Novel alpha-fluoroalkyl substituted fatty alcohol compound as well as preparation method and application thereof

Abstract

The invention relates to the technical field of organic synthesis, in particular to a novel alpha-fluoroalkyl substituted fatty alcohol compound as well as a preparation method and application thereof, the molecular structural formula of the novel alpha-fluoroalkyl substituted fatty alcohol compound is as follows: # imgabs0, and the fluoroalkyl alcohol compound can also be used for synthesizing a medicine FFA4 for treating diabetes, a medicine Apo7033 for treating nephropathy and the like. The preparation method provided by the invention realizes free radical three-component reaction in which alpha-fluoroalkyl-alpha-silyl methanol, olefin and a nucleophilic reagent participate, is a new reaction mode, provides a simple and efficient method for synthesizing fluoroalkyl alcohol and fluoroalkyl silyl ether, and in addition, the method can be used for synthesizing fluoroalkyl alcohol by a one-pot method through simple desilicication treatment. The preparation method is simple in reaction condition, efficient and mild. The method has good functional group tolerance and substrate universality, and shows complementarity of a single-electron reaction and a double-electron reaction.

Description

Technical Field

[0001] The invention relates to the technical field of organic synthesis, and in particular to a novel α-fluoroalkyl substituted fatty alcohol compound, a preparation method and application thereof. Background Art

[0002] Among the numerous fluorine-containing compounds, many compounds containing trifluoroethanol structural units have unique biological activities, such as the important structural units of drug molecules Befloxatone and antitumor agents. [a) Wouters, J.; Moureau, F.; Evrard, G.; Koenig, J.-J.; Jegham, S.; George, P.; Durant, F. A Versible Monoamine Oxidase A Inhibitor, Befloxatone: Structural Approach of Its Mechanism Of Action. Bioorg. Med. Chem. 1999, 7, 1683. b) Biadatti, T.; Thoreau, E.; Voegel, J.; Jomard, A. Analogues of Vitamin D. PCT Int. Appl. WO2004020379A1. 2004.] Moreover, fluoroalkyl alcohols are also an important class of organic synthesis intermediates, which can be used to synthesize a series of useful fluorine-containing organic compounds. Therefore, the synthesis of fluoroalkyl alcohol compounds has always been a research hotspot in organic fluorine chemistry.There are three main methods reported in the literature, such as the nucleophilic addition reaction of trifluoromethylating agents to aldehydes and ketones [Umemoto, T. Electrophilic Perfluoroalkylating Agents. Chem. Rev. 1996, 96, 1757.], the reduction reaction of trifluoromethyl ketone compounds [Huang, H.; Zong, H.; Bian, G.; Song, L. Chemo- and Enantioselective Addition and β-Hydrogen Transfer Reduction of Carbonyl Compounds with Diethylzinc Reagent in One Pot Catalyzed by a Single Chiral Organometallic Catalyst. J. Org. Chem. 2015, 80, 12614.] and the nucleophilic addition reaction involving trifluoroacetaldehyde [Cabrera, JM; Tauber, J.; Zhang, W.; Xiang, M.; Krische, MJ Selection between Diastereomeric Kinetic vs Thermodynamic Carbonyl Binding Modes Enables Enantioselective Iridium-Catalyzed anti-(α-Aryl)allylation of Aqueous Fluoral Hydrate and Difluoroacetaldehyde Ethyl Hemiacetal. J. Am. Chem. Soc. 2018, 140, 9392.]. The traditional synthesis of these molecules relies on the two-electron reaction process. Although it can be used to synthesize many fluoroalkyl alcohol compounds, it is still limited by the limitations of the two-electron reaction itself, such as poor functional group compatibility, difficult substrate synthesis, and cumbersome operation steps. Therefore, developing new strategies to achieve the synthesis of fluoroalkyl alcohols is still a scientific issue worth exploring. Here, a new strategy is proposed, that is, a method based on a single-electron process to directly introduce tri(di)fluoroethanol units into molecules. This method develops a class of organosilicon reagents α-fluoroalkyl-α-silylmethanol, which is used to generate carbon radicals through the free radical 1,2-SiT process, and undergoes free radical addition reactions with olefins and nucleophilic reagent compounds to obtain a series of compounds containing trifluoroethanol units. This method effectively inhibits side reactions such as β-fluorine elimination that occur in the two-electron process. Summary of the invention

[0003] One of the purposes of the present invention is to provide a novel α-fluoroalkyl substituted fatty alcohol compound, which can be used to synthesize drugs for treating diabetes and kidney disease.

[0004] The second object of the present invention is to provide a novel method for preparing α-fluoroalkyl substituted fatty alcohol compounds, which is simple and efficient. By using synthetic fluoroalkyl silyl ethers, the synthesis of fluoroalkyl alcohol compounds can also be achieved in one pot.

[0005] The third object of the present invention is to provide an application of a novel α-fluoroalkyl substituted fatty alcohol compound.

[0006] The scheme adopted by the present invention to achieve one of the purposes is: a new type of α-fluoroalkyl substituted fatty alcohol compound, the molecular structure of which is as follows:

[0007]

[0008] Among them, R 1 , R 2 is any one of aryl, heteroaryl, alkyl, and heteroatom, and may be the same or different; R 3 is any one of aryl, heteroaryl, alkyl, alkenyl, alkynyl, ester, cyano, nitro, sulfonyl, heteroatom, and hydrogen atom; R f CF3, CF2H, CFH2.

[0009] Preferably, the alkyl group has 1-20 carbon atoms and is a straight chain structure, a cyclic structure or a branched structure; the alkyl group carries one or more substituents. When there are multiple substituents, the substituents may be the same or different and the positions may be the same or different.

[0010] Preferably, the aryl group carries one or more substituents; when having multiple substituents, the substituents may be the same or different.

[0011] The scheme adopted by the present invention to achieve the second purpose is: a method for preparing the α-fluoroalkyl substituted fatty alcohol compound, comprising mixing α-fluoroalkyl-α-silylmethanol A, olefin B, nucleophilic reagent C, catalyst, oxidant and organic solvent, stirring and reacting at a certain temperature, separating and purifying, and then performing desiliconization treatment to obtain the α-fluoroalkyl substituted fatty alcohol compound;

[0012] Wherein, the molecular structure formula of the α-fluoroalkyl-α-silylmethanol A is

[0013] The molecular structural formula of the olefin B is:

[0014] The molecular structural formula of the nucleophilic reagent C is:

[0015] Preferably, the catalyst is at least one of Mn(OAc)2·4H2O, Mn(acac)2·4H2O, MnCl2·4H2O, MnF2, MnBr2, Mn(OAc)2, and Mn(acac)2.

[0016] Preferably, the oxidant is tert-butyl perbenzoate substituted with at least one of a hydrogen atom, a heteroatom, a halogen atom, an alkyl group, a heteroaryl group, and an aryl group.

[0017] Preferably, the organic solvent is methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, ether, dimethyl ethyl diether, methyl tert-butyl ether, 1,4-epoxyhexane, 1,3-epoxypentane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C 4-12 Saturated alkanes, C 3-12 Fluorinated or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C 3-12 At least one of the saturated alkyl nitriles.

[0018] Preferably, the molar ratio of the α-fluoroalkyl-α-silylmethanol A, olefin B, nucleophile C and oxidant is 1:1-3:1-3:1-3; the amount of the catalyst is 1%-10% of the molar amount of α-fluoroalkyl-α-silylmethanol A, and the concentration of α-fluoroalkyl-α-silylmethanol A in the mixed solution is between 0.1M and 1M.

[0019] Preferably, the reaction temperature is 0-100°C and the temperature of the desiliconization treatment is -10-10°C.

[0020] The desiliconization process is to cool the reaction solution to -10-10°C, add TBAF and react for 30 minutes, followed by post-treatment.

[0021] The invention performs post-treatment on the reaction product after the reaction is completed, including purification methods such as extraction, concentration and column chromatography.

[0022] The extraction process can be carried out using a separatory funnel under normal pressure.

[0023] The concentration process can be carried out by atmospheric distillation, reduced pressure distillation and the like, for example, vacuum concentration using a rotary evaporator.

[0024] The purification process is to obtain a pure product by column chromatography.

[0025] The scheme adopted by the present invention to achieve the third purpose is: an application of the α-fluoroalkyl substituted fatty alcohol compound, wherein the α-fluoroalkyl substituted fatty alcohol compound can be used to prepare a drug for treating diabetes or a drug for treating kidney disease.

[0026] The reaction formula of the method of the present invention can be expressed as follows:

[0027]

[0028] Wherein, the compound of formula A represents α-fluoroalkyl-α-silylmethanol, the compound of formula B represents olefin, the compound of formula C represents a nucleophile, and the compound of formula G represents various fluoroalkyl alcohol compounds.

[0029] The present invention has the following advantages and beneficial effects:

[0030] (1) The preparation method of the present invention realizes a free radical three-component reaction involving α-fluoroalkyl-α-silylmethanol, olefin and nucleophile, which is a new reaction mode and provides a simple and efficient method for synthesizing fluoroalkyl alcohols and fluoroalkyl silyl ethers. In addition, the method can synthesize fluoroalkyl alcohols in one pot after a simple desiliconization treatment.

[0031] (2) The preparation method of the present invention has simple, efficient and mild reaction conditions.

[0032] (3) The reaction conditions involved in the preparation method of the present invention have good functional group tolerance and substrate universality. In this type of free radical reaction, functional groups such as aldehydes, ketones, and alcohols that are difficult to be compatible in two-electron reactions can be retained during the reaction process, demonstrating the complementarity of one-electron reactions and two-electron reactions.

[0033] (4) The preparation method of the present invention can be used for post-modification of complex bioactive molecules and drug molecules. The synthesized fluoroalkyl alcohol compounds can also be used to synthesize FFA4, a drug for treating diabetes, Apo7033, a drug for treating kidney disease, and the like. DETAILED DESCRIPTION

[0034] For a better understanding of the present invention, the following examples are provided to further illustrate the present invention, but the present invention is not limited to the following examples.

[0035] Embodiment 1:

[0036]

[0037] In a glove box, A (64.8 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G1 (white solid 87.5 mg, yield 76%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.20–8.11(m,2H),7.62–7.57(m,1H),7.54–7.46(m,6H),7.40–7.33(m,4H),7.3 1–7.24(m,2H),5.55(td,J=56.0,3.6Hz,1H),3.99–3.76(m,1H),3.48–3.07(m,2H),1.78(d,J=5.8Hz,1H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.1,144.5,144.2,133.2,131.4,129.7,128.7,128.7,127.7 ,127.6,125.9,125.9,115.8(t,J=244.6Hz),85.3,68.2(t,J=23.6Hz),37.1(t,J=3.0Hz). 19 F NMR (376MHz, CDCl3, 25℃) δ–128.7––132.7(m,2F).

[0038] Embodiment 2:

[0039]

[0040] In a glove box, A (64.8 mg, 0.3 mmol), B (223 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G2 (white solid 89.5 mg, yield 66%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.78–7.70(m,2H),7.59–7.51(m,1H),7.40–7.33(m,4H),7.33–7.26(m,4H),7 .12–7.02(m,2H),6.09–5.74(m,1H),5.53(td,J=15.7Hz,1H),3.06(d,J=1.0Hz,1H),2.97–2.67(m,2H). 13 C NMR (151MHz, CDCl3, 25℃) δ166.0,145.0,143.7,133.8,133.7,133.2,129.8,128.9,128 .5,128.4,127.2,127.2,113.9(t,J=245.6Hz),75.7,69.0(dd,J=25.9,22.6Hz),38.8. 19 F NMR (376MHz, CDCl3, 25℃) δ–126.1––132.6(m,2F).

[0041] Embodiment 3:

[0042]

[0043] In a glove box, A (64.8 mg, 0.3 mmol), B (302.4 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G3 (white solid 139 mg, yield 85%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.76–7.69(m,2H),7.56(s,1H),7.47–7.35(m,4H),7.32–7.27(m,2 H),7.27–7.17(m,4H),6.08–5.72(m,1H),5.62–5.47(m,1H),3.09(s,1H),2.97–2.66(m,2H). 13 C NMR (151MHz, CDCl3, 25℃) δ166.0,145.5,144.1,133.9,131.8131.5,129.8,128.4,128.3, 127.5,127.5,121.8,121.4,113.9(t,J=245.5Hz),75.7,68.9(dd,J=26.1,22.5Hz),38.6. 19 F NMR (376MHz, CDCl3, 25℃) δ–126.7––132.0 (m, 2F).

[0044] Embodiment 4:

[0045]

[0046] In a glove box, A (64.8 mg, 0.3 mmol), B (194.4 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G4 (yellow solid 81.7 mg, yield 65%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.81–7.73(m,2H),7.59–7.50(m,1H),7.43–7.31(m,6H),7.00(t,J=8.7Hz ,2H),6.79(t,J=8.7Hz,2H),6.06–5.73(m,1H),5.58–5.44(m,1H),2.97(s,1H),2.95–2.71(m,2H).. 13 C NMR (151MHz, CDCl3, 25℃) δ165.9, 162.7 (d, J = 43.0Hz), 161.1 (d, J = 42.6Hz), 142.5 (d, J = 3.2Hz), 141.2 (d, J = 3.2Hz), 133.8, 129.8, 128 .6,128.4,127.6(d,J=8.0Hz),115.5(d,J=21.3Hz),115.1(d,J=21.3Hz),113.9(t,J=245.6Hz),75.8,69.2(dd,J=25.8,22.5Hz),39.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–114.6––116.3(m,2F),–126.1––132.2(m,2F).

[0047] Embodiment 5:

[0048]

[0049] In a glove box, A (64.8 mg, 0.3 mmol), B (252 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G5 (white solid 118.5 mg, yield 81%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.03 (dd, J=9.3, 1.9Hz, 2H), 7.88–7.82 (m, 1H), 7.80–7.69 (m, 3H), 7.57–7.44 (m,7H),7.41–7.28(m,4H),7.15-7.07(m,2H),6.09–5.78(m,1H),5.73–5.62(m,1H),3.25–2.98(m,3H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.8,143.7,142.6,133.2,133.1,133.1,132.7,132.4,129.5,128.7,128.5,128.4,128.3,128.2,128 .0,127.7,127.4,126.5,126.5,126.2,126.0,124.7,124.2,124.1,114.1(t,J=245.7Hz),76.6,69.2(dd,J=25.6,22.4Hz),38.7. 19 F NMR (376MHz, CDCl3, 25℃) δ–126.9––131.8(m,2F).

[0050] Embodiment 6:

[0051]

[0052] In a glove box, A (64.8 mg, 0.3 mmol), B (155 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G6 (yellow solid 91.1 mg, yield 67%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.75(d,J=7.7Hz,2H),7.54(t,J=7.5Hz,1H),7.46(s,1H),7.42–7.33(m,3H),7.33–7.25(m,3H),7. 25–7.17(m,1H),7.00(t,J=7.9Hz,1H),6.82(d,J=7.9Hz,1H),5.88(m,1H),5.63–5.47(m,1H),3.26(s,1H),3.04–2.62(m,2H). 13 CNMR (151MHz, CDCl3, 25℃) δ166.0,148.4,146.9,134.8,134.4,133.8,130.1,129.9,129.7,128.3,128.3 ,127.9,127.3,126.1,125.9,123.9,123.8,113.9(t,J=245.6Hz),75.6,68.9(dd,J=26.0,22.8Hz),38.7. 19 F NMR (376MHz, CDCl3, 25℃) δ–124.8––133.7(m, 2F).

[0053] Embodiment 7:

[0054]

[0055] In a glove box, A (64.8 mg, 0.3 mmol), B (230 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G7 (white solid 96.0 mg, yield 70%, dr: 3.5:1). 1 H NMR (400MHz, CDCl3, 25℃) δ7.82–7.72(m,2H),7.61–7.39(m,10H),7.38–7.31(m,4H),7.31–7.27(m, 1H),7.21–7.13(m,1H),7.03–6.95(m,1H),6.09–5.74(m,1H),5.67–5.50(m,1H),3.07–2.79(m,3H). 13 C NMR (151MHz, CDCl3, 25℃, C+C') δ165.9,146.8,145.7,145.5,144.5,140.6,140. 6,140.3,139.9,133.5,133.5,130.0,129.8,128.9,128.9,128.7,128.6,128.4, 128.3,128.3,127.6,127.5,127.4,127.3,127.2,127.1,127.1,127.0,126.3,1 26.3,125.8,125.8,114.1(t,J=245.4Hz),76.4,76.2,69.4(t,J=22.5Hz),39.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–127.4––131.5 (m, 2F)

[0056] Embodiment 8:

[0057]

[0058] In a glove box, A (64.8 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (136.8 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), 4-OMe-TBPB (201.6 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G8 (yellow solid 58 mg, yield 47%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.09(d,J=8.9Hz,2H),7.49–7.45(m,4H),7.35(q,J=7.6Hz,4H),7.29–7.26(m,1 H),7.26–7.22(m,1H),6.97(d,J=8.9Hz,2H),5.56(td,J=56.0,3.5Hz,1H),3.88(s,3H),3.39–3.04(m,2H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.7,163.9,146.7,145.7,132.1,128.6,128.3,127.4,127.0, 125.8, 125.8, 121.3, 114.2 (d, J = 244.7Hz), 113.5, 76.4, 69.2 (dd, J = 22.2Hz), 55.6, 39.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–126.6––133.0 (m, 2F).

[0059] Embodiment 9:

[0060]

[0061] In a glove box, A (64.8 mg, 0.3 mmol), B (233 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G9 (white solid 90.5 mg, yield 65.5%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.11(m,2H),7.63–7.58(m,1H),7.51–7.44(m,6H),7.39–7.26(m,5H),5.56(m,1H),3.80(m,1H),3.50–2.90(m,2H). 13 C NMR (151MHz, CDCl3, 25℃, major) δ165.0,144.0,143.3,133.4,131.8,131.2,129.7,128.8, 128.7, 128.0, 127.8, 125.8, 121.8, 115.7 (t, J = 244.7Hz), 84.9, 68.2 (t, J = 23.8Hz), 36.9. 13 C NMR (151MHz, CDCl3, 25℃, minor) δ165.2,143.7,143.7,133.3,131.8,131.2,129.7,128.9, 128.7,128.0,127.8,125.8,121.8,115.0(t,J=244.5Hz),84.9,68.1(t,J=23.8Hz),36.7. 19 FNMR (376MHz, CDCl3, 25℃) δ–124.7––140.5(m,2F).

[0062] Embodiment 10:

[0063]

[0064] In a glove box, A (64.8 mg, 0.3 mmol), B (193 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G10 (white solid 86.3 mg, yield 69.1%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.17–8.07(m,2H),7.68–7.54(m,1H),7.53–7.43(m,4H),7.43– 7.33(m,4H),7.32–7.26(m,2H),5.90–5.05(m,1H),3.94–3.68(m,1H),3.50–2.89(m,2H). 13 C NMR (151MHz, CDCl3, 25℃, major) δ165.0,144.0,142.8,133.6,133.4,131.2,129.7,128.8, 128.7,127.9,127.8,127.5,125.8,115.8(t,J=244.6Hz),84.9,68.2(t,J=23.9Hz),36.9. 13 C NMR (151MHz, CDCl3, 25℃, minor) δ165.2,143.7,143.2,133.6,133.3,131.2,129.7,128.9, 128.7,127.9,127.8,127.5,125.8,115.8(t,J=244.7Hz),84.9,68.2(t,J=23.7Hz),36.7. 19 F NMR (376MHz, CDCl3, 25℃) δ–124.6––139.1(m,2F).

[0065] Embodiment 11:

[0066]

[0067] In a glove box, A (64.8 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (228.0 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), 4-Cl-TBPB (201.6 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G11 (yellow solid 108.1 mg, yield 86%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.73–7.64(m,2H),7.46–7.38(m,4H),7.36–7.29(m,4H),7.27–7.20(m,1 H),7.18–7.11(m,2H),7.03–6.90(m,1H),6.05–5.69(m,1H),5.62–5.49(m,1H),3.07–2.73(m,3H). 13 C NMR (151MHz, CDCl3, 25℃) δ164.9,146.7,145.5,139.9,131.3,128.7,128.6,128.3,127.6, 127.4,127.0,125.8,125.8,114.0(t,J=245.2Hz),76.3,69.5(dd,J=25.1,22.2Hz),39.1. 19 F NMR (376MHz, CDCl3, 25℃) δ–127.1––133.6(m,2F).

[0068] Embodiment 12:

[0069]

[0070] In a glove box, A (64.8 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (123.0 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), 4-Me-TBPB (187 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G12 (yellow solid 86.9 mg, yield 73%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.03(d,J=7.7Hz,2H),7.48(m,4H),7.36(q,J=8.3Hz,4H),7.28 (m,4H),5.55(td,J=55.9,3.4Hz,1H),3.99–3.71(m,1H),3.54–2.97(m,2H),2.44(s,3H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.2,144.6,144.3,144.0,129.8,129.4,128.7,128.7 ,127.7,127.6,125.9,115.9(t,J=244.6Hz),85.1,68.2(t,J=23.6Hz),37.2,21.8. 19 F NMR (376MHz, CDCl3, 25℃) δ–104.6––149.1(m,2F).

[0071] Embodiment 13:

[0072]

[0073] In a glove box, A (64.8 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (180.9 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), 4-Br-TBPB (245.7 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G13 (white solid 61.9 mg, yield 46%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.64–7.57(m,2H),7.52–7.46(m,2H),7.45–7.38(m,4H),7.35–7.28(m,2H),7.26–7.2 1(m,1H),7.14(dd,J=8.4,7.3Hz,2H),6.97(t,J=7.4Hz,1H),5.87(m,1H),5.61–5.45(m,1H),3.01–2.75(m,3H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.1,146.7,145.5,131.6,131.4,128.7,128.7,128.3,127 .8,127.6,127.1,125.8,125.8,114.0(t,J=245.2Hz),69.5(dd,J=25.1,22.3Hz),39.1. 19 F NMR (376MHz, CDCl3, 25℃) δ–127.4––132.0 (m, 2F).

[0074] Embodiment 14:

[0075]

[0076] In a glove box, A (64.8 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (180.9 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), tert-butyl naphthalene-2-peroxycarboxylate (245.7 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G14 (yellow solid 90.5 mg, yield 70%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.30(s,1H),7.94–7.84(m,2H),7.83–7.77(s,2H),7.64–7.52(m,2H),7.48–7.41(m,4H),7.39–7. 29(m,2H),7.26–7.21(m,1H),7.16–7.08(m,2H),6.91–6.80(m,1H),6.13–5.76(m,1H),5.68–5.50(m,1H),3.08–2.81(m,3H). 13 C NMR (151MHz, CDCl3, 25℃) δ166.0,146.8,145.6,135.8,132.3,131.7,129.6,128.7,128.6,128.3,128.1, 127.9,127.5,127.0,126.8,126.2,125.8,125.3,114.1(t,J=245.1Hz),76.4,69.5(t,J=25.1Hz),39.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–127.6––132.0 (m, 2F).

[0077] Embodiment 15:

[0078]

[0079] In a glove box, A (70.2 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G15 (white solid 59.9 mg, yield 50%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.18–8.08(m,2H),7.64–7.57(m,1H),7.52-7.45(m,6 H),7.41-7.32(m,4H),7.32-7.26(m,2H),4.08-3.92(m,1H),3.60-3.06(m,2H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.2,144.2,143.8,133.3,131.3,129.7,128.8,128.8,128 .7,127.9,127.8,125.9,125.8,125.0(q,J=273.2Hz),85.0,67.8(q,J=31.3Hz),37.2. 19 FNMR (376MHz, CDCl3, 25℃) δ–80.2 (d, J=6.7Hz, 2F).

[0080] Embodiment 16:

[0081]

[0082] In a glove box, A (70.2 mg, 0.3 mmol), B (194.4 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G16 (white solid 72.6 mg, yield 58%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.08 (dd, J=8.1, 1.4Hz, 2H), 7.66–7.56 (m, 1H), 7.52– 7.37(m,6H),7.06(dt,J=18.7,8.6Hz,4H),4.01–3.88(m,1H),,3.5–2.97(m,2H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.1, 163.0 (d, J = 5.4Hz), 161.3 (d, J = 5.4Hz), 139.9 (d, J = 3.3Hz), 139.6 (d, J = 3.3Hz), 133.5, 131.1, 129.7, 128. 8,127.9(d,J=8.1Hz),127.7(d,J=8.1Hz),124.9(q,J=281.8Hz),115.8(d,J=20.7Hz),115.7(d,J=20.4Hz),84.3,67.7(q,J=31.5Hz),37.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–80.3 (d, J=6.7Hz, 3F), –113.8––114.1 (m, 2F).

[0083] Embodiment 17:

[0084]

[0085] In a glove box, A (70.2 mg, 0.3 mmol), B (230 mg, 0.3 mmol, 3.0 equiv.), C (110 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), TBPB (175 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G17 (white solid 76.2 mg, yield 58%, dr: 2.4:1). 1 H NMR (400MHz, CDCl3, 25℃) δ8.15 (dd, J=8.3, 1.4Hz, 2H), 7.63–7.49 (m, 11H), 7.46–7.27(m,6H),4.33–3.91(m,1H),3.68–3.06(m,2H),1.99–1.83(m,1H). 13 C NMR (151MHz, CDCl3, 25℃, major) δ165.2,144.1,142.8,140.5,140.4,133.3,131.3,129.8,129.0,128.8, 128.7,127.9,127.7,127.5,127.2,126.3,125.9,125.0(q,J=281.1Hz),85.0,67.9(q,J=31.6Hz),37.2. 13 C NMR (151MHz, CDCl3, 25℃, minor) δ165.3,143.8,143.1,140.6,140.4,133.3,131.3,129.8,128.9,128.9, 128.7,127.8,127.6,127.4,127.2,126.4,125.8,125.0(q,J=281.1Hz),84.9,67.9(q,J=31.6Hz),37.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–80.1 (m, 3F).

[0086] Embodiment 18:

[0087]

[0088] In a glove box, A (70.2 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (180.9 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), tert-butyl naphthalene-2-peroxycarboxylate (245.7 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G18 (white solid 98.2 mg, yield 73%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.70(s,1H),8.15(dd,J=8.6,1.7Hz,1H),8.00(dd,J=8.0,1.4Hz,1H) ,7.95–7.86(m,2H),7.64–7.51(m,6H),7.45–7.27(m,6H),4.14–4.00(m,1H),3.65–3.14(m,2H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.3,144.1,143.8,135.6,132.5,131.2,129.5,128.8,128.7,128.5,128.4,128 .4,127.8,127.8,127.7,126.8,125.8,125.8,125.2,125.0(q,J=281.8Hz),85.1,67.8(q,J=31.3Hz),37.2. 19 F NMR (376MHz, CDCl3, 25℃) δ–80.1 (d, J = 7.3Hz, 3F).

[0089] Embodiment 19:

[0090]

[0091] In a glove box, A (70.2 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (136.8 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), 4-OMe-TBPB (201.6 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G19 (white solid 50 mg, yield 50%). 1 H NMR (400MHz, CDCl3, 25℃) δ7.77–7.68(m,2H),7.45–7.31(m,6H),7.26–7.21(m,1H),7.14–7.03( m,2H),6.94–6.87(m,1H),6.85–6.79(m,2H),5.89–5.76(m,1H),3.85(s,3H),3.07–2.72(m,3H). 13 C NMR (151MHz, CDCl3, 25℃) δ165.0,164.0,146.5,145.2,132.2,128.7,128.2,127.5,126.9 ,125.8,125.7,124.3(q,J=281.1Hz),120.9,113.5,76.2,67.3(q,J=31.9Hz),55.6,40.0. 19 F NMR (376MHz, CDCl3, 25℃) δ–77.2 (d, J = 7.3Hz, 3F).

[0092] Embodiment 20:

[0093]

[0094] In a glove box, A (70.2 mg, 0.3 mmol), B (162 mg, 0.3 mmol, 3.0 equiv.), C (123.0 mg, 0.9 mmol, 3.0 equiv.), Mn (OAc) 2 (2.6 mg, 0.015 mmol, 5 mol%), 4-Me-TBPB (187 mg, 0.9 mmol, 3.0 equiv.), 4MS (30 mg), and dry DCM (0.5 ml) were added to a dry 10 ml reaction tube equipped with a magnetic stirrer. The reaction tube was sealed and removed from the glove box. The reaction mixture was stirred at 100 ° C for 1 hour. Then TBAF was added at 0 ° C for 30 minutes. The reaction mixture was quenched with saturated sodium bicarbonate aqueous solution (10 mL), extracted with ethyl acetate (3×10 mL), and the organic phase was combined, washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The crude product was purified by silica gel column chromatography (200-300 mesh) and eluted with PE / EA (10 / 1-4 / 1, v / v) to give the target compound G20 (white solid 74.6 mg, yield 60%). 1 H NMR (400MHz, CDCl3, 25℃) δ8.07–7.99(m,2H),7.51–7.45(m,4H),7.41–7.32( m,4H),7.32–7.24(m,4H),4.07–3.93(m,1H),3.54–3.09(m,2H),2.44(s,3H). 13 CNMR (151MHz, CDCl3, 25℃) δ165.2,144.3,144.1,143.9,129.8,129.4,128.8,128.7,128.6 ,127.8,127.7,125.9,125.8,125.0(q,J=281.6Hz),84.8,67.8(q,J=31.4Hz),37.4,21.8. 19 F NMR (376MHz, CDCl3, 25℃) δ–80.1 (d, J = 7.3Hz, 3F).

[0095] Application Example 1

[0096] The α-fluoroalkyl substituted fatty alcohol compounds prepared in Example 1-20 were used to synthesize FFA4, a drug for treating diabetes.

[0097] Application Example 2

[0098] The α-fluoroalkyl substituted fatty alcohol compounds prepared in Example 1-20 were used to synthesize Apo7033, a drug for treating kidney disease.

[0099] The above is only a preferred embodiment of the present invention, which certainly cannot be used to limit the scope of rights of the present invention. It should be pointed out that for ordinary technicians in this technical field, several improvements and changes can be made without departing from the principle of the present invention, and these improvements and changes are also regarded as the protection scope of the present invention.

Claims

1. A novel α-fluoroalkyl substituted fatty alcohol compound, characterized in that: Its molecular structure is shown below: Among them, R 1 , R 2 is any one of aryl, heteroaryl, alkyl, and heteroatom, and may be the same or different; R 3 is any one of aryl, heteroaryl, alkyl, alkenyl, alkynyl, ester, cyano, nitro, sulfonyl, heteroatom, and hydrogen atom; R f CF3, CF2H, CFH2.

2. The novel α-fluoroalkyl substituted fatty alcohol compound according to claim 1, characterized in that: The alkyl group has 1 to 20 carbon atoms and is a straight chain structure, a cyclic structure or a branched structure; the alkyl group carries one or more substituents. When there are multiple substituents, the substituents may be the same or different, and the positions may be the same or different.

3. The novel α-fluoroalkyl substituted fatty alcohol compound according to claim 1, characterized in that: The aryl group has one or more substituents; when having multiple substituents, the substituents may be the same or different.

4. A method for preparing an α-fluoroalkyl substituted fatty alcohol compound according to any one of claims 1 to 3, characterized in that: The α-fluoroalkyl-α-silylmethanol A, olefin B, nucleophilic reagent C, catalyst, oxidant and organic solvent are mixed, stirred at a certain temperature for reaction, separated and purified, and then subjected to desiliconization treatment to obtain the α-fluoroalkyl substituted fatty alcohol compound; Wherein, the molecular structure formula of the α-fluoroalkyl-α-silylmethanol A is The molecular structural formula of the olefin B is: The molecular structural formula of the nucleophilic reagent C is:

5. The method for preparing an α-fluoroalkyl substituted fatty alcohol compound according to claim 4, characterized in that: The catalyst is at least one of Mn(OAc)2·4H2O, Mn(acac)2·4H2O, MnCl2·4H2O, MnF2, MnBr2, Mn(OAc)2, and Mn(acac)2.

6. The method for preparing an α-fluoroalkyl substituted fatty alcohol compound according to claim 4, characterized in that: The oxidant is tert-butyl peroxybenzoate substituted with at least one of a hydrogen atom, a heteroatom, a halogen atom, an alkyl group, a heteroaryl group, and an aryl group.

7. The method for preparing an α-fluoroalkyl substituted fatty alcohol compound according to claim 4, characterized in that: The organic solvent is methanol, ethanol, isopropanol, tert-butyl alcohol, tetrahydrofuran, 2-methyltetrahydrofuran, ether, dimethyl ethyl diether, methyl tert-butyl ether, 1,4-epoxyhexane, 1,3-epoxypentane, dichloromethane, 1,2-dichloroethane, chloroform, carbon tetrachloride, C 4-12 Saturated alkanes, C 3-12 Fluorinated or chlorinated alkanes, benzene, toluene, xylene, trimethylbenzene, dimethyl sulfoxide, N,N-dimethylformamide, N,N-dimethylacetamide, acetone, N-methylpyrrolidone, acetonitrile, C 3-12 At least one of the saturated alkyl nitriles.

8. The method for preparing an α-fluoroalkyl substituted fatty alcohol compound according to claim 4, characterized in that: The molar ratio of the α-fluoroalkyl-α-silylmethanol A, olefin B, nucleophilic reagent C and oxidant is 1:1-3:1-3:1-3; the amount of the catalyst is 1%-10% of the molar amount of the α-fluoroalkyl-α-silylmethanol A, and the concentration of the α-fluoroalkyl-α-silylmethanol A in the mixed solution is between 0.1M and 1M.

9. The method for preparing an α-fluoroalkyl substituted fatty alcohol compound according to claim 4, characterized in that: The reaction temperature is 0-100°C, and the temperature of the desiliconization treatment is -10-10°C.

10. Use of an α-fluoroalkyl substituted fatty alcohol compound according to any one of claims 1 to 3, characterized in that: The α-fluoroalkyl substituted fatty alcohol compound can be used to prepare a drug for treating diabetes or a drug for treating kidney disease.

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