Copper salt of anhydrous fluorosulfonyldifluoroacetate, its preparation method and application

Abstract

The present invention relates to an anhydrous copper (II) fluorosulfonyldifluoroacetate, a preparation method thereof and an application thereof. Cuprous hydride and fluorosulfonyldifluoroacetic acid are used as raw materials to react in a solvent. After the reaction is completed, filtration is carried out, and the solvent is removed to obtain the anhydrous copper (II) fluorosulfonyldifluoroacetate; the anhydrous copper (II) fluorosulfonyldifluoroacetate is used for introducing a trifluoromethyl group into a bioactive molecule or a drug molecule or as a carboxylic acid deoxygenation fluorination reagent. Compared with the prior art, the method of the present invention has mild reaction conditions, simple operation, and the post-treatment of the product avoids the trouble of dehydration, and is an efficient method for preparing anhydrous copper (II) fluorosulfonyldifluoroacetate.

Description

Technical Field

[0001] The present invention relates to the technical field of organofluorine chemistry, and particularly relates to an anhydrous copper fluorosulfonyldifluoroacetate salt, a preparation method thereof and an application thereof. Background Art

[0002] As a "star" group among fluorine-containing functional groups, the trifluoromethyl group can significantly change the physical and chemical properties of molecules and has a wide range of applications in many fields such as pharmaceuticals and materials. However, there are no natural products containing trifluoromethyl groups in nature, and they can only be obtained through artificial synthesis. After the long-term efforts of organic chemists, there have been endless methods for efficiently introducing trifluoromethyl groups into molecules, and a variety of efficient trifluoromethylation methods have been developed (Chemical Reviews, 2015, 115, 683. Chemical Reviews, 2015, 115, 650. Chemical Society Reviews, 2014, 43, 6598.).

[0003] Currently, the methods for introducing trifluoromethyl groups are mainly divided into two categories: indirect introduction methods and direct introduction methods. (1) Indirect trifluoromethylation methods are to convert specific carbon-heteroatom bonds into carbon-fluorine bonds through fluorination reactions, thereby achieving the introduction of trifluoromethyl groups. For example, the most general method for preparing trifluoromethylbenzene industrially at present is the indirect nucleophilic fluorination method. It mainly goes through two steps. First, toluene is directly chlorinated with chlorine to obtain trichloromethylbenzene, and then through the fluorine-chlorine exchange process of the Swarts reaction, trifluoromethylbenzene is obtained. However, this method has many limitations, with harsh reaction conditions and poor functional group tolerance. (2) Direct trifluoromethylation methods refer to directly introducing the entire trifluoromethyl functional group into the molecule, thus avoiding multi-step reactions. Different from the indirect introduction method, the direct introduction method has advantages such as mildness, high reaction efficiency and environmental friendliness. The development of direct trifluoromethylation methods depends on the continuous innovation of trifluoromethyl reagents.

[0004] Among many trifluoromethylation reagents, Chen's reagent (FSO 2 CF 2 COOMe) is a highly efficient and practical trifluoromethylation reagent (Journal of Chemical Society, Chemical Communications, 1989, 705). It is prepared from the cheap and easily available industrial raw material tetrafluoroethylene-β-sultone (quantitatively prepared from tetrafluoroethylene and sulfur trioxide), and can be conveniently prepared on a large scale. Through Chen's reagent, the first example of copper-catalyzed trifluoromethylation reaction of organic halides was achieved (Chinese Journal of Chemistry, 2020, 38, 202.). In recent years, from Chen's reagent acid (FSO 2 CF 2 CO2 H) Derived copper salt of Chen reagent (copper fluorosulfonyldifluoroacetate, Cu(O 2 CCF 2 SO 2 F) 2 ) is a diverse fluoroalkylation reagent that can be used as a nucleophilic trifluoromethylation reagent (RSC Advances, 2016, 6, 50250.) or as a deoxyfluorination reagent (Tetrahedron Letters, 2020, 61, 152624.). However, due to its own structural characteristics, it is prone to complex with water, and it is very difficult to obtain an anhydrous salt. Once complexed with water, the reaction efficiency and yield will be greatly reduced. Therefore, how to conveniently prepare anhydrous copper fluorosulfonyldifluoroacetate has a significant impact on its application and is also one of the key factors for its successful application and promotion. Summary of the Invention

[0005] The purpose of the present invention is to provide an anhydrous copper salt of fluorosulfonyldifluoroacetic acid, its preparation method and application, to overcome the defect of difficult removal of water molecules in the target copper salt in the prior art.

[0006] The purpose of the present invention can be achieved by the following technical solutions: A preparation method of an anhydrous copper salt of fluorosulfonyldifluoroacetic acid, using cuprous hydride (CuH) and fluorosulfonyldifluoroacetic acid as raw materials to react in a solvent. After the reaction is completed, vacuum filtration is carried out under reduced pressure, and the filtrate is rotary evaporated to obtain an anhydrous copper salt of fluorosulfonyldifluoroacetic acid. The reaction general formula is:

[0007] 2FSO 2 CF 2 COOH + 2CuH → Cu(O 2 CCF 2 SO 2 F) 2 + 2H 2 ↑ + Cu

[0008] Preferably, the solvent is an organic solvent, which is any one or a combination of several of diethyl ether, tetrahydrofuran (THF), ethyl acetate (CH 3 COOEt).

[0009] More preferably, the solvent is diethyl ether.

[0010] Preferably, the reaction temperature is 0 - 40 °C.

[0011] More preferably, the reaction temperature is 25 °C.

[0012] Preferably, the reaction time is 1 - 72 hours.

[0013] More preferably, the reaction time is 36 hours.

[0014] Preferably, the molar ratio of cuprous hydride to fluorosulfonyldifluoroacetic acid is (1.0 - 4.0):1.

[0015] More preferably, the molar ratio of cuprous hydride to fluorosulfonyldifluoroacetic acid is 2.0:1.

[0016] Preferably, the molar volume ratio of cuprous hydride to the solvent is (0.01 - 1.5) mmol / mL.

[0017] More preferably, the molar volume ratio of cuprous hydride to the solvent is 0.5 mmol / mL.

[0018] Anhydrous copper fluorosulfonyldifluoroacetate is prepared by the above preparation method, and its chemical formula is: Cu(O 2 CCF 2 SO 2 F) 2 .

[0019] An application of the above anhydrous copper fluorosulfonyldifluoroacetate, wherein the anhydrous copper fluorosulfonyldifluoroacetate is used in the nucleophilic trifluoromethylation reaction of aryl halides and the deoxygenation fluorination reaction of carboxylic acids.

[0020] An application of the above anhydrous copper fluorosulfonyldifluoroacetate, wherein the anhydrous copper fluorosulfonyldifluoroacetate is used to introduce a trifluoromethyl group into a bioactive molecule or a drug molecule, and the specific reaction general formula is as follows:

[0021]

[0022] Preferably, the molar ratio of the anhydrous copper fluorosulfonyldifluoroacetate I to the bioactive molecule or the drug molecule A is (1:1) - (3:1).

[0023] More preferably, the molar ratio of the anhydrous copper fluorosulfonyldifluoroacetate I to the bioactive molecule or the drug molecule A is 1.5:1.

[0024] Preferably, the bioactive molecule or the drug molecule includes aryl iodide or heteroaryl iodide.

[0025] Further preferably, the bioactive molecule or drug molecule includes: iodouridine, the raw material of trifluridine, and its derivatives; 4-methoxy analogue of iodorabeprazole, the raw material of lansoprazole, and its derivatives; iodoalkyl aniline propyl ether, the raw material of fluoxetine, and its derivatives; 3-(tert-butyl)-6-iodo-8,10a-methanoazuleno[5,6-f]indeno[1,2-b][1,2,3]triazolone and its derivatives; 4-[7-[6-cyano-5-iodopyridin-3-yl]-8-oxo-6-thia-5,7-diazaspiro[3.4]oct-5-yl]-2-fluoro-N-methylbenzamide, the raw material of apalutamide, and its derivatives.

[0026] Preferably, the anhydrous copper fluorosulfonyldifluoroacetate decomposes in a solvent to release carbon dioxide and sulfur dioxide, and is converted into an active trifluoromethyl copper species (CuCF 3 ) under the adjustment of copper powder, and then reacts with the bioactive molecule or drug molecule in an inert atmosphere to form the target trifluoromethylated product, and the reaction is carried out at 0-120 °C.

[0027] Further preferably, the molar ratio of the anhydrous copper fluorosulfonyldifluoroacetate to the copper powder is 1:(0.5-2).

[0028] Even more preferably, the molar ratio of the anhydrous copper fluorosulfonyldifluoroacetate to the copper powder is 1:1.

[0029] Further preferably, the reaction time is 1-12 hours.

[0030] Even more preferably, the reaction time is 2-5 hours.

[0031] Further preferably, the reaction temperature is 10-120 °C.

[0032] Even more preferably, the reaction temperature is 20-60 °C.

[0033] Further preferably, the inert atmosphere is an argon atmosphere.

[0034] Further preferably, the molar volume ratio of the anhydrous copper fluorosulfonyldifluoroacetate to the solvent is (0.01-1.5) mmol / mL.

[0035] Even more preferably, the molar volume ratio of the anhydrous copper fluorosulfonyldifluoroacetate to the solvent is 0.2 mmol / mL.

[0036] Further preferably, the solvent is any one or a mixture of several of acetonitrile (CH 3 CN), N,N'-dimethylformamide (DMF), N,N'-dimethylethylamide (DMAc), N-methylpyrrolidone (NMP), dimethyl sulfoxide (DMSO).

[0037] More preferably, the solvent is N,N'-dimethylformamide.

[0038] Preferably, the specific reaction formula is as follows:

[0039]

[0040] An application of the above-mentioned copper salt of anhydrous fluorosulfonyldifluoroacetic acid, using the copper salt of anhydrous fluorosulfonyldifluoroacetic acid as a carboxylic acid deoxygenation fluorination reagent, the specific reaction formula is as follows:

[0041]

[0042] Preferably, in the absence of copper powder in the solvent, the copper salt of anhydrous fluorosulfonyldifluoroacetic acid mainly decomposes into difluorocarbene and fluoride anion (M(O 2 CCF 2 SO 2 F) z →Cu 2+ +[:CF2]+F - ), and then reacts with various carboxylic acid compounds to form the corresponding acyl fluoride compounds.

[0043] More preferably, the solvent is selected from any one or a mixture of several of acetonitrile (MeCN), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAc), N-methylpyrrolidone (NMP), and dimethyl sulfoxide (DMSO).

[0044] Even more preferably, the solvent is acetonitrile (MeCN).

[0045] More preferably, the molar volume ratio of the copper salt of anhydrous fluorosulfonyldifluoroacetic acid to the solvent is (0.01 - 1.5) mmol / mL.

[0046] Even more preferably, the molar volume ratio of the copper salt of anhydrous fluorosulfonyldifluoroacetic acid to the solvent is 0.2 mmol / mL.

[0047] More preferably, the reaction time is 1 - 60 minutes.

[0048] Even more preferably, the reaction time is 10 minutes.

[0049] More preferably, the reaction temperature is 10 - 120 °C.

[0050] Even more preferably, the reaction temperature is 20 - 60 °C.

[0051] Further preferably, the reaction is carried out under an argon atmosphere.

[0052] Preferably, the R group of the carboxylic acid compound B is selected from: a substituted or unsubstituted benzene ring, a substituted or unsubstituted naphthalene ring, a substituted or unsubstituted α,β-unsaturated acid, a substituted or unsubstituted alkyl carboxylic acid. The substitution means being substituted by one or more of the following substituents: aldehyde group, halogen, phenyl, -CN, nitro, fluorine-substituted C1-C4 alkyl.

[0053] Preferably, the molar ratio of the anhydrous copper (I) fluorosulfonyldifluoroacetate to the carboxylic acid compound B is (1:1) to (3:1).

[0054] Preferably, the molar ratio of the anhydrous copper (I) fluorosulfonyldifluoroacetate to the carboxylic acid compound B is 2:1.

[0055] The present invention discloses a synthesis method of anhydrous copper (I) fluorosulfonyldifluoroacetate with simple preparation process, mild reaction conditions, easy reaction treatment, high product activity and low cost. At the same time, its application in the synthesis of trifluoromethyl-containing drug molecules or important drug intermediates is studied. It is believed that this method will strongly promote the development of this reagent and play a role in the practical application of the reagent.

[0056] Compared with the prior art, the present invention has the following advantages:

[0057] 1. The copper (I) fluorosulfonyldifluoroacetate of the present invention can be used as both a trifluoromethylation reagent and a decarboxylative fluorination reagent. The reaction conditions are mild, the operation is simple, and the post-treatment of the product eliminates the trouble of dehydration. It is an efficient method for preparing anhydrous copper (I) fluorosulfonyldifluoroacetate.

[0058] 2. The present invention can overcome the defect in the prior art that it is difficult to remove water molecules in the target copper salt, and apply it to the trifluoromethylation reaction of some important molecules and the deoxyfluorination reaction of carboxylic acids.

[0059] 3. The copper (I) fluorosulfonyldifluoroacetate obtained by the present invention has extremely low water content and has better reaction activity than the anhydrous copper (I) fluorosulfonyldifluoroacetate prepared from basic copper carbonate in practical applications, and can be applied to the trifluoromethyl introduction step of some important bioactive molecules or drug molecules.

[0060] 4. The copper (I) fluorosulfonyldifluoroacetate obtained by the present invention has extremely low water content and has better reaction activity than the anhydrous copper (I) fluorosulfonyldifluoroacetate prepared from basic copper carbonate in practical applications. In addition to being used in nucleophilic trifluoromethylation reactions, it can also be used as a carboxylic acid deoxyfluorination reagent.

[0061] 5. The starting materials of the present invention, fluorosulfonyldifluoroacetic acid and copper hydride, are both inexpensive and readily available industrial raw materials. The reaction of fluorosulfonyldifluoroacetic acid and copper hydride does not produce water. Therefore, after the reaction, the reaction solvent can be removed by simple distillation to obtain anhydrous fluorosulfonyldifluoroacetate. The reaction is simple and efficient, the post-treatment is concise, and the cost is low, which is very suitable for large-scale preparation.

[0062] 6. The anhydrous copper fluorosulfonyldifluoroacetate prepared by the present invention has extremely low water content, and the post-treatment is simple and will not cause damage to the copper salt itself. The prepared copper salt has better purity, and the trifluoromethylation reaction and the deoxyfluorination reaction of carboxylic acids carried out with it have higher yields. BRIEF DESCRIPTION OF THE DRAWINGS

[0063] Figure 1 For the product Cu(O 2 CCF 2 SO 2 F) 2 X-ray structure diagram prepared in Example 5.

[0064] Figure 2 For trifluridine's 1 1H NMR.

[0065] Figure 3 For trifluridine's 19 19F NMR.

[0066] Figure 4 For trifluridine's 13 13C NMR. DETAILED DESCRIPTION OF THE INVENTION

[0067] The present invention will be described in detail below with reference to the accompanying drawings and specific examples. The following examples are implemented on the premise of the technical solution of the present invention, and the detailed implementation manners and specific operation processes are given. However, the protection scope of the present invention is not limited to the following examples. The experimental methods without specific conditions noted in the following examples are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are calculated by weight.

[0068] I. Preparation of anhydrous copper fluorosulfonyldifluoroacetate

[0069] The preparation method of the anhydrous copper fluorosulfonyldifluoroacetate of the present invention includes the following steps:

[0070]

[0071] Add cuprous hydride, fluorosulfonyl difluoroacetic acid and a solvent to a round-bottom flask and stir to react. After the reaction is completed, filter the mixture through diatomaceous earth or a silica gel thin layer, then rinse with the solvent, collect the filtrate, and remove the solvent under reduced pressure to obtain the desired anhydrous copper salt of fluorosulfonyl difluoroacetic acid.

[0072] All anhydrous copper salts of fluorosulfonyl difluoroacetic acid in the present invention are prepared according to this method.

[0073] Example 1

[0074] Synthesis of anhydrous copper salt of fluorosulfonyl difluoroacetic acid:

[0075] Using cuprous hydride and fluorosulfonyl difluoroacetic acid as template substrates, and ether (Et 2 O) as the solvent, react for 12 h to obtain the target product, anhydrous copper salt of fluorosulfonyl difluoroacetic acid. The reaction is as follows:

[0076]

[0077] Place a magnetic stir bar in a 25 mL single-necked flask, weigh 0.62 g (9.6 mmol) of cuprous hydride and 0.85 g (4.8 mmol) of fluorosulfonyl difluoroacetic acid and add them thereto. Add 5 mL of ether (Et 2 O) as the solvent at room temperature, stir and react at room temperature for 12 h. After the reaction is completed, filter under reduced pressure, rotary evaporate the filtrate, and remove the ether under reduced pressure to obtain the target blue-green anhydrous solid, copper salt of fluorosulfonyl difluoroacetic acid (Cu(O 2 CCF 2 SO 2 F) 2 ), with a yield of 70%.

[0078] Example 2

[0079] Synthesis of anhydrous copper salt of fluorosulfonyl difluoroacetic acid:

[0080] Using cuprous hydride and fluorosulfonyl difluoroacetic acid as template substrates, and ether (Et 2 O) as the solvent, react for 24 h to obtain the target product, anhydrous copper salt of fluorosulfonyl difluoroacetic acid. The reaction is as follows:

[0081]

[0082] Place a magnetic stir bar in a 25 mL single-necked flask, weigh 0.62 g (9.6 mmol) of cuprous hydride and 0.85 g (4.8 mmol) of fluorosulfonyl difluoroacetic acid and add them thereto. Add 5 mL of ether (Et 2O) As a solvent, stir the reaction at room temperature for 24 h. After the reaction is completed, perform suction filtration under reduced pressure, rotary evaporate the filtrate, and remove diethyl ether under reduced pressure to obtain the target blue-green anhydrous solid copper(II) fluorosulfonyldifluoroacetate (Cu(O 2 CCF 2 SO 2 F) 2 ), with a yield of 77%.

[0083] Example 3

[0084] Synthesis of anhydrous copper(II) fluorosulfonyldifluoroacetate:

[0085] Using cuprous hydride and fluorosulfonyldifluoroacetic acid as the template substrates, and diethyl ether (Et 2 O) as the solvent, react for 48 h to obtain the target product anhydrous copper(II) fluorosulfonyldifluoroacetate. The reaction is as follows:

[0086]

[0087] Place a magnetic stir bar in a 25 mL single-necked flask, weigh 0.62 g (9.6 mmol) of cuprous hydride and 0.85 g (4.8 mmol) of fluorosulfonyldifluoroacetic acid and add them thereto. Add 5 mL of diethyl ether (Et 2 O) as the solvent, stir the reaction at room temperature for 48 h. After the reaction is completed, perform suction filtration under reduced pressure, rotary evaporate the filtrate, and remove diethyl ether under reduced pressure to obtain the target blue-green anhydrous solid copper(II) fluorosulfonyldifluoroacetate (Cu(O 2 CCF 2 SO 2 F) 2 ), with a yield of 87%.

[0088] Example 4

[0089] On the basis of the above examples, conditions such as reaction solvent, temperature, time, and feed ratio were screened, as shown in Table 1.

[0090] Table 1 Screening of reaction conditions

[0091]

[0092]

[0093]

[0094] Note: In the table, Concentration has fluorosulfonyldifluoroacetic acid as the numerator and the solution volume as the denominator.

[0095] Based on the above experimental condition screening, the optimal conditions for preparing anhydrous copper fluorosulfonyldifluoroacetate are as follows: cuprous hydride (9.6 mmol, 2.0 equiv.), fluorosulfonyldifluoroacetic acid (4.8 mmol, 1.0 equiv.), and diethyl ether (Et 2 O) as the solvent, and stirring the reaction at room temperature for 60 h.

[0096] Example 5

[0097] Preparation of anhydrous copper fluorosulfonyldifluoroacetate from cuprous hydride:

[0098]

[0099] In a 500 mL three-necked flask equipped with an electromagnetic stirrer and a constant-pressure dropping funnel, add cuprous hydride (258.2 g, 4 mol) and diethyl ether (200 mL). Slowly add fluorosulfonyldifluoroacetic acid FSO 2 CF 2 COOH (356.2 g, 2 mol) dropwise from the dropping funnel under stirring at room temperature. After the addition is complete, stir at room temperature for 60 h. After the reaction is complete, perform suction filtration under reduced pressure, rotary evaporate the filtrate, and remove diethyl ether under reduced pressure to obtain the target blue-green anhydrous solid copper fluorosulfonyldifluoroacetate (Cu(O 2 CCF 2 SO 2 F) 2 )(375 g, 0.9 mol), with a yield of 90%.

[0100] 19 F NMR (376 MHz; CDCl 3 ) δ (ppm): 60.20 (s, 1F), -61.27 (s, 2F). IR (ATR): ν max 1705, 1463, 1384, 1235, 1179, 806, 653 cm -1 .

[0101] The X-ray structure diagram of the product Cu(O 2 CCF 2 SO 2 F) 2 prepared in this example is as shown in Figure 1 .

[0102] Comparative Example 1

[0103] Preparation of anhydrous copper fluorosulfonyldifluoroacetate from basic copper carbonate:

[0104]

[0105] In a 500 mL three-necked flask equipped with an electromagnetic stirrer and a constant-pressure dropping funnel, add basic copper carbonate (220 g, 1 mol) and diethyl ether (200 mL). Slowly add fluorosulfonyldifluoroacetic acid FSO 2 CF 2 COOH (356.2 g, 2 mol) from the dropping funnel under stirring at room temperature. After the addition is complete, stir at room temperature for 60 h. After the reaction is complete, filter under reduced pressure, rotary evaporate the filtrate, remove diethyl ether under reduced pressure, and then heat to 60 °C under reduced pressure and vacuum for drying for 72 h to obtain the target blue-green anhydrous solid copper fluorosulfonyldifluoroacetate (380 g, 0.91 mol), with a yield of 91%.

[0106] II. Comparison of Reactivity with Anhydrous Copper Fluorosulfonyldifluoroacetate Salt Prepared from Basic Copper Carbonate

[0107] Example 6

[0108] Synthesis of trifluridine:

[0109]

[0110] Add anhydrous copper fluorosulfonyldifluoroacetate salt (250 mg, 0.6 mmol) prepared from cuprous hydride in Example 5, Cu powder (39 mg, 0.6 mmol), and idoxuridine (142 mg, 0.4 mmol) to the reaction flask. Evacuate and replace with Ar three times. Add 4 mL of DMF under liquid nitrogen cooling, slowly warm back to room temperature, stir for 3 h, stop the reaction, add diethyl ether (15 mL), wash with water three times, dry, rotary evaporate, and then perform flash column chromatography to obtain white solid trifluridine (94.7 mg, 0.32 mmol), with a yield of 80%.

[0111] The 1 1H NMR, 19 19F NMR, 13 13C NMR are as Figures 3 - 4 shown:

[0112] 1 1H NMR (600 MHz; CD 3 OD) δ (ppm): 2.25–2.29 (m, 1H), 2.35–2.39 (m, 1H), 3.75 (dd, 1H, J = 3, 12 Hz), 3.84 (dd, 1H, J 1 = 12 Hz, J 2 = 3 Hz), 3.97 (m, 1H), 4.41 (m, 1H), 6.24 (m, 1H), 8.79 (s, 1H); 13 13C NMR (151 MHz; CD 3OD) δ (ppm): 42.2, 62.2, 71.7, 87.6, 89.34, 105.35 (q, J = 33 Hz), 123.98 (q, J = 269 Hz), 143.82 (q, J = 6 Hz), 151.37, 161.27; 19 F NMR (376 MHz; CD 3 OD) δ (ppm): -63.4 (s, 3F, CF 3 ).

[0113] Comparative Example 2

[0114] Synthesis of trifluridine:

[0115]

[0116] Add cupric fluorosulfonyldifluoroacetate prepared from cupric carbonate basic (250 mg, 0.6 mmol), Cu powder (39 mg, 0.6 mmol), and iododeoxyuridine (142 mg, 0.4 mmol) to a reaction flask. Evacuate and backfill with Ar three times. Add 4 mL of DMF under liquid nitrogen cooling, slowly warm to room temperature, stir for 3 h, stop the reaction, add ether (15 mL), wash with water three times, dry, rotary evaporate, and then perform flash column chromatography to obtain white solid trifluridine (68.1 mg, 0.23 mmol), with a yield of 58%.

[0117] Example 7

[0118] Preparation of fluoxetine:

[0119]

[0120] Add iodide 1 (7.4 g, 20.0 mmol), Cu powder (2.54 g, 40.0 mmol), and cupric fluorosulfonyldifluoroacetate prepared from cuprous hydride in Example 5 (16.7 g, 40.0 mmol) to a reaction flask. Add solvent DMF (200 g) under liquid nitrogen freezing, gradually warm to room temperature, stir and react for 2 h. Then add sodium hydroxide (26.8 g, 240 mmol) and water (200 g) to the system, stir for 6 h, filter, wash with water (2 × 100 mL), and dry at 50 °C to obtain product 2 as a white solid (4.95 g, 16 mmol), with a yield of 80%.

[0121] 1 H NMR (600 MHz, CDCl 3)δ(ppm): 2.02–2.21 (m, 2H), 2.41 (s, 3H), 2.69–2.76 (t, 2H, J = 6.6 Hz), 5.26–5.32 (m, 1H), 6.87–6.92 (d, 2H, J = 8.6 Hz), 7.25–7.34 (m, 5H), 7.40–7.44 (d, 2H, J = 8.6 Hz); IR (Neat): 2959, 2733, 2447, 1615, 1329, 1245, 1165, 1109, 843 cm -1 。

[0122] Comparative Example 3

[0123] Preparation of Fluoxetine:

[0124]

[0125] Add iodide 1 (7.4 g, 20.0 mmol), Cu powder (2.54 g, 40.0 mmol), and anhydrous copper fluorosulfonyldifluoroacetate prepared from basic copper carbonate in Comparative Example 1 (16.7 g, 40.0 mmol) into a reaction flask. Add the solvent DMF (200 g) under liquid nitrogen freezing. Stir the reaction at room temperature for 2 hours, gradually return to room temperature, stir the reaction for another 2 hours. Then add sodium hydroxide (26.8 g, 240 mmol) and water (200 mL) to the system, stir for 6 hours, filter, wash with water (2 × 100 mL), and dry at 50 °C to obtain Product 2 as a white solid (4.02 g, 13 mmol), with a yield of 65%.

[0126] Example 8

[0127] Synthesis of Lansoprazole:

[0128]

[0129] Add iodide 1 (8.6 g, 20.0 mmol), Cu powder (2.54 g, 40.0 mmol), and anhydrous copper fluorosulfonyldifluoroacetate prepared from cuprous hydride in Example 5 (16.7 g, 40.0 mmol) into a reaction flask. Add the solvent DMF (200 g) under liquid nitrogen freezing. Stir the reaction at room temperature for 3 hours, filter after the reaction is complete, wash with water (2 × 100 mL), and dry at 50 °C to obtain Product 2 as a white solid (6.34 g) with a yield of 80%.

[0130] 1 H NMR (600 MHz; CDCl 3)δ(ppm): δ 8.40 (1H, d, J = 5.7 Hz), 7.53 (2H, dd, J = 6.0, 3.2 Hz), 7.18 (2H, dd, J = 6.0, 3.2 Hz), 6.72 (1H, d, J = 5.7 Hz), 4.41 (2H, q, J = 7.7 Hz), 4.40 (2H, s), 2.31 (3H, s); IR (KBr) 3553, 3053, 1893, 1658, 1577, 1444, 1409, 1284, 1254, 1162, 1109, 976, 857, 745, 664, 576.

[0131] Comparative Example 4

[0132] Synthesis of lansoprazole:

[0133]

[0134] Add iodide 1 (8.6 g, 20.0 mmol), Cu powder (2.54 g, 40.0 mmol), and anhydrous copper fluorosulfonyldifluoroacetate prepared from basic copper carbonate in Comparative Example 1 (16.7 g, 40.0 mmol) into a reaction flask, and add the solvent DMF (200 g) under liquid nitrogen freezing. After restoring to room temperature, stir the reaction for 3 hours. After the reaction is completed, filter, wash with water (2 × 100 mL), and dry at 50 °C to obtain product 2 as a white solid (5.58 g) with a yield of 70%.

[0135] Example 9

[0136] Deoxyfluorination reaction of carboxylic acid:

[0137]

[0138] Add anhydrous copper fluorosulfonyldifluoroacetate prepared from cuprous hydride in Example 5 (188 mg, 0.45 mmol) and p-methoxybenzoic acid (46 mg, 0.3 mmol) into a reaction flask, evacuate and replace with N 2 gas three times, add the solvent MeCN (4.5 mL), stir at room temperature for 15 min, stop the reaction, and use 4-(trifluoromethoxy)anisole as an internal standard substance to confirm that the fluorine spectrum yield of the target product is 85% by 19 19F-NMR.

[0139] 19 19F NMR (376 MHz; CDCl 3 ) δ (ppm): -64.4 (s, 3F, CF 3 3).

[0140] Comparative Example 5

[0141] Deoxygenofluorination reaction of carboxylic acid:

[0142]

[0143] Add cupric fluorosulfonyldifluoroacetate (188 mg, 0.45 mmol) prepared from basic copper carbonate in Example 1, p-methoxybenzoic acid (46 mg, 0.3 mmol) into a reaction flask, evacuate and refill with N 2 gas three times, add solvent MeCN (4.5 mL), stir at room temperature for 15 min, stop the reaction. Using 4-(trifluoromethoxy)anisole as the internal standard substance, the fluorine spectrum yield of the target product is confirmed to be 75% by 19 19F-NMR.

[0144] III. Reactivity comparison with Chen's reagent (FSO 2 CF 2 COOMe)

[0145] Example 10

[0146]

[0147] Add iodide 1 (35.6 g, 80.0 mmol), Cu (1.01 g, 16.0 mmol) into a reaction flask, add solvent DMF (505 g) under liquid nitrogen freezing. Then add 2,6-dimethylpyridine (1.7 g, 16.0 mmol), add anhydrous cupric fluorosulfonyldifluoroacetate (33.4 g, 80 mmol) prepared from cuprous hydride, stir at room temperature and continue the reaction for 3 hours. Then add sodium hydroxide (26.8 g, 240 mmol) to the reaction, and then add an aqueous solution (290 mL) containing N-2-(2-hydroxyethyl)ethylenediaminetriacetic acid (29 g, 80 mmol), continue stirring for 2 hours. Then filter, wash with water (2×150 mL), and dry at 50 °C to obtain product 2 as a brown solid (29.9 g), with a yield of 90%.

[0148] 1 1H NMR (600 MHz, CDCl 3) δ (ppm): 7.87 (dd, J = 9.1, 1.7 Hz, 1H), 7.69 (d, J = 9.1 Hz, 1H), 3.66 (q, J = 17.6 Hz, 2H), 3.12 (dd, J = 7.4, 4.0 Hz, 1H), 2.37 - 2.28 (m, 1H), 2.09 (d, J = 11.4 Hz, 1H), 2.02 (dd, J = 11.5, 4.1 Hz, 1H), 1.96 (ddd, J = 12.5, 11.3, 5.3 Hz, 1H), 1.86 (s, 9H), 1.83 - 1.77 (m, 1H), 1.76 - 1.69 (m, 1H); 13 13C NMR (150 MHz, CDCl 3 ) δ (ppm): 197.5, 174.4, 145.5, 144.3, 134.2, 129.6, 126.5, 123.3 (q, J = 275.8 Hz), 117.6 (q, J = 29.4 Hz), 111.7, 61.6, 57.5, 51.3, 40.9, 38.8, 36.6, 29.8, 27.3; HRMS (ES+) Calcd for C 20 H 21 F 3 N 3 O (MH + ) 376.1637, Found 376.1635.

[0149] Comparative Example 6

[0150]

[0151] Add iodide 1 (35.6 g, 80.0 mmol) and CuI (3.05 g, 16.0 mmol) to a reaction flask, and add the solvent DMF (505 g). Then add 2,6 - lutidine (1.7 g, 16.0 mmol) and methyl fluorosulfonyldifluoroacetate (31.2 g, 160 mmol), stir and heat to 90 °C. Continue the reaction for 3 hours, then cool to 20 °C, add sodium hydroxide (26.8 g, 240 mmol) to the reaction, and then add an aqueous solution (290 mL) containing N - 2 - (hydroxyethyl)ethylenediaminetriacetic acid (29 g, 80 mmol), and continue stirring for 2 hours. Then filter, wash with water (2 × 150 g), and dry at 50 °C to obtain product 2 as a brown solid (25.6 g), with a yield of 77%.

[0152] Example 11

[0153]

[0154] In a reaction flask, anhydrous copper(II) fluorosulfonyldifluoroacetate (188 mg, 0.45 mmol) prepared from cuprous hydride, Cu powder (29 mg, 0.45 mmol), and 2-iodopyridine (62 mg, 0.3 mmol) were added. After evacuating and filling with N 2 gas three times, the solvent DMF (4.0 mL) was added, and the mixture was stirred at room temperature for 3 hours. The reaction was stopped, and 4-(trifluoromethoxy)anisole was used as an internal standard substance. The formation of the target product was confirmed by 19 19F-NMR, and the yield of the fluorine spectrum was 85%.

[0155] 19 19F NMR (376 MHz; CDCl 3 3) δ (ppm): -62.8 (s, 3F, CF 3 3); MS (EI) m / z = 147.0 (M + +).

[0156] Comparative Example 7

[0157]

[0158] In a reaction flask, methyl fluorosulfonyldifluoroacetate (FSO 2 2CF 2 2COOMe, 0.9 mmol), CuI (0.028 g, 0.18 mmol), and 2-iodopyridine (0.3 mmol) were added. After evacuating and filling with N 2 gas three times, the solvent DMF (4.0 mL) was added, and the mixture was stirred at 80 °C for 3 hours. The reaction was stopped, and 4-(trifluoromethoxy)anisole was used as an internal standard substance. The formation of the target product was confirmed by 19 19F-NMR, and the yield of the fluorine spectrum was 65%.

[0159] In the present invention, fluorosulfonyldifluoroacetic acid is reacted with cuprous hydride CuH to efficiently and simply prepare an anhydrous copper salt of fluorosulfonyldifluoroacetic acid. The reaction conditions are mild and the post-treatment is simple. The anhydrous copper salt of fluorosulfonyldifluoroacetic acid can be used as a highly efficient and practical trifluoromethylation reagent and a deoxyfluorination reagent for carboxylic acids.

[0160] All documents mentioned in the present invention are incorporated herein by reference as if each document was individually incorporated by reference. In addition, it should be understood that after reading the above teachings of the present invention, those skilled in the art can make various changes or modifications to the present invention, and these equivalent forms also fall within the scope defined by the appended claims of the present application.

Claims

1. A preparation method of anhydrous copper fluorosulfonyldifluoroacetate, characterized in that, using cuprous hydride and fluorosulfonyldifluoroacetic acid as raw materials to react in a solvent, and after the reaction is completed, filtering to obtain anhydrous copper fluorosulfonyldifluoroacetate.

2. The preparation method of anhydrous copper fluorosulfonyldifluoroacetate according to claim 1, characterized in that, the solvent is any one or a combination of several of diethyl ether, tetrahydrofuran, and ethyl acetate.

3. The preparation method of anhydrous copper fluorosulfonyldifluoroacetate according to claim 1, characterized in that, the reaction temperature is 0 to 40 °C and the time is 1 to 72 hours.

4. The preparation method of anhydrous copper fluorosulfonyldifluoroacetate according to claim 1, characterized in that, the molar ratio of cuprous hydride to fluorosulfonyldifluoroacetic acid is (1.0 to 4.0):1; the molar volume ratio of cuprous hydride to the solvent is (0.01 - 1.5) mmol / mL.

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