Synthesis method of 2-fluorocyclopropane carboxylic acid

Abstract

The invention provides a synthesis method of 2-fluorocyclopropane formate, and relates to the technical field of medicine synthesis. The preparation method comprises the following steps: carrying out addition reaction on propiolate and triethylamine trihydrofluoride to obtain 3-fluoroacrylate; the 3-fluoroacrylate and trimethylsulfone iodide are subjected to a cyclization reaction, and 2-fluorocyclopropane formate is obtained; and carrying out hydrolysis reaction on the 2-fluorocyclopropane formate under an alkaline condition, and acidifying to obtain the 2-fluorocyclopropane formic acid. The synthesis method provided by the invention is short in synthesis route and high in product yield; the used raw materials are low in cost and wide in source, the production cost is low, the reaction condition is mild, the reaction safety is high, the operation is simple, and the method is suitable for industrial production. The test result of the embodiment shows that the total yield of the 2-fluorocyclopropane formic acid is more than 64.9%.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical synthesis, and in particular to a method for synthesizing 2-fluorocyclopropanecarboxylic acid. Background Art

[0002] Sitafloxacin has a broad-spectrum antibacterial effect, with significant antibacterial activity against Gram-negative bacteria, as well as strong antibacterial activity against Gram-positive bacteria, anaerobic bacteria, mycoplasma, chlamydia, etc. It also has a good bactericidal effect on many common clinical fluoroquinolone-resistant strains. Sitafloxacin contains a side chain of monofluorocyclopropane. Studies have shown that the introduction of this group in the structure significantly improves the selectivity of sitafloxacin for bacterial enzymes and helps reduce the toxic side effects of quinolone drugs. The key intermediate of this fragment is 2-fluorocyclopropanecarboxylic acid.

[0003] At present, there are two methods for synthesizing 2-fluorocyclopropanecarboxylic acid. Method 1: Butadiene and dichlorofluorocarbene react to obtain 1-chloro-1-fluoro-2-vinylcyclopropane, and then oxidize, esterify, dechlorinate, and hydrolyze to obtain 2-fluorocyclopropanecarboxylic acid. However, the above process route is long, and the total yield of the product is only 21.2%, which is low.

[0004]

[0005] Method 2: tert-butyl acrylate and (chloromethyl)sulfinylbenzene react at ultra-low temperature to obtain a sulfoxide intermediate, which is then reacted with fluorine gas to eliminate and hydrolyze to obtain 2-fluorocyclopropanecarboxylic acid. However, the total yield of the product of the above method is only 15.2%, which is low.

[0006] Summary of the invention

[0007] In view of this, the object of the present invention is to provide a method for synthesizing 2-fluorocyclopropanecarboxylic acid. The method for synthesizing 2-fluorocyclopropanecarboxylic acid provided by the present invention has a high total yield.

[0008] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0009] The present invention provides a method for synthesizing 2-fluorocyclopropanecarboxylic acid, comprising the following steps:

[0010] Propylene ester is subjected to addition reaction with triethylamine trihydrofluoride to obtain 3-fluoroacrylate;

[0011] The 3-fluoroacrylate is subjected to a cyclization reaction with trimethylsulfone iodide to obtain 2-fluorocyclopropanecarboxylate;

[0012] The 2-fluorocyclopropanecarboxylic acid ester is subjected to a hydrolysis reaction under alkaline conditions and then acidified to obtain 2-fluorocyclopropanecarboxylic acid.

[0013] Preferably, the propiolate ester includes one or more of methyl propiolate, ethyl propiolate and propyl propiolate;

[0014] The molar ratio of the propiolate to triethylamine trihydrofluoride is 1:1-2.

[0015] Preferably, the addition reaction is carried out in the presence of a promoter, and the promoter includes CsF and / or Cs2CO3;

[0016] The molar ratio of the propiolate to the accelerator is 1:1 to 1.8.

[0017] Preferably, the temperature of the addition reaction is 15 to 35° C. and the time is 8 to 20 hours;

[0018] The organic solvent used in the addition reaction includes sulfolane and / or dioxane.

[0019] Preferably, the molar ratio of the 3-fluoroacrylate to trimethylsulfone iodide is 1:1.2-1.8.

[0020] Preferably, the cyclization reaction is carried out in the presence of an alkaline reagent, wherein the alkaline reagent comprises an alkali metal hydride and / or an alkali metal alcoholate;

[0021] The molar ratio of the 3-fluoroacrylate to the alkaline agent is 1:1.2-1.8;

[0022] The organic solvent used in the cyclization reaction includes one or more of N,N-dimethylformamide, dimethyl sulfoxide and dioxane.

[0023] Preferably, the temperature of the cyclization reaction is 25 to 35° C., and the time is 1 to 3 hours; the cyclization reaction is carried out under a protective atmosphere.

[0024] Preferably, the alkaline agent used in the alkaline condition includes an alkali metal hydroxide;

[0025] The molar ratio of the 2-fluorocyclopropanecarboxylate to the alkaline reagent is 1:1.35-2.

[0026] Preferably, the temperature of the hydrolysis reaction is 20-35°C and the time is 2.5-5h;

[0027] The solvent used in the hydrolysis reaction includes a mixed solvent of an organic solvent and water, and the organic solvent includes a lower alcohol and / or a furan solvent.

[0028] Preferably, the pH value of the acidified system is 1-2.

[0029] The present invention conducts an addition reaction between propiolate and triethylamine trihydrofluoride to obtain 3-fluoroacrylate, conducts a ring-forming reaction with trimethylsulfone iodide to obtain 2-fluorocyclopropanecarboxylate, and then conducts a hydrolysis reaction under alkaline conditions and acidifies to obtain 2-fluorocyclopropanecarboxylic acid. The synthesis method provided by the present invention has a short synthesis route and a high product yield; the raw materials used are low in cost and have a wide source, the production cost is low, the reaction conditions are mild, the reaction safety is high, and the operation is simple, which is suitable for industrial production. As shown in the test results of the embodiment, the total yield of 2-fluorocyclopropanecarboxylic acid is above 64.9%. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] Figure 1 The hydrogen spectrum of ethyl 2-fluorocyclopropanecarboxylate prepared in Example;

[0031] Figure 2 This is the hydrogen spectrum of 2-fluorocyclopropanecarboxylic acid prepared in Example. DETAILED DESCRIPTION

[0032] The present invention provides a method for synthesizing 2-fluorocyclopropanecarboxylic acid, comprising the following steps:

[0033] Propylene ester is subjected to addition reaction with triethylamine trihydrofluoride to obtain 3-fluoroacrylate;

[0034] The 3-fluoroacrylate is subjected to a cyclization reaction with trimethylsulfone iodide to obtain 2-fluorocyclopropanecarboxylate;

[0035] The 2-fluorocyclopropanecarboxylic acid ester is subjected to a hydrolysis reaction under alkaline conditions and then acidified to obtain 2-fluorocyclopropanecarboxylic acid.

[0036] In the present invention, the synthetic route of the 2-fluorocyclopropanecarboxylic acid is as follows:

[0037]

[0038] Wherein, R includes methyl, ethyl or propyl.

[0039] Unless otherwise specified, the materials and equipment used in the present invention are all commercially available products in the art.

[0040] The invention carries out addition reaction of propiolate and triethylamine trihydrofluoride to obtain 3-fluoroacrylate.

[0041] In a specific embodiment of the present invention, the addition reaction preferably comprises: mixing propiolate, triethylamine trihydrofluoride, a promoter and an organic solvent (referred to as the first organic solvent) to carry out an addition reaction.

[0042] In the present invention, the propiolate preferably includes one or more of ethyl propiolate, methyl propiolate (i.e., R is methyl), (i.e., R is ethyl) and propyl propiolate (i.e., R is propyl). In the present invention, the molar ratio of the propiolate to triethylamine trihydrofluoride is preferably 1:1-2, and in specific embodiments can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0043] In the present invention, the promoter preferably includes CsF and / or Cs2CO3. In the present invention, the molar ratio of the propiolate to the promoter is preferably 1:1 to 1.8, and in specific embodiments can be 1:1, 1:1.1, 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1:1.8.

[0044] In the present invention, the first organic solvent preferably includes sulfolane and / or dioxane. In the present invention, in the present invention, the usage ratio of the propiolate ester to the first organic solvent is preferably 1 mol: 200-500 mL, and in specific embodiments can be 1 mol: 200 mL, 1 mol: 250 mL, 1 mol: 300 mL, 1 mol: 303 mL, 1 mol: 323 mL, 1 mol: 350 mL, 1 mol: 400 mL, 1 mol: 450 mL or 1 mol: 500 mL.

[0045] In the present invention, the temperature of the addition reaction is preferably 15-35°C, and in specific embodiments it can be 15°C, 20°C, 25°C, 30°C or 35°C; the time of the addition reaction is preferably 8-20h, and in specific embodiments it can be 8h, 9h, 10h, 11h, 12h, 13h, 14h, 15h, 16h, 17h, 18h, 19h or 20h.

[0046] After the addition reaction is completed, the present invention preferably further comprises a post-treatment, wherein the post-treatment preferably comprises: distilling the addition reaction liquid obtained by the addition reaction to obtain a first fraction, adding an aqueous hydrochloric acid solution to the first fraction, extracting the obtained aqueous phase with ethyl acetate, drying the obtained organic phase with a desiccant, filtering to remove the desiccant, adding hydroquinone for distillation, and collecting a second fraction, wherein the second fraction is 2-fluorocyclopropanecarboxylate. In the present invention, the concentration of the aqueous hydrochloric acid solution is preferably 10 to 20 wt%, and in a specific embodiment can be 10 wt%, 11 wt%, 12 wt%, 13 wt%, 14 wt%, 15 wt%, 16 wt%, 17 wt%, 18 wt%, 19 wt% or 20 wt%. In the present invention, the usage ratio of the propiolate ester to the aqueous hydrochloric acid solution is preferably 1 mol: 120-180 mL, and in specific embodiments, it can be 1 mol: 120 mL, 1 mol: 130 mL, 1 mol: 140 mL, 1 mol: 150 mL, 1 mol: 160 mL, 1 mol: 170 mL or 1 mol: 180 mL. In the present invention, the usage ratio of the propiolate ester to hydroquinone is preferably 1 mol: 0.1-0.2 g, and in specific embodiments, it can be 1 mol: 0.1 g, 1 mol: 0.15 g or 1 mol: 0.2 g. In the present invention, the number of extractions is preferably 2-4 times, more preferably 3 times. In the present invention, the desiccant preferably includes anhydrous magnesium sulfate and / or anhydrous sodium sulfate.

[0047] After obtaining 3-fluoroacrylate, the present invention conducts a ring-forming reaction between the 3-fluoroacrylate and trimethylsulfone iodide to obtain 2-fluorocyclopropanecarboxylate.

[0048] In a specific embodiment of the present invention, the cyclization reaction preferably includes: mixing the 3-fluoroacrylate, trimethylsulfone iodide, an alkaline reagent (referred to as the first alkaline reagent) and an organic solvent (referred to as the second organic solvent) to perform a cyclization reaction.

[0049] In the present invention, the molar ratio of the 3-fluoroacrylate to trimethylsulfone iodide is preferably 1:1.2-1.8, and in specific embodiments may be 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1:1.8.

[0050] In the present invention, the first alkaline agent preferably includes alkali metal hydride and / or alkali metal alcoholate; the alkali metal hydride preferably includes sodium hydride and / or potassium hydride; the alkali metal alcoholate preferably includes sodium tert-butoxide and / or potassium tert-butoxide. In the present invention, the molar ratio of the 3-fluoroacrylate to the first alkaline agent is preferably 1:1.2-1.8, and in specific embodiments can be 1:1.2, 1:1.3, 1:1.4, 1:1.5, 1:1.6, 1:1.7 or 1:1.8.

[0051] In the present invention, the second organic solvent preferably includes one or more of N,N-dimethylformamide (DMF), dimethyl sulfoxide (DMSO) and dioxane. In the present invention, the usage ratio of the 3-fluoroacrylate to the second organic solvent is preferably 1 mol: 1.6 to 4 L, and in specific embodiments, it can be 1 mol: 1.6 L, 1 mol: 2 L, 1 mol: 2.5 L, 1 mol: 2.8 L, 1 mol: 3 L, 1 mol: 3.3 L, 1 mol: 3.5 L or 1 mol: 4 L.

[0052] In the present invention, the mixing preferably comprises: mixing the first alkaline reagent with part of the second organic solvent, adding trimethyl sulfoxide iodide under a protective atmosphere, premixing, and then adding a mixed solution of 3-fluoroacrylate and the remaining second organic solvent (i.e., 3-fluoroacrylate solution). In the present invention, the amount ratio of the 3-fluoroacrylate to the remaining second organic solvent is preferably 1 mol: 0.8-2L, and in a specific embodiment, it can be 1 mol: 0.8L, 1 mol: 0.9L, 1 mol: 1L, 1 mol: 1.5L or 1 mol: 2L. In the present invention, the premixing temperature is preferably 25-35°C, and in a specific embodiment, it can be 25°C, 30°C or 35°C; the premixing time is preferably 1-3h, and in a specific embodiment, it can be 1h, 1.5h, 2h, 2.5h or 3h. In the present invention, the protective atmosphere preferably comprises nitrogen, argon or helium.

[0053] In the present invention, the temperature of the cyclization reaction is preferably 25-35°C, and in specific embodiments it can be 25°C, 30°C or 35°C; the time of the cyclization reaction is preferably 1-3h, and in specific embodiments it can be 1h, 1.5h, 2h, 2.5h or 3h; the cyclization reaction is preferably carried out under a protective atmosphere, and the protective atmosphere preferably includes nitrogen, argon or helium.

[0054] After the cyclization reaction is completed, the present invention preferably further comprises post-treatment, and the post-treatment preferably comprises: adding hydrochloric acid aqueous solution and extractant to the obtained cyclization reaction solution for extraction, washing the obtained organic phase with saturated brine, drying with a desiccant, filtering to remove the desiccant, concentrating and purifying with a silica gel column to obtain 2-fluorocyclopropanecarboxylate. In the present invention, the concentration of the hydrochloric acid aqueous solution is preferably 1-2.5 mol / L, and in specific embodiments it can be 1 mol / L, 1.5 mol / L, 2 mol / L or 2.5 mol / L. In the present invention, the amount ratio of the propiolate ester to the hydrochloric acid aqueous solution is preferably 1 mol: 4-5 L, and in specific embodiments it can be 1 mol: 4 L, 1 mol: 4.2 L, 1 mol: 4.5 L, 1 mol: 4.7 L or 1 mol: 5 L. In the present invention, the number of extractions is preferably 2-4 times, more preferably 3 times; the extractant preferably comprises dichloromethane and / or ethyl acetate. In the present invention, the desiccant preferably comprises anhydrous magnesium sulfate and / or anhydrous sodium sulfate. In the present invention, the concentration preferably includes concentration under reduced pressure. In the present invention, the eluent used in the silica gel column purification preferably includes ethyl acetate-petroleum ether or ethyl acetate-n-hexane; the volume ratio of ethyl acetate to petroleum ether in the ethyl acetate-petroleum ether is preferably 1:5-10, and in specific embodiments, it can be 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10; the volume ratio of ethyl acetate to n-hexane in the ethyl acetate-n-hexane is preferably 1:5-10, and in specific embodiments, it can be 1:5, 1:6, 1:7, 1:8, 1:9 or 1:10.

[0055] After obtaining 2-fluorocyclopropanecarboxylic acid ester, the present invention performs a hydrolysis reaction on the 2-fluorocyclopropanecarboxylic acid ester under alkaline conditions and then acidifies the ester to obtain 2-fluorocyclopropanecarboxylic acid.

[0056] In a specific embodiment of the present invention, the hydrolysis reaction under alkaline conditions preferably includes: mixing the 2-fluorocyclopropanecarboxylate, an alkaline reagent (denoted as the second alkaline reagent) and a mixed solvent of an organic solvent (denoted as the third organic solvent) and water to perform a hydrolysis reaction.

[0057] In the present invention, the second alkaline agent preferably includes an alkali metal hydroxide, and the alkali metal hydroxide preferably includes one or more of sodium hydroxide, potassium hydroxide and lithium hydroxide. In the present invention, the molar ratio of the 2-fluorocyclopropanecarboxylate to the second alkaline agent is preferably 1:1.35-2, and in specific embodiments can be 1:1.35, 1:1.4, 1:1.5, 1:1.6, 1:1.7, 1:1.8, 1:1.9 or 1:2.

[0058] In the present invention, the third organic solvent preferably includes lower alcohols and / or furan solvents; the furan solvents preferably include tetrahydrofuran and / or 2-methyltetrahydrofuran; the lower alcohols preferably include methanol and / or ethanol; the volume fraction of the third organic solvent in the mixed solvent is preferably 20-50%, and in specific embodiments it can be 20%, 25%, 30%, 35%, 40%, 45% or 50%.

[0059] In the present invention, the usage ratio of the 2-fluorocyclopropanecarboxylate to the mixed solvent is preferably 1 mol: 1 to 3 L, and in specific embodiments may be 1 mol: 1 L, 1 mol: 1.5 L, 1 mol: 2 L, 1 mol: 2.5 L or 1 mol: 3 L.

[0060] In the present invention, the mixing preferably includes: adding a second alkaline agent to the mixed solvent, mixing until the second alkaline agent is dissolved, and then adding 2-fluorocyclopropanecarboxylate.

[0061] In the present invention, the temperature of the hydrolysis reaction is preferably 20-35°C, and in specific embodiments it can be 20°C, 25°C, 30°C or 35°C; the hydrolysis reaction time is preferably 2.5-5h, and in specific embodiments it can be 2.5h, 3h, 3.5h, 4h, 4.5h or 5h.

[0062] After the hydrolysis reaction is completed, the present invention preferably further comprises adding water to the obtained hydrolysis reaction solution, and then acidifying. In the present invention, the amount ratio of the 2-fluorocyclopropanecarboxylate to the water added after the hydrolysis reaction is preferably 1 mol: 1 to 3 L, and in specific embodiments can be 1 mol: 1 L, 1 mol: 1.5 L, 1 mol: 2 L, 1 mol: 2.5 L or 1 mol: 3 L.

[0063] In the present invention, the pH value of the acidification is preferably 1-2, and in specific embodiments it can be 1, 1.1, 1.2, 1.3, 1.4, 1.5, 1.6, 1.7, 1.8, 1.9 or 2; the acid used in the acidification preferably includes one or more of hydrochloric acid, sulfuric acid and acetic acid; the acid is preferably used in the form of an acid aqueous solution, and the concentration of the acid aqueous solution is preferably 1-2.5 mol / L, and in specific embodiments it can be 1 mol / L, 1.5 mol / L, 2 mol / L or 2.5 mol / L.

[0064] After the acidification is completed, the present invention preferably further includes post-treatment, and the post-treatment preferably includes: extracting the acidified reaction liquid obtained by the acidification with methyl tert-butyl ether, drying the obtained organic phase with a desiccant, filtering to remove the desiccant, and concentrating the obtained liquid component to constant weight to obtain 2-fluorocyclopropanecarboxylic acid. In the present invention, the number of extractions is preferably 2 to 4 times, more preferably 3 times. In the present invention, the desiccant preferably includes anhydrous magnesium sulfate and / or anhydrous sodium sulfate. In the present invention, the concentration preferably includes reduced pressure concentration.

[0065] In order to further illustrate the present invention, the synthesis method of 2-fluorocyclopropanecarboxylic acid provided by the present invention is described in detail below in conjunction with examples, but they should not be construed as limiting the scope of protection of the present invention.

[0066] Example 1

[0067]

[0068] Add ethyl propiolate (0.495 mol), triethylamine trihydrofluoride (TEA-HF, 0.75 mol), CsF (0.85 mol), sulfolane (150 mL), and stir at 25 ° C for 15 h. After the reaction is completed, distill the mixture to obtain a fraction (boiling point 85-97 ° C). Add 75 mL of 10 wt% HCl aqueous solution to the fraction, and extract the aqueous phase with ethyl acetate 3 times (100 mL of ethyl acetate per time). Combine the organic phases, dry with anhydrous magnesium sulfate, filter to remove magnesium sulfate, add 0.05 g of hydroquinone and distill, collect the fraction with a boiling point of 95-98 ° C, which is 3-fluoroacrylate (45.6 g, yield 78%).

[0069] Sodium hydride (0.256 mol, concentration of 60 wt%, solvent is mineral oil) was suspended in anhydrous DMF (500 mL), trimethyl sulfoxide iodide (0.256 mol) was added under nitrogen atmosphere and stirred at 25°C for 1 h, 3-fluoroacrylate (0.213 mol) was dissolved in anhydrous DMF (200 mL) and added to the above mixture, stirred at 25°C for reaction, TLC analysis confirmed that the raw material reaction was complete, the resulting reaction solution was added to 1L 2M HCl aqueous solution, extracted with dichloromethane 3 times (single dichloromethane amount 200 mL), the organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column (eluent is ethyl acetate / petroleum ether, volume ratio = 1:5-10) to obtain ethyl 2-fluorocyclopropanecarboxylate (24.85 g, 0.188 mol, yield is 88.3%). Figure 1 This is the hydrogen spectrum of ethyl 2-fluorocyclopropanecarboxylate. It can be seen that ethyl 2-fluorocyclopropanecarboxylate is successfully prepared.

[0070] Add 100mL of 30v / v% ethanol aqueous solution, slowly add sodium hydroxide (0.135mol) under stirring, add ethyl 2-fluorocyclopropanecarboxylate (0.1mol) after complete dissolution, continue to react at 25°C for 3h, add 100mL of water, adjust the pH value to 1-2 with 2M HCl aqueous solution, extract with MTBE 3 times (single MTBE amount is 80mL), combine the organic phases, dry with anhydrous sodium sulfate, filter out sodium sulfate, and concentrate to constant weight to obtain 2-fluorocyclopropanecarboxylic acid (9.8g, yield is 94.2%). Figure 2 This is the hydrogen spectrum of 2-fluorocyclopropanecarboxylic acid. It can be seen that 2-fluorocyclopropanecarboxylic acid is successfully prepared.

[0071] Example 2

[0072] Ethyl propiolate (2.475 mol), triethylamine trihydrofluoride (TEA-HF, 250 mL, 3.25 mol), CsF (3.5 mol), sulfolane (800 mL) were added and stirred at 25°C for 18 h. After the reaction was completed, the mixture was distilled to obtain a fraction (boiling point 85-97°C). 375 mL of 10 wt% HCl aqueous solution was added to the fraction, and the aqueous phase was extracted with ethyl acetate 3 times (500 mL of ethyl acetate per time). The organic phases were combined, dried over anhydrous magnesium sulfate, filtered to remove magnesium sulfate, and distilled after adding 0.05 g of hydroquinone. The fraction with a boiling point of 95-98°C was collected, which was ethyl 3-fluoroacrylate (232.7 g, yield 79.6%).

[0073] Sodium hydride (1.28 mol, concentration of 60 wt%, solvent is mineral oil) was suspended in anhydrous DMF (2 L), trimethyl sulfoxide iodide (1.28 mol) was added under nitrogen atmosphere and stirred at 25 ° C for 1 h, 3-fluoroacrylate (1.07 mol) was dissolved in anhydrous DMF (1 L), and added to the above mixture, and stirred at 25 ° C for 3 h. After the reaction was completed, the resulting reaction solution was added to 5L 2M HCl ice water solution, extracted with ethyl acetate 3 times (single ethyl acetate amount 500 mL), the organic phases were combined, washed once with saturated brine, dried over anhydrous magnesium sulfate, filtered, concentrated under reduced pressure, and purified on a silica gel column (eluent is ethyl acetate / n-hexane, volume ratio = 1: 5-10) to obtain ethyl 2-fluorocyclopropanecarboxylate (122.9 g, 0.93 mol, yield 86.9%). The hydrogen spectrum of ethyl 2-fluorocyclopropanecarboxylate is similar to Figure 1 Consistent.

[0074] Add 500mL of 30v / v% ethanol aqueous solution, slowly add sodium hydroxide (0.675mol) under stirring, and after complete dissolution, add 2-fluorocyclopropanecarboxylic acid ethyl ester (0.5mol), continue to react at 25°C for 3.5h, add 500mL of water, adjust the pH value to 1-2 with 2M HCl aqueous solution, extract with MTBE 3 times (single MTBE amount is 300mL), combine the organic phases, dry with anhydrous sodium sulfate, filter out sodium sulfate, and concentrate to constant weight to obtain 2-fluorocyclopropanecarboxylic acid (50.4g, yield is 96.9%). The hydrogen spectrum of 2-fluorocyclopropanecarboxylic acid is similar to Figure 2 Consistent.

[0075] The above is only a preferred embodiment of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and modifications can be made without departing from the principle of the present invention. These improvements and modifications should also be regarded as the scope of protection of the present invention.

Claims

1. A method for synthesizing 2-fluorocyclopropanecarboxylic acid, characterized in that: The following steps are involved: Propylene ester is subjected to addition reaction with triethylamine trihydrofluoride to obtain 3-fluoroacrylate; The 3-fluoroacrylate is subjected to a cyclization reaction with trimethylsulfone iodide to obtain 2-fluorocyclopropanecarboxylate; The 2-fluorocyclopropanecarboxylic acid ester is subjected to a hydrolysis reaction under alkaline conditions and then acidified to obtain 2-fluorocyclopropanecarboxylic acid.

2. The synthesis method according to claim 1, characterized in that The propiolate ester includes one or more of methyl propiolate, ethyl propiolate and propyl propiolate; The molar ratio of the propiolate to triethylamine trihydrofluoride is 1:1-2.

3. The synthesis method according to claim 1, characterized in that The addition reaction is carried out in the presence of a promoter, wherein the promoter includes CsF and / or Cs2CO3; The molar ratio of the propiolate to the accelerator is 1:1 to 1.

8.

4. The synthesis method according to any one of claims 1 to 3, characterized in that The temperature of the addition reaction is 15 to 35° C. and the time is 8 to 20 hours; The organic solvent used in the addition reaction includes sulfolane and / or dioxane.

5. The synthesis method according to claim 1, characterized in that The molar ratio of the 3-fluoroacrylate to trimethylsulfone iodide is 1:1.2-1.

8.

6. The synthesis method according to claim 1, characterized in that The cyclization reaction is carried out in the presence of an alkaline reagent, wherein the alkaline reagent includes an alkali metal hydride and / or an alkali metal alcoholate; The molar ratio of the 3-fluoroacrylate to the alkaline agent is 1:1.2-1.8; The organic solvent used in the cyclization reaction includes one or more of N,N-dimethylformamide, dimethyl sulfoxide and dioxane.

7. The synthesis method according to claim 1, 5 or 6, characterized in that: The temperature of the cyclization reaction is 25-35° C., and the time is 1-3 hours; the cyclization reaction is carried out under a protective atmosphere.

8. The synthesis method according to claim 1, characterized in that The alkaline reagent used in the alkaline condition includes an alkali metal hydroxide; The molar ratio of the 2-fluorocyclopropanecarboxylate to the alkaline reagent is 1:1.35-2.

9. The synthesis method according to claim 1 or 8, characterized in that: The temperature of the hydrolysis reaction is 20-35°C and the time is 2.5-5h; The solvent used in the hydrolysis reaction includes a mixed solvent of an organic solvent and water, and the organic solvent includes a lower alcohol and / or a furan solvent.

10. The synthesis method according to claim 1, characterized in that The pH value of the acidified system is 1-2.

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