finally obtain the target product, perfluorocarboxylic acid ester vinyl ether. The route is shown in the following formula. However, although DuPont successfully synthesized this type of compound, the high cost of the starting materials and generally low reaction yields prevented its commercial application (see Sullivan, R. J. Org. Chem. 34, 1841–1844 (1969)).

[0004]

[0005] In the 1980s, DuPont further reported another method for synthesizing perfluorocarboxylic acid ester vinyl ether monomers, which reduced the number of CF2 groups compared to previously reported compounds, as shown in the following formula. Resins polymerized using this monomer exhibited certain differences in properties (see Wiley, DW&Del, W.US2988537; England, DC&Del, W.US4131740).

[0006]

[0007] In the 1970s, Asahi Glass Co., Ltd. of Japan successfully developed commercialized... The key to the perfluorocarboxylic acid membrane lies in the synthesis of the perfluorocarboxylic acid ester vinyl ether monomer, as shown in the following route. This synthetic strategy uses tetrafluoroethylene and iodine as starting materials. First, a perfluorodiiodine compound is prepared by the telomerization reaction of iodine with tetrafluoroethylene. Subsequently, this compound is reacted sequentially with fuming sulfuric acid and methanol to obtain a methyl ester-containing acyl fluoride intermediate. This intermediate is further subjected to an addition reaction with hexafluoropropylene oxide, and finally, through alkalization and thermal cracking, it is efficiently converted into the target product of perfluorocarboxylic acid ester vinyl ether (see Machida, MY & Yokohama, SKUS4151200; Machida, MY, Yokohama, SM & Tokyo, SSUS4153804).

[0008]

[0009] In the 1990s, Asahi Glass Co., Ltd. reported a method for synthesizing perfluorocarboxylic acid ester vinyl ethers, as shown in the following synthetic route. This method is similar to that of DuPont, with the main difference being the acyl fluoride thermal decomposition step. Asahi Glass Co., Ltd. uses nitrogen dilution and heating for thermal decomposition, thus avoiding the use of strong bases (see Yamabe, M., Munekata, S., Kaneko, I. & Ukihashi, HJ Fluorine. Chem. 94, 65–68 (1999)).

[0010]

[0011] In the 1980s, Hoechst AG of Germany pioneered the electrolytic synthesis of perfluorocarboxylate vinyl ether monomers. This method, centered on the electrolysis of HSO3F, aimed to generate disulfonyl fluoride, as shown in the following formula. Due to the involvement of strong oxidants and a highly acidic environment in the electrolysis process, the reactor required extremely high corrosion resistance; therefore, specially formulated glassy carbon was used as the anode material, and platinum as the cathode. The generated disulfonyl fluoride then underwent a telomerization reaction with tetrafluoroethylene, producing tetrafluorosuccinyl difluoride under fluoride salt catalysis. This tetrafluorosuccinyl difluoride was then converted into a methyl ester-containing acyl fluoride intermediate via esterification. Further, this intermediate underwent an addition reaction with hexafluoropropylene oxide, ultimately yielding the perfluorocarboxylate vinyl ether monomer via thermal decarboxylation (see Hofheim am Taunus, GS & Langgons, WSUS4454072; Eschborn, HMUS4466926).

[0012]

[0013] In the 1990s, the Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, studied the synthesis of α-methoxycarbonyl difluoroacetyl fluoride, a key precursor of perfluorocarboxylate vinyl ethers. The specific synthetic route is shown in the following formula. The perfluorocarboxylate vinyl ether monomer obtained in this study was consistent with the product reported by DuPont. Although the reaction steps of this synthetic route are increased, the intermediates involved have important application value (see Hu Changming, et al. Acta Chimica Sinica, 1986(44):310–313; He Yonghai, et al. Organic Chemistry, 1991(11):179–182).

[0014]

[0015] Currently, although several methods for synthesizing perfluorocarboxylic acid ester vinyl ether monomers have been reported, most of them are for industrial applications. membrane and The monomers required for the membrane are the target compounds. Among them, the synthetic route developed by DuPont and Asahi Glass is relatively mature and has achieved industrial application and commercialization, using inexpensive tetrafluoroethylene as the starting material. However, tetrafluoroethylene polymerization is explosive and requires extremely sophisticated reaction equipment. Furthermore, Asahi Glass uses tetrafluoroethylene for telomerization to prepare perfluorodiiodine compounds, which are highly toxic, with a median lethal dose (LC50) of [missing information]. 50 The concentration is approximately 70 ppm, therefore the reaction process and post-treatment require extreme caution.

[0016] Given the application potential of perfluorocarboxylic acid ester vinyl ether monomers in many fields, developing a safe, reliable, low-cost, and environmentally friendly efficient synthetic route is of great research significance. Summary of the Invention

[0017] This invention aims to overcome the technical difficulties in existing methods for preparing vinyl ether monomers of perfluorocarboxylate esters, such as high hazard of raw materials, demanding equipment requirements, or cumbersome synthetic routes. To this end, this invention provides a novel method for synthesizing vinyl ether monomers of perfluorocarboxylate esters and their key intermediates. This route has one or more of the following advantages: significantly improved operational safety, effectively reduced production costs, and a more environmentally friendly approach.

[0018] This invention provides a method for preparing a compound as shown in Formula II, comprising the following step S1:

[0019] In an organic solvent, under the action of zinc (Zn), the compound shown in Formula I undergoes a coupling reaction as shown in the following formula to give the compound shown in Formula II.

[0020]

[0021] X is chlorine, bromine, or iodine;

[0022] R 1 Independently for C 1-6 alkyl.

[0023] In one particular scheme, X is bromine.

[0024] In one of the schemes, R 1 It can be methyl or ethyl, for example, ethyl.

[0025] In one embodiment, the compound shown in Formula I is

[0026] In one embodiment, the compound shown in Formula II is

[0027] In one embodiment, the organic solvent is an ether solvent, for example, the organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane and methyl tert-butyl ether, and tetrahydrofuran is another example.

[0028] In one embodiment, the ratio of the number of moles of the compound as shown in Formula I to the volume of the solvent is (0.01-100) mol:1 L, for example (0.1-30) mol:1 L, or (0.1-10) mol:1 L, or even 0.5 mol:1 L, 1 mol:1 L, 2 mol:1 L, 3 mol:1 L, or 5 mol:1 L.

[0029] In one embodiment, the molar ratio of zinc to the compound shown in Formula I is (0.1-10):1, for example (0.1-3):1, for another example (0.5-1):1, and for yet another example 0.8:1.

[0030] In one embodiment, the reaction system of the coupling reaction further includes a catalyst, which is selected from one or more of nickel-based catalysts, copper-based catalysts, iron-based catalysts, and palladium-based catalysts, such as nickel-based catalysts.

[0031] In one embodiment, the nickel catalyst is selected from nickel chloride, nickel chloride hexahydrate, nickel bromide, nickel iodide, nickel bromide trihydrate, nickel perchlorate hexahydrate, nickel tetrafluoroborate hexahydrate, ethylene glycol dimethyl ether nickel bromide, tris(2,2'-bipyridine) nickel bromide, (2,2'-bipyridine) dibromide, 1,10-o-phenanthroline nickel dibromide, bis(triphenylphosphine) nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, 1,3-bis(diphenylphosphine propane) dichloride, etc. One or more of tricyclohexylphosphine nickel chloride and bis(cyclopentadiene) nickel, such as nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel bromide, tris(2,2'-bipyridine) nickel bromide, (2,2'-bipyridine) dibromide, 1,10-o-phenanthroline nickel dibromide, 1,2-bis(diphenylphosphine)ethane nickel chloride and 1,3-bis(diphenylphosphine propane) dichloride, and for example, nickel chloride or (2,2'-bipyridine) dibromide.

[0032] In one embodiment, the copper catalyst is copper sulfate.

[0033] In one embodiment, the iron-based catalyst is an iron halide, such as ferrous bromide.

[0034] In one embodiment, the palladium catalyst is a palladium halide, such as palladium iodide or palladium bromide.

[0035] In one embodiment, the molar ratio of the catalyst to the compound shown in Formula I is (0.00001-1):1, for example (0.00001-0.5):1, or (0.00009-0.11):1, or even 0.0001:1, 0.0002:1, 0.002:1, 0.005:1, 0.01:1, 0.05:1, or 0.1:1.

[0036] In one embodiment, the reaction system of the coupling reaction further includes a ligand selected from one or more compounds shown as formula L1 and formula L2:

[0037]

[0038] Among them, ring A and ring B are independently 5-12 membered heteroaryl or 5-12 membered heterocycle;

[0039] n1 and n2 are independently 0, 1, 2, 3, 4 or 5;

[0040] R a and R b Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-12 Aryl or 5-12 heteroaryl groups;

[0041] Or, an R a An R b Together with the atoms bonded to it, they form C 6-12 aryl, 5-12 heteroaryl, with one or more R c Replacement C 6-12 aryl or aryl with one or more R c Substituted 5-12 heteroaryl groups;

[0042] R c Independently for C 1-6 Alkyl or -OC 1-6 alkyl;

[0043] R 1-1 R 1-2 and R 1-3 Independently for C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, -C 1-6 Alkylene-P(R) 1-1a (R) 1-1b ), by one or more R 1-1c Replacement C 3-12 cycloalkyl, with one or more R 1-1c Substituted 3-12 membered heterocyclic alkyl groups, with one or more R 1-1c Replacement C 6-12 aryl or aryl with one or more R 1-1c Substituted 5-12 heteroaryl groups;

[0044] Or, R 1-1 R 1-2 Together with phosphorus atoms, they form 5-12 membered phosphorus heterocycles or are bounded by one or more R atoms. 1-1c A substituted 5-12 membered phosphorus heterocycle, wherein the heteroatom in the 5-12 membered phosphorus heterocycle is phosphorus and the number of heteroatoms is 1;

[0045] R 1-1c Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-12 aryl, 5-12 heteroaryl, with one or more R 1-1c-1 Replacement C 6-12 aryl or aryl with one or more R 1-1c-1 Substituted 5-12 heteroaryl R 1-1c-1 Independently for C 1-6 Alkyl, -OC 1-6 Alkyl or -C 0-6 Alkylene-P(R) 1-1a-1 (R) 1-1b-1 );

[0046] R 1-1a and R 1-1b Independently for C 6-12 Aryl or 5-12 heteroaryl groups;

[0047] Or, R 1-1a R 1-1b Together with phosphorus atoms, they form 5-12 membered phosphorus heterocycles or are bounded by one or more R atoms. 1-1 c-substituted 5-12 membered phosphorus heterocycles, wherein the heteroatom in the 5-12 membered phosphorus heterocycle is phosphorus and the number of heteroatoms is 1;

[0048] The heteroatoms in the 5-12 membered heteroaryl group and the 5-12 membered heterocycle are independently one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

[0049] In one embodiment, the ligand is a compound as shown in Formula L1.

[0050] In one embodiment, ring A and ring B are independently 5-6 membered heteroaryl or 5-6 membered heterocycles, wherein the 5-6 membered heterocycle contains one double bond; for example, ring A and ring B are independently pyridinyl, quinolinyl or dihydrooxazolyl, or pyridinyl or dihydrooxazolyl.

[0051] In one of the schemes, R a and R b Independently for C 1-6 Alkyl or C 6-12 Aryl groups, such as methyl, tert-butyl, or phenyl.

[0052] In one scheme, an R a An R b Together with the atoms bonded to it, they form C 6-12 Aryl groups, such as phenyl groups.

[0053] In one of the schemes, R 1-1 R 1-2 and R 1-3 Independently for C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-12 Aryl, -C 1-6 Alkylene-P(R) 1-1a (R) 1-1b ) or by one or more R 1-1c Replacement C 6-12 Aryl; for example, R 1-1 R 1-2 and R 1-3 Independently tert-butyl, cyclohexyl, phenyl, naphthyl,

[0054] In one of the schemes, R 1-1 R 1-2 Together with phosphorus atoms, they form 5-6 membered phosphorus heterocycles or are bound by one or more R atoms. 1-1c Substituted 5-6 membered phosphorus heterocycles, for example

[0055] In one of the schemes, R 1-1a R 1-1b Together with phosphorus atoms, they form 5-6 membered phosphorus heterocycles or are bound by one or more R atoms. 1-1c Substituted 5-6 membered phosphorus heterocycles, for example

[0056] In one embodiment, the ligand is selected from 6,6'-dimethyl-2,2'-bipyridine, 2,2'-bipyridine, 6,6'-di-tert-butyl-2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2,2-bis(2-azolin), (4S,4'S)-4,4'-diisopropyl-4,4',5,5'-tetrahydro-2,2'-bisoxazole, (S,S)- 2,2'-Isopropylidene bis(4-phenyl-2-oxazoline), 2-(4,5-dihydro-2-oxazolyl)quinoline, (S)-4-tert-butyl-2-(2-azaphenyl)oxazoline, tris(2,6-dimethoxyphenyl)phosphine, tris[2-(diphenylphosphine)ethyl]phosphine, 2-(di-tert-butylphosphine)-1,1'-binaphthyl, 1,5-bis(diphenylphosphine)pentane, tricyclohexylphosphine, S-(-)-2,2'-bis One of the following: (diphenylphosphine)-1,1'-binaphthyl, (2R,4R)-2,4-bis(diphenylphosphine)pentane, 1,2-bis(biphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, (+)-1,2-bis((2R,5R)-2,5-diethylphosphinoyl)benzene, and 3-(tert-butoxy)-2',6'-diisopropyl-6-methoxy-[1,1'-biphenyl]-2-yl)dicyclohexylphosphine One or more, such as one or more selected from 6,6'-dimethyl-2,2'-bipyridine, 2,2'-bipyridine, 6,6'-di-tert-butyl-2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2,2-bis(2-azolin) and (S)-4-tert-butyl-2-(2-azaphenyl)oxazoline, and for example 6,6'-dimethyl-2,2'-bipyridine.

[0057] In one embodiment, the reaction system of the coupling reaction further includes a catalyst and a ligand. Preferably, the catalyst is selected from one or more of nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel bromide, tris(2,2'-bipyridine) nickel bromide, (2,2'-bipyridine) dibromide, 1,10-o-phenanthroline nickel dibromide, 1,2-bis(diphenylphosphine)ethane nickel chloride, and 1,3-bis(diphenylphosphine propane) dichloride; the ligand is a compound as shown in Formula L1 in any embodiment.

[0058] In one embodiment, the molar ratio of the ligand to the compound shown in Formula I is (0.0001-1):1, for example (0.001-0.5):1, or (0.001-0.1):1, or even 0.006:1.

[0059] In one embodiment, the coupling reaction is carried out at a temperature of -80°C to 100°C, for example -40°C to 80°C, or for example 45°C to 65°C.

[0060] In one embodiment, the coupling reaction temperature is -10℃, -30℃, -40℃, 0℃, room temperature, 40℃, 50℃, 60℃, or 80℃.

[0061] The process of the coupling reaction is monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), with the reaction endpoint being the disappearance or cessation of the reaction of the compound shown in Formula II. In one embodiment, the reaction time is 0.5-5 hours, for example, 2 hours.

[0062] The coupling reaction is followed by conventional post-processing, which in one embodiment is selected from one or more of the following steps: filtration, solvent removal, or purification (e.g., distillation purification).

[0063] In one embodiment, the coupling reaction does not require light exposure.

[0064] In one embodiment, the coupling reaction is carried out in an air atmosphere.

[0065] This invention provides a method for preparing a compound as shown in Formula III, comprising the following step S2:

[0066] In a solvent, under alkaline conditions, the compound shown in Formula II undergoes a hydrolysis reaction as shown in the following formula to give the compound shown in Formula III.

[0067]

[0068] Among them, R 1 Independently for C 1-6 alkyl.

[0069] In one of the schemes, R 1 It can be either methyl or ethyl.

[0070] In one embodiment, the compound shown in Formula III is

[0071] In one embodiment, the solvent is an alcohol solvent, such as one or more selected from methanol, ethanol, isopropanol and tert-butanol, for example, ethanol.

[0072] In one embodiment, the ratio of the number of moles of the compound as shown in Formula II to the volume of the solvent is (0.01-10) mol:1 L, for example (0.1-1) mol:1 L, or for example 0.5 mol:1 L.

[0073] In one embodiment, the base is an inorganic base, such as one or more selected from potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide, and lithium hydroxide, for example, potassium carbonate.

[0074] In one embodiment, the molar ratio of the base to the compound shown in Formula II is (0.8-1):1, for example, 1:1.

[0075] In one embodiment, the hydrolysis reaction is carried out at a temperature of -20°C to 30°C, for example -10°C to 10°C, or even 0°C.

[0076] The hydrolysis reaction is monitored using conventional monitoring methods in the art (e.g., TLC, LC-MS), with the reaction ending when the compound shown in Formula II disappears or ceases to react. In one embodiment, the reaction time is 0.5-5 hours, for example, 3 hours.

[0077] The hydrolysis reaction is followed by conventional post-treatment processes, such as acidification.

[0078] In one embodiment, the acid is added to the hydrolysis reaction system in the form of an aqueous solution of the acid.

[0079] In one embodiment, the acid is HCl or H2SO4, for example HCl, or for example a 1 mol / L aqueous solution of hydrochloric acid.

[0080] In one embodiment, after the acidification is completed, the pH value of the reaction system is 0.1-3, for example, pH value is 1.

[0081] In one embodiment, the acidification process further includes one or more of the following post-processing steps: extraction (e.g., extraction with ethyl acetate or methyl tert-butyl ether) and solvent removal.

[0082] In one embodiment, the method for preparing the compound shown in Formula III further includes a method for preparing the compound shown in Formula II, comprising the following step S1:

[0083] In an organic solvent, with the aid of zinc, the compound shown in Formula I undergoes a coupling reaction as shown in the following formula to give the compound shown in Formula II.

[0084]

[0085] X, R 1 The definition is as described in any of the preceding schemes, and the conditions and operations for preparing the compound as shown in Formula II may also be as described in any of the preceding schemes.

[0086] This invention provides a method for preparing a compound as shown in Formula VIII, comprising step S1 as described above.

[0087]

[0088] R 1 C 1-6 Alkyl groups, such as methyl or ethyl;

[0089] Preferably, the method for preparing the compound shown in Formula VIII further includes step S2 as described above.

[0090] This invention provides the use of compounds of formulas I, II and III in the preparation of compounds of formula VIII.

[0091]

[0092] R 1 Independently for C 1-6 Alkyl, such as methyl or ethyl; X is chlorine, bromine or iodine, such as bromine.

[0093] In this invention, room temperature (RT or rt refers to room temperature) refers to ambient temperature, which is 10℃-35℃.

[0094] Based on common knowledge in the field, the above-mentioned preferred conditions can be combined arbitrarily to obtain various preferred embodiments of the present invention.

[0095] The reagents and raw materials used in this invention are all commercially available.

[0096] The positive and progressive effects of this invention are as follows:

[0097] The intermediate compound 2 involved in this application is prepared by existing techniques involving the polymerization of tetrafluoroethylene, a reaction with potential explosion risks and demanding requirements for experimental equipment. To overcome these shortcomings, this application innovatively uses inexpensive and readily available raw materials to synthesize intermediate compound 2 through a simpler and safer coupling reaction, with precise control over the ester hydrolysis step to ultimately obtain the perfluorocarboxylic acid ester vinyl ether monomer. This synthetic route is a novel technical solution with one or more of the following advantages: high safety, low cost, and environmental friendliness. Detailed Implementation

[0098] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0099] Screening Example 1:

[0100] Screening Example 1-1

[0101]

[0102] Under air conditions, zinc powder (5.2 g, 80 mmol, 0.80 equiv.), nickel dichloride (65 mg, 0.50 mmol, 0.50 mol%), and 6,6'-dimethyl-2,2'-bipyridine (111 mg, 0.600 mmol, 0.600 mol%) were added to dry THF (50 mL, 2.0 M) solvent, followed by the slow addition of ethyl bromide (20.3 g, 100 mmol, 1.00 equiv.). The reaction was stirred at 50 °C for 2 h, and the yield (83% yield) was determined by NMR fluorine spectrometry. 1 H NMR (500MHz, CDCl3) δ4.41 (q, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H); 13 C NMR (126MHz, CDCl3) δ160.0–159.2 (m), 108.2 (tt, J = 265.2, 31.4Hz), 64.4, 13.8; 19 F NMR(376MHz,CDCl3)δ-120.2–-120.3(m)ppm.HRMS(EI)calcd.for C8H 10 F4O4[M] + m / z 246.1653,found 246.1652.IR(KBr):ν max =3537,2991,1781,1376,1321,1180,1015,752cm-1 .

[0103] Compound 2 was prepared using the same steps as in Screening Example 1-1 above, with only some reaction conditions or reactants changed (the parts not listed in Table 1 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0104] Table 1

[0105] Filtering example number Metal types Yield (%) 1-1 Activated zinc powder 83(78) 1-2 Unactivated zinc powder 83 1-3 manganese powder 0 1-4 aluminum powder 0 1-5 magnesium powder 0

[0106] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the value in parentheses is the separation yield (100 mmol scale).

[0107] To activate the zinc powder, it was first pretreated with dilute hydrochloric acid, specifically by stirring in a 1M hydrochloric acid solution for 5 minutes to remove the surface oxide layer. Subsequently, it was washed sequentially with deionized water, acetone, and diethyl ether to thoroughly remove residual acid, salts, and organic impurities. Finally, it was dried by vacuum filtration to obtain activated zinc powder.

[0108] Screening Example 2

[0109] Compound 2 was prepared using the same steps as in Screening Example 1-1, with only some reaction conditions or reactants changed (the parts not listed in Table 2 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0110] Table 2

[0111] Filtering example number Catalyst types Yield (%) 1-1 Nickel chloride 83(78) 2-1 cobalt bromide / 2-2 Copper acetate 35 2-3 Palladium iodide 42 2-4 Ferrous bromide 21 2-5 No catalyst added 9 2-6 Palladium bromide 39

[0112] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the value in parentheses is the separation yield (100 mmol scale).

[0113] Screening Example 3

[0114] Compound 2 was prepared using the same steps as in Screening Example 1-1 above, with only some reaction conditions or reactants changed (the parts not listed in Table 3 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0115] Table 3

[0116]

[0117]

[0118] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the values ​​in parentheses represent the separation yield (100 mmol scale).

[0119] Screening Example 4

[0120] Compound 2 was prepared using the same steps as in Screening Example 1-1 above, with only some reaction conditions or reactants changed (the parts not listed in Table 4 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0121] Table 4

[0122]

[0123]

[0124] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the values ​​in parentheses represent the separation yield (100 mmol scale).

[0125] Screening Example 5

[0126] Compound 2 was prepared using the same steps as in Screening Example 1-1, with only some reaction conditions or reactants changed (the parts not listed in Table 5 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0127] Table 5

[0128] Filtering example number Solvent types Yield (%) 1-1 Tetrahydrofuran 83(78) 5-1 2-Methyltetrahydrofuran 54 5-2 Diethyl ether / 5-3 Ethylene glycol dimethyl ether / 5-4 1,4-Dioxane / 5-5 Methyl tert-butyl ether / 5-6 N-Methylpyrrolidone / 5-7 N,N-Dimethylacetamide / 5-8 Dimethyl sulfoxide / 5-9 dichloromethane / 5-10 chlorobenzene / 5-11 Toluene / 5-12 Ethyl acetate / 5-13 Acetonitrile /

[0129] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the values ​​in parentheses represent the separation yield (100 mmol scale).

[0130] Screening Example 6

[0131] Compound 2 was prepared using the same steps as in Screening Example 1-1 above, with only some reaction conditions or reactants changed (the parts not listed in Table 6 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0132] Table 6

[0133] Filtering example number Nickel catalyst dosage Yield (%) 1-1 0.5 mol% 83(78) 6-1 0.01％ 72 6-2 0.02％ 78 6-3 0.2％ 80 6-4 1 mol% 83 6-5 5mol% 83 6-6 10 mol% 83

[0134] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the values ​​in parentheses represent the separation yield (100 mmol scale).

[0135] Screening Example 7

[0136] Compound 3 was prepared using the same steps as in Screening Example 1-1 above, with only some reaction conditions or reactants changed (the parts not listed in Table 7 represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0137] Table 7

[0138] Filtering example number Effect of reaction concentration Yield (%) 1-1 2.0M 83(78) 7-1 1.0M 82 7-2 0.5M 75 7-3 3.0M 79 7-4 5.0M 77

[0139] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the values ​​in parentheses represent the separation yield (100 mmol scale).

[0140] The reaction concentration refers to the concentration of ethyl bromide difluoroacetate.

[0141] Screening Example 8

[0142] Compound 3 was prepared using the same steps as in Screening Example 1-1 above, with only some reaction conditions or reactants changed (the parts not listed in Table 8 below represent the corresponding contents in Screening Example 1-1). The yield was determined after the reaction was completed, and the results are as follows:

[0143] Table 8

[0144] Filtering example number temperature Yield (%) 1-1 50℃ 83(78) 8-1 -40℃ 44 8-2 -30℃ 49 8-3 -10℃ 58 8-4 0℃ 63 8-5 room temperature 72 8-6 40℃ 79 8-7 60℃ 81 8-8 80℃ 76

[0145] Note: Trifluorotoluene was used as an internal standard, and the yield was determined by NMR fluorine spectroscopy; the values ​​in parentheses represent the separation yield (100 mmol scale).

[0146] Example 1

[0147]

[0148] Under air conditions, zinc powder (1.57 kg, 24.0 mol, 0.800 equiv.), nickel dichloride (19.4 g, 150 mmol, 0.500 mol%), and 6,6'-dimethyl-2,2'-bipyridine (33.2 g, 180 mmol, 0.600 mol%) were added to dry THF (15 L, 2.0 M) solvent, followed by the slow addition of ethyl bromodifluoroacetate (6.1 kg, 30 mol, 1.0 equiv.). After the addition was complete, the mixture was stirred continuously at 50 °C for 2 h. After the reaction was completed, the mixture was filtered through diatomaceous earth to remove solid impurities, and the resulting filtrate was subjected to vacuum distillation to remove the solvent. Further purification of the target product was achieved by subsequent distillation to obtain the target product (2.66 kg, 72% yield). 1 H NMR (500MHz, CDCl3) δ4.41 (q, J = 7.2Hz, 2H), 1.38 (t, J = 7.2Hz, 3H); 13 C NMR (126MHz, CDCl3) δ160.0–159.2 (m), 108.2 (tt, J = 265.2, 31.4Hz), 64.4, 13.8; 19 F NMR(376MHz,CDCl3)δ-120.2–-120.3(m)ppm.HRMS(EI)calcd.for C8H10 F4O4[M] + m / z 246.1653,found 246.1652.IR(KBr):ν max =3537,2991,1781,1376,1321,1180,1015,752cm -1 .

[0149] Example 2

[0150]

[0151] Potassium carbonate (829 g, 6.00 mol, 1.00 equiv.) was added to ultra-dry ethanol (12 L, 0.5 M) solvent, followed by diethyl tetrafluorosuccinate (1.48 kg, 6.00 mol, 1.00 equiv.) at 0 °C. After the addition was complete, the mixture was stirred continuously at 0 °C for 3 h. After the reaction was complete, the ethanol was removed by vacuum distillation. The residue was acidified to pH 1 with 1 M hydrochloric acid aqueous solution, and then extracted with ethyl acetate (3 L × 3). The combined organic phases were dried and concentrated to give the target product (1.14 kg, 87% yield). 1 HNMR (400MHz, CDCl3) δ10.57 (s, 1H), 4.41 (q, J = 7.1Hz, 2H), 1.37 (t, J = 7.1Hz, 3H); 13 C NMR (126MHz, Acetone-d6) δ161.9–160.8(m),160.3(t,J=29.5Hz),112.44–106.72(m),109.4(tt,J=262.2,30.0Hz),64.9,14.0; 19 F NMR(376MHz, CDCl3)δ-120.5,-120.8ppm.HRMS(ESINegative Ion Mode)calcd.for C6H5F4O4[M–H] + m / z 217.0124, found 217.0118.

[0152] Example 3

[0153]

[0154] 4-Ethoxy-2,2,3,3-tetrafluoro-4-oxobutyric acid (1.09 kg, 5.00 mol, 1.00 equiv.) and sodium fluoride (210 g, 5.00 mol, 1.00 equiv.) were added to a flask, followed by the slow addition of Ishikawa reagent (1.3 kg, 6.0 mol, 1.2 equiv.). After the addition was complete, the mixture was stirred at room temperature for 2 h, followed by vacuum distillation to obtain the target product (902 g, 82% yield). 1 H NMR (500MHz, CD2Cl2) δ4.50 (q, J = 7.2Hz, 2H), 1.42 (t, J = 7.2Hz, 3H); 13 C NMR (126MHz, CD2Cl2) δ159.0 (t, J = 29.1Hz), 149.6 (dt, J = 375.1, 35.3Hz), 110.7–104.8 (m), 110.6–104.7 (m), 65.7, 13.6; 19 F NMR(376MHz,CD2Cl2)δ24.4–23.8(m),-120.0–-120.7(m),-120.8–-121.4(m)ppm.HRMS(FI)calcd.for C6H7F4O4[M+H2O–HF] + m / z 219.0275, found219.0272.

[0155] Example 4

[0156]

[0157] Ethyl 2,2,3,3,4-pentafluoro-4-oxobutyrate (902 g, 4.10 mol, 1.00 equiv.) and cesium fluoride (31.1 g, 205 mmol, 5.00 mol%) were added to dry tetraethylene glycol dimethyl ether (820 mL, 5.00 M) under an argon atmosphere and at -30 °C. Hexafluoropropylene oxide (813 g, 4.90 mol, 1.20 equiv.) was then slowly introduced. After the addition was complete, the mixture was stirred continuously at -30 °C for 8 h, and the crude product was obtained by vacuum distillation. No further purification was required, and the mixture was directly used for the next reaction. The crude product and potassium carbonate (680 g, 4.92 mol, 1.20 equiv.) were added to dry tetraethylene glycol dimethyl ether (2.1 L, 2.0 M). After the feed was completed, the reaction was stirred at 120℃ for 4 hours, followed by vacuum distillation to remove low-boiling-point impurities, yielding the crude potassium carboxylate product. HRMS (ESINegative Ion Mode) calcd. for C9H5F 10 O5[M–K] +m / z382.9983, found 382.9971.

[0158] Example 5

[0159]

[0160] The crude potassium carboxylate product was subjected to thermal pyrolysis at 250 °C and 3 mmHg. The pyrolysis process lasted for 30 minutes, and the resulting pyrolysis products were captured by a collection device placed in a dry ice-acetone cold trap. The collected crude product was then purified by distillation to obtain the target product (591 g, 45% yield). 1 ¹H NMR (500MHz, acetone-d6) δ 4.52 (q, J = 7.1Hz, 2H), 1.39 (t, J = 7.1Hz, 3H); 13 C NMRδ158.7(t,J=29.1Hz),152.0–143.4(m),150.5–144.5(m),115.1–103.4(m),112.3–104.2(m),65.3,13.8; 19 F NMR(376MHz, Acetone-d6)δ-85.2–-85.9(m),-114.7–-115.3(m),-119.3–-119.6(m) ,-122.0–-123.1(m),-126.7–-127.1(m),-134.9–-135.8(m)ppm.HRMS(FI)calcd.for C8H5F9O3[M] + m / z 320.0089, found 320.0085.

[0161] Example 6

[0162]

[0163] Under air conditions, zinc powder (5.2 g, 80 mmol, 0.80 equiv.), nickel dichloride (65 mg, 0.50 mmol, 0.50 mol%), and 6,6'-dimethyl-2,2'-bipyridine (111 mg, 0.600 mmol, 0.600 mol%) were added to dry THF (50 mL, 2.0 M) solvent, followed by the slow addition of methyl difluorobromoacetate (18.9 g, 100 mmol, 1.00 equiv.). After the addition was complete, the mixture was stirred continuously at 50 °C for 2 h. After the reaction was complete, the mixture was filtered through diatomaceous earth to remove solid impurities, and the resulting filtrate was subjected to vacuum distillation to remove the solvent. Further purification of the target product was achieved by subsequent distillation to obtain the target product (14.6 g, 67% yield). 1H NMR(600MHz,CDCl3)δ3.97(3,1H); 13 C NMR(151MHz,CDCl3)δ160.3–159.5(m),108.0(tt,J=265.6,31.7Hz),54.4; 19 F NMR(565MHz,CDCl3)δ-120.0ppm.HRMS(EI)calcd.for C6H7F4O4[M+H] + m / z 219.0275,found219.0271.IR(KBr):ν max =3553,2968,1782 1444,1329,1102,1003,754cm -1 。

Claims

1. A method for preparing a compound as shown in Formula II, characterized in that, It includes the following steps S1: In an organic solvent, with the aid of zinc, the compound shown in Formula I undergoes a coupling reaction as shown in the following formula to give the compound shown in Formula II. X is chlorine, bromine, or iodine; R 1 Independently for C 1-6 alkyl.

2. The method for preparing the compound as shown in Formula II according to claim 1, characterized in that, It meets one or more of the following conditions: (1) X is bromine; (2)R 1 Independently methyl or ethyl, such as ethyl; Preferably, the compound shown in Formula I is The compound shown in Formula II is (3) The organic solvent is an ether solvent, for example, the organic solvent is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, diethyl ether, ethylene glycol dimethyl ether, 1,4-dioxane and methyl tert-butyl ether, for example tetrahydrofuran; (4) The ratio of the number of moles of the compound shown in Formula I to the volume of the solvent is (0.01-100) mol:1L, for example (0.1-30) mol:1L, for example (0.1-10) mol:1L, and for example 0.5 mol:1L, 1 mol:1L, 2 mol:1L, 3 mol:1L or 5 mol:1L; (5) The molar ratio of zinc to the compound shown in Formula I is (0.1-10):1, for example (0.1-3):1, for example (0.5-1):1, and for example 0.8:1; (6) The temperature of the coupling reaction is -80°C to 100°C, for example -40°C to 80°C, or for example 45°C to 65°C; (7) After the coupling reaction is completed, a post-processing is also included, which is selected from one or more of the following steps: filtration, solvent removal or purification, for example, the purification is distillation purification; (8) The coupling reaction does not require light exposure; (9) The coupling reaction is carried out in air.

3. The method for preparing the compound of formula II as described in claim 1 or 2, characterized in that, It meets one or two of the following conditions: (1) The reaction system of the coupling reaction also includes a catalyst, which is selected from one or more of nickel catalysts, copper catalysts, iron catalysts and palladium catalysts, such as nickel catalysts; (2) The reaction system of the coupling reaction further includes a ligand, which is selected from one or more compounds as shown in Formula L1 and Formula L2: Among them, ring A and ring B are independently 5-12 membered heteroaryl or 5-12 membered heterocycle; n1 and n2 are independently 0, 1, 2, 3, 4 or 5; R a and R b Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-12 Aryl or 5-12 heteroaryl groups; Or, an R a An R b Together with the atoms bonded to it, they form C 6-12 aryl, 5-12 heteroaryl, with one or more R c Replacement C 6-12 aryl or aryl with one or more R c Substituted 5-12 heteroaryl groups; R c Independently for C 1-6 Alkyl or -OC 1-6 alkyl; R 1-1 R 1-2 and R 1-3 Independently for C 1-6 Alkyl, C 3-12 Cycloalkyl, 3-12 membered heterocycloalkyl, C 6-12 Aryl, 5-12 heteroaryl, -C 1-6 Alkylene-P(R) 1-1a (R) 1-1b ), by one or more R 1-1c Replacement C 3-12 cycloalkyl, with one or more R 1-1c Substituted 3-12 membered heterocyclic alkyl groups, with one or more R 1-1c Replacement C 6-12 aryl or aryl with one or more R 1-1c Substituted 5-12 heteroaryl groups; Or, R 1-1 R 1-2 Together with phosphorus atoms, they form 5-12 membered phosphorus heterocycles or are bounded by one or more R atoms. 1-1c A substituted 5-12 membered phosphorus heterocycle, wherein the heteroatom in the 5-12 membered phosphorus heterocycle is phosphorus and the number of heteroatoms is 1; R 1-1c Independently for C 1-6 Alkyl, -OC 1-6 Alkyl, C 6-12 aryl, 5-12 heteroaryl, with one or more R 1-1c-1 Replacement C 6-12 aryl or aryl with one or more R 1-1c-1 Substituted 5-12 heteroaryl R 1-1c-1 Independently for C 1-6 Alkyl, -OC 1-6 Alkyl or -C 0-6 Alkylene-P(R) 1-1a-1 (R) 1-1b-1 ), R 1-1a and R 1-1b Independently for C 6-12 Aryl or 5-12 heteroaryl groups; Or, R 1-1a R 1-1b Together with phosphorus atoms, they form 5-12 membered phosphorus heterocycles or are bounded by one or more R atoms. 1-1 c-substituted 5-12 membered phosphorus heterocycles; The heteroatoms in the 5-12 membered heteroaryl group and the 5-12 membered heterocycle are independently one or more of N, O and S, and the number of heteroatoms is independently 1, 2, 3, 4 or 5.

4. The method for preparing the compound as shown in Formula II according to claim 3, characterized in that, It meets one or more of the following conditions: (1) The nickel catalyst is selected from nickel chloride, nickel chloride hexahydrate, nickel bromide, nickel iodide, nickel bromide trihydrate, nickel perchlorate hexahydrate, nickel tetrafluoroborate hexahydrate, ethylene glycol dimethyl ether nickel bromide, tris(2,2'-bipyridine) nickel bromide, (2,2'-bipyridine) dibromide, 1,10-o-phenanthroline nickel dibromide, bis(triphenylphosphine) nickel chloride, 1,2-bis(diphenylphosphine)ethane nickel chloride, 1,3-bis(diphenylphosphine propane) dibromide, and bis(triphenylphosphine) nickel chloride. One or more of cyclohexylphosphine nickel chloride and bis(cyclopentadiene) nickel, such as nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel bromide, tris(2,2'-bipyridine) nickel bromide, (2,2'-bipyridine) dibromide, 1,10-o-phenanthroline nickel dibromide, 1,2-bis(diphenylphosphine)ethane nickel chloride and 1,3-bis(diphenylphosphine propane) dibromide, and for example, nickel chloride or (2,2'-bipyridine) dibromide; (2) The copper catalyst is copper sulfate; (3) The iron-based catalyst is an iron halide, such as ferrous bromide; (4) The palladium catalyst is a palladium halide, such as palladium iodide or palladium bromide; (5) The molar ratio of the catalyst to the compound shown in Formula I is (0.00001-1):1, for example (0.00001-0.5):1, for example (0.00009-0.11):1, and for example 0.0001:1, 0.0002:1, 0.002:1, 0.005:1, 0.01:1, 0.05:1 or 0.1:1; (6) The ligand is a compound as shown in Formula L1; (7) Ring A and ring B are independently 5-6 membered heteroaryl or 5-6 membered heterocycle, wherein the 5-6 membered heterocycle contains one double bond; for example, ring A and ring B are independently pyridinyl, quinolinyl or dihydrooxazolyl, or for example pyridinyl or dihydrooxazolyl. (8)R a and R b Independently for C 1-6 Alkyl or C 6-12 Aryl groups, such as methyl, tert-butyl, or phenyl; (9) An R a An R b Together with the atoms bonded to it, they form C 6-12 Aryl groups, such as phenyl groups; (10)R 1-1 R 1-2 and R 1-3 Independently for C 1-6 Alkyl, C 3-6 cycloalkyl, C 6-12 Aryl, -C 1-6 Alkylene-P(R) 1-1a (R) 1 -1b ) or by one or more R 1-1c Replacement C 6-12 Aryl; for example, R 1-1 R 1-2 and R 1-3 Independently tert-butyl, cyclohexyl, phenyl, naphthyl, (11)R 1-1 R 1-2 Together with phosphorus atoms, they form 5-6 membered phosphorus heterocycles or are bound by one or more R atoms. 1-1c Substituted 5-6 membered phosphorus heterocycles, for example (12)R 1-1a R 1-1b Together with phosphorus atoms, they form 5-6 membered phosphorus heterocycles or are bound by one or more R atoms. 1-1c Substituted 5-6 membered phosphorus heterocycles, for example (13) The molar ratio of the ligand to the compound shown in Formula I is (0.0001-1):1, for example (0.001-0.5):1, for example (0.001-0.1):1, and for example 0.006:1; Preferably, the ligand is selected from 6,6'-dimethyl-2,2'-bipyridine, 2,2'-bipyridine, 6,6'-di-tert-butyl-2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2,2-bis(2-azolin), (4S,4'S)-4,4'-diisopropyl-4,4',5,5'-tetrahydro-2,2'-bisoxazole, (S,S)-2, 2'-Isopropylidene bis(4-phenyl-2-oxazoline), 2-(4,5-dihydro-2-oxazolyl)quinoline, (S)-4-tert-butyl-2-(2-azaphenyl)oxazoline, tris(2,6-dimethoxyphenyl)phosphine, tris[2-(diphenylphosphine)ethyl]phosphine, 2-(di-tert-butylphosphine)-1,1'-binaphthyl, 1,5-bis(diphenylphosphine)pentane, tricyclohexylphosphine, S-(-)-2,2'-bis( One of the following: (2R,4R)-1,1'-binaphthyl, (2R,4R)-2,4-bis(diphenylphosphine)pentane, 1,2-bis(biphenylphosphine)ethane, 1,3-bis(diphenylphosphine)propane, (+)-1,2-bis((2R,5R)-2,5-diethylphosphine)benzene, and 3-(tert-butoxy)-2',6'-diisopropyl-6-methoxy-[1,1'-biphenyl]-2-yl)dicyclohexylphosphine One or more, such as one or more selected from 6,6'-dimethyl-2,2'-bipyridine, 2,2'-bipyridine, 6,6'-di-tert-butyl-2,2'-bipyridine, 1,10-phenanthroline, 2,9-dimethyl-1,10-phenanthroline, 2,2-bis(2-azolin) and (S)-4-tert-butyl-2-(2-azaphenyl)oxazoline, and for example 6,6'-dimethyl-2,2'-bipyridine.

5. The method for preparing the compound as shown in Formula II according to claim 3, characterized in that, The reaction system of the coupling reaction further includes a catalyst and a ligand. Preferably, the catalyst is selected from one or more of nickel chloride, nickel bromide, nickel iodide, ethylene glycol dimethyl ether nickel bromide, tris(2,2'-bipyridine) nickel bromide, (2,2'-bipyridine) dibromide, 1,10-o-phenanthroline nickel dibromide, 1,2-bis(diphenylphosphine)ethane nickel chloride, and 1,3-bis(diphenylphosphine propane) dichloride; the ligand is a compound of formula L1 as described in claim 3 or 4.

6. A method for preparing a compound as shown in Formula III, characterized in that, It includes the following step S2: In a solvent, under alkaline conditions, the compound shown in Formula II undergoes a hydrolysis reaction as shown in the following formula to give the compound shown in Formula III. Among them, R 1 Independently for C 1-6 Alkyl groups, such as R 1 It can be either methyl or ethyl.

7. The method for preparing the compound as shown in Formula III according to claim 6, characterized in that, It meets one or more of the following conditions: (1) The solvent is an alcohol solvent, such as one or more selected from methanol, ethanol, isopropanol and tert-butanol, for example ethanol; (2) The ratio of the number of moles of the compound shown in Formula II to the volume of the solvent is (0.01-10) mol: 1 L, for example (0.1-1) mol: 1 L, or for example 0.5 mol: 1 L; (3) The base is an inorganic base, for example selected from one or more of potassium carbonate, sodium carbonate, lithium carbonate, sodium hydroxide, potassium hydroxide and lithium hydroxide, and potassium carbonate for example; (4) The molar ratio of the base to the compound shown in Formula II is (0.8-1):1, for example 1:1; (5) The temperature of the hydrolysis reaction is -20°C to 30°C, for example -10°C to 10°C, or for example 0°C; (6) After the hydrolysis reaction is completed, acidification is also included, wherein the acid is added to the hydrolysis reaction system in the form of an aqueous solution of the acid; the acid may be HCl or H2SO4, for example HCl, or for example a 1 mol / L aqueous solution of hydrochloric acid; Preferably, after the acidification is completed, the pH value of the reaction system is 0.1-3, for example, pH value is 1; More preferably, the acidification process further includes one or more of the following post-processing steps: extraction and solvent removal.

8. The method for preparing the compound of formula III as described in claim 6, characterized in that, The method for preparing the compound shown in Formula III also includes a method for preparing the compound shown in Formula II, comprising the following step S1: In an organic solvent, with the aid of zinc, the compound shown in Formula I undergoes a coupling reaction as shown in the following formula to give the compound shown in Formula II. X and R 1 The definition is as described in claim 1 or 2, and the conditions and operations of the method for preparing the compound as shown in Formula II are further described in any one of claims 2-5.

9. A method for preparing a compound as shown in Formula VIII, characterized in that, It includes step S1 as described in any one of claims 1-5, R 1 C 1-6 Alkyl groups, such as methyl or ethyl; Preferably, the method for preparing the compound as shown in Formula VIII further includes step S2 as described in claim 6 or 7.

10. The use of a compound of formulas I, II and III in the preparation of a compound of formula VIII. R 1 Independently for C 1-6 Alkyl, such as methyl or ethyl; X is chlorine, bromine or iodine, such as bromine.

Images