Preparation method of gem-difluoroalkenylation reagent and 1-amino-2-difluoromethylene cyclopentane derivative

Abstract

The invention discloses a preparation method of a gem-difluoro alkenylation reagent and a 1-amino-2-difluoro methylene cyclopentane derivative, which comprises the following steps: in alkali and a solution, tert-butyl mercaptan and a difluoro reagent react to obtain a compound with a structural formula III; reacting the compound as shown in the structural formula III with lewis acid under the oxidation of an oxidizing agent to obtain a compound as shown in a structural formula II; reacting the compound of the structural formula II with a bromination reagent under the action of strong base to obtain a compound of a structural formula I; wherein R is tert-butyl, cyclohexyl or isopropyl. The gem-difluoroolefin compound can be directly obtained through addition, free radical migration and beta-elimination of alkyne. Beta-sulfuryl (C-S) subjected to the reaction is easier to generate than beta-fluorine elimination, and meanwhile, generated sulfuryl free radicals can be further converted into SO2 gas and isobutene gas, so that side reactions are reduced, and the reaction yield is increased. # imgabs0 #

Description

Technical Field

[0001] The present invention belongs to the field of organic chemistry, and particularly relates to a gem-difluoroalkenylation reagent and a preparation method of 1-amino-2-difluoromethylenecyclopentane derivatives. Background Art

[0002] Fluorine atoms have the largest electronegativity and the smallest atomic radius except for hydrogen, and have unique physical and chemical properties, playing an important role in the fields of medicine, pesticides, and materials chemistry. Introducing fluorine atoms into medicinal chemistry can regulate the lipophilicity and metabolic stability of drug molecules, thereby enhancing the efficacy of drug molecules (Chem. Soc. Rev. 2008, 37, 308 - 319; J. Med. Chem. 2008, 51, 4359 - 4369; Acc. Chem. Res. 2014, 47, 2878 - 2886). Gem-difluoroalkenes can be regarded as isosteres of carbonyl groups, mimicking the properties of carbonyl groups to improve the biological activity, metabolic stability, and target specificity of drugs. For example, difluoromethylene artemisinin can mimic artemisinin to improve antimalarial activity (J. Fluor. Chem. 2006, 127, 637 - 642). OV329, as a γ-aminobutyric acid transaminase inhibitor, has an inhibitory effect on γ-aminobutyric acid transaminase that is 1870 times that of the marketed drug Vigabatrin and has smaller side effects (Epilepsia, 2021, 62, 3091 - 3104). In addition, gem-difluoroalkenes can also be used as multifunctional precursors for the synthesis of other fluorine-containing compounds. For example, the difunctionalization reaction of gem-difluoroalkenes can prepare trifluoromethylated products with important medicinal value (Chem. Commun. 2020, 56, 10442 - 10452).

[0003] The synthesis of traditional gem-difluoroalkene compounds relies on the transformation of carbonyl groups, mainly through the Wittig reaction, Homer-Wadsworth-Emmons (HWE) reaction, and Julia-Kocienski alkenylation reaction. However, these synthesis methods require the preparation of very special fluorinated precursors or strong basic and other harsh reaction conditions, limiting the scope of application of the reaction. Recently, the β-fluorine elimination of α-trifluoromethyl alkenes has been attempted to prepare gem-difluoroalkene compounds, but the bond energy of the C-F bond is usually very large (BDE = 500 ± 50 kJ mol-1), and the α-trifluoromethyl alkenes need to be activated by a benzene ring, thus limiting the substrate scope. Summary of the Invention

[0004] The technical problem to be solved by the present invention is that the existing methods for preparing gem-difluoroalkenes have great limitations. To this end, the present invention provides a gem-difluoroalkenylation reagent and a preparation method of 1-amino-2-difluoromethylenecyclopentane derivatives.

[0005] The present invention provides a method for preparing a compound represented by formula I, which mainly comprises the following steps:

[0006]

[0007] Wherein R is tert-butyl, cyclohexyl or isopropyl.

[0008] Step 1: Using a thiol compound as the starting material, reacting with a difluorine reagent TMSCF2Br through a substitution reaction and then removing the TMS protecting group to obtain a compound of structural formula III;

[0009] Step 2: Reacting the compound of structural formula III with an oxidant under the catalysis of a Lewis acid RuCl3 to obtain a compound of structural formula II;

[0010] Step 3: Deprotonating the compound of structural formula II with a strong base and reacting with a brominating reagent to obtain the final compound of structural formula I.

[0011] In the said Step 1, the base used is KOH, NaOH or LDA;

[0012] In the said Step 1, the difluorine reagent used is TMSCF2Br;

[0013] In the said Step 1, the molar ratio of the thiol to the base is 1:2 to 1:10;

[0014] In the said Step 1, the molar ratio of the thiol to TMSCF2Br is 1:1 to 1:5;

[0015] In the said Step 1, the reaction temperature is -20°C to 10°C.

[0016] In the said Step 2, the Lewis acid used is RuCl3;

[0017] In the said Step 2, the oxidant used is NaIO4, H2O2 or mCPBA;

[0018] In the said Step 2, the solvents used are CH3CN, CCl4, H2O. Preferably, the molar ratio of the solvents CH3CN, CCl4, H2O is 0.9 to 1.1:1.8 to 2.2:8 to 15, being 1:1.9:10.8;

[0019] In the said Step 2, the molar ratio of the compound of structural formula III to the Lewis acid is 100:1 to 1000:1;

[0020] In the said Step 2, the molar ratio of the compound of structural formula III to the oxidant is 1:1 to 1:5.

[0021] In Step 3, the base used is one or more of LiHMDS, LDA, and KOt-Bu;

[0022] In Step 3, the brominating reagent used is NBS or bromine;

[0023] In Step 3, the molar ratio of the compound of Structural Formula II to the base is 1:1 to 1:5;

[0024] In Step 3, the molar ratio of the compound of Structural Formula II to the brominating reagent is 1:1 to 1:5.

[0025] In Step 3, the reaction solvent used is THF (tetrahydrofuran).

[0026] In Step 3, the reaction temperature used is from -73°C to -83°C. Further preferably, the reaction temperature used is -78°C.

[0027] The present invention also provides a method for synthesizing a 1-amino-2-difluoromethylene cyclopentane derivative, as shown in the following Structural Formula IV, which includes the following steps: Under a nitrogen atmosphere, the compound of Structural Formula I, the compound of Structural Formula V, a photocatalyst, a base, and a solvent are added and mixed. The mixed system is irradiated with a 24W blue lamp and stirred at room temperature of 25°C for 12h, and then treated to obtain the 1-amino-2-difluoromethylene cyclopentane derivative of Structural Formula IV:

[0028]

[0029] wherein, R 1 is an aryl or an alkyl; R 2 is an ester group; R 3 and R 4 are an ester group, an alkyl, or hydrogen; R 5 can be represented as an alkyl, and the definition of R is as described above.

[0030] In some embodiments, the photocatalyst is any one of Ir(ppy)2(dtbbpy)PF6, fac-Ir(ppy)3, and 4CzIPN.

[0031] In some embodiments, the organic solvent is any one of ethyl acetate (EA), trifluorotoluene (PhCF3), N,N'-dimethylformamide (DMF), N,N'-dimethylacetamide (DMAc), and 1,2-dichloroethane (DCE).

[0032] In some embodiments, the base is any one of cesium carbonate (Cs2CO3) and 4-dimethylaminopyridine (DMAP).

[0033] In some embodiments, the molar ratio of the compound of structural formula V to the compound of structural formula I is 1:1 to 1:3.

[0034] In some embodiments, the molar ratio of the alkynamide to tert-butylsulfone dibromodifluoromethyl is preferably 1:1 to 1:3.

[0035] In some embodiments, the molar ratio of the compound of structural formula V to the base is 1:1 to 1:3.

[0036] In some embodiments, the molar ratio of the compound of structural formula V to the catalyst is 100:1 to 20:1.

[0037] In some embodiments, the reaction temperature is 15 to 35 °C, and the reaction time is 8 to 16 h. Further preferably, the reaction temperature is about 25 °C at room temperature, and the reaction time is about 12 h.

[0038] In some embodiments, the reaction needs to be carried out in a sealed container under the protection of an inert gas. The purpose is to prevent the adverse effects of oxygen on the free radical reaction.

[0039] In some embodiments, the post-treatment of the reaction includes: quenching, extraction, washing the organic phase, drying, and column chromatography separation.

[0040] In some embodiments, the quenching is carried out by adding water, the extraction is carried out with ethyl acetate, the organic phase is washed with saturated brine, the drying is carried out with anhydrous sodium sulfate, and the column chromatography separation is carried out with silica gel column chromatography.

[0041] Compared with the prior art, the present invention has the following advantages:

[0042] The present invention provides a gem-difluoroalkenylation reagent and its preparation method and application. The gem-difluoroalkenylation reagent of the present invention can directly obtain gem-difluoroalkene compounds through the addition of alkynes, radical migration, and β-elimination. The β-sulfone (C-S) elimination experienced in the reaction is more likely to occur than β-fluorine elimination, and the generated sulfonyl radical can be further converted into SO2 gas and isobutene gas, reducing side reactions and improving the reaction yield. Detailed Embodiments

[0043] The present invention will be further illustrated by the following examples, but the present invention is not limited to the scope of the examples. The experimental methods not specified in the following examples are carried out according to conventional methods and conditions, or selected according to the product instructions.

[0044] The preparation method of the gem-difluoroalkenylation reagent of the present invention includes the following steps:

[0045]

[0046] Step 1: Dissolve mercaptan (100 mmol) in DCM solution (15588 mmol). While stirring at 0 °C, add 20% aqueous KOH solution (6 equivalents, i.e., the molar ratio of KOH to mercaptan is 6:1), and then add TMSCF2Br solution (2 equivalents, i.e., the molar ratio of TMSCF2Br to mercaptan is 2:1). Continue stirring for 30 minutes. Finally, add water, extract the reaction mixture with DCM three times, combine the organic phases, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and distill under reduced pressure to obtain a colorless liquid product III.

[0047]

[0048] Step 2: Add the compound of structural formula III (90 mmol), CCl4 (927 mmol), CH3CN (1725 mmol), H2O (10000 mmol), and RuCl3 (1 mol%, 0.9 mmol) to a reaction flask. Then add NaIO4 (2.5 equivalents, i.e., the molar ratio of NaIO4 to the compound of structural formula III is 2.5:1), and react at room temperature (25 °C) for 12 hours. After the reaction is completed, add saturated NaHCO3 solution to neutralize the reaction. After filtration, extract the filtrate with ethyl acetate three times, combine the organic phases, wash with saturated sodium chloride solution and dry over anhydrous sodium sulfate, evaporate the solvent to obtain product II, which can be directly used in the next step without further post-treatment.

[0049]

[0050] Step 3: Under a nitrogen atmosphere, add the compound of structural formula II, NBS (3 equivalents, the molar ratio of NBS to the compound of structural formula II is 3:1), and THF to a reaction flask. After cooling the reaction to -78 °C, add LiHMDS (3 equivalents, the molar ratio of LiHMDS to the compound of structural formula II is 3:1), and continue the reaction for 3 hours. After the reaction is completed, quench with saturated ammonium chloride, extract the reaction mixture with ethyl acetate three times, combine the organic phases, wash with saturated sodium chloride solution and dry over anhydrous sodium sulfate, evaporate the solvent, and separate by column chromatography (PE:EA = 10:1, silica gel column chromatography) to obtain a colorless liquid product I.

[0051]

[0052] Product I-a, colorless liquid, total yield 71%. 1 H NMR (600 MHz, Chloroform-d) δ1.60(s,9H); 13CNMR(151MHz,Chloroform-d)δ125.1(t,J=354.1Hz),64.0,24.5; 19 F NMR(565MHz,Chloroform-d)δ-49.3.

[0053]

[0054] Product I-b, colorless liquid, total yield 60%. 1 H NMR(600MHz,Chloroform-d)δ3.42(tt,J=12.1,3.6Hz,1H),2.25(d,J=9.2Hz,1H),1.98(dt,J=13.5,3.5Hz,2H),1.81-1.66(m,3H),1.44-1.23(m,3H); 13 C NMR(151MHz,Chloroform-d)δ122.53(t,J=351.1Hz),59.1,25.4,25.1,24.8; 19 F NMR(565MHz,Chloroform-d)δ-55.0.

[0055]

[0056] Product I-c, colorless liquid, total yield 48%. 1 H NMR(400MHz,Chloroform-d)δ3.72-3.57(m,1H),1.53(d,J=7.0Hz,6H); 13 C NMR(101MHz,Chloroform-d)δ122.4(t,J=351.0Hz),51.5,15.8; 19 F NMR(565MHz,Chloroform-d)δ-54.8.

[0057] Gem-difluoroalkenylation reaction of alkynamide, comprising the following steps:

[0058] Step 1, under a nitrogen atmosphere, add alkynamide (0.2 mmol) and gem-difluoroalkenylation reagent (0.4 mmol) to an ethyl acetate solution (2 mL) of Ir(ppy)2(dtbbpy)PF6 (1 mol%) and cesium carbonate (0.4 mmol), and then irradiate the system with a 24W blue lamp at room temperature (25 °C) for 12 hours.

[0059] Step 2: After the reaction is completed, add water to the reaction system to quench the reaction. Extract the reaction three times with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride solution and dry over anhydrous sodium sulfate. Rotavaporize the solvent and perform column chromatography to obtain the corresponding product.

[0060] The diastereoselectivity and relative configuration of the products obtained in this invention were determined by nuclear magnetic resonance spectrometer and X-ray single crystal diffractometer respectively.

[0061] Application Example 1:

[0062] In 2022, Studer et al. reported the visible-light-catalyzed gem-difluoroalkenylation reaction of alkynes using CF2Br2 as a gem-difluoroalkenylating reagent (ACS Catal. 2022, 12, 11934 - 11941). Indene products could be obtained in 48% yield for 2-isobutylphenylacetylene in this report. In this invention, the same product could be obtained in 61% yield using the novel gem-difluoroalkenylating reagent I-a in the reaction, which is superior to the existing literature reports.

[0063]

[0064] Application Example 2:

[0065]

[0066] Under a nitrogen atmosphere, alkynamide 1a (0.2 mmol) and gem-difluoroalkenylating reagent I-a (0.4 mmol) were added to an ethyl acetate solution containing Ir(ppy)2(dtbbpy)PF6 (0.004 mmol) and cesium carbonate (0.4 mmol). Then the system was placed under irradiation with a 24 W blue light and reacted at room temperature (25 °C) for 12 hours. After the reaction was completed, add water to the reaction system to quench the reaction. Extract the reaction three times with ethyl acetate. Combine the organic phases, wash with saturated sodium chloride solution and dry over anhydrous sodium sulfate. Rotavaporize the solvent and perform column chromatography (PE:EA = 40:1, silica gel column chromatography) to obtain the colorless liquid product 3a with a yield of 71% and dr > 20:1.

[0067] Data characterization of product 2a: 11H NMR (600 MHz, Chloroform-d) δ 7.34 (t, J = 7.7 Hz, 2H), 7.28 - 7.25 (m, 1H), 7.14 (d, J = 7.6 Hz, 2H), 5.43 - 4.98 (br, 1H), 4.26 - 4.04 (m, 4H), 2.86 (dd, J = 15.8, 2.1 Hz, 1H), 2.83 - 2.73 (m, 1H), 2.30 (d, J = 15.9 Hz, 1H), 1.72 - 1.64 (m, 1H), 1.58 - 1.54 (m, 1H), 1.53 - 1.33 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.47, 170.11, 154.40, 151.21 (t, J = 287.0 Hz), 139.88, 128.90, 128.75, 126.98, 89.24 (t, J = 19.8 Hz), 80.54, 62.27, 61.36, 61.29, 60.26, 47.47, 34.20, 32.66, 28.17, 21.14, 14.54, 13.98, 13.86. 19 19F NMR (565 MHz, Chloroform-d) δ -87.47, -88.14 (d, J = 51.2 Hz).

[0068] Application Example 3:

[0069]

[0070] Under a nitrogen atmosphere, propargylamide 1a (0.2 mmol) and gem-difluoroalkenylation reagent I-b (0.4 mmol) were added to an ethyl acetate solution containing Ir(ppy)2(dtbbpy)PF6 (0.04 mmol%) and cesium carbonate (0.4 mmol). Then, the system was placed under irradiation with a 24 W blue lamp and reacted at room temperature (25 °C) for 12 hours. After the reaction was completed, water was added to the reaction system to quench the reaction. The reaction mixture was extracted with ethyl acetate three times. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was purified by column chromatography (PE:EA = 40:1, silica gel column chromatography) to obtain a colorless liquid product 3a with a yield of 44% and a dr > 20:1.

[0071] Application Example 4:

[0072]

[0073] Under a nitrogen atmosphere, propargylamide 1a (0.2 mmol) and gem-difluoroalkenylation reagent I-c (0.4 mmol) were added to an ethyl acetate solution containing Ir(ppy)2(dtbbpy)PF6 (0.04 mmol%) and cesium carbonate (0.4 mmol). Then, the system was placed under irradiation with a 24 W blue lamp and reacted at room temperature (25 °C) for 12 hours. After the reaction was completed, water was added to the reaction system to quench the reaction. The reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was separated by column chromatography (PE:EA = 40:1, silica gel column chromatography) to obtain a colorless liquid product 3a with a yield of 30% and a dr > 20:1.

[0074] Application Example 5:

[0075]

[0076] Under a nitrogen atmosphere, propargylamide 1b (0.2 mmol) and gem-difluoroalkenylation reagent I-a (0.4 mmol) were added to an ethyl acetate solution containing Ir(ppy)2(dtbbpy)PF6 (0.04 mmol%) and cesium carbonate (0.4 mmol). Then, the system was placed under irradiation with a 24 W blue lamp and reacted at room temperature (25 °C) for 12 hours. After the reaction was completed, water was added to the reaction system to quench the reaction. The reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate, the solvent was evaporated, and the residue was separated by column chromatography (PE:EA = 40:1, silica gel column chromatography) to obtain a colorless liquid product 2b with a yield of 77% and a dr > 20:1.

[0077] Data characterization of product 2b: 1 H NMR (600 MHz, Chloroform-d) δ 7.21 - 7.06 (m, 2H), 7.04 (t, J = 8.3 Hz, 2H), 5.50 - 4.94 (br, 1H), 4.24 - 4.08 (m, 4H), 2.87 (dd, J = 15.9, 2.2 Hz, 1H), 2.79 - 2.62 (m, 1H), 2.25 (d, J = 15.3 Hz, 1H), 1.71 - 1.65 (m, 1H), 1.57 - 1.52 (m, 1H), 1.52 - 1.28 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). 1313C NMR (151 MHz, Chloroform-d) δ 170.45, 170.04, 161.36 (d, J = 247.0 Hz), 154.42, 151.26 (t, J = 287.3 Hz), 135.59, 130.74 (d, J = 8.6 Hz), 115.68 (d, J = 22.8 Hz), 89.13 (t, J = 19.8 Hz), 80.73, 61.85, 61.47, 61.37, 60.26, 47.52, 34.21, 32.70, 28.17, 21.18, 14.58, 14.00, 13.89. 19 19F NMR (377 MHz, Chloroform-d) δ -87.17, -87.87 (d, J = 51.0 Hz), -114.74.

[0078] Application Example 6:

[0079]

[0080] This example has the same settings as Example 2, except that: when adding raw materials, raw material 1c is used instead of 1a, and a colorless liquid target product 2c is obtained with a yield of 78% and a dr > 20:1.

[0081] Data characterization of product 2c: 1 1H NMR (600 MHz, Chloroform-d) δ 7.32 (d, J = 8.6 Hz, 2H), 7.08 (d, J = 8.2 Hz, 2H), 5.43 - 4.90 (br, 1H), 4.25 - 4.08 (m, 4H), 2.88 (d, J = 15.8 Hz, 1H), 2.80 - 2.67 (m, 1H), 2.32 (d, J = 15.9 Hz, 1H), 1.72 - 1.64 (m, 1H), 1.55 - 1.50 (m, 1H), 1.50 - 1.33 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.38, 170.02, 154.09, 151.19 (t, J = 287.0 Hz), 138.55, 132.71, 130.16, 128.97, 89.08 (t, J = 19.8 Hz), 80.96, 62.37, 61.45, 61.35, 60.19, 47.49, 34.13, 32.65, 28.14, 21.15, 14.52, 13.98, 13.87. 19F NMR (377 MHz, Chloroform-d) δ -87.41, -87.78 (d, J = 50.5 Hz).

[0082] Application Example 7:

[0083]

[0084] This example has the same settings as Example 2, except that when adding raw materials, raw material 1d is used instead of 1a, obtaining the colorless liquid target product 2d with a yield of 70% and dr > 20:1.

[0085] Data characterization of product 2d: 1 H NMR (600 MHz, Chloroform-d) δ 7.50 - 7.44 (m, 2H), 7.02 (d, J = 8.3 Hz, 2H), 5.33 - 4.98 (br, 1H), 4.25 - 4.07 (m, 4H), 2.88 (d, J = 15.8 Hz, 1H), 2.81 - 2.67 (m, 1H), 2.33 (d, J = 15.8 Hz, 1H), 1.69 - 1.64 (m, 1H), 1.54 - 1.49 (m, 1H), 1.49 - 1.33 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.1 Hz, 3H). 13 C NMR (151 MHz, Chloroform-d) δ 170.39, 170.04, 154.02, 151.19 (t, J = 287.0 Hz), 139.14, 131.97, 130.49, 120.74, 89.07 (t, J = 19.8 Hz), 81.03, 62.42, 61.48, 61.38, 60.19, 47.50, 34.12, 32.65, 28.16, 21.16, 14.53, 13.99, 13.89. 19 F NMR (377 MHz, Chloroform-d) δ -87.46, -87.75 (d, J = 49.2 Hz).

[0086] Application Example 8:

[0087]

[0088] This example has the same settings as Example 2, except that when adding raw materials, raw material 1e is used instead of 1a, obtaining the colorless liquid target product 2e with a yield of 74% and dr > 20:1.

[0089] Data characterization of product 2e: 11H NMR (600 MHz, Chloroform-d) δ 7.66 (d, J = 8.2 Hz, 2H), 6.90 (d, J = 8.2 Hz, 2H), 5.31 - 4.94 (br, 1H), 4.25 - 4.10 (m, 4H), 2.88 (d, J = 15.9 Hz, 1H), 2.81 - 2.69 (m, 1H), 2.34 (d, J = 16.0 Hz, 1H), 1.72 - 1.62 (m, 1H), 1.53 - 1.49 (m, 1H), 1.49 - 1.34 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.38, 170.03, 153.95, 151.16 (t, J = 287.0 Hz), 139.97, 137.95, 130.70, 92.14, 89.07 (t, J = 19.8 Hz), 81.04, 62.50, 61.47, 61.37, 60.18, 47.50, 34.11, 32.64, 28.17, 21.16, 14.53, 14.01, 13.91. 19 19F NMR (377 MHz, Chloroform-d) δ -87.20--88.04 (m).

[0090] Application Example 9:

[0091]

[0092] Under a nitrogen atmosphere, propargylamide 1f (0.2 mmol) and gem-difluoroalkenylation reagent I-a (0.4 mmol) were added to an ethyl acetate solution containing fac-Ir(ppy)3 (0.04 mmol%) and DMAP (0.4 mmol), and then the system was placed under irradiation with a 24 W blue lamp and reacted at room temperature (25 °C) for 12 hours. After the reaction was completed, water was added to the reaction system to quench the reaction, and the reaction mixture was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and the residue was separated by column chromatography (PE:EA = 40:1, silica gel column chromatography) to obtain a colorless liquid product 2f with a yield of 64% and a dr > 20:1.

[0093] Data characterization of product 2f: 11H NMR (600 MHz, Chloroform-d) δ 7.21 (d, J = 8.0 Hz, 2H), 7.12 - 7.00 (m, 2H), 5.33 - 5.01 (br, 1H), 4.23 - 4.09 (m, 4H), 2.86 (dd, J = 15.8, 2.1 Hz, 1H), 2.78 - 2.69 (m, 1H), 2.48 (s, 3H), 2.29 (d, J = 15.9 Hz, 1H), 1.71 - 1.65 (m, 1H), 1.57 - 1.52 (m, 1H), 1.52 - 1.33 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.92 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.46, 170.09, 154.43, 151.20 (t, J = 286.9 Hz), 137.25, 136.80, 129.33, 126.59, 89.18 (t, J = 19.8 Hz), 80.69, 62.28, 61.42, 61.33, 60.26, 47.51, 34.18, 32.70, 28.21, 21.18, 15.68, 14.59, 14.01, 13.90. 19 19F NMR (377 MHz, Chloroform-d) δ -87.40, -88.02 (d, J = 51.1 Hz).

[0094] Application Example 10:

[0095]

[0096] Under a nitrogen atmosphere, 1 g (0.2 mmol) of alkynyl amide and gem-difluoroalkenylation reagent I-a (0.4 mmol) were added to an ethyl acetate solution containing fac-Ir(ppy)3 (0.04 mmol%) and DMAP (0.4 mmol), and then the system was placed under irradiation with a 24 W blue lamp and reacted at room temperature (25 °C) for 12 hours. After the reaction was completed, water was added to the reaction system to quench the reaction, and the reaction was extracted three times with ethyl acetate. The organic phases were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. The solvent was evaporated, and column chromatography (PE:EA = 40:1, silica gel column chromatography) was used to separate and obtain 2 g of a colorless liquid product with a yield of 74% and a dr > 20:1.

[0097] Data characterization of product 2g: 11H NMR (400 MHz, Chloroform-d) δ 7.16 - 6.93 (m, 2H), 6.86 (d, J = 8.3 Hz, 2H), 5.40 - 5.02 (br, 1H), 4.26 - 4.04 (m, 4H), 3.80 (s, 3H), 2.84 (dd, J = 15.8, 2.6 Hz, 1H), 2.79 - 2.64 (m, 1H), 2.22 (d, J = 15.5 Hz, 1H), 1.69 - 1.47 (m, 3H), 1.50 - 1.28 (m, 3H), 1.26 (t, J = 7.1 Hz, 3H), 1.21 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.52, 170.09, 158.29, 154.82, 151.25 (t, J = 286.9 Hz), 132.06, 130.25, 113.94, 89.26 (t, J = 20.0 Hz), 80.11, 62.94, 61.37, 61.29, 60.32, 55.29, 47.45, 34.25, 32.73, 28.20, 21.16, 14.61, 13.99, 13.87. 19 19F NMR (377 MHz, Chloroform-d) δ -87.21, -88.28 (d, J = 51.4 Hz).

[0098] Application Example 11:

[0099]

[0100] This example has the same settings as Example 2, except that: when adding raw materials, raw material 1h is used instead of 1a, and a colorless liquid target product 2h is obtained with a yield of 81% and a dr > 20:1.

[0101] Data characterization of product 2h: 11H NMR (600 MHz, Chloroform-d) δ 7.96 - 7.94 (m, 2H), 7.27 (d, J = 8.4 Hz, 2H), 5.19 - 5.03 (br, 1H), 4.24 - 4.10 (m, 4H), 2.91 (dd, J = 16.0, 2.2 Hz, 1H), 2.89 - 2.81 (m, 1H), 2.61 (s, 3H), 2.46 (d, J = 16.0 Hz, 1H), 1.70 - 1.64 (m, 1H), 1.51 - 1.47 (m, 1H), 1.46 - 1.40 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.23 (t, J = 7.1 Hz, 3H), 0.90 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 197.19, 170.35, 170.08, 153.62, 151.11 (t, J = 287.0 Hz), 145.24, 135.11, 128.90, 128.21, 89.07 (t, J = 19.9 Hz), 81.33, 63.20, 61.47, 61.38, 60.13, 47.44, 34.03, 32.56, 28.13, 26.52, 21.11, 14.42, 13.96, 13.87. 19 19F NMR (565 MHz, Chloroform-d) δ -87.64 (d, J = 51.5 Hz), -88.05.

[0102] Application Example 12:

[0103]

[0104] This example is set the same as Example 2, with the difference that: when adding raw materials, raw material 1i is used instead of 1a to obtain the colorless liquid target product 2i, with a yield of 73% and a dr > 20:1.

[0105] Data characterization of product 2i: 11H NMR (600 MHz, Chloroform-d) δ 6.88 (s, 1H), 6.75 (s, 2H), 5.24 - 4.95 (br, 1H), 4.24 - 4.08 (m, 4H), 2.86 (dd, J = 15.8, 2.4 Hz, 1H), 2.84 - 2.79 (m, 1H), 2.34 (dd, J = 14.7, 6.9 Hz, 1H), 2.29 (s, 6H), 1.68 - 1.63 (m, 1H), 1.58 - 1.53 (m, 1H), 1.53 - 1.37 (m, 11H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.53, 170.21, 154.48, 151.17 (t, J = 286.7 Hz), 139.84, 138.18, 128.67, 126.44, 89.24 (t, J = 19.7 Hz), 80.45, 62.74, 61.35, 61.27, 60.25, 47.41, 34.23, 32.55, 28.24, 21.25, 21.14, 14.47, 13.98, 13.87. 19 19F NMR (565 MHz, Chloroform-d) δ -87.76, -88.40 (d, J = 52.0 Hz).

[0106] Application Example 13:

[0107]

[0108] This example is set the same as Example 2, the difference is that when adding raw materials, raw material 1j is used instead of 1a, and a colorless liquid target product 2j is obtained, with a yield of 73% and dr > 20:1.

[0109] Data characterization of product 2j: 11H NMR (600 MHz, Chloroform-d) δ 6.76 (d, J = 8.0 Hz, 1H), 6.70 - 6.49 (m, 2H), 5.99 (s, 2H), 5.37 - 4.94 (br, 1H), 4.24 - 4.08 (m, 4H), 2.86 (dd, J = 15.8, 2.6 Hz, 1H), 2.77 - 2.66 (m, 1H), 2.29 (d, J = 15.9 Hz, 1H), 1.69 - 1.64 (m, 1H), 1.58 - 1.48 (m, 3H), 1.48 - 1.29 (m, 9H), 1.26 (t, J = 7.1 Hz, 3H), 1.22 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.2 Hz, 3H). 13 13C NMR (151 MHz, Chloroform-d) δ 170.51, 170.07, 154.69, 151.25 (t, J = 288.2 Hz), 147.69, 146.53, 133.10, 122.59, 110.23, 107.86, 101.46, 89.17 (t, J = 19.9 Hz), 80.39, 62.54, 61.42, 61.32, 60.29, 47.40, 34.28, 32.71, 28.20, 21.15, 14.61, 13.99, 13.89. 19 19F NMR (565 MHz, Chloroform-d) δ -87.10, -88.00 (d, J = 55.4 Hz).

[0110] Application Example 14:

[0111]

[0112] This example has the same settings as Example 2, except that: when adding raw materials, raw material 1k is used instead of 1a, and a colorless liquid target product 2k is obtained with a yield of 73% and dr > 20:1.

[0113] Data characterization of product 2k: 1 1H NMR (600 MHz, Chloroform-d) δ 8.58 (s, 2H), 7.16 (d, J = 5.0 Hz, 2H), 5.08 - 4.90 (br, 1H), 4.27 - 4.12 (m, 4H), 3.05 - 2.97 (m, 1H), 2.95 (d, 1H), 2.65 (d, J = 16.1 Hz, 1H), 1.71 - 1.64 (m, 1H), 1.47 - 1.43 (m, 9H), 1.43 - 1.36 (m, 3H), 1.26 (tt, J = 9.0, 4.6 Hz, 7H), 0.88 (t, 3H).13 C NMR(151MHz,Chloroform-d)δ170.23,170.16,152.85,150.95(t,J=286.7Hz),150.31,149.49,121.81,88.97(d d, J=21.0, 19.1Hz), 82.02, 63.87, 61.50, 61.43, 60.03, 47.26, 33.79, 32.47, 28.09, 21.09, 14.28, 13.96, 13.89. 19 F NMR (377MHz, Chloroform-d) δ -87.63 (d, J = 53.7Hz), -89.10.

[0114] Cell experiments:

[0115] CPP-115 is a class of γ-aminobutyric acid transaminase inhibitors with higher affinity and lower retinal toxicity than Vigabatrin (HY-15399). The compound prepared by the present invention has the same skeleton structure as CPP-115, and is predicted to have a certain ability to inhibit γ-aminobutyric acid transaminase. Therefore, we conducted cell experiments on the inhibitory ability of compounds 2a-2k and CPP-115 on γ-aminobutyric acid transaminase. The experimental results show that compounds 2a-2k have certain activity in inhibiting γ-aminobutyric acid transaminase, but are not better than CPP-115. It is still necessary to explore and synthesize this type of active species in the future.

[0116]

[0117] The above is only an embodiment of the present invention, and the common knowledge such as the known specific structure and characteristics in the scheme is not described in detail here. It should be pointed out that for those skilled in the art, several deformations and improvements can be made without departing from the structure of the present invention, which should also be regarded as the protection scope of the present invention, and these will not affect the effect of the implementation of the present invention and the practicality of the patent. The scope of protection required by this application shall be based on the content of its claims, and the specific implementation methods and other records in the specification can be used to interpret the content of the claims.

Claims

1. A method for preparing a gem-difluoroalkenylation reagent, characterized in that, It includes the following steps: Step 1: In an alkali and a solution, tert-butyl mercaptan reacts with a difluoro reagent to obtain a compound of Structural Formula III; Step 2: The compound of Structural Formula III reacts with a Lewis acid under the oxidation of an oxidant to obtain a compound of Structural Formula II; Step 3: The compound of Structural Formula II reacts with a brominating reagent under the action of a strong base to obtain a compound of Structural Formula I; Among them, R in Formula I, II, III and R-SH has the same meaning, and R is tert-butyl, cyclohexyl or isopropyl.

2. The preparation method of the gem-difluoroalkenylation reagent according to claim 1, wherein, Step 1 satisfies one or more of the following conditions: In Step 1, the alkali used is KOH, NaOH or LDA; In Step 1, the difluoro reagent used is TMSCF2Br; In Step 1, the molar ratio of mercaptan to alkali is 1:2 to 1:10; In Step 1, the molar ratio of mercaptan to difluoro reagent is 1:1 to 1:5; In Step 1, the reaction temperature is -20°C to 10°C.

3. The preparation method of the gem-difluoroalkenylation reagent according to claim 1, wherein Step 2 satisfies one or more of the following conditions: In Step 2, the Lewis acid used is RuCl3; In Step 2, the oxidant used is NaIO4, H2O2 or mCPBA; In Step 2, the solvent used for the reaction is CH3CN, CCl4 and H2O; In Step 2, the molar ratio of the compound of Structural Formula III to the Lewis acid is 100:1 to 1000:1; In Step 2, the molar ratio of the compound of Structural Formula III to the oxidant is 1:1 to 1:

5.

4. The preparation method of the gem-difluoroalkenylation reagent according to claim 3, characterized in that, The molar ratio of the said CH3CN, CCl4, H2O is 0.9 to 1.1:1.8 to 2.2:8 to 15.

5. The preparation method of the gem-difluoroalkenylation reagent according to claim 1, wherein, Step 3 satisfies one or more of the following conditions: In Step 3, the strong base used is one or more of LiHMDS, LDA, KOt-Bu; In Step 3, the brominating reagent used is NBS or bromine; In Step 3, the molar ratio of the compound of Structural Formula II to the strong base is 1:1 to 1:5; In Step 3, the molar ratio of the compound of Structural Formula II to the brominating reagent is 1:1 to 1:

5.

6. The preparation method of the gem-difluoroalkenylation reagent according to claim 1, wherein, In Step 3, the reaction temperature is -73°C to -83°C.

7. A method for preparing a 1-amino-2-difluoromethylene cyclopentane derivative, characterized in that: Using the compound of Structural Formula I and the compound of Structural Formula V as raw materials, adding a photocatalyst, a base and an organic solvent, stirring and post-treating under a nitrogen atmosphere and blue light irradiation to obtain a compound of Structural Formula IV, which is a 1-amino-2-difluoromethylene cyclopentane derivative; Among them, R 1 is an aryl or an alkyl; R 2 is an ester group; R 3 and R 4 are an ester group, an alkyl or hydrogen; R 5 is an alkyl; R is a tert-butyl group, a cyclohexyl group or an isopropyl group.

8. The preparation method according to claim 7, characterized in that: The said photocatalyst is any one of Ir(ppy)2(dtbbpy)PF6, fac-Ir(ppy)3, 4CzIPN; The said base is one of cesium carbonate, 4-dimethylaminopyridine; The said organic solvent is one of ethyl acetate, trifluorotoluene, N,N'-dimethylformamide, N,N'-dimethylacetamide, 1,2-dichloroethane.

9. The preparation method according to claim 8, characterized in that, The molar ratio of the said compound of Structural Formula I to the compound of Structural Formula V is 1:1 to 3:1; The molar ratio of the said compound of Structural Formula V to the base is 1:1 to 1:3; The molar ratio of the said compound of Structural Formula V to the photocatalyst is 100:1 to 20:

1.

10. The preparation method according to claim 8, characterized in that, The said post-treatment includes: quenching, extraction, washing the organic phase, drying and column chromatography separation.

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