A method for constructing a fluorine-containing compound by catalyzing decarboxylation of an alkyl carboxylic acid by a ketone compound

Abstract

The application discloses a method for constructing fluorine-containing compounds by decarboxylation of alkyl carboxylic acid catalyzed by ketone compounds. The method uses alkyl carboxylic acid with a structure as shown in formula as a reaction raw material, and performs reaction under the joint action of ketone compounds, fluorine-containing reagents and alkali to obtain fluorides shown in formula (1) and formula (2), wherein R 1 are respectively and independently selected from hydrogen, a heterocyclic ring, substituted or unsubstituted aryl, and substituted or unsubstituted hydrocarbyl; R 2 are respectively and independently selected from hydrogen, a heterocyclic ring, substituted or unsubstituted aryl, and substituted or unsubstituted hydrocarbyl; R 3 are respectively and independently selected from hydrogen, a heterocyclic ring, substituted or unsubstituted aryl, and substituted or unsubstituted hydrocarbyl. The reaction method has the advantages of low cost, mild conditions, high reaction efficiency, high yield and high selectivity, and the like. The ketone compounds are used to replace traditional metal catalysts, which can not only provide a fluorine-containing compound library with various structures for candidate drug screening, but also can be applied to positron emission tomography imaging.

Description

Technical Field

[0001] This invention belongs to the field of organic compound synthesis technology, specifically relating to a method for constructing fluorine-containing compounds by catalytic decarboxylation of alkyl carboxylic acids using ketone compounds. Background Technology

[0002] The construction of carbon-fluorine bonds is a crucial research topic in organic reactions. On the one hand, the enzymes required for this construction are lacking in nature; on the other hand, fluorine-containing drugs such as sofosbuvir, fleroxacin, and florfenicol are widely used in antibacterial and antiviral drugs (Equation 1). Therefore, developing simple, green, and efficient new methods for constructing carbon-fluorine bonds has significant practical and application value.

[0003]

[0004] Compared to traditional thermodynamic reactions, introducing light sources into organic reactions can, on the one hand, excite photocatalysts such as iridium photocatalysts, acridine salts, and decapentotates, thereby enabling a variety of new reactions and breaking through the limitations of traditional thermodynamic reactions; on the other hand, the light-absorbing properties of some small organic molecules also provide the possibility for the discovery and development of new photocatalysts, thus enabling the development of greener and more efficient organic chemical reactions.

[0005]

[0006] In 2014, Sammis's group first applied photocatalysis to the decarboxylation fluorination reaction (Equation 2), realizing the ruthenium-catalyzed decarboxylation fluorination of phenoxyacetic acid derivatives. However, this method is only applicable to activated carboxylic acid substrates such as phenoxyacetic acid or phenylacetic acid, and requires a high-power light source, which limits its application to some extent. In 2015, MacMillan's group improved this reaction by using Ir[dF(CF3)ppy]2(dtbbpy)PF6 as a photocatalyst (Equation 3), enabling various alkyl carboxylic acid compounds to be converted into their corresponding fluorides more efficiently. Subsequently, Ye Jinxing's group reported the decarboxylation fluorination reaction using Mes-AcrClO4 as an organic photocatalyst. This reaction is green and does not require a transition metal, but the reaction time is long and the substrate applicability is limited (Equation 4).

[0007]

[0008] Early research on photocatalytic decarboxylation reactions primarily utilized traditional ruthenium-based, iridium-based, and acridine-based photocatalysts. While some progress has been made in decarboxylation fluorination, the use of toxic precious metals and the high cost of these photocatalysts have limited the practical application of this reaction, especially for large-scale industrial production. Due to the high cost and widespread biotoxicity of precious metal catalysts, there is a need to develop novel decarboxylation photocatalysts and catalytic schemes to replace traditional photocatalysts such as iridium and ruthenium-based catalysts. Summary of the Invention

[0009] To overcome the problems existing in the prior art, one objective of this invention is to provide a method for the photo-induced decarboxylation of alkyl carboxylic acids to construct fluorinated compounds using ketone compounds. This method avoids the use of toxic and expensive heavy metal catalysts, and utilizes inexpensive, readily available, and environmentally friendly ketone compounds as catalysts. Simultaneously, it enables highly efficient and selective decarboxylation and fluorination reactions of most different carboxylic acids on a minute-scale basis. This method allows for large-scale preparation without significant yield reduction during scale-up. A second objective of this invention is to provide the application of this method in positron emission tomography (PET).

[0010] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0011] The first aspect of the present invention provides a method for constructing a fluorinated compound by catalytic decarboxylation of an alkyl carboxylic acid by ketone compounds, comprising the following steps: under light irradiation, using an alkyl carboxylic acid having the formula (1) as a reactant, and under the combined action of a ketone compound, a fluorinated reagent and a base, a reaction is carried out to obtain a fluorinated compound having the formula (2);

[0012]

[0013] In equations (1) and (2), R 1 Each group is independently selected from hydrogen, heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted hydrocarbon groups; R 2 Each group is independently selected from hydrogen, heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted hydrocarbon groups; R 3 Each is independently selected from hydrogen, heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted hydrocarbon groups.

[0014] Generally, the term "substituted" means that at least one hydrogen atom present on a group (e.g., a carbon or nitrogen atom) is substituted by a permissible substituent, such as a substituent that, upon substitution, produces a stable compound, for example, a compound that does not spontaneously undergo transformation (e.g., by rearrangement, cyclization, elimination, or other reactions). Unless otherwise stated, a "substituted" group has substituents at one or more substituted positions of the group, and when more than one position is substituted in any given structure, the substituents at each position are either the same or different.

[0015] Preferably, the substituents in the substituted aryl group and the substituted hydrocarbon group are each independently selected from one or more of the following: halogen (any one or more of fluorine, chlorine, bromine, and iodine), hydroxyl, carboxyl, acetal, amino, primary amino, secondary amino, ester, carbonyl, amide, cyano, substituted or unsubstituted aliphatic alkyl, substituted or unsubstituted alkoxy, substituted or unsubstituted cycloalkyl, substituted or unsubstituted heterocycloalkyl, substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted sulfonyl, and substituted or unsubstituted sulfonic acid.

[0016] In some embodiments of the present invention, the alkyl carboxylic acid is selected from any one or more of the following compounds: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid 1-Benzyl-5-oxo-3-pyrrolidinecarboxylic acid DL-Benzylsuccinic acid 4-(4-chlorophenyl)cyclohexanecarboxylic acid 7-Boc-7-azaspiro[3.5]nonane-2-carboxylic acid 2-Benzyl-3-phenylpropionic acid 2-Butyloctanoic acid Tropine 3-Methyl-1-Boc-3-piperidinecarboxylic acid 2,2-Dimethyl-3-(Boc-amino)propionic acid 2-((2-carboxy-2-methylpropoxy)carbonyl)benzoic acid Bicyclo[2,2,2]octane-1,4-cyclohexanedicarboxylic acid monomethyl ester 1-Boc-4-fluoro-4-piperidinecarboxylic acid (1R,4R)-4-((1,3-dioxo-1,3-dihydro-isoindol-2-yl)methyl)cyclohexane-1-carboxylic acid 11-Bromoundecanoic acid N,N-Dimethylsuccinic acid Lauric acid Diethylphosphonobutyric acid 4-Cyano-3-phenylpropionic acid 3-(pyridyl)propionic acid 2-(1,1,3-trioxo-1,2-benzothiazol-2-yl)acetic acid 4-Biphenylacetic acid 5-(1-Benzyl-1H-1,2,3-triazol-4-yl)valerate

[0017] Fenofibrate (1R,4R)-4-((1,3-dioxo-1,3-dihydro-isoindol-2-yl)methyl)cyclohexane-1-carboxylic acid Boc-L-glutamate-1-tert-butyl ester Ambrisentan Artesunate Dehydrocholic acid 3-Oxo-androst-4-ene-17beta-carboxylic acid 2-Benzyl-2-methylmalonic acid

[0018] Preferably, the ketone compound includes any one or more of alkyl diketones, aromatic ketones, and aromatic diketone compounds.

[0019] More preferably, the alkyl dione compound includes any one or more of 2,3-butanedione, 2,3-hexanedione, and 3,4-hexanedione.

[0020] More preferably, the aromatic ketone includes any one or more of acetophenone, benzophenone, 9-fluorenone, thioxanone, and 9-thioxanone.

[0021] More preferably, the aromatic diketone compound includes any one or more of anthraquinone, phenanthrenequinone, and biphenylmethyl.

[0022] Preferably, the amount of the ketone compound, measured in moles, is 0.1% to 50% of the alkyl carboxylic acid with the structure shown in formula (1). More preferably, it is 0.5% to 40%. Even more preferably, it is 1% to 30%. Still more preferably, it is 5% to 20%. Even more preferably, it is 0.1%, 0.5%, 1%, 2%, 3%, 4%, 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, or 50%.

[0023] Preferably, the fluorinated reagent is an electrophilic fluorine source, specifically an N-alkyl-N'-fluoro1,4-diazabicyclo[2,2,2]octane fluorinating agent. More preferably, the fluorinated reagent includes one or more of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (Selectfluor), 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octane tetrafluoroborate and their derivatives.

[0024] Preferably, the amount of the fluorinated reagent, measured in moles, is 0 to 20 equivalents of the alkyl carboxylic acid with the structure shown in formula (I). More preferably, it is 0.5 to 20 equivalents. Even more preferably, it is 1 to 10 equivalents. Still more preferably, it is 1.5 to 5 equivalents. Even more preferably, it is 0.1, 0.5, 1, 1.5, 2, 2.1, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 equivalents.

[0025] Preferably, the base includes organic and inorganic bases. The organic base is a nitrogen-containing system with lone pairs of electrons, including alkylamines (such as triethylamine, tri-n-butylamine, diethylamine, morpholine, N-methylmorpholine, N-ethylmorpholine, cyclohexylamine, diisopropylamine, triethylenediamine, tetramethylguanidine, N,N-diisopropylethylamine, 1,8-diazobispyrocyclo[5.4.0]undecyl-7-ene, 1,4-diazabicyclo[2.2.2]octane), or nitrogen-substituted aromatic heterocycles (such as pyridine, 4-dimethylaminopyridine, 2-dimethylaminopyridine, 2-methylpyridine, 2-methoxypyridine, 2-methylpyridine, 2-pyridinecarboxylic acid, 2,6-dimethylpyridine, 2,6-di-tert-butylpyridine, 2-methoxy-6-methylpyridine, 2,6-dimethoxypyridine, 2,6-diaminopyridine, 2,4,6... One or more of the following: trimethylpyridine, 2,6-di-tert-butyl-4-methylpyridine, 2,4,6-trifluoropyridine, 2,4,6-trichloropyridine, 2,4,6-tris(trifluoromethyl)pyridine, isoquinoline, quinoline, 2-methylquinoline, and quinine. The inorganic base includes one or more of lithium carbonate, sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, potassium bicarbonate, cesium bicarbonate, ammonium bicarbonate, lithium phosphate, sodium phosphate, potassium phosphate, sodium monohydrogen phosphate, sodium dihydrogen phosphate, potassium monohydrogen phosphate, potassium dihydrogen phosphate, lithium tert-butoxide, sodium tert-butoxide, potassium tert-butoxide, sodium ethoxide, lithium hydroxide, sodium hydroxide, potassium hydroxide, lithium fluoride, sodium fluoride, potassium fluoride, cesium fluoride, sodium acetate, potassium acetate, sodium formate, sodium trifluoroacetate, sodium benzoate, and potassium benzoate.

[0026] More preferably, the base is selected from weakly basic inorganic bases. Even more preferably, the base is disodium hydrogen phosphate.

[0027] On the one hand, compared with organic bases, inorganic bases have less odor, lower cost, and more stable properties; on the other hand, the base dissolves in water after the reaction, facilitating product separation.

[0028] Preferably, the amount of base used, measured in moles, is 0 to 20 equivalents of the alkyl carboxylic acid with the structure shown in formula (I). More preferably, it is 0.5 to 20 equivalents. Even more preferably, it is 1 to 10 equivalents. Still more preferably, it is 1 to 5 equivalents. Even more preferably, it is 0.1, 0.5, 1, 1.5, 1.8, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 15, or 20 equivalents.

[0029] Preferably, the illumination is light energy provided by placing the reaction system under any one of ultraviolet or visible light.

[0030] More preferably, the visible light includes monochromatic or mixed light with a wavelength of less than or equal to 600 nm, and more preferably includes monochromatic or mixed light with a wavelength of less than or equal to 500 nm.

[0031] In addition to being able to carry out the reaction under ultraviolet light, the present invention can also be carried out under visible light. Compared with the reaction system that can only use medium-wave ultraviolet light which is harmful to the human eye, the reaction system of the present invention is greener and safer.

[0032] More preferably, the wavelength of the light used for illumination is 350–550 nm. Even more preferably, it is 350–525 nm. Even more preferably, it is 350–500 nm. Even more preferably, it is 350–450 nm. For example, 350 nm, 380 nm, 400 nm, 420 nm, 450 nm, 458 nm, 500 nm, 525 nm, and 550 nm.

[0033] Preferably, the reaction is carried out in a solvent-free environment or in a solvent. More preferably, it is carried out in a solvent. Further preferably, the solvent comprises one or a mixture of two of water and an organic solvent. Still preferably, the solvent is water or a mixture of water and an organic solvent.

[0034] In some embodiments of the present invention, the organic solvent includes one or more of hydrocarbon solvents, halogenated hydrocarbon solvents, nitro hydrocarbon solvents, ether solvents, nitrile solvents, ester solvents, ketone solvents, alcohol solvents, amine solvents, amide solvents, sulfone solvents, and sulfoxide solvents.

[0035] In some embodiments of the present invention, the hydrocarbon solvent includes one or more of benzene, toluene, and saturated alkane compounds;

[0036] The halogenated hydrocarbon solvents include one or more of trifluoromethylbenzene, chlorobenzene, dichloromethane, 1,2-dichloroethane, 1,1,2,2-tetrachloroethane, chloroform, and carbon tetrachloride;

[0037] The nitro hydrocarbon solvents include one or more of nitrobenzene and nitromethane;

[0038] The ether solvents include one or more of tetrahydrofuran, 1,4-dioxane, methyl tert-butyl ether, and diethyl ether;

[0039] The nitrile solvents include one or more of acetonitrile, benzonitrile, and tert-butylacetonitrile;

[0040] The ester solvent includes one or more of ethyl acetate, n-butyl acetate, and isobutyl acetate;

[0041] The ketone solvents include one or more of acetone, methyl ethyl ketone, 2-methyl-3-butanone, 3,3-dimethyl-2-butanone, 2,4-dimethyl-3-pentanone, and acetophenone;

[0042] The alcohol solvents include one or more of methanol, ethanol, tert-butanol, and n-butanol;

[0043] The amine solvent includes one or more of triethylamine, diethylamine, and diisopropylethylamine;

[0044] The amide solvents include one or more of dimethylformamide and dimethylacetamide;

[0045] The sulfone solvent includes dimethyl sulfone;

[0046] The sulfoxide solvents include dimethyl sulfoxide.

[0047] In some embodiments of the present invention, the solvent is water, a mixture of hydrocarbon solvents and water, a mixture of nitro hydrocarbon solvents and water, a mixture of ether solvents and water, a mixture of nitrile solvents and water, a mixture of ester solvents and water, a mixture of ketone solvents and water, a mixture of alcohol solvents and water, a mixture of amine solvents and water, a mixture of amide solvents and water, a mixture of sulfone solvents and water, or a mixture of sulfoxide solvents and water. Preferably, the solvent is water, a mixture of ketone solvents and water, or a mixture of nitrile solvents and water. More preferably, the solvent is water, a mixture of acetone and water, or a mixture of acetonitrile and water.

[0048] In some embodiments of the present invention, the volume ratio of water to organic solvent is 1:0.2 to 2, preferably 1:0.5 to 1.5, and more preferably 1:0.8 to 1.2. Examples include 1:0.2, 1:0.5, 1:0.8, 1:1, 1:1.2, 1:1.5, 1:1.8, and 1:2.

[0049] In some embodiments of the present invention, the amount of solvent used is appropriate, that is, it can be adjusted according to general techniques in the art and actual needs, as long as it can fully dissolve or disperse the reaction raw materials. As an example, the ratio of the solvent to the alkyl carboxylic acid with the structure shown in formula (1) is 1 mL: 0.01 to 2 mmol, preferably 1 mL: 0.05 to 1.5 mmol, more preferably 1 mL: 0.1 to 1 mmol. For example, 1 mL: 0.01 mmol, 1 mL: 0.02 mmol, 1 mL: 0.05 mmol, 1 mL: 0.1 mmol, 1 mL: 0.12 mmol, 1 mL: 0.15 mmol, 1 mL: 0.2 mmol, 1 mL: 0.3 mmol, 1 mL: 0.4 mmol, 1 mL: 0.5 mmol, 1 mL: 0.6 mmol, 1 mL: 0.7 mmol, 1 mL: 0.8 mmol, 1 mL: 0.9 mmol, 1 mL: 1 mmol, 1 mL: 1.5 mmol, 1 mL: 2 mmol, etc.

[0050] Preferably, the reaction time is 1 min to 10 days. More preferably, 1 min to 7 days. Even more preferably, 5 min to 5 days, even more preferably 5 min to 24 hours, and still more preferably 5 min to 1 hour. For example, 1 min, 1.5 min, 2 min, 2.5 min, 5 min, 7.5 min, 10 min, 20 min, 30 min, 1 hour, 2 hours, 4 hours, 6 hours, 12 hours, 16 hours, 20 hours, 24 hours, 5 days, and 10 days. The reaction time will vary depending on the scale of the reaction, the reaction temperature, and the ratio of the reactants.

[0051] Preferably, after the reaction is completed, the resulting mixture can be further separated and purified to obtain a purer final product. Those skilled in the art are familiar with separation and purification methods, such as extraction, column chromatography, distillation, decantation, filtration, centrifugation, washing, evaporation, stripping, and adsorption, or a combination of at least two of these methods, for example, extraction and column chromatography.

[0052] Of course, if necessary, the obtained reaction mixture can be directly introduced into other processes to produce other products. Optionally, the reaction mixture can be pretreated, for example, by one or more of concentration, extraction, and vacuum distillation, before being introduced into other processes to obtain a crude or pure product.

[0053] In some embodiments of the present invention, the post-processing steps after the reaction can be as follows: After the reaction is completed, the reaction mixture is cooled, concentrated under reduced pressure, and the concentrated residue is subjected to column chromatography. The eluent used in the column chromatography process includes any one or more combinations of dichloromethane, n-hexane, ethyl acetate, n-pentane, methanol, and petroleum ether, such as n-hexane-ethyl acetate, dichloromethane-methanol, petroleum ether-ethyl acetate, n-hexane:ethyl acetate, etc.

[0054] As one example, the column chromatography uses hexane-ethyl acetate as the eluent, wherein the volume ratio of hexane to ethyl acetate is 5–100:1, for example, 5:1, 10:1, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, 80:1, 90:1, or 100:1. As a second example, the column chromatography uses dichloromethane-methanol as the eluent, wherein the volume ratio of dichloromethane to methanol is 20–80:1, preferably 30–60:1, for example, 20:1, 30:1, 40:1, 50:1, 60:1, 70:1, or 80:1. As a third example, the column chromatography uses petroleum ether-ethyl acetate as the eluent, wherein the volume ratio of petroleum ether to ethyl acetate is 10–200:1, for example, 10:1, 20:1, 30:1, 40:1, 50:1, 80:1, 100:1, 200:1, etc. As another third example, the column chromatography uses dichloromethane-methanol as the eluent, wherein the volume ratio of dichloromethane to methanol is 50–150:1, for example, 50:1, 60:1, 70:1, 90:1, 100:1, 120:1, 150:1. During elution, dichloromethane can be used alone first, followed by dichloromethane-methanol elution.

[0055] In some embodiments of the present invention, the column chromatography uses a silica gel column, wherein the silica gel is 300-400 mesh silica gel.

[0056] In some embodiments of the present invention, an extraction step is included before column chromatography. As an example, the extraction solvent used in the extraction step includes water-dichloromethane, and the extracted product is enriched in the organic phase.

[0057] Preferably, the reaction is carried out in a protective atmosphere. More preferably, it is carried out in nitrogen or argon. To avoid the adverse effects of oxygen on the reaction, the solvent used in the reaction needs to be deoxygenated before use.

[0058] Preferably, the reaction is carried out at 15–40°C.

[0059] The second aspect of the present invention also provides the application of the method described in the first aspect in positron emission tomography (PET).

[0060] The beneficial effects of this invention are:

[0061] The reaction method of this invention has the advantages of low cost, mild conditions, high efficiency, high yield and selectivity. By using ketone compounds to replace traditional metal catalysts, it can not only provide a diverse library of fluorides for candidate drug screening, but also has the potential to be applied to positron emission tomography imaging.

[0062] Specifically, the present invention has the following advantages:

[0063] a) Ketones are inexpensive, readily available, and environmentally friendly;

[0064] b) The reaction conditions are mild and possess high efficiency and selectivity;

[0065] c) The reaction substrates have high tolerance for functional groups and a wide range of substrate sources;

[0066] d) The reaction can be scaled up to the gram scale for preparation;

[0067] e) The product has high yield and purity.

[0068] Furthermore, this invention provides a method for constructing fluorinated compounds from alkyl carboxylic acids by catalytic decarboxylation using ketone compounds. Using primary, secondary, or tertiary alkyl carboxylic acids as reactants, the decarboxylation and fluorination reaction occurs rapidly under sunlight or artificial light sources (containing light waves of 365 nm-458 nm wavelengths) to yield the corresponding alkyl fluorides. This method offers advantages such as low cost, mild conditions, high efficiency, high yield, and high selectivity, providing a new synthetic strategy for alkyl fluorides. In addition, this invention uses ketone compounds as photocatalysts, which can replace traditional photocatalysts such as iridium and ruthenium photocatalysts to achieve decarboxylation and fluorination reactions of various carboxylic acids. Because this invention avoids the use of metal catalysts, offers rapid reaction times, and is compatible with complex substrates, it not only provides a diverse library of fluorides for candidate drug screening but also makes it possible to apply this method to PET (positron emission tomography) imaging, demonstrating promising application prospects and research value. Attached Figure Description

[0069] Figure 1 This refers to the blue light spectrum range used in this embodiment;

[0070] Figure 2 This refers to the white light spectral range used in this embodiment. Detailed Implementation

[0071] The technical solution of the present invention is further illustrated below with reference to specific embodiments. Unless otherwise specified, the raw materials used in the following embodiments can be obtained from conventional commercial sources or prepared and separated through simple synthesis; unless otherwise specified, the processes employed are conventional processes in the art.

[0072] The spectral ranges of blue and white light used in the following examples are as follows: Figure 1 , 2 As shown.

[0073] Example 1

[0074] The synthetic equation for 2-(5-fluoropentyl)isoindole-1,3-dione is shown below:

[0075]

[0076] At room temperature (20°C), 6-(N-phthalimino)hexanoic acid (0.4 mmol, 1 equivalent), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (1.28 mmol, 3.2 equivalent), and disodium hydrogen phosphate (0.84 mmol, 2.1 equivalent) were added to a 25 mL Shrek reaction tube. Nitrogen gas was purged three times, and acetonitrile (2.8 mL) and water (1.2 mL) were added respectively after pre-purging to remove oxygen. Then, 2,3-butanedione (0.04 mmol, 40 μL, 1 M acetonitrile solution) was added to the above reaction solution. The reaction was carried out under a 458 nm LED lamp (6... The reaction was stirred under light for 10 minutes, then water and dichloromethane were added for extraction. The organic phase was collected and dried over anhydrous sodium sulfate. After filtration and solvent removal by rotary evaporation, the product (eluent: dichloromethane) was obtained by column chromatography. The product was a pale yellow oily liquid with a yield of 82%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400 MHz, chloroform-d) δ 7.79–7.77 (m, 2H), 7.67–7.65 (m, 2H), 4.38 (dt,

[0077] J=47.6,6.0 Hz,2H),3.64(t,J=7.2 Hz,2H),1.74–1.62(m,4H),1.45–1.37(m,2H). 19 F NMR

[0078] (377 MHz, CDCl3)δ-218.5. 13C NMR (101 MHz, CDCl3) δ168.2, 133.7, 131.9, 123.0, 83.6 (d, J = 165.4 Hz), 37.5, 29.8 (d, J = 20.1 Hz), 28.0, 22.4 (d, J = 5.1 Hz). HRMS (ESI): calcd forC 13 H 14 FNO2Na + [M+Na] + :258.0900; found 258.0902.

[0079] Example 2

[0080] The synthetic equation for 1-bromo-10-fluorodecane is shown below:

[0081]

[0082] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of 11-bromoundecanoic acid, and petroleum ether is used as the eluent for column chromatography. Other operations are the same as in Example 1. The product of this embodiment is a colorless oily liquid with a yield of 78%; the NMR spectrum data of the obtained product are as follows: 1 ¹H NMR (400 MHz, chloroform-d) δ 4.42 (dt, J = 47.6, 6.0 Hz, 2H), 3.39 (t, J = 6.8 Hz, 2H), 1.87–1.80 (m, 2H), 1.72–1.61 (m, 2H), 1.45–1.36 (m, 2H), 1.29 (s, 8H). 19 F NMR (377 MHz, CDCl3) δ-218.1. 13 CNMR (101 MHz, CDCl3) δ84.1 (d, J = 164.8 Hz), 33.9, 32.8, 30.3 (d, J = 19.3 Hz), 29.3, 29.3, 29.1, 28.7, 28.1, 25.1 (d, J = 5.7 Hz).

[0083] Example 3

[0084] The synthetic equation for 3-fluoroN,N-dimethylpropionamide is shown below:

[0085]

[0086] The synthesis method in this embodiment differs from that in Example 1 in that the carboxylic acid 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of N,N-dimethylsuccinic acid, and the eluent used in column chromatography is petroleum ether:ethyl acetate = 5:1, followed by a petroleum ether:ethyl acetate = 2:1. Other operations are the same as in Example 1. The product of this embodiment is a pale yellow oily liquid with a yield of 59%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400 MHz, chloroform-d) δ 4.75 (dt, J = 46.4, 6.4 Hz, 2H), 3.00 (s, 3H), 2.93 (s, 3H), 2.71 (dt, J = 22.4, 6.4 Hz, 2H). 19 F NMR (376 MHz, CDCl3) δ-219.9. 13 C NMR (101 MHz, CDCl3) δ169.4 (d, J = 7.7 Hz), 80.3 (d, J = 164.6 Hz), 37.2, 35.2, 33.9 (d, J = 21.2 Hz). HRMS (EI): calcd for C5H 10 ONF(M) ·+ :119.0741; found 119.0742.

[0087] Example 4

[0088] The synthetic equation for 1-fluoroundecane is shown below:

[0089]

[0090] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of lauric acid, and n-pentane is used as the eluent for column chromatography. Other operations are the same as in Example 1. The product of this embodiment is a colorless oily liquid with a yield of 72%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400 MHz, chloroform-d) δ 4.43 (dt, J = 47.6 Hz, J = 6.0 Hz, 2H), 1.75–1.62 (m, 2H), 1.41–1.27 (m, 16H), 0.89 (t, J = 6.4 Hz, 3H). 19 F NMR (376 MHz, CDCl3) δ-218.1. 13C NMR (101MHz, CDCl3) δ84.2 (d, J = 165.6 Hz), 31.9, 30.4 (d, J = 19.2 Hz), 29.6, 29.6, 29.5, 29.4, 29.3, 25.2 (d, J = 5.1 Hz), 22.7, 14.1. HRMS (EI): calcd for C 11 H 22 (M-HF) ·+ :154.1716; found 154.1718.

[0091] Example 5

[0092] The synthetic equation for 3-fluoropropyl diethyl phosphate is shown below:

[0093]

[0094] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of diethylphosphonobutyric acid, and the eluent used for column chromatography is dichloromethane:methanol = 100:1 or dichloromethane:methanol = 50:1. Other operations are the same as in Example 1. The product of this embodiment is a light yellow oily liquid with a yield of 50%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 4.42 (dt, J = 46.8 Hz, J = 6.0 Hz, 2H), 4.10–3.99 (m, 4H), 2.00–1.88 (m, 2H), 1.83–1.75 (m, 2H), 1.27 (t, J = 7.2 Hz, 6H). 19 F NMR (376MHz, CDCl3) δ-220.1. 13 C NMR (101MHz, CDCl3) δ83.2 (dd, J=166.7Hz, J=16.2Hz), 61.5 (d, J=6.1Hz), 23.7 (dd, J= 20.2Hz, J=4.0Hz), 21.4 (dd, J=143.4Hz, J=5.1Hz), 16.3 (d, J=6.1Hz). HRMS (EI): calcd for C7H 17 O3FP(M+H) ·+ :199.0894; found199.0898.

[0095] Example 6

[0096] The synthetic equation for 4-(2-fluoroethyl)benzonitrile is shown below:

[0097]

[0098] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of 4-cyano-3-phenylpropionic acid, and the eluent used for column chromatography is petroleum ether:ethyl acetate = 50:1. Other operations are the same as in Example 1. The product of this embodiment is a colorless oily liquid with a yield of 73%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.59 (d, J = 8.4 Hz, 2H), 7.35 (d, J = 8.0 Hz, 2H), 4.65 (dt, J = 47.2, 6.0 Hz, 2H), 3.06 (dt, J = 25.6, 6.0 Hz, 2H). 19 F NMR (376MHz, CDCl3) δ-216.9. 13 C NMR (101MHz, CDCl3) δ143.0 (d, J = 4.0Hz), 132.2, 129.7, 118.7, 110.57, 83.0 (d, J = 169.7Hz), 36.8 (d, J = 21.2Hz). HRMS (EI): calcd for C9H8NF (M) ·+ :149.0635; found149.0634.

[0099] Example 7

[0100] The synthetic equation for 3-(2-fluoroethyl)pyridine is shown below:

[0101]

[0102] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of 3-(pyridyl)propionic acid, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 1. The product of this embodiment is a pale yellow oily liquid with a yield of 47%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 8.53–8.51 (m, 2H), 7.60 (dt, J = 8.0, 2.0 Hz, 1H), 7.29–7.25 (m, 1H), 4.66 (dt, J = 47.2, 6.0 Hz, 2H), 3.03 (dt, J = 24.8, 6.4 Hz, 2H). 19 FNMR (376MHz, CDCl3) δ -216.7. 13C NMR (101MHz, CDCl3) δ150.1, 148.0, 136.5, 132.8 (d, J = 4.4Hz), 123.4, 83.3 (d, J = 170.1Hz), 34.0 (d, J = 21.0Hz). HRMS (EI): calcd for C7H8NF (M) ·+ :125.0635; found125.0636.

[0103] Example 8

[0104] The synthetic equation for 1-benzyl-4-(4-fluorobutyl)-1H-1,2,3-triazole is shown below:

[0105]

[0106] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of 5-(1-benzyl-1H-1,2,3-triazol-4-yl)valeric acid, and the eluent used for column chromatography is petroleum ether:ethyl acetate = 2:1. Other operations are the same as in Example 1. The product of this embodiment is a pale yellow oily liquid with a yield of 48%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (600MHz, chloroform-d) δ 7.33–7.32 (m, 3H), 7.23–7.20 (m, 3H), 5.46 (s, 2H), 4.41 (dt, J = 47.4, 6.0 Hz, 2H), 2.71 (t, J = 3.6 Hz, 2H), 1.77–1.68 (m, 4H). 19 F NMR (376MHz, CDCl3) δ-218.4. 13 C NMR (151MHz, CDCl3) δ147.9,134.8,128.8,128.4,127.7,120.6,83.5(d,J=164.4Hz),53.7,29.6(d,J=19.8Hz),24.9,24.9(d,J=5.0Hz).HRMS(EI):calcd for C 13 H 16 N3F(M) ·+ :233.1323; found233.1324.

[0107] Example 9

[0108] The synthetic equation for 1,1-dioxide of 2-(fluoromethyl)benzo[d]isothiazol-3(2H)-one is shown below:

[0109]

[0110] The synthesis method in this embodiment differs from that in Example 1 in that the carboxylic acid 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of 2-(1,1,3-trioxo-1,2-benzothiazol-2-yl)acetic acid, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 1. The product of this embodiment is a white solid with a yield of 88%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 8.10 (d, J = 7.6Hz, 1H), 7.97–7.85 (m, 3H), 5.84 (d, J = 52.0Hz, 2H). 19 F NMR (376MHz, CDCl3) δ-174.9. 13 C NMR (101MHz, CDCl3) δ157.9 (d, J = 2.4Hz), 137.4, 135.8, 134.7, 126.1, 125.8, 121.3, 75.7 (d, J = 207.7Hz). HRMS (EI): calcd for C8H5O3NFS (M) ·+ :213.9969; found 213.9967.

[0111] Example 10

[0112] The synthetic equation for 4-(fluoromethyl)-1,1'-biphenyl is shown below:

[0113]

[0114] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of 4-biphenylacetic acid, and petroleum ether is used as the eluent for column chromatography. Other operations are the same as in Example 1. The product of this embodiment is a white solid with a yield of 76%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.70–7.64 (m, 4H), 7.53–7.49 (m, 4H), 7.44–7.40 (m, 1H), 5.47 (d, J = 48.0 Hz, 2H). 19 F NMR (376MHz, CDCl3) δ-206.1. 13C NMR (101MHz, CDCl3) δ141.7 (d, J = 3.0Hz), 140.5, 135.1 (d, J = 17.0Hz), 128.8, 128.0 (d, J = 5.9Hz), 127.5, 127.3, 127.1, 84.3 (d, J = 167.0Hz). HRMS (EI):calcd for C 13 H 11 F(M) ·+ :186.0839; found186.0839.

[0115] Example 11

[0116] The synthetic equation for 4-fluoro-1-toluenesulfonylpiperidine is shown below:

[0117]

[0118] At room temperature (20°C), 1-[(4-tolyl)sulfonyl]-4-piperidinic acid (0.4 mmol, 1 equivalent), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (0.84 mmol, 2.1 equivalent), and disodium hydrogen phosphate (0.84 mmol, 2.1 equivalent) were added to a 25 mL Shrek reaction tube. Nitrogen gas was purged three times, and acetonitrile (2.0 mL) and water (2.0 mL), which had been pre-purged to remove oxygen, were added respectively. Then, 2,3-butanedione (0.04 mmol, 40 μL, 1 M acetonitrile solution) was added to the above reaction solution. The reaction was carried out at 458 nm. The reaction was stirred for 5 minutes under LED light (6W), then water and dichloromethane were added for extraction. The organic phase was collected and dried over anhydrous sodium sulfate. After filtration and solvent removal by rotary evaporation, the product (eluent: dichloromethane) was obtained by column chromatography. The product was a white solid with a yield of 92%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.64–7.61 (m, 2H), 7.32–7.30 (m, 2H), 4.79–4.63 (m, 1H), 3.32–3.27 (m, 2H), 2.89–2.83 (m, 2H), 2.41 (s, 3H), 1.96–1.85 (m, 4H). 19 F NMR (376MHz, CDCl3) δ-185.4. 13C NMR (101MHz, CDCl3) δ143.6, 132.9, 129.6, 127.5, 86.2 (d, J = 172.0Hz), 41.74 (d, J = 20.2Hz), 30.4 (d, J = 17.0Hz), 21.4.HRMS (ESI): calcd for C 12 H 16 FNO2SNa + [M+Na] + :280.0778; found 280.0780.

[0119] Example 12

[0120] The synthetic equation for 1-chloro-4-(4-fluorocyclohexyl)benzene is shown below:

[0121]

[0122] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 4-(4-chlorophenyl)cyclohexanecarboxylic acid, and the eluent used for column chromatography is n-pentane. Other operations are the same as in Example 11. The product of this embodiment is a colorless oily liquid with a yield of 60% and a dr (3.48:1). The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.31–7.28 (m, 2H), 7.20–7.14 (m, 2H), 5.01–4.86 (m, 0.8H, major), 4.70–4.50 (m, 0.23H, minor), 2.61–2.50 (m, 1H), 2.28–2.15 (m, 2H), 2.02–1.79 (m, 2H), 1.76–1.71 (m, 2H), 1.69–1.47 (m, 2H). 19 F NMR(376MHz, CDCl3)δ-170.04(minor),-185.3(major). 13C NMR (101MHz, CDCl3) δ145.4 (major), 144.3 (d, J = 2.9Hz) (minor), 131.8 (minor), 131.6 (major) ),128.5(minor),128.4(major),128.1(major),128.0(minor),91.8(d,J=173.1Hz)(minor),8 8.0(d,J=168.0Hz)(major),42.8(major),42.4(d,J=2.1Hz)(minor),32.8(d,J=18.6Hz)(mino r),31.6(d,J=12.2Hz)(minor),31.0(d,J=21.4Hz)(major),27.9(major).HRMS(EI):calcdfor C 12 H 14 ClF(M) ·+ :212.0763; found 212.0763.

[0123] Example 13

[0124] The synthetic equation for 1-benzyl-4-fluoropyrrolidine-2-one is shown below:

[0125]

[0126] The synthesis method in this embodiment differs from that in Example 11 in that: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 1-benzyl-5-oxo-3-pyrrolidinecarboxylic acid; dichloromethane is used as the eluent for column chromatography, with a dichloromethane:methanol ratio of 100:1. Other operations are the same as in Example 11. The product of this embodiment is a pale yellow liquid with a yield of 56%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.36–7.21 (m, 5H), 5.29–5.13 (m, 1H), 4.54–4.45 (m, 2H), 3.61–3.40 (m, 2H), 2.83–2.63 (m, 2H). 19 FNMR (376MHz, CDCl3) δ-173.1. 13 C NMR (101MHz, CDCl3) δ171.3,135.5,128.7,127.8,127.6,85.8(d,J=179.1Hz),53.4(d,J=25.6Hz),46.0,38.6(d,J=24.2Hz).HRMS(ESI):calcd for C11 H 12 FNONa[M+Na] + :216.0795; found 216.0796.

[0127] Example 14

[0128] The synthetic equation for tert-butyl 2-fluoro-7-azaspiro[3.5]nonane-7-carboxylic acid is shown below:

[0129]

[0130] The synthesis method in this embodiment differs from that in Example 11 in that: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 7-tert-butyloxycarbonyl-7-azaspiro[3.5]nonane-2-carboxylic acid; the mixture is stirred under light for 2.5 minutes; and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 69%; it is a single isomer; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 5.09–4.89 (m, 1H), 3.46–3.23 (m, 4H), 2.29–2.20 (m, 2H), 1.99–1.87 (m, 2H), 1.72–1.51 (m, 2H), 1.44–1.39 (m, 11H). 19 F NMR (376MHz, CDCl3) δ-168.9. 13 C NMR (101MHz, CDCl3) δ 154.7, 84.6 (d, J = 208.4Hz), 79.2, 40.3 (d, J = 20.0Hz), 39.0, 36.5, 30.4 (d, J = 13.3Hz), 28.3.HRMS (EI): calcd for C 13 H 22 O2NF(M) ·+ :243.1629; found 243.1630.

[0131] Example 15

[0132] The synthetic equation for 3-fluoro-4-phenylbutyric acid is shown below:

[0133]

[0134] The synthesis method in this embodiment differs from that in Example 11 in that: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of DL-benzylsuccinic acid; dichloromethane is used as the eluent for column chromatography, and the ratio of dichloromethane to methanol is 100:1. Other operations are the same as in Example 11. The product of this embodiment is a pale yellow solid with a yield of 61%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 9.67 (brs, 1H), 7.39–7.26 (m, 5H), 5.32–5.11 (m, 1H), 3.15–2.96 (m, 2H), 2.81–2.60 (m, 2H). 19 F NMR (376MHz, CDCl3) δ-177.7. 13 C NMR (101MHz, CDCl3) δ176.3 (d, J = 5.7Hz), 135.8 (d, J = 5.3Hz), 129.4, 128.6, 127. 0,90.1(d,J=208.4Hz),40.9(d,J=21.3Hz),39.3(d,J=24.3Hz).HRMS(ESI):calcd for C 10 H 10 FO2 - [MH] - :181.0670; found 181.0667.

[0135] Example 16

[0136] The synthetic equation for 1,3-diphenyl-2-fluoropropane is shown below:

[0137]

[0138] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 2-benzyl-3-phenylpropionic acid, and petroleum ether is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a colorless oily liquid with a yield of 88%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.47–7.35 (m, 10H), 5.13–4.97 (m, 1H), 3.17–2.98 (m, 4H). 19 F NMR (377MHz, CDCl3) δ-176.8. 13C NMR (101MHz, CDCl3) δ137.1 (d, J = 3.9Hz), 129.4, 128.4, 126.6, 94.6 (d, J = 175.2Hz), 41.0 (d, J = 21.4Hz). HRMS (EI): calcdfor C 15 H 15 F(M) ·+ :214.1152; found 214.1152.

[0139] Example 17

[0140] The synthetic equation for 5-fluoroundecane is shown below:

[0141]

[0142] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 2-butyloctanoic acid, and n-pentane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a colorless oily liquid with a yield of 76%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 4.55–4.36 (m, 3H), 1.66–1.54 (m, 3H), 1.53–1.41 (m, 3H), 1.37–1.26 (m, 10H), 0.94–0.87 (m, 6H). 19 F NMR (376MHz, CDCl3) δ-180.0. 13 CNMR (101MHz, CDCl3) δ94.6 (d, J = 167.2Hz), 35.3, 35.1, 35.0, 34.8, 31.8, 29.2, 27.3(d,J=4.4Hz),25.1(d,J=4.4Hz),22.6,14.0(d,J=8.0Hz).HRMS(EI):calcd for C 11 H 22 (M-HF) ·+ :154.1716; found154.1716.

[0143] Example 18

[0144] The synthetic equation for 2-fluoro-2-phenylethanol is shown below:

[0145]

[0146] The synthesis method in this embodiment differs from that in Example 11 in that: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of tropine acid; the eluent used in column chromatography is petroleum ether:ethyl acetate = 10:1, followed by a petroleum ether:ethyl acetate ratio of 5:1. Other operations are the same as in Example 11. The product of this embodiment is a colorless oily liquid with a yield of 65%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.42–7.34 (m, 5H), 5.64–5.49 (m, 1H), 3.98–3.77 (m, 2H). 19 F NMR (565MHz, CDCl3) δ-186.7. 13 C NMR (101MHz, CDCl3) δ 136.4 (d, J = 19.9Hz), 128.71 (d, J = 1.8Hz), 128.51, 125.7 (d, J = 7.3Hz), 94.8 (d, J = 172.9Hz), 66.4 (d, J = 24.8Hz). HRMS (EI): calcd for C8H9OF(M) ·+ :140.0632; found140.0632.

[0147] Example 19

[0148] The synthetic equation for (2-fluoro-2-methylpropyl)carbamate tert-butyl ester is shown below:

[0149]

[0150] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 2,2-dimethyl-3-(Boc-amino)propionic acid, the mixture is stirred under light for 1.5 minutes, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a pale yellow oily liquid with a yield of 73%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 4.95 (brs, 1H), 3.24–3.17 (m, 2H), 1.38 (s, 9H), 1.30 (d, J = 2.4Hz, 3H), 1.24 (d, J = 2.4Hz, 3H). 19 F NMR (377MHz, CDCl3) δ-144.7. 13C NMR (101MHz, CDCl3) δ156.1,95.2(d,J=167.3Hz),79.2,48.9(d,J=22.1Hz),28.2,24.0(d,J=24.0Hz).HRMS(ESI):calcd forC9H 18 FNO2Na + [M+Na] + :214.1213; found 214.1214.

[0151] Example 20

[0152] The synthetic equation for 2-((2-fluoro-2-methylpropoxy)carbonyl)benzoic acid is shown below:

[0153]

[0154] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 2-((2-carboxy-2-methylpropoxy)carbonyl)benzoic acid, and the eluent used for column chromatography is dichloromethane:methanol = 50:1. Other operations are the same as in Example 11. The product of this embodiment is a pale yellow solid with a yield of 57%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (600MHz, chloroform-d) δ 10.14 (brs, 1H), 7.90 (d, J = 7.2Hz, 1H), 7.73 (d, J = 7.2Hz, 1H), 7.60 (dt, J = 18.6, 7.8Hz, 2H), 4.33 (d, J = 19.8Hz, 2H), 1.46 (s, 3H), 1.42 (s, 3H). 19 F NMR (565MHz, CDCl3) δ-145.6. 13 CNMR (151MHz, CDCl3) δ172.2,167.6,132.6,132.1,131.0,130.2,129.6,128.8, 93.1(d,J=170.0Hz),70.4(d,J=25.2Hz),23.6(d,J=24.0Hz).HRMS(ESI):calcd for C 12 H 12 FO4 - [MH] - :239.0725; found239.0720.

[0155] Example 21

[0156] The synthetic equation for (2-fluoro-2-methylpropyl)carbamate tert-butyl ester is shown below:

[0157]

[0158] The synthesis method in this embodiment differs from that in Example 11 in that: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 3-methyl-1-tert-butoxycarbonyl-3-piperidinecarboxylic acid; the mixture is stirred under light for 1.5 minutes; and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a colorless liquid with a yield of 80%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 3.78–3.74 (m, 2H), 3.06–2.83 (m, 2H), 1.90–1.69 (m, 2H), 1.57–1.40 (m, 11H), 1.28 (d, J = 20.8 Hz, 3H). 19 F NMR (376MHz, CDCl3) δ-152.3,-152.9. 13 C NMR (101MHz, CDCl3) δ154.9,91.0(d,J=173.2Hz),79.5,52.8(d,J=19.4Hz),51.5(d,J=21 .2Hz),43.7,42.7,35.2(d,J=22.7Hz),28.3,24.2(d,J=24.0Hz),21.3.HRMS(ESI):calcd for C 11 H 20 FNO2Na + [M+Na] + :240.1370; found 240.1370.

[0159] Example 22

[0160] The synthetic equation for methyl 4-fluorobicyclo[2,2,2]octane-1-carboxylate is shown below:

[0161]

[0162] The synthesis method in this embodiment differs from that in Example 11 in that: 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of bicyclo[2,2,2]octane-1,4-cyclohexanedicarboxylic acid monomethyl ester; the mixture is stirred under light for 1.5 minutes; and the eluent used for column chromatography is petroleum ether:ethyl acetate = 50:1. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 43%; the NMR spectrum and mass spectrometry data of the obtained product are as follows:1 ¹H NMR (400 MHz, chloroform-d) δ 3.61 (s, 3H), 1.98–1.94 (m, 6H), 1.83–1.77 (m, 6H). 19 F NMR (376MHz, CDCl3) δ-153.2. 13 C NMR (101MHz, CDCl3) δ177.0 (d, J = 3.6Hz), 93.9 (d, J = 184.6Hz), 51.8, 38.14 (d, J = 3.7Hz), 30.4 (d, J = 19.6Hz), 29.6 (d, J = 10.3Hz). HRMS (EI): calcd forC 10 H 15 O2F(M) ·+ :186.1051; found 186.1052.

[0163] Example 23

[0164] The synthetic equation for 4,4-difluoropiperidine-1-carboxylic acid tert-butyl ester is shown below:

[0165]

[0166] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 1-tert-butoxycarbonyl-4-fluoro-4-piperidinecarboxylic acid, and the eluent used for column chromatography is petroleum ether:ethyl acetate = 50:1. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 61%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 H NMR (400MHz, chloroform-d) δ3.50 (t, J = 6.0Hz, 4H), 1.97–1.84 (m, 4H), 1.43 (s, 9H). 19 F NMR (376MHz, CDCl3) δ -97.89. 13 C NMR(101MHz, CDCl3)δ154.2,121.8(t,J=242.9Hz),80.1,40.7,33.9(t,J=23.3Hz),28.2.HRMS(EI):calcd for C 10 H 15 O2F(M) ·+ :186.1051; found 186.1052.

[0167] Example 24

[0168] The synthetic equation for 2-((4-fluorocyclohexyl)methyl)isoindoline-1,3-dione is shown below:

[0169]

[0170] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of (1R,4R)-4-((1,3-dioxo-1,3-dihydro-isoindol-2-yl)methyl)cyclohexane-1-carboxylic acid, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 94% and a dr (3:1). The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 HNMR (400MHz, chloroform-d) δ7.81–7.78(m,1H),7.71–7.67(m,1H),4.82–4.68(m,0.75H,major),4.53–4.33(m,0.25H,minor ),3.54–3.50(m,2H),2.09–1.93(m,2H),1.87–1.73(m,1.5H,major),1.55–1.33(m,5H),1.14–1.04(m,1.5H,minor). 19 F NMR(376MHz, CDCl3)δ-170.7(minor),-184.6(major). 13 C NMR (101MHz, CDCl3) δ168.4(major),168.3(minor),133.8(minor),133.7(major),131.8(major) ,131.8(minor),123.1(minor),123.0(major),91.7(d,J=172.4Hz)(minor),88.3(d,J=168.6Hz) (major),43.3(major),42.7(d,J=3.1Hz)(minor),35.7(major),35.6(minor),31.4(d,J=19.1Hz )(minor),29.8(d,J=21.3Hz)(major),27.6(d,J=11.6Hz)(minor),24.4(major).HRMS(EI):calcd for C 15 H 16 O2NF(M) ·+ :261.1160; found 263.1161.

[0171] Example 25

[0172] The synthetic equation for (4-chlorophenyl)(4-((2-fluoropropane-2-yl)oxy)phenyl)methyl ketone is shown below:

[0173]

[0174] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of fenofibrate acid, and the eluent used for column chromatography is n-pentane:diethyl ether = 10:1. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 69%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (600 MHz, chloroform-d) δ 7.79–7.77 (m, 2H), 7.75–7.73 (m, 2H), 7.47–7.46 (m, 2H), 7.24 (d, J = 8.4 Hz, 2H), 1.68 (s, 3H), 1.66 (s, 3H). 19 F NMR (565MHz, CDCl3) δ -89.9. 13 C NMR (151MHz, CDCl3) δ194.6,157.7,138.7,135.9,132.6,131.7,131.2,128.5,121.4(d,J=1.9Hz),116.3,114.8,25.5(d,J=29.6Hz).HRMS(EI):calcd forC 16 H 14 O2ClF(M) ·+ :292.0661; found 292.0661.

[0175] Example 26

[0176] The synthetic equation for tert-butyl (S)-2-((tert-butyloxycarbonyl)amino)-4-fluorobutyrate is shown below:

[0177]

[0178] The synthesis method in this embodiment differs from that in Example 1 in that 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of Boc-L-glutamic acid-1-tert-butyl ester, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 1. The product of this embodiment is a colorless oily liquid with a yield of 64%. The NMR spectrum and mass spectrometry data of the obtained product are as follows: 1¹H NMR (400 MHz, chloroform-d) δ 5.22 (brs, 1H), 4.58–4.42 (m, 2H), 4.25 (m, 1H), 2.20–2.02 (m, 2H), 1.43 (s, 9H), 1.40 (s, 9H). 19 F NMR (376MHz, CDCl3) δ-219.5. 13 CNMR(101MHz, CDCl3)δ171.0,155.2,82.1,80.4(d,J=166.0Hz),79.7,51.1,33.2(d,J=19.9Hz),28.2,27.8.HRMS(ESI):calcd for C 13 H 24 FNO4Na + [M+Na] + :300.1578; found300.1582.

[0179] Example 27

[0180] The synthetic equation for 2-(1-fluoro-2-methoxy-2,2-diphenylethoxy)-4,6-dimethylpyrimidine is shown below:

[0181]

[0182] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of ambesentan, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 87%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 H NMR (600MHz, chloroform-d) δ7.59–7.51(m,4H),7.46(d,J=54.6Hz,1H),7.38–7.35(m,4H),7.32–7.28(m,2H),6.74(s,1H),3.38(s,3H),2.42(s,6H). 19 F NMR (565MHz, CDCl3) δ-135.6. 13 C NMR (151MHz, CDCl3) δ169.6,162.7,139.9,139.9(d,J=2.5Hz),128.7,128.7,127.7,127.6, 115.9,106.1(d,J=156.9Hz),83.3(d,J=14.5Hz),53.1(d,J=1.4Hz),23.6.HRMS(ESI):calcd for C21 H 22 FN2O2 + [M+H] + :353.1652; found 353.1660.

[0183] Example 28

[0184] The synthetic equation for (3R,5aS,6R,8aS,9R,10S,12R,12aR)-3,6,9-trimethyldecahydro-12H-3,12-epoxy[1,2]dioxaspirin[4,3-i]isocyanene-10-yl 3-fluoropropionate is shown below:

[0185]

[0186] The synthesis method in this embodiment differs from that in Example 1 in that: 6-(N-phthalimino)hexanoic acid is replaced with an equimolar amount of artesunate; the eluent used in column chromatography is petroleum ether:ethyl acetate = 20:1, followed by a petroleum ether:ethyl acetate ratio of 10:1. Other operations are the same as in Example 1. The product of this embodiment is a white solid with a yield of 29%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 5.81 (d, J = 9.6, 1H), 5.43 (s, 1H), 4.82–4.62 (m, 2H), 2.85–2.75 (m, 2H), 2.60–2.51 (m, 1H), 2.40–2.32 (m, 1H), 2.04–1.99 (m, 1H), 1.91–1.84 (m, 1H), 1.79–1.68 (m, 2H), 1.64–1.59 (m, 1H), 1.50–1.23 (m, 7H), 1.05–0.98 (m, 1H), 0.95 (d, J = 5.2Hz, 3H), 0.84 (d, J = 7.2Hz, 3H). 19 F NMR (377MHz, CDCl3) δ-219.4. 13 C NMR(101MHz, CDCl3)δ168.9(d,J=6.0Hz),104.4,92.2,91.5,80.1,78.9(d,J=167.9Hz),51.5,4 5.2,37.2,36.2,35.6(d,J=22.8Hz),34.0,31.7,25.9,24.5,21.9,20.1,11.9.HRMS(ESI):calcd for C 18 H 27 FO6Na + [M+Na] +:381.1675; found381.1684.

[0187] Example 29

[0188] The synthetic equation for (8R,9S,10S,13R,14S,17R)-17-((R)-4-fluorobutan-2-yl)-10,13-dimethyldodecylhydro-3H-cyclopenten[a]phenanthrene-3,7,12(2H,4H)-trione is shown below:

[0189]

[0190] At room temperature (20°C), dehydrocholic acid (0.1 mmol, 1 equivalent), bibenzoyl (0.01 mmol, 10 mol%), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (0.32 mmol, 3.2 equivalent), and disodium hydrogen phosphate (0.21 mmol, 2.1 equivalent) were added to a 25 mL Shrek reaction tube. The inert gas was purged three times, and acetonitrile (0.7 mL) and water (0.3 mL), which had been pre-purged to remove oxygen, were added respectively. The reaction was carried out at 400 nm. The reaction was stirred for 1 hour under LED (6W) illumination, then water and dichloromethane were added for extraction. The organic phase was collected and dried over anhydrous sodium sulfate. After filtration and solvent drying, the product was obtained by column chromatography (eluent: dichloromethane: methanol = 200:1). The product was a white solid with a yield of 67%. The NMR spectrum, mass spectrometry, and high-resolution data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 4.57–4.41 (m, 2H), 2.93–2.80 (m, 3H), 2.37–2.10 (m, 8H), 2.09–1.80 (m, 6H), 1.66–1.56 (m, 1H), 1.49–1.35 (m, 5H), 1.34–1.23 (m, 2H), 1.07 (s, 3H), 0.88 (d, J = 6.4Hz, 3H). 19 FNMR (565MHz, CDCl3) δ-218.4. 13 C NMR (151MHz, CDCl3) δ211.8, 208.9, 208.5, 82.3 (d, J = 162.3Hz), 56.8, 51.7, 48.9, 46.7, 45.9, 45.4, 44.9, 42.7 ,38.5,36.4,35.9(d,J=19.2Hz),35.9,35.2,32.5(d,J=4.7Hz),27.7,25.0,21.8,18.8,11.7.HRMS(EI):calcd for C 23 H 33O3F(M) ·+ 376.2408; found 376.2409.

[0191] Example 30

[0192] The synthetic equation for (8R,9S,10R,13S,14S)-17-fluoro-10,13-dimethyl-1,2,6,7,8,9,10,11,12,13,14,15,16,17-tetradecano-3H-cyclopenten[a]phenanthrene-3-one is shown below:

[0193]

[0194] The synthesis method in this embodiment differs from that in Example 11 in that the carboxylic acid 1-[(4-tolyl)sulfonyl]-4-piperidinecarboxylic acid is replaced with an equimolar amount of 3-oxo-androst-4-ene-17beta-carboxylic acid, and dichloromethane is used as the eluent for column chromatography. Other operations are the same as in Example 11. The product of this embodiment is a white solid with a yield of 38%; the NMR spectrum and mass spectrometry data of the obtained product are as follows: 1 ¹H NMR (400 MHz, chloroform-d) δ 5.71 (s, ¹H), 4.56 (d, J = 5.2 Hz, ¹H), 4.42 (d, J = 5.2 Hz, ¹H), 2.45–2.33 (m, ³H), 2.31–2.23 (m, ¹H), 2.17–2.05 (m, ¹H), 2.04–1.99 (m, ¹H), 1.89–1 .77(m,3H),1.75–1.57(m,5H),1.56–1.48(m,1H),1.46–1.38(m,2H),1.26–1.19( m,1H),1.17(s,3H),1.12–1.04(m,1H),1.00–0.93(m,1H),0.68(d,J=2.0Hz,3H). 19 FNMR (377MHz, CDCl3) δ -177.6. 13 C NMR (101MHz, CDCl3) δ199.4, 171.0, 123.8, 100.7 (d, J = 180.8Hz), 53.4, 48.4, 45.0 (d, J = 17.9Hz), 38.6, 35.6 (d, J=8.7Hz),33.9,32.8,32.1,30.6(d,J=5.7Hz),30.2,30.0,24.2,20.3,17.4,15.3(d,J=7.4Hz).HRMS(EI):calcd for C 19 H 27 OF(M) ·+:290.2041; found 290.2042.

[0195] Example 31

[0196] The synthetic equation for (2,2-difluoropropyl)benzene is shown below:

[0197]

[0198] At room temperature (20°C), 2-benzyl-2-methylmalonic acid (0.4 mmol, 1 equivalent), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (2.88 mmol, 7.2 equivalent), and disodium hydrogen phosphate (1.68 mmol, 4.2 equivalent) were added to a 25 mL Shrek reaction tube. The inert gas was purged three times, and acetonitrile (2.0 mL) and water (2.0 mL), which had been pre-purged to remove oxygen, were added respectively. Then, 2,3-butanedione (0.04 mmol, 40 μL, 1 M acetonitrile solution) was added to the above reaction solution. The reaction was carried out at 458 nm. The reaction was stirred for 5 minutes under LED light, then water and dichloromethane were added for extraction. The organic phase was collected and dried over anhydrous sodium sulfate. After filtration and solvent removal by rotary evaporation, the product (eluent: n-pentane) was obtained by column chromatography. The product was a colorless liquid with a yield of 73%. The NMR spectrum, mass spectrometry, and high-resolution data of the obtained product are as follows: 1 ¹H NMR (400MHz, chloroform-d) δ 7.40–7.31 (m, 5H), 3.19 (t, J = 15.6 Hz, 2H), 1.58 (t, J = 18.4 Hz, 3H). 19 FNMR (376MHz, CDCl3) δ -88.9. 13 C NMR (101MHz, CDCl3) δ 133.7 (t, J = 5.1Hz), 130.2, 128.4, 127.3, 123.4 (t, J = 240.2Hz), 44.4 (t, J = 26.1Hz), 22.8 (t, J = 27.8Hz). HRMS (EI): calcdfor C9H 10 F(M) ·+ :156.0745; found 156.0744.

[0199] Example 32

[0200] The synthetic equation for 2-((4-fluorocyclohexyl)methyl)isoindoline-1,3-dione is shown below:

[0201]

[0202] At room temperature (20°C), (1R,4R)-4-((1,3-dioxo-1,3-dihydro-isoindol-2-yl)methyl)cyclohexane-1-carboxylic acid (5 mmol, 1 equivalent), 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt (10.5 mmol, 2.1 equivalent), and disodium hydrogen phosphate (10.5 mmol, 2.1 equivalent) were added to a 125 mL Shrek reaction tube. The inert gas was purged three times, and acetonitrile (20 mL) and water (20 mL) without prior deoxygenation were added respectively. Then, 2,3-butanedione (0.5 mmol, 10 mol%) was added to the above reaction solution, and the reaction was carried out at 458 nm. The reaction was stirred for 5 minutes under LED light (2×20W), then water and dichloromethane were added for extraction. The organic phase was collected and dried with anhydrous sodium sulfate. After filtration and solvent drying, the product was separated by column chromatography to obtain 1.144 g of product (eluent: dichloromethane). The product was a white solid with a yield of 87% and a dr (2.8:1). The nuclear magnetic resonance spectrum and mass spectrometry data of the obtained product were the same as those in Example 24.

[0203] Examples 33-40

[0204] The difference between Examples 33-40 and Example 11 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, a series of different ketone catalysts were screened by replacing the inorganic base disodium hydrogen phosphate with the organic base 2,6-dimethylpyridine, the reaction time was 2 hours, and the light source was 400 nm.

[0205] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 11. The yields of the corresponding products from Examples 33-40 are shown in Table 1 below:

[0206] Table 1 Yields of the corresponding products in Examples 33-40

[0207] serial number Ketone catalysts Reaction yield (%) Example 33 Benzophenone 84 Example 34 9-fluorenone 71 Example 35 Anthraquinone 52 Example 36 Tonone 85 Example 37 9-Thioxanone 60 Example 38 phenanthrenequinone 42 Example 39 biphenyl 88 Example 40 2,3-Butanedione 76

[0208] As can be seen from Table 1 above, when the experimental conditions are: using 2,6-dimethylpyridine as the base, the reaction time is 2 hours, and the light source is 400 nm, the reaction can obtain a good yield (76%-88%) when catalyzed by benzophenone, thionyl ketone, bibenzoyl and 2,3-butanedione.

[0209] Examples 41-48

[0210] The difference between Examples 41-48 and Example 11 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, 2,6-dimethylpyridine was used as the base, a series of different ketone catalysts were screened, the reaction time was shortened to 20 minutes for Examples 33-40, and the light source was 400 nm.

[0211] Other raw materials, feeding ratios, solution concentrations, and reaction temperatures were the same as in Example 11. The yields of the corresponding products in Examples 41-48 are shown in Table 2 below.

[0212] Table 2 Yields of the corresponding products in Examples 41-48

[0213]

[0214]

[0215] As can be seen from Table 2 above, when the reaction time is shortened to 20 minutes, the reaction can achieve good yields (77%-84%) when using anthraquinone, biphenyl methyl ether, and 2,3-butanedione.

[0216] Examples 49-56

[0217] The difference between Examples 49-56 and Example 11 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, 2,6-dimethylpyridine was used as the base, a series of different ketone catalysts were screened, the reaction time was 2 hours, and the light source was changed to 458 nm for Examples 33-40.

[0218] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 11. The yields of the corresponding products from Examples 49-56 are shown in Table 3 below:

[0219] Table 3 Yields of the corresponding products in Examples 49-56

[0220] serial number Ketone catalysts Reaction yield (%) Example 49 Benzophenone Trace Example 50 9-fluorenone 77 Example 51 Anthraquinone 82 Example 52 Tonone Trace Example 53 9-Thioxanone 63 Example 54 phenanthrenequinone 43 Example 55 biphenyl 60 Example 56 2,3-Butanedione 75

[0221] As shown in Table 3 above, when the reaction light source is adjusted to 458 nm and 9-fluorenone, anthraquinone, and 2,3-butanedione are used, the reaction can achieve good yields (75%-82%). Comparing the experimental results in Tables 1, 2, and 3, the inventors found that anthraquinone, bibenzoyl, and 2,3-butanedione are potentially ideal catalyst sources. Therefore, further screening of the reaction effects of these three catalysts at shorter timescales is conducted.

[0222] Examples 57-62

[0223] The difference between Examples 57-62 and Example 11 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, 2,6-dimethylpyridine was used as the base, a series of different ketone catalysts were screened, the reaction time was 5 minutes, and the light source was 458 nm.

[0224] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 11. The yields of the corresponding products from Examples 57-62 are shown in Table 4 below.

[0225] Table 4 Yields of the corresponding products in Examples 57-62

[0226] serial number Ketone catalysts wavelength Reaction yield (%) Example 57 Anthraquinone 458nm 24 Example 58 Anthraquinone 400nm 89 Example 59 biphenyl 458nm 72 Example 60 biphenyl 400nm 32 Example 61 2,3-Butanedione 458nm 90 Example 62 2,3-Butanedione 400nm 90

[0227] As can be seen from Table 4 above, when using 2,3-butanedione as a catalyst at shorter timescales, the yield is excellent at both 458 nm and 400 nm, indicating that this catalyst is the best among many ketone catalysts. Here, the following examples use Example 61 as the optimal condition for the next screening step.

[0228] Examples 63-65

[0229] The difference between Examples 63-65 and Example 61 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, and a series of different electrophilic fluorine sources were screened.

[0230] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 61. The yields of the corresponding products from Examples 63-65 are shown in Table 5 below.

[0231] Table 5 Yields of the corresponding products in Examples 63-65

[0232]

[0233] As can be seen from Table 5 above, there is almost no reaction when other types of electrophilic fluorine sources such as N-fluorobisbenzenesulfonamide and N-fluoropyridine salt are used, while the yield is moderately high when 1-fluoro-4-methyl-1,4-diazabicyclo[2.2.2]octanetetrafluoroborate is used. This result highlights the importance of 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octanedi(tetrafluoroborate) salt as a fluorine source.

[0234] Examples 66-75

[0235] The difference between Examples 66-75 and Example 61 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, and a series of different solvent systems were screened.

[0236] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 61. The yields of the corresponding products from Examples 66-75 are shown in Table 6 below.

[0237] Table 6 Yields of the corresponding products in Examples 66-75

[0238] serial number solvent Reaction yield (%) Example 66 Acetonitrile 44 Example 67 water 47 Example 68 acetone Trace Example 69 dichloroethane Not detected Example 70 Ethyl acetate Not detected Example 71 1,4-Dioxane Not detected Example 72 N,N-Dimethylformamide Not detected Example 73 methanol Not detected Example 74 Acetone:water = 1:1 76 Example 75 Dichloroethane:water = 1:1 8

[0239] As can be seen from Table 6 above, a moderate yield can be obtained when using a single solvent such as acetonitrile and water, while the reaction effect is very poor when using other solvents. For mixed solvent systems, the mixture of acetonitrile and water has the best effect, and the mixture of acetone and water can also obtain a good yield.

[0240] Examples 76-95

[0241] The difference between Examples 76-95 and Example 61 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, and a series of different organic and inorganic bases were screened.

[0242] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 61. The yields of the corresponding products from Examples 76-95 are shown in Table 7 below.

[0243] Table 7 Yields of the corresponding products in Examples 76-95

[0244]

[0245]

[0246] As shown in Table 7 above, besides the organic base 2,6-dimethylpyridine, which yields excellent results, some inorganic weak bases such as potassium bicarbonate, sodium bicarbonate, and disodium hydrogen phosphate can also achieve similar effects. Among them, disodium hydrogen phosphate shows the best results. Based on this, the following examples use Example 89 as the optimal condition for the next screening step.

[0247] Examples 96-102

[0248] The difference between Examples 96-102 and Example 89 is that the conditions were optimized at a scale of 0.1 mmol carboxylic acid, and a series of different light sources were screened.

[0249] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 89. The yields of the corresponding products from Examples 96-102 are shown in Table 8 below.

[0250] Table 8 Yields of the corresponding products in Examples 96-102

[0251] serial number light source Time (minutes) Reaction yield (%) Example 96 Green light (525nm) 5 Not detected Example 97 White light 5 52 Example 98 Universe light (400nm) 5 92 Example 99 365nm 5 87 Example 100 sunlight 5 56 Example 101 sunlight 10 72 Example 102 sunlight 15 74

[0252] As shown in Table 8 above, this reaction proceeds well not only under blue light at 458 nm, but also under violet light and even ultraviolet light at 365 nm. However, when using white light, the reaction only achieves a moderate yield, and when using green light, the reaction essentially does not occur. This result is consistent with the ultraviolet-visible absorption (340 nm-460 nm) of 2,3-butanedione. Furthermore, this reaction can also be carried out under sunlight, achieving a yield of 74% when the reaction time is 15 minutes.

[0253] Examples 103-106

[0254] The difference between Examples 103-106 and Example 89 is that the controlled experiments were conducted at a scale of 0.1 mmol of carboxylic acid.

[0255] Other raw materials, feed ratios, solution concentrations, and reaction temperatures were the same as in Example 89. The yields of the corresponding products from Examples 103-106 are shown in Table 9 below:

[0256] Table 9 Yields of the corresponding products in Examples 103-106

[0257]

[0258]

[0259] As can be seen from Table 9 above, organic ketone catalysts, light sources, and bases all play key roles in the efficient occurrence of the reaction, and heating cannot replace the reaction effect of light sources.

[0260] In summary, as can be clearly seen from all the above embodiments, when the method of the present invention is adopted, that is, when a reaction system consisting of ketone compounds as catalysts (especially 2,3-butanedione), fluorine-containing reagents (especially 1-chloromethyl-4-fluoro-1,4-diazabicyclo[2.2.2]octane di(tetrafluoroborate) salt), bases (especially disodium hydrogen phosphate) and suitable organic solvents (especially a mixed solvent of acetonitrile:water = 1:1) is used, different alkyl carboxylic acids can undergo decarboxylation fluorination to obtain the corresponding fluorides, and gram-scale preparation can be completed in a short time, providing a new synthetic route for the efficient synthesis of such compounds.

[0261] The above embodiments are preferred embodiments of the present invention, but the embodiments of the present invention are not limited to the above embodiments. Any changes, modifications, substitutions, combinations, or simplifications made without departing from the spirit and principle of the present invention shall be considered equivalent substitutions and shall be included within the protection scope of the present invention.

Claims

1. A method for constructing fluorine-containing compounds by catalytic decarboxylation of alkyl carboxylic acids using ketone compounds, characterized in that, The process includes the following steps: under light conditions, using an alkyl carboxylic acid as shown in formula (1) as the reactant, the reaction is carried out under the combined action of a ketone compound, a fluorine-containing reagent and a base to obtain a fluorine-containing compound as shown in formula (2); In equations (1) and (2), R 1 Each group is independently selected from hydrogen, heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted hydrocarbon groups; R 2 Each group is independently selected from hydrogen, heterocyclic, substituted or unsubstituted aryl, or substituted or unsubstituted hydrocarbon groups; R 3 Each is independently selected from hydrogen, heterocyclic, substituted or unsubstituted aryl, substituted or unsubstituted hydrocarbon groups; The alkyl carboxylic acid is selected from compounds with the following structures: The fluorinated reagent is an N-alkyl-N'-fluoro1,4-diazabicyclo[2,2,2]octane fluorinating agent; The reaction is carried out in a solvent; the solvent is selected from water, nitrile solvents, mixtures of ketone solvents and water, or mixtures of nitrile solvents and water; When the wavelength of the light used for illumination is sunlight or light with a wavelength range of 350-500 nm, the ketone compound is selected from any one or more of alkyl diketones, aromatic ketones, and aromatic diketone compounds; when the wavelength of the light used for illumination is 458 nm, the ketone compound is selected from any one or more of alkyl diketones, aromatic ketones, and aromatic diketone compounds, wherein the aromatic ketone is selected from any one or more of acetophenone, 9-fluorenone, and 9-thioxanone.

2. The method for constructing fluorine-containing compounds by catalytic decarboxylation of alkyl carboxylic acids according to claim 1, characterized in that, The amount of the ketone compound used, measured in moles, is 0.1% to 50% of the alkyl carboxylic acid with the structure shown in formula (1). And / or, in moles, the amount of the fluorinated reagent is 0.1 to 20 equivalents of the alkyl carboxylic acid with the structure shown in formula (1). And / or, in moles, the amount of the base used is 0.1 to 20 equivalents of the alkyl carboxylic acid with the structure shown in formula (1).

3. The method for constructing fluorine-containing compounds by catalytic decarboxylation of alkyl carboxylic acids according to claim 1, characterized in that, The reaction time ranges from 1 minute to 10 days.

4. The method for constructing fluorine-containing compounds by catalytic decarboxylation of alkyl carboxylic acids according to claim 1, characterized in that, The reaction was carried out at 15–40 °C.

5. The application of the method according to any one of claims 1 to 4 in positron emission tomography (PET).

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