Preparation method of selective beta-silyl aryl acetic acid compound

Abstract

The invention relates to the technical field of compound synthesis, and provides a selective beta-silyl aryl acetic acid compound preparation method, which comprises: adding aryl olefin ArR3C = CR1R2 and a silicon anion reagent into an organic solvent, and carrying out an addition reaction to obtain an active carbon negative intermediate reaction liquid, the silicon anion reagent is a combination of an organic disilicon reagent RR 'R ''Si-SiRR' R'' and a strong base, or a silicon-based metal organic reagent RR 'R ''Si-M; and introducing dry carbon dioxide into the reaction solution, carrying out nucleophilic addition reaction, and carrying out acidification post-treatment to obtain the beta-silyl aryl acetic acid compound. According to the method, silicon and carboxyl can be introduced into aryl olefin through one-pot reaction and two-step operation, operation is simple, conditions are mild, high efficiency is achieved, a transition heavy metal catalyst or an expensive silicon-boron reagent does not need to be used, and the method has high application value in the aspect of structural modification and transformation of aryl acetic acid drugs.

Description

Technical Field

[0001] The present application relates to the technical field of compound synthesis, and in particular to a method for preparing a selective β-silyl aryl acetic acid compound. Background Art

[0002] As a type of structural unit with great synthetic value, arylacetic acid structures are widely present in drug molecules. Figure 1 The nonsteroidal anti-inflammatory drugs shown in ibuprofen, naproxen, phenclorac, diclofenac, flurbiprofen, antibacterial drugs carbenicillin, histamine 1 H receptor antagonist fexofenadine, etc. Organosilicon compounds have important uses in pharmaceutical chemistry, material chemistry and synthetic chemistry due to their unique physical and chemical properties.

[0003] Introducing silicon groups into biologically active molecules such as drugs can significantly improve their physicochemical properties, increase their activity and selectivity. For example, silicon groups play an important role in regulating the physicochemical properties of the parent nucleus and improving the selectivity of topoisomerase I inhibitors.

[0004] In recent years, scientists have developed a series of methods for carboxylation of aromatic olefins. However, through simple chemical transformation, it is very rare to introduce organosilicon functional groups and carboxyl groups into aromatic olefins at the same time. A 2018 document (Angew.Chem., Int.Ed., 2018, 57, 17220-17224.) discloses a light-mediated free radical aromatic olefin silicon carboxylation method. This method requires the use of relatively active silanes and photocatalysts. This reaction mode is only applicable to some electron-deficient terminal olefins, and the application of the method is greatly limited. In addition, expensive photocatalysts and complex illumination conditions also limit its potential applications. The method disclosed in the 2023 ChemRxiv preprint (ChemRxiv.2023; doi:10.26434 / chemrxiv-2023-mfjth) utilizes the borosilicate reaction of aromatic olefins and silicon-based borate (PhMe2SiBpin), deborates under the action of potassium tert-butoxide, and then reacts with carbon dioxide to synthesize silicon-based carboxylic acid derivatives. However, this method requires the use of expensive silicon-based borate reagents, the synthesis process of raw materials is very complicated, and the introduced silicon group is limited to dimethylphenyl (PhMe2Si-), which is very limited in scope.

[0005] Therefore, it is of great significance to develop a selective silylation-carboxylation method for aromatic olefin compounds with mild conditions, simple operation, no need for transition metals and photocatalysts, and universal substrates. Summary of the invention

[0006] To solve the above problems, the present application provides a selective preparation method of β-silyl aryl acetic acid compounds. The method has the advantages of simple operation, mild reaction conditions, good substrate compatibility, and no need to use transition metals or photocatalysts.

[0007] This application adopts the following technical solutions:

[0008] The present application proposes a method for preparing a selective β-silyl aryl acetic acid compound, the method comprising:

[0009] Step (1), the aromatic olefin ArR 3 C=CR 1 R 2 and adding an organic solvent to a silicon anion reagent, and after a certain period of addition reaction, an activated carbon negative intermediate reaction liquid is obtained in situ, wherein the silicon anion reagent is a combination of an organic disilicon reagent RR′R″Si-SiRR′R″ and a strong base, or the silicon anion reagent is a silicon-based metal organic reagent RR′R″Si-M;

[0010] Step (2), introducing dry carbon dioxide into the reaction solution, carrying out a nucleophilic addition reaction for a certain period of time, and obtaining a β-silyl aryl acetic acid compound after acidification and post-treatment;

[0011] The synthetic route is as follows:

[0012]

[0013] wherein Ar is at least selected from benzene, substituted benzene, naphthalene, pyridine, quinoline, benzofuran or benzothiophenol, and R 1 , R 2 , R 3 are selected from at least hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl, R, R', R" are selected from at least alkyl or phenyl, and M is selected from at least lithium, sodium, potassium or magnesium.

[0014] Preferably, in step (1), the aromatic olefin ArR 3 C=CR 1 R 2 , the molar ratio of the organosilane reagent RR′R″Si-SiRR′R″ and the strong base is:

[0015] Aryl olefins 3 C=CR 1 R 2 : Organic disilicon reagent RR′R″Si-SiRR′R″: strong base = 1:(1~1.5):(1.5~3).

[0016] Preferably, in step (1), the aromatic olefin ArR 3 C=CR1 R 2 The molar ratio of the silicon-based metal organic reagent RR′R″Si-M is:

[0017] Aryl olefins 3 C=CR 1 R 2 : Silicon-based metal organic reagent RR′R″Si-M=1:(1~1.5).

[0018] Preferably, in step (1), the aromatic olefin ArR 3 C=CR 1 R 2 May include but are not limited to: Styrene 2-Methoxystyrene 3-Methoxystyrene 4-Methoxystyrene 4-Phenylstyrene 4-Methylthiostyrene 4-Chlorostyrene 1-Allyl-4-vinylbenzene α-Methylstyrene 4-Methoxy-α-methylstyrene 4-Methylthio-α-methylstyrene 4-Dimethylamino-α-methylstyrene 4-5-Morpholinyl-α-methylstyrene α-Methyl-2-naphthylethylene α-n-Butyl-styrene α-Isopropyl-styrene α-Cyclobutyl-styrene α-Cyclopentyl-styrene α-Cyclohexyl-styrene 1,1-Diphenylethylene 1,2-Diphenylethylene 2,2-Dimethylstyrene 1,2-Dihydronaphthalene (E)-N,N-Dimethyl-3-phenyl-2-propen-1-amine 4-Isopropenyltoluene 4,4'-(ethylene-1,1-diyl)-bis-(N,N-diethylaniline) 4,4'-(ethylene-1,1-diyl)-bis(methoxybenzene) 9,9-Dimethyl-10-methylene-9,10-dihydroanthracene 2,4-Diethyl-9-methylene-9H-thioxanthene 9-Methylene-9H-fluorene 4-Isobutyl-styrene 4-Isobutyl-α-methylstyrene or 2-methoxy-6-(propylene-2-methyl)-naphthalene One of;

[0027] Preferably, in step (1), the organic solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, cyclohexane, hexane, methyl tert-butyl ether, ethyl ether, benzyl ether, ethylene glycol dimethyl ether, toluene, and methyltetrahydrofuran.

[0028] Preferably, in step (1), the strong base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, tert-butyl lithium, n-butyl lithium, phenyl lithium, and methyl lithium.

[0029] Preferably, in step (1), during the addition reaction, the solution changes rapidly from colorless and transparent to dark red or reddish brown. Alternatively, during the addition reaction, the solution changes rapidly from colorless and transparent to dark green. The aryl olefin reacts with the silicon anion to introduce a silicon group at the β position of the aryl olefin to obtain an activated carbon anion intermediate reaction solution.

[0030] Preferably, in step (2), the reaction temperature of the nucleophilic addition reaction is -40°C to room temperature, and the reaction time is 30s to 3min. During the nucleophilic addition reaction, the solution rapidly changes from dark red or reddish brown to light yellow, and finally completely fades. Alternatively, during the nucleophilic addition reaction, the solution rapidly changes from dark green to light green, and finally completely fades. The nucleophilic addition reaction is a carboxylation reaction.

[0031] Preferably, in step (2), dry carbon dioxide is introduced at a temperature ranging from -20°C to room temperature, and the pressure is greater than or equal to one standard atmospheric pressure. The carbon dioxide can be dried using a pre-drying device.

[0032] Preferably, in step (2), a nucleophilic addition reaction is carried out, and a β-silyl aryl acetic acid compound is obtained by acidification and post-treatment, comprising:

[0033] The salt solution after the nucleophilic addition reaction is added with 1-2 mol / L hydrochloric acid to adjust the pH value to acidic;

[0034] After extraction with ethyl acetate or dichloromethane, the organic phases are combined;

[0035] Dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product;

[0036] The crude product is purified by chromatography or recrystallization to obtain the selective silylation-carboxylation product of aromatic olefins.

[0037] Compared with the prior art, the method proposed in this application can introduce silicon and carboxyl groups into aromatic olefins through "one-pot reaction and two-step operation", and has the advantages of simple operation, mild conditions, high efficiency, and no need to use transition heavy metal catalysts or expensive silicon boron reagents, etc., and has broad research value and broad industrial application prospects. Through the method proposed in this application, a series of high-value β-silylated aromatic acetic acid derivatives can be synthesized, which has high application value in the structural modification and transformation of aromatic acetic acid drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0038] The drawings described herein are used to provide a further understanding of the present application and constitute a part of the present application. The illustrative embodiments of the present application and their descriptions are used to explain the present application and do not constitute an improper limitation on the present application. In the drawings:

[0039] Figure 1 A schematic diagram showing the structure of existing drug molecules;

[0040] Figure 2 A synthetic route diagram showing the preparation method of the selective β-silyl aryl acetic acid compounds of the present application;

[0041] Figure 3 The NMR of Example 1 is shown 1 H spectrum;

[0042] Figure 4 The NMR of Example 1 is shown 13 C spectrum;

[0043] Figure 5 The NMR of Example 17 is shown 1 H spectrum;

[0044] Figure 6 The NMR of Example 17 is shown 13 C spectrum;

[0045] Figure 7 The NMR of Example 19 is shown 1 H spectrum;

[0046] Figure 8 The NMR of Example 19 is shown 13 C spectrum. DETAILED DESCRIPTION

[0047] The exemplary embodiments of the present application will be described in more detail below. However, it should be understood that the present application can be implemented in various forms and should not be limited by the embodiments set forth herein. On the contrary, these embodiments are provided to enable a more thorough understanding of the present application and to enable the scope of the present application to be fully communicated to those skilled in the art.

[0048] The disclosure of the present invention provides many different embodiments or examples to realize different structures of the present invention. In order to simplify the disclosure of the present invention, the components and settings of specific examples are described in the present invention. Of course, they are only examples, and the purpose is not to limit the present invention. In addition, the present invention can repeat reference numbers and / or reference letters in different examples, and this repetition is for the purpose of simplicity and clarity, which itself does not indicate the relationship between the various embodiments and / or settings discussed. In addition, the present invention provides various specific examples of processes and materials, but those of ordinary skill in the art can be aware of the application of other processes and / or the use of other materials.

[0049] Generally, the terms may be understood at least in part based on the usage of the above invention. For example, the term "one or more" used in the present invention depends at least in part on the above invention, and may be used to describe any component, structure or feature in a singular form, or may be used to describe a combination of components, structures or features in a plural form. Similarly, terms such as "one", "an" or "the" may also be understood at least in part based on the above invention as conveying singular usage or conveying plural usage. In addition, the term "based on..." may be understood as not necessarily intended to convey a set of exclusive factors, but may alternatively, at least in part depending on the context, allow for the presence of additional factors that do not necessarily have to be explicitly described.

[0050] The concept of the present application is that, for the synthesis of silicon-containing arylacetic acid drugs, starting from aryl olefins, silicon and carboxyl groups are simultaneously introduced into both ends of the carbon-carbon double bond (C=C) of aryl olefins through a highly selective chemical transformation method, so as to achieve the purpose of efficiently obtaining important β-silyl-functionalized arylacetic acid compounds. This method is expected to provide a simple and efficient synthetic route for the structural modification of arylacetic acid drug molecules or the development of new drugs.

[0051] Figure 1 The schematic diagram of the structure of existing drug molecules is shown. Figure 2 The synthetic route diagram of the selective preparation method of β-silyl aryl acetic acid compounds of the present application is shown. On this basis, the technical solution of the present application is further explained in combination with the examples.

[0052] Example 1

[0053] The selective preparation method of β-silyl aryl acetic acid compounds in Example 1 synthesizes 3-(dimethyl(phenyl)silyl)-2-phenylpropionic acid, and its structural formula is as follows:

[0054]

[0055] Preparation method 1:

[0056] In a glove box filled with argon, 20.8 mg (0.20 mmol) of styrene, 54.1 mg (0.20 mmol) of diphenyltetramethyldisilane, 33.6 mg (0.30 mmol) of potassium tert-butoxide and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 35.3 mg of a colorless oil with a yield of 62%.

[0057] Preparation method 2:

[0058] In a glove box filled with argon, 20.8 mg (0.20 mmol) of styrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The mixture was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the mixture was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The mixture was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 40.5 mg of a colorless oil with a yield of 71%.

[0059] The product characterization data are as follows:

[0060] 1 H NMR (400MHz, CDCl3): δ7.46-7.40(m, 2H), 7.34-7.28(m, 3H), 7.29-7.24(m, 5H), 3.61(t, J =7.8Hz, 1H), 1.64 (dd, J=14.8, 7.4Hz, 1H), 1.38 (dd, J=14.8, 8.3Hz, 1H), 0.14 (s, 6H)ppm.

[0061] 13 C{ 1H} NMR (100MHz, CDCl3): δ180.8, 140.1, 138.1, 133.6, 129.1, 128.6, 128.1, 127.8, 127.5, 47.2, 20.3, -2.7, -3.1ppm.

[0062] HRMS(ESI): calculated for C 17 H 19 O2Si - [MH] - 283.1160; found 283.1156.

[0063] NMR of Example 1 1 H spectrum Figure 3 As shown, the NMR of Example 1 13 C spectrum Figure 4 shown.

[0064] Example 2

[0065] The selective preparation method of β-silyl aryl acetic acid compounds in Example 2 is used to synthesize 3-(dimethyl(phenyl)silyl)-2-(2-methoxy-phenyl)propionic acid, and its structural formula is as follows:

[0066]

[0067] Preparation method:

[0068] In a glove box filled with argon, 26.8 mg (0.20 mmol) of 2-methoxystyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The mixture was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the mixture was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The mixture was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 37.7 mg of a colorless oil with a yield of 60%.

[0069] The product characterization data are as follows:

[0070] 1H NMR (400MHz, CDCl3): δ7.50-7.40 (m, 2H), 7.34-7.28 (m, 3H), 7.24-7.17 (m, 2H), 6.89 (td, J=7.5, 1.1Hz, 1H), 6.81 (d, J=7.6Hz, 1H), 4.12 (dd, J=8.9, 6.6Hz, 1H), 3.76 (s, 3H), 1.62 (dd, J=14.8, 6.6Hz, 1H), 1.40 (dd, J=14.9, 9.0Hz, 1H), 0.15 (s, 3H), 0.13 (s, 3H)ppm.

[0071] 13 C{ 1 H} NMR (100MHz, CDCl3): δ180.9, 156.6, 138.7, 133.6, 128.9, 128.7, 128.4, 127.7, 120.7, 110.8, 55.4, 39.9, 19.0, -2.8, -3.0ppm.

[0072] HRMS(ESI): calculated for C 18 H 21 O3Si - [MH] - 313.1265; found 313.1268.

[0073] Example 3

[0074] The selective preparation method of β-silyl aryl acetic acid compounds in Example 3 is used to synthesize 3-(dimethyl(phenyl)silyl)-2-(3-methoxy-phenyl)propionic acid, and its structural formula is as follows:

[0075]

[0076] Preparation method:

[0077] In a glove box filled with argon, 26.8 mg (0.20 mmol) of 3-methoxystyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The mixture was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the mixture was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The mixture was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 39.6 mg of a colorless oil with a yield of 63%.

[0078] The product characterization data are as follows:

[0079] 1 H NMR (400MHz, CDCl3): δ7.46-7.40 (m, 2H), 7.35-7.29 (m, 3H), 7.19 (td, J=7.6, 1.0Hz, 1H), 6.85 (d, J=7.7Hz, 1H), 6.81-6.74 (m, 2 H), 3.76 (s, 3H), 3.57 (t, J=7.8Hz, 1H), 1.62 (dd, J=14.8, 7.4Hz, 1H), 1.36 (dd, J=14.8, 8.3Hz, 1H), 0.16 (s, 3H), 0.14 (s, 3H)ppm.

[0080] 13 C{ 1 H} NMR (100MHz, CDCl3): δ180.0, 159.7, 141.6, 138.1, 133.6, 129.6, 129.1, 127.8, 120.5, 113.7, 113.0, 55.2, 47.1, 20.3, -2.7, -3.0ppm.

[0081] HRMS(ESI): calculated for C 18 H 21 O3Si - [MH] - 313.1265; found 313.1268.

[0082] Example 4

[0083] The selective preparation method of β-silyl aryl acetic acid compounds in Example 4 synthesizes 2-((1,1'-biphenyl)-4-yl)-3-(dimethyl(phenyl)silyl)propionic acid, and its structural formula is as follows:

[0084]

[0085] Preparation method:

[0086] In a glove box filled with argon, 36.0 mg (0.20 mmol) of 4-phenylstyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 46.8 mg of a colorless oil with a yield of 65%.

[0087] The product characterization data are as follows:

[0088] 1 H NMR (400MHz, CDCl3): δ7.45-7.36(m, 3H), 7.35-7.29(m, 2H), 7.28-7.22(m, 5H), 7.20-7.09(m, 9H), 3.48( t, J=7.8Hz, 1H), 1.50 (dd, J=14.8, 7.4Hz, 1H), 1.24 (dd, J=14.8, 8.4Hz, 1H), 0.04 (s, 3H), 0.01 (s, 3H)ppm.

[0089] 13 C{ 1 H} NMR (100MHz, CDCl3): δ180.0, 140.7, 140.4, 139.1, 138.0, 133.6, 129.1, 128.8, 128.4, 127.8, 127.6, 127.3, 127.1, 46.7, 20.3, -2.8, -3.0ppm.

[0090] HRMS(ESI): calculated for C 23 H 23 O2Si - [MH] -359.1473; found 359.1469.

[0091] Example 5

[0092] The selective preparation method of β-silyl aryl acetic acid compounds in Example 5 synthesizes 3-(dimethyl(phenyl)silyl)-2-methyl-2-phenylpropionic acid, and its structural formula is as follows:

[0093]

[0094] Preparation method:

[0095] In a glove box filled with argon, 23.6 mg (0.20 mmol) of α-methylstyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 40.7 mg of a colorless oil with a yield of 68%.

[0096] The product characterization data are as follows:

[0097] 1 H NMR (400MHz, CDCl3): δ7.32-7.26 (m, 2H), 7.21 (d, J=7.2Hz, 2H), 7.15-7.09 (m, 5H), 7.07-7.02 (m, 1H), 1.59 (d, J=14.7Hz, 1H),

[0098] 1.47 (d, J=14.6Hz, 1H), 1.37 (s, 3H), 0.00 (s, 3H), -0.05 (s, 3H)ppm.

[0099] 13 C{ 1 H} NMR (100MHz, CDCl3): δ183.5, 144.6, 139.5, 133.6, 128.9, 128.4, 127.8, 126.9, 126.0, 48.6, 28.0, 25.4, -1.5, -1.6ppm.

[0100] HRMS(ESI): calculated for C18 H 21 O2Si - [MH] - 297.1316; found 297.1315.

[0101] Example 6

[0102] The selective preparation method of β-silyl aryl acetic acid compounds in Example 6 is used to synthesize 3-(dimethyl(phenyl)silyl)-2-methyl-2-(4-(methylthio)phenyl)propionic acid, and its structural formula is as follows:

[0103]

[0104] Preparation method:

[0105] In a glove box filled with argon, 32.8 mg (0.20 mmol) of 4-methylthio-α-methylstyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 33.1 mg of a colorless oil with a yield of 48%.

[0106] The product characterization data are as follows:

[0107] 1 H NMR (400MHz, CDCl3): δ7.49-7.36 (m, 2H), 7.35-7.27 (m, 5H), 7.18 (d, J=8.6Hz, 2H), 2.47 (s, 3 H), 1.74 (d, J=14.7Hz, 1H), 1.63 (d, J=14.7Hz, 1H), 1.54 (s, 3H), 0.20 (s, 3H), 0.18 (s, 3H)ppm.

[0108] 13 C{ 1 H} NMR (100MHz, CDCl3): δ182.9, 141.4, 139.4, 137.0, 133.5, 128.9, 127.8, 126.6, 126.5, 48.1, 27.9, 25.2, 15.9, -1.5ppm.

[0109] HRMS(ESI): calculated for C 19 H 23 O2SSi - [MH] - 343.1194; found 343.1191.

[0110] Example 7

[0111] The selective preparation method of β-silyl aryl acetic acid compounds in Example 7 is used to synthesize 3-(dimethyl(phenyl)silyl)-2-methyl-2-(4-morpholinylphenyl)propionic acid, and its structural formula is as follows:

[0112]

[0113] Preparation method:

[0114] In a glove box filled with argon, 40.6 (0.20 mmol) of 4-morpholinyl-α-methylstyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 53.7 mg of a colorless oil with a yield of 70%.

[0115] The product characterization data are as follows:

[0116] 1 H NMR (400MHz, CDCl3): δ7.51-7.39 (m, 2H), 7.36-7.26 (m, 5H), 6.83 (d, J=8.7Hz, 2H), 3.90-3.82 (m, 4H), 3.1 8-3.08 (m, 4H), 1.74 (d, J=14.7Hz, 1H), 1.62 (d, J=14.7Hz, 1H), 1.53 (s, 3H), 0.19 (s, 3H), 0.18 (s, 3H)ppm.

[0117] 13 C{ 1H} NMR (100MHz, CDCl3): δ182.7, 149.9, 139.7, 136.1, 133.5, 128.8, 127.7, 126.8, 115.4, 66.9, 49.3, 47.6, 27.8, 25.2, -1.51, -1.52ppm.

[0118] HRMS(ESI): calculated for C 22 H 28 NO3Si - [MH] - 382.1844; found 382.1840.

[0119] Example 8

[0120] The selective preparation method of β-silyl aryl acetic acid compounds in Example 8 synthesizes 3-(dimethyl(phenyl)silyl)-2,2-diphenylpropionic acid, and its structural formula is as follows:

[0121]

[0122] Preparation method:

[0123] In a glove box filled with argon, 36.0 mg (0.20 mmol) of 1,1-diphenylethylene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 60.7 mg of a colorless oil with a yield of 84%.

[0124] The product characterization data are as follows:

[0125] 1 H NMR (400MHz, CDCl3): δ7.49-7.44(m, 2H), 7.44-7.36(m, 4H), 7.35-7.31(m, 5H), 7.31-7.26(m, 4H), 2.14(s, 2H), 0.00(s, 6H)ppm.

[0126] 13 C{ 1H} NMR (100MHz, CDCl3): δ181.0, 144.6, 139.9, 133.7, 128.8, 128.7, 127.9, 127.6, 126.9, 58.3, 28.4, -2.1ppm.

[0127] HRMS(ESI): calculated for C 23 H 23 O2Si - [MH] - 359.1473; found 359.1470.

[0128] Example 9

[0129] The selective preparation method of β-silyl aryl acetic acid compounds in Example 9 synthesizes 3-(methyl(diphenyl)silyl)-2,2-diphenylpropionic acid, and its structural formula is as follows:

[0130]

[0131] Preparation method:

[0132] In a glove box filled with argon, 36.0 mg (0.20 mmol) of 1,1-diphenylethylene, 0.3 mL (1 mol / L tetrahydrofuran solution) of methyldiphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 69.5 mg of a colorless oil with a yield of 82%.

[0133] The product characterization data are as follows:

[0134] 1 H NMR (400MHz, CDCl3): δ7.42-7.36(m, 4H), 7.34-7.28(m, 4H), 7.26-7.12(m, 12H), 2.47(s, 2H), 0.12(s, 3H)ppm.

[0135] 13 C{ 1H} NMR (100MHz, CDCl3): δ180.5, 144.3, 137.4, 134.7, 128.9, 128.8, 127.9, 127.5, 126.9, 58.1, 26.8, -3.8ppm.

[0136] HRMS(ESI): calculated for C 28 H 25 O2Si - [MH] - 421.1629; found 421.1625.

[0137] Example 10

[0138] The selective preparation method of β-silyl aryl acetic acid compounds in Example 10 synthesizes 3-(triphenylsilyl)-2,2-diphenylpropionic acid, and its structural formula is as follows:

[0139]

[0140] Preparation method:

[0141] In a glove box filled with argon, 36.0 mg (0.20 mmol) of 1,1-diphenylethylene, 0.3 mL (1 mol / L tetrahydrofuran solution) of triphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The mixture was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the mixture was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The mixture was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 68.0 mg of a colorless oil with a yield of 70%.

[0142] The product characterization data are as follows:

[0143] 1 H NMR (400MHz, CDCl3): δ7.35-7.27(m, 12H), 7.25-7.21(m, 7H), 7.21-7.14(m, 6H), 2.82(s, 2H)ppm.

[0144] 13 C{ 1H} NMR (100MHz, CDCl3): δ179.4, 144.3, 136.1, 135.0, 129.1, 128.9, 127.9, 127.4, 126.9, 58.2, 25.9ppm.

[0145] HRMS(ESI): calculated for C 33 H 27 O2Si - [MH] - 483.1786; found 483.1781.

[0146] Embodiment 11

[0147] The selective preparation method of β-silyl aryl acetic acid compounds in Example 11 is used to synthesize 9-((dimethyl(phenyl)silyl)methyl)-10,10-dimethyl-9,10-dihydroanthracene-9-carboxylic acid, and its structural formula is as follows:

[0148]

[0149] Preparation method:

[0150] In a glove box filled with argon, 44.0 mg (0.20 mmol) of 9,9-dimethyl-10-methylene-9,10-dihydroanthracene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 68.1 mg of a colorless oil with a yield of 85%.

[0151] The product characterization data are as follows:

[0152] 1 H NMR (400MHz, CDCl3): δ7.54 (dd, J=8.3, 1.4Hz, 2H), 7.34-7.29 (m, 4H), 7.25-7.21 ( m, 1H), 7.20-7.11 (m, 6H), 2.14 (s, 2H), 1.81 (s, 3H), 1.61 (s, 3H), -0.52 (s, 6H)ppm.

[0153] 13 C{ 1 H}NMR (100MHz, CDCl3): δ181.4, 142.3, 139.7, 134.3, 133.2, 128.5, 127.9 , 127.5, 127.4, 127.3, 126.4, 51.0, 37.4, 37.0, 31.8, 30.3, 24.9, -2.9ppm.

[0154] HRMS(ESI): calculated for C 26 H 27 O2Si - [MH] - 399.1786; found 399.1782.

[0155] Example 12

[0156] The selective preparation method of β-silyl aryl acetic acid compounds in Example 12 is used to synthesize 9-((dimethyl(phenyl)silyl)methyl)-2,4-diethyl-9H-thioxanthen-9-carboxylic acid, and its structural formula is as follows:

[0157]

[0158] Preparation method:

[0159] In a glove box filled with argon, 53.2 mg (0.20 mmol) of 2,4-diethyl-9-methylene-9H-thioxanthine, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 54.6 mg of a colorless oil with a yield of 61%.

[0160] The product characterization data are as follows:

[0161] 1H NMR (400MHz, CDCl3): δ7.46-7.35 (m, 5H), 7.35-7.30 (m, 2H), 7.29-7.26 (m, 2H), 7.07 (s, 1H), 7.02 (s, 1H), 2.83 (q, J=7. 5Hz, 2H), 2.69 (q, J=7.6Hz, 2H), 2.04 (s, 2H), 1.39 (t, J=7.5Hz, 3H), 1.33 (t, J=7.6Hz, 3H), 0.02 (s, 3H), 0.01 (s, 3H)ppm.

[0162] 13 C{ 1 H}NMR (100MHz, CDCl3): δ180.4, 141.8, 139.9, 139.3, 135.7, 134.9, 133.4, 130.6, 128.5, 127.8 , 127.4, 127.3, 126.9, 126.5, 126.2, 126.0, 56.0, 28.7, 28.6, 26.9, 15.7, 14.0, -2.4, -2.5ppm.

[0163] HRMS(ESI): calculated for C 27 H 29 O2SSi - [MH] - 445.1663; found 445.1660.

[0164] Embodiment 13

[0165] The selective preparation method of β-silyl aryl acetic acid compounds in Example 13 synthesizes 9-((dimethyl(phenyl)silyl)methyl)-9H-fluorene-9-carboxylic acid, and its structural formula is as follows:

[0166]

[0167] Preparation method:

[0168] In a glove box filled with argon, 35.6 mg (0.20 mmol) of 9-methylene-9H-fluorene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 50.2 mg of a colorless oil with a yield of 70%.

[0169] The product characterization data are as follows:

[0170] 1 H NMR (400MHz, CDCl3): δ7.67 (d, J=7.5Hz, 2H), 7.46 (d, J=7.7Hz, 2H), 7.35 (td, J=7.5, 1.1Hz, 2H), 7.21 (dd, J=7.5, 1.1Hz, 2H), 7.19-7.17(m, 1H), 7.16-7.14(m, 1H), 7.12-7.06(m, 2H), 2.11(s, 2H), -0.05(s, 6H)ppm.

[0171] 13 C{ 1 H} NMR (100MHz, CDCl3): δ179.9, 145.6, 140.8, 139.1, 133.1, 128.6, 128.4, 127.6, 127.5, 125.4, 120.0, 58.6, 25.0, -2.9ppm.

[0172] HRMS(ESI): calculated for C 23 H 21 O2Si - [MH] - 357.1316; found 357.1310.

[0173] Embodiment 14

[0174] The selective preparation method of β-silyl aryl acetic acid compounds in Example 14 is used to synthesize 2,2-bis(4-(diethylamino)phenyl)-3-(dimethyl(phenyl)silyl)propionic acid, and its structural formula is as follows:

[0175]

[0176] Preparation method:

[0177] In a glove box filled with argon, 4,4'-(ethylene-1,1-diyl)-bis-(N,N-diethylaniline) 64.5 mg (0.20 mmol), dimethylphenylsilyl lithium 0.3 mL (1 mol / L tetrahydrofuran solution), and ultra-dry tetrahydrofuran 1 mL were added to the Schlenk tube, and stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. After sealing, the glove box was removed and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the above reaction solution, and the reaction was stirred at -20°C for 2-3 minutes; after the reaction was completed (fading), the lid was opened and 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2, and ethyl acetate was used for extraction (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain 92.5 mg of a colorless oil with a yield of 92%.

[0178] The product characterization data are as follows:

[0179] 1 H NMR (400MHz, CDCl3): δ7.45-7.38(m, 2H), 7.32-7.24(m, 3H), 7.21-7.13(m, 4H), 6.62-6 .52 (m, 4H), 3.33 (q, J=7.1Hz, 8H), 2.01 (s, 2H), 1.15 (t, J=7.1Hz, 12H), 0.00 (s, 6H)ppm.

[0180] 13 C{ 1 H} NMR (100MHz, CDCl3): δ181.6, 146.4, 140.8, 133.7, 131.9, 129.6, 128.3, 127.4, 111.3, 56.5, 44.4, 28.6, 12.6, -1.8ppm.

[0181] HRMS(ESI): calculated for C 31 H 41 N2O2Si - [MH] - 501.2943; found 501.2939.

[0182] Embodiment 15

[0183] The selective preparation method of β-silyl aryl acetic acid compounds in Example 15 synthesizes 3-(dimethyl(phenyl)silyl)-2,3-diphenylpropionic acid, and its structural formula is as follows:

[0184]

[0185] Preparation method:

[0186] In a glove box filled with argon, 36.0 mg (0.20 mmol) of 1,2-diphenylethylene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 44.0 mg of a colorless oil with a yield of 61%.

[0187] The product characterization data are as follows:

[0188] 1 H NMR (400MHz, CDCl3): δ7.38-7.33(m, 2H), 7.22-7.18(m, 2H), 7.14-7.09(m, 2H), 7.09-7.02(m, 3H), 7.02-6.8 3 (m, 4H), 6.72 (d, J=7.0Hz, 2H), 4.06 (d, J=12.7Hz, 1H), 3.26 (d, J=12.7Hz, 1H), 0.26 (s, 3H), 0.20 (s, 3H)ppm.

[0189] 13 C{ 1 H} NMR (100MHz, CDCl3): δ179.1, 139.8, 137.9, 136.3, 134.4, 129.3, 129.1, 129.0, 128.1, 127.7, 127.4, 127.1, 124.6, 52.1, 38.6, -2.9, -4.6ppm.

[0190] HRMS(ESI): calculated for C 23 H 23 O2Si - [MH] - 359.1473; found 359.1469.

[0191] Example 16

[0192] The selective preparation method of β-silyl aryl acetic acid compounds in Example 16 synthesizes 4-(2-(dimethyl(phenyl)silyl)-1,2-diphenylethyl)pyridine, and its structural formula is as follows:

[0193]

[0194] Preparation method:

[0195] In a glove box filled with argon, 26.4 mg (0.20 mmol) of 2,2-dimethylstyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The mixture was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the mixture was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The mixture was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 26.4 mg of a colorless oil with a yield of 42%.

[0196] The product characterization data are as follows:

[0197] 1 H NMR (400MHz, CDCl3): δ7.55-7.46(m, 2H), 7.40-7.34(m, 2H), 7.32-7.27(m , 6H), 3.59(s, 1H), 1.17(s, 3H), 0.94(s, 3H), 0.27(s, 3H), 0.20(s, 3H)ppm.

[0198] 13 C{ 1 H} NMR (100MHz, CDCl3): δ179.2, 137.1, 135.3, 134.8, 130.6, 129.1, 127.9, 127.5, 127.5, 56.9, 24.6, 21.8, 21.0, -4.6, -5.0ppm.

[0199] HRMS(ESI): calculated for C 19 H 23 O2Si - [MH] - 311.1473; found 311.1468.

[0200] Embodiment 17

[0201] The selective preparation method of β-silyl aryl acetic acid compounds in Example 17 is used to synthesize 3-(dimethylphenyl)silyl)-2-(4-isobutylphenyl)propionic acid, an analog of the drug molecule ibuprofen, whose structural formula is as follows:

[0202]

[0203] Preparation method:

[0204] In a glove box filled with argon, 32.5 mg (0.20 mmol) of 4-isobutyl-styrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 49.0 mg of a colorless oil with a yield of 72%.

[0205] The product characterization data are as follows:

[0206] 1 H NMR (400MHz, CDCl3): δ7.47-7.35 (m, 2H), 7.33-7.27 (m, 3H), 7.19-7.12 (m, 2H), 7.08-7.01 (m, 2H), 3.60-3.52 (m, 1H), 2.43 (d, J=7.2H z, 2H), 1.89-1.76 (m, 1H), 1.61 (dd, J=14.8, 7.2Hz, 1H), 1.37 (dd, J=14.8, 8.6Hz, 1H), 0.88 (d, J=6.6Hz, 6H), 0.11 (d, J=2.0Hz, 6H) ppm.

[0207] 13 C{ 1 H} NMR (100MHz, CDCl3): δ180.2, 141.0, 138.3, 137.3, 133.6, 129.3, 129.1, 127.8, 127.8, 46.7, 45.1, 30.2, 22.4, 22.4, 20.4, -2.7, -3.1ppm.

[0208] HRMS(ESI): calculated for C21 H 27 O2Si - [MH] - 339.1786; found 339.1780.

[0209] NMR of Example 17 1 H spectrum Figure 5 As shown, the NMR of Example 1 13 C spectrum Figure 6 shown.

[0210] Embodiment 18

[0211] The selective preparation method of β-silyl aryl acetic acid compounds in Example 18 is used to synthesize the analog of the drug molecule ibuprofen, 3-(dimethylphenyl)silyl)-2-(4-isobutylphenyl)-2-methylpropionic acid, whose structural formula is as follows:

[0212]

[0213] Preparation method:

[0214] In a glove box filled with argon, 34.9 mg (0.20 mmol) of 4-isobutyl-α-methylstyrene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to the Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The reaction solution was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the reaction was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The reaction vessel was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 65.5 mg of a colorless oil with a yield of 92%.

[0215] The product characterization data are as follows:

[0216] 1 H NMR (400MHz, CDCl3): δ7.55-7.45 (m, 2H), 7.40-7.26 (m, 5H), 7.16-7.02 (m, 2H), 2.48 (d, J=6.6Hz, 2H), 1.96 -1.84 (m, 1H), 1.82-1.72 (m, 1H), 1.72-1.62 (m, 1H), 1.56 (s, 3H), 0.99-0.87 (m, 6H), 0.25-0.02 (m, 6H)ppm.

[0217] 13 C{ 1 H} NMR (100MHz, CDCl3): δ 183.5, 141.9, 140.3, 139.7, 133.6, 129.1, 128.9, 127.7, 125.8, 48.2, 45.0, 30.2, 28.1, 25.3, 22.4, -1.5, -1.6ppm.

[0218] HRMS(ESI): calculated for C 22 H 29 O2Si - [MH] - 353.1942; found 353.1935.

[0219] Embodiment 19

[0220] The selective preparation method of β-silyl aryl acetic acid compounds in Example 19 is used to synthesize the analog of the drug molecule naproxen, 3-(dimethylphenyl)silyl)-2-(6-methoxynaphthalen-2-yl) 2-methylpropionic acid, whose structural formula is as follows:

[0221]

[0222] Preparation method:

[0223] In a glove box filled with argon, 40.0 mg (0.20 mmol) of 2-methoxy-6-(propylene-2-yl)-naphthalene, 0.3 mL (1 mol / L tetrahydrofuran solution) of dimethylphenylsilyl lithium and 1 mL of ultra-dry tetrahydrofuran were added to a Schlenk tube, and the mixture was stirred at room temperature (25°C) for 30 minutes to obtain an activated carbon negative intermediate reaction solution. The mixture was sealed and removed from the glove box and transferred to a -20°C low-temperature bath. Dry carbon dioxide was introduced into the reaction solution, and the mixture was stirred at -20°C for 2-3 minutes. After the reaction was completed (fading), the lid was opened and a 1 mol / L dilute hydrochloric acid solution was added to the reaction vessel to adjust the pH to 2. The mixture was extracted with ethyl acetate (5 mL*3 times), the organic phases were combined, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain a crude product. The crude product was purified by column chromatography to obtain 65.5 mg of a colorless oil with a yield of 92%.

[0224] The product characterization data are as follows:

[0225] 1H NMR (400MHz, CDCl3): δ7.78-7.73 (m, 1H), 7.72-7.64 (m, 2H), 7.54-7.49 (m, 1H), 7.48-7.40 (m, 2H), 7.34-7.27 (m, 3H), 7.17 (dd, J=8.9, 2 .5Hz, 1H), 7.12 (d, J=2.5Hz, 1H), 3.94 (s, 3H), 1.88 (d, J=14.7Hz, 1H), 1.77 (d, J=14.7Hz, 1H), 1.66 (s, 3H), 0.21 (s, 3H), 0.18 (s, 3H)ppm.

[0226] 13 C{ 1 H}NMR (100MHz, CDCl3): δ182.8, 157.8, 139.7, 139.5, 133.6, 133.4, 129.7, 128.9, 128 .7, 127.7, 126.9, 125.3, 124.3, 118.9, 105.5, 55.3, 48.5, 27.9, 25.4, -1.5, -1.6ppm.

[0227] HRMS(ESI): calculated for C 23 H 25 O3Si - [MH] - 377.1578; found 377.1572.

[0228] Nuclear Magnetic Resonance of Example 19 1 H spectrum Figure 7 As shown, the NMR of Example 1 13 C spectrum Figure 8 shown.

[0229] The above is only a specific implementation of the present application. Under the above teachings of the present application, those skilled in the art can make other improvements or modifications based on the above embodiments. Those skilled in the art should understand that the above specific description is only to better explain the purpose of the present application, and the protection scope of the present application shall be based on the protection scope of the claims.

[0230] In addition, those skilled in the art will appreciate that, although some embodiments described herein include certain features included in other embodiments but not other features, the combination of features of different embodiments is meant to be within the scope of the present application and form different embodiments. For example, in the claims below, any one of the claimed embodiments may be used in any combination.

Claims

1. A method for preparing a selective β-silyl aryl acetic acid compound, characterized in that: The method comprises: Step (1), the aromatic olefin ArR 3 C=CR 1 R 2 and a silicon anion reagent are added to an organic solvent to carry out an addition reaction to obtain an activated carbon negative intermediate reaction liquid, wherein the silicon anion reagent is a combination of an organic disilicon reagent RR′R″Si-SiRR′R″ and a strong base, or the silicon anion reagent is a silicon-based metal organic reagent RR′R″Si-M; Step (2), introducing dry carbon dioxide into the reaction solution to carry out a nucleophilic addition reaction, and then acidifying and post-treating to obtain a β-silyl aryl acetic acid compound; The synthetic route is as follows: wherein Ar is at least selected from benzene, substituted benzene, naphthalene, pyridine, quinoline, benzofuran or benzothiophenol, and R 1 , R 2 , R 3 are selected from at least hydrogen, methyl, ethyl, propyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or aryl, R, R', R" are selected from at least alkyl or phenyl, and M is selected from at least lithium, sodium, potassium or magnesium.

2. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (1), the aromatic olefin ArR 3 C=CR 1 R 2 , the molar ratio of the organosilane reagent RR′R″Si-SiRR′R″ and the strong base is: Aryl olefins 3 C=CR 1 R 2 : Organic disilicon reagent RR′R″Si-SiRR′R″: strong base = 1:(1~1.5):(1.5~3).

3. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (1), the aromatic olefin ArR 3 C=CR 1 R 2 The molar ratio of the silicon-based metal organic reagent RR′R″Si-M is: Aryl olefins 3 C=CR 1 R 2 : Silicon-based metal organic reagent RR′R″Si-M=1:(1~1.5).

4. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (1), the aromatic olefin ArR 3 C=CR 1 R 2 Including styrene, 2-methoxystyrene, 3-methoxystyrene, 4-methoxystyrene, 4-phenylstyrene, 4-methylthiostyrene, 4-chlorostyrene, 1-allyl-4-vinylbenzene, α-methylstyrene, 4-methoxy-α-methylstyrene, 4-methylthio-α-methylstyrene, 4-dimethylamino-α-methylstyrene, 4-morpholinyl-α-methylstyrene, α-methyl-2-naphthylethylene, α-n-butyl-styrene, α-isopropyl-styrene, α-cyclobutyl-styrene, α-cyclopentyl-styrene, α-cyclohexyl-styrene, 1,1-diphenylethylene, 1,2-diphenylethylene One of ethylene, 2,2-dimethylstyrene, 1,2-dihydronaphthalene, (E)-N,N-dimethyl-3-phenyl-2-propene-1-amine, 4-isopropenyltoluene, 4,4'-(ethylene-1,1-diyl)-bis-(N,N-diethylaniline), 4,4'-(ethylene-1,1-diyl)-bismethoxybenzene, 9,9-dimethyl-10-methylene-9,10-dihydroanthracene, 2,4-diethyl-9-methylene-9H-thioxanthene, 9-methylene-9H-fluorene, 4-isobutyl-styrene, 4-isobutyl-α-methylstyrene or 2-methoxy-6-(propene-2-yl)-naphthalene.

5. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (1), the organic solvent is selected from one or more of tetrahydrofuran, 1,4-dioxane, cyclohexane, hexane, methyl tert-butyl ether, ethyl ether, benzyl ether, ethylene glycol dimethyl ether, toluene, and methyltetrahydrofuran.

6. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (1), the strong base is selected from one or more of potassium tert-butoxide, sodium tert-butoxide, lithium tert-butoxide, potassium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, lithium bis(trimethylsilyl)amide, potassium methoxide, sodium methoxide, potassium ethoxide, sodium ethoxide, tert-butyl lithium, n-butyl lithium, phenyl lithium, and methyl lithium.

7. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (2), the reaction temperature of the nucleophilic addition reaction is -40°C to room temperature, and the reaction time is 30s to 3min.

8. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (2), the dry carbon dioxide is introduced at a temperature ranging from -20°C to room temperature, and the pressure is greater than or equal to one standard atmospheric pressure.

9. The method for preparing the selective β-silyl aryl acetic acid compound according to claim 1, characterized in that: In the step (2), the nucleophilic addition reaction is carried out, and the β-silyl aryl acetic acid compound is obtained by acidification and post-treatment, comprising: Add 1-2 mol / L hydrochloric acid to the salt solution after the nucleophilic addition reaction to adjust the pH value to acidic; After extraction with ethyl acetate or dichloromethane, the organic phases are combined; Dry with anhydrous sodium sulfate, filter, and concentrate under reduced pressure to obtain a crude product; The crude product is separated by chromatography or purified by recrystallization to obtain the aromatic olefin selective silylation-carboxylation product.

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