CN111303028B - A 4-cyano-2-difluoromethyl-substituted quinoline compound and its synthesis method - Google Patents

Abstract

The invention provides a 4-cyano-2-difluoromethyl substituted quinoline compound and a synthesis method thereof. In the synthesis reaction, under the action of a photocatalyst, ortho-alkenyl aryl isonitrile is taken as a substrate and reacts with difluoromethyl triphenyl phosphonium bromide to synthesize the 4-cyano-2-difluoromethyl substituted quinoline compound. The synthesized 4-cyano-2-difluoromethyl substituted quinoline compound contains quinoline ring, difluoromethyl and cyano functional groups, and the quinoline ring, the difluoromethyl and the cyano functional groups have excellent activity in the aspect of biomedicine, thereby providing an effective thought for the design and synthesis of medicaments. The synthetic method provided by the invention is simple to operate, has good substrate universality and has step economy.

Description

A kind of 4-cyano-2-difluoromethyl-substituted quinoline compound and its synthetic method

technical field

The invention relates to the technical field of organic chemical synthesis, in particular to a 4-cyano-2-difluoromethyl-substituted quinoline compound and a synthesis method.

Background technique

Quinoline compounds are widely used in medicine, materials and dyes. For example, 2-fluoroalkylated quinolins can not only be used as anti-protozoal drugs, anti-tuberculosis drugs, PDE4 inhibitors, cardiovascular drugs, VR1 receptor antagonists and anti-infective drugs, but also as ligands for metal-catalyzed reactions . In addition, many antimalarial drugs, insecticides, anti-inflammatory drugs, and antidepressants contain quinoline skeletons, and quinoline skeletons are also important intermediates for the total synthesis of some alkaloids. Therefore, starting from simple substrates to synthesize quinoline compounds or directly modifying the quinoline skeleton to introduce various substituents has attracted strong interest of chemists.

According to the retrosynthetic analysis of quinoline molecular structure, the key step in the synthesis of quinoline skeleton lies in the construction of pyridine ring. And the base-catalyzed domino reaction, transition metal-catalyzed cyclization reaction or free radical cyclization reaction can realize the construction of nitrogen heterocyclic compounds through the ortho alkenyl aryl isocyanide free radical The reaction enables the synthesis of quinoline-like backbones.

Organofluorine compounds are widely used in medicine, agriculture, and life and material sciences because of their unique metabolic stability, lipophilicity, and biological properties. Therefore, it is of great importance to develop new synthetic methods to introduce fluorine or haloalkyl groups into organic molecules. significance. The use of mild conditions to introduce difluoromethyl groups into organic molecules has been extensively studied in the past few decades. Among them, the addition reaction of difluoromethyl radicals with unsaturated hydrocarbons is one of the commonly used strategies for introducing difluoromethyl groups. Visible light has the advantages of being green, clean, and sustainable. Recently, photoredox catalysis has emerged as a powerful strategy for radical reactions. A key feature of this process is the ability of visible light to initiate organic reactions via photocatalyst excitation followed by single-electron transfer. Therefore, chemists have worked hard to develop difluoromethylation reactions using visible light redox reactions. The cyano group is a type of substituent with strong electron-withdrawing properties, which can act as an isostere of the carbonyl group to change the physical properties of some small molecules, thereby enhancing the interaction with the target protein and improving its drug activity. Therefore, considering the characteristics of the metabolic stability of organic fluorine compounds and the characteristics of the cyano group to enhance the drug activity, how to synthesize quinolines containing difluoromethyl and cyano groups using ortho-alkenyl aryl isocyanides as substrates. Things have become a problem that people urgently need to solve.

Contents of the invention

The invention provides a 4-cyano-2-difluoromethyl-substituted quinoline compound and its synthesis method, which realizes the synthesis of quinolines containing difluoromethyl and cyano groups using ortho alkenyl aryl isocyanides as substrates. phyllochemicals.

The application provides a 4-cyano-2-difluoromethyl-substituted quinoline compound, which has a general structural formula as shown in I:

Wherein, R is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, and heteroaryl is ^one , two or three of pyridyl, thienyl, and furyl; The group is one, two or three of C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I;

R ² is selected from one, two or three of C1-C5 hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I.

Based on the compound of the above-mentioned formula I, the application also provides a synthetic method of a 4-cyano-2-difluoromethyl-substituted quinoline compound, the method comprising:

S01: add ortho alkenyl aryl isonitrile, difluoromethyltriphenylphosphorus bromide, photocatalyst and solvent in sequence in the reactor.

The o-alkenyl aryl isonitrile, difluoromethyltriphenylphosphorus bromide, photocatalyst and solvent are respectively measured according to a predetermined ratio. Add ortho alkenyl aryl isonitrile, difluoromethyltriphenylphosphorus bromide, photocatalyst and solvent in sequence in the reactor. In the present application, the molar ratio of ortho alkenyl aryl isonitrile to difluoromethyltriphenylphosphine bromide is 1:1.1-2. The amount of photocatalyst is 2 mol% of the amount of ortho alkenyl aryl isonitrile. The amount of solvent used is 0.5-10 mL of solvent per millimole of ortho alkenyl aryl isonitrile. More preferably, the molar ratio of ortho alkenyl aryl isonitrile to difluoromethyl triphenylphosphine bromide is 1:1.5.

In the present application, the synthetic reaction formula of ortho alkenyl aryl isocyanide is:

Wherein, R is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, and said heteroaryl is ^one , two or three of pyridyl, thienyl, or furyl; said phenyl The substituents on are C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I in one, two or three;

R ² is selected from one, two or three of C1-C5 hydrogen, alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I.

Taking (E)-2-(2-isocyanophenyl)-3-phenylacrylonitrile, i.e. the ortho-alkenyl aryl isonitrile 1a in Example 1, as an example, it will be specifically described according to the above synthesis reaction formula Synthesis of ortho alkenyl aryl isocyanides. The remaining ortho-alkenyl aryl isonitriles are only different from (E)-2-(2-isocyanophenyl)-3-phenylacrylonitrile 1a in substituents, but the synthesis steps are the same.

S1: Add benzaldehyde and piperidine to a methanol solution containing o-nitrophenylacetonitrile. The reaction system was heated to reflux at 70°C. After 4 hours of reaction, it was cooled to room temperature, and a yellow precipitate was collected. The precipitate was recrystallized from methanol to obtain (E)-2-(2-nitrophenyl)-3-phenylacrylonitrile as a yellow solid product, as shown in Formula II.

S2: Mix (E)-2-(2-nitrophenyl)-3-phenylacrylonitrile, Sn powder and ethanol and stir at room temperature. HCl was slowly added dropwise to the mixture at 0 °C. After the dropwise addition was completed, it was stirred at room temperature for another 2 hours. The mixture was quenched with saturated NaHCO ₃ solution and extracted with CH ₂ Cl ₂ . The combined organic layers _were dried over anhydrous _Na2SO4 , filtered, concentrated under reduced pressure, and the residue was purified by flash column chromatography using hexane and ethyl acetate as eluents to give (E)-2-( 2-aminophenyl)-3-phenylacrylonitrile, as shown in formula III.

S3: In a dry three-necked flask equipped with a dropping funnel, add (E)-2-(2-aminophenyl)-3-phenylacrylonitrile and THF under nitrogen, and cool to 0°C. The formic acetic anhydride prepared by reacting acetic anhydride and formic acid at 55°C for 2 hours was transferred to the dropping funnel, and added dropwise to the solution containing (E)-2-(2-aminophenyl)-3-benzene at 0°C. in a solution of acrylonitrile. After the dropwise addition was complete, the mixture was warmed up to room temperature and stirred for 2 hours. After the reaction was complete, the mixture was quenched with saturated NaHCO ₃ solution and extracted three times with CH ₂ Cl ₂ . The extract was dried over Na ₂ SO ₄ and concentrated under reduced pressure to obtain (E)-N-(2-(1-cyano-2-phenylethenyl)phenyl)formamide as a light white solid, as shown in formula 1a.

S4: In a dry three-necked flask equipped with a dropping funnel, add THF, NEt ₃ and (E)-N-(2-(1-cyano-2-phenylethenyl)phenyl) under nitrogen atmosphere formamide and cooled to 0 °C. Then _POCl3 was added dropwise, and after the dropwise addition was complete, the mixture was stirred at 0°C for 2 hours. After the reaction was completed, the mixture was quenched with saturated _Na2CO3 solution and stirred for ₁ hour. The reaction mixture was extracted with _CH2Cl2 , the combined organic layers _were dried _over anhydrous _Na2SO4 , filtered, concentrated under reduced pressure, and the compound was purified by column to give (E)-2-(2-isocyanophenyl)- 3-phenylacrylonitrile, as shown in formula V.

NMR (NuclearMagnetic Resonance Spectroscopy, nuclear magnetic resonance spectrum) is carried out to the prepared (E)-2-(2-isocyanophenyl)-3-phenylacrylonitrile 1a, obtain the H spectrogram shown in accompanying drawing 2, The C spectrogram shown in accompanying drawing 3, and following data:

¹ HNMR (400MHz, CDCl ₃ ) δ7.93-7.91 (m, 2H), 7.58-7.56 (m, 1H), 7.52-7.42 (m, 7H);

¹³ C NMR (100MHz, CDCl ₃ ) δ169.8, 149.0, 132.9, 132.2, 131.5, 130.0, 129.9, 129.5, 129.1, 128.4, 124.5, 117.1, 106.6;

HRMS(ESI):calcd for C ₁₆ H ₁₀ N ₂ ([M+H] ⁺ )231.0917,found.231.0921.

In this application, the photocatalyst is selected from eosin Y, eosin B, rose bengal, 4CzIPN (Chinese name: 2,4,5,6-tetra(9-carbazolyl)-isophthalonitrile), fac- One or more of Ir(ppy) ₃ (Chinese name: face-tri(2-phenylpyridine) iridium complex). The solvent is selected from N,N-dimethylformamide (English name: N,N-Dimethylformamide; English abbreviation: DMF), N,N-dimethylacetamide (English name: N,N-Dimethylacetamide; English abbreviation: DMAc), dimethyl sulfoxide (English name: Dimethyl sulfoxide; English abbreviation: DMSO), dichloromethane, acetonitrile, 1,4-dioxane (English name: 1,4-dioxane), 1,2- One or both of dichloroethane (English name: 1,2-Dichloroethane; English abbreviation: DCE), tetrahydrofuran (English name: Tetrahydrofuran; English abbreviation: THF), ethanol, and methanol.

S02: Under the conditions of visible light irradiation and nitrogen atmosphere, stir and react at room temperature to obtain the product.

Under the conditions of visible light irradiation and nitrogen atmosphere, the reaction was stirred at room temperature to obtain the product. Wherein, the generation reaction formula of product is:

In the above reaction formula, the label 1 is the ortho-alkenyl aryl isocyanide, the label 2 is difluoromethyltriphenylphosphonium bromide, and the label 3 is the 4-cyano-2-difluoromethane with structural formula I Substituted quinoline compounds. In this application, the visible light can be an LED lamp with a power of 10W, and the stirring time is 12h.

S03: Use a rotary evaporator to remove the solvent in the product to obtain a crude product.

S04: The crude product was subjected to column chromatography to obtain 4-cyano-2-difluoromethyl-substituted quinolines.

The crude product was subjected to column chromatography to obtain 4-cyano-2-difluoromethyl-substituted quinolines. Wherein, the eluent of the column chromatography is a mixed solvent of petroleum ether and ethyl acetate.

In the present application, in order to analyze the influence of photocatalyst and solvent on the quinoline compound substituted by synthetic 4-cyano-2-difluoromethyl, the application also uses a kind of 4-cyano-2-difluoromethyl The substituted quinoline compound was taken as an example for condition optimization and screening, and the specific data are shown in Table 1. Among them, the structural formula and synthetic reaction formula of the 4-cyano-2-difluoromethyl-substituted quinoline compound used in the condition optimization and screening are as follows:

Structural formula:

Synthesis reaction formula:

The conditions of the synthesis reaction are: nitrogen condition, 0.2mmol o-alkenyl aryl isonitrile 1a, 0.3mmol difluoromethyltriphenylphosphorus bromide, photocatalyst, 1mL solvent, 10W blue LEDs irradiation reaction for 12h. The synthesis conditions specially marked in Table 2 are different from the conditions of the synthesis reaction, namely ^c) 8W blue LEDs; ^d) no light; ^e) in air.

Table 1: The relevant data of the comparative example based on embodiment 1

It can be seen from Table 1 that in the experiment numbered 4, when the photocatalyst was 2mol% fac-Ir(ppy) ₃ , the solvent was DMAc, and 10W blue LEDs were irradiated, the synthesized 4-cyano-2-difluoromethyl The substituted quinolines had a higher yield, ie 70%.

The technical solutions provided by the embodiments of the present invention may include the following beneficial effects:

In the 4-cyano-2-difluoromethyl-substituted quinoline compound and the synthesis method provided by the invention, under the action of photocatalyst, the ortho-alkenyl aryl isocyanide is used as a substrate, and difluoroform The 4-cyano-2-difluoromethyl substituted quinolines were synthesized by the reaction of triphenylphosphonium bromide. The synthesized 4-cyano-2-difluoromethyl substituted quinoline compounds contain quinoline ring, difluoromethyl and cyano functional groups, and the quinoline ring, difluoromethyl and cyano functional groups are widely used in biomedicine It has superior activity and provides an effective idea for the design and synthesis of drugs. The synthesis method provided by the invention has simple operation, good substrate universality and step economy.

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive of the invention.

Description of drawings

In order to illustrate the technical solution of the present application more clearly, the accompanying drawings used in the embodiments will be briefly introduced below. Obviously, for those of ordinary skill in the art, on the premise of not paying creative labor, Additional drawings can also be derived from these drawings.

Figure 1 is a schematic flow diagram of the synthesis method of 4-cyano-2-difluoromethyl-substituted quinoline compounds provided by the examples of the present invention;

Fig. 2 is the H spectrogram of (E)-2-(2-isocyanophenyl)-3-phenylacrylonitrile 1a provided by the embodiment of the present invention;

Fig. 3 is the C spectrogram of (E)-2-(2-isocyanophenyl)-3-phenylacrylonitrile 1a provided by the embodiment of the present invention;

Fig. 4 is the H spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3a in Example 1 provided by the examples of the present invention;

Figure 5 is the C spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3a in Example 1 provided by the Examples of the present invention;

Figure 6 is the F spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3a in Example 1 provided by the examples of the present invention;

Figure 7 is the H spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3b in Example 2 provided by the examples of the present invention;

Figure 8 is the C spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3b in Example 2 provided by the examples of the present invention;

Figure 9 is the F spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3b in Example 2 provided by the examples of the present invention;

Figure 10 is the H spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3c in Example 3 provided by the examples of the present invention;

Figure 11 is the C spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3c in Example 3 provided by the examples of the present invention;

Figure 12 is the F spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3c in Example 3 provided in the examples of the present invention;

Figure 13 is the H spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3d in Example 4 provided by the Examples of the present invention;

Figure 14 is the C spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3d in Example 4 provided by the Examples of the present invention;

Figure 15 is the F spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3d in Example 4 provided by the Examples of the present invention;

Figure 16 is the H spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3e in Example 5 provided by the Examples of the present invention;

Figure 17 is the C spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3e in Example 5 provided by the Examples of the present invention;

Figure 18 is the F spectrum of the 4-cyano-2-difluoromethyl-substituted quinoline compound 3e in Example 5 provided by the Examples of the present invention.

Detailed ways

The present invention will be further described below with specific embodiments. In this application, there are many options for photocatalysts and solvents, and there are many embodiments. For the convenience of describing the content of the present invention and reducing the space, only the optimal conditions determined in the content of the invention are used in the following examples: photocatalyst fac- Ir(ppy) ₃ , solvent DMAc, and 10W blue LEDs irradiation are taken as examples for illustration, but this does not limit the protection scope of the present invention.

Please refer to the accompanying drawing 1, which shows a schematic flow diagram of the synthesis method of the 4-cyano-2-difluoromethyl-substituted quinoline compounds provided in the examples of the present application. The description of the following specific embodiments is based on the accompanying drawing 1 .

Example 1

The embodiment of the present invention provides a 4-cyano-2-difluoromethyl-substituted quinoline compound 3a, the 4-cyano-2-difluoromethyl-substituted quinoline compound 3a has the following structural formula:

The embodiment of the present invention also provides a synthesis method of 4-cyano-2-difluoromethyl-substituted quinoline compound 3a, which specifically includes:

S101: Add 0.2mmol (46.1mg) ortho alkenyl aryl isonitrile 1a, 0.3mmol (117.8mg) difluoromethyltriphenylphosphonium bromide 2, 2mol% (2.6mg) fac- Ir(ppy) ₃ , 1 mL N,N-dimethylformamide (DMAc);

S102: Under the conditions of blue light LED irradiation with a power of 10W and a nitrogen atmosphere, stir at room temperature for 12 hours to obtain the product; wherein, the formation reaction formula of the product is:

S103: After the reaction is finished, use a rotary evaporator to remove the solvent in the product to obtain a crude product;

S104: Using a mixed solvent of petroleum ether and ethyl acetate as the eluent, the crude product was subjected to column chromatography to obtain 39.2 mg of 4-cyano-2-difluoromethyl-substituted quinoline compound 3a, with an isolated yield of 70 %.

NMR (NuclearMagnetic Resonance Spectroscopy, nuclear magnetic resonance spectrum) is carried out to the quinoline compound 3a that the substituted 4-cyano-2-difluoromethyl that prepares obtains, obtain the H spectrogram shown in accompanying drawing 4, shown in accompanying drawing 5 The C spectrogram, the F spectrogram shown in accompanying drawing 6 and following data:

¹ H NMR (400MHz, CDC _l3 ) δ8.35 (d, J = 8.4Hz, 1H), 8.29 (dd, J = 0.8, 8.4Hz, 1H), 7.97-7.93 (m, 1H), 7.90-7.86 ( m,1H),7.59-7.57(m,3H),7.49-7.46(m,2H),6.69(t,J=54.0Hz,1H);

¹³ C NMR (100MHz, CDC _l3 ) δ149.9(t, J=23.1Hz), 146.3, 137.7, 132.9, 131.7, 131.0, 130.8, 129.8, 129.7, 128.8, 126.4, 125.2, 120.7, 114.3, 112.6(t ,J=241.3Hz);

¹⁹ F NMR (377MHz, CDC ₁₃ ) δ-112.6 (s, 2F);

HRMS (ESI): calcd for C ₁₇ H ₁₀ F ₂ N ₂ ([M ₊ H] ⁺ ) 281.0885, found. 281.089.

Example 2

The embodiment of the present invention provides a 4-cyano-2-difluoromethyl-substituted quinoline compound 3b, the 4-cyano-2-difluoromethyl-substituted quinoline compound 3b has the following structural formula:

The embodiment of the present invention also provides a synthesis method of 4-cyano-2-difluoromethyl-substituted quinoline compound 3b, which specifically includes:

S201: Add 0.2mmol (31.2mg) ortho alkenyl aryl isonitrile 1b, 0.3mmol (117.8mg) difluoromethyltriphenylphosphine bromide 2, 2mol% (2.6mg) fac- Ir(ppy) ₃ , 1 mL N,N-dimethylformamide (DMAc);

S202: Under the condition of 10W blue LED irradiation and nitrogen atmosphere, stir at room temperature for 12 hours to obtain the product; wherein, the formation reaction formula of the product is:

S203: After the reaction is completed, use a rotary evaporator to remove the solvent in the product to obtain a crude product;

S204: Using a mixed solvent of petroleum ether and ethyl acetate as the eluent, the crude product was subjected to column chromatography to obtain 39.2 mg of 4-cyano-2-difluoromethyl-substituted quinoline compound 3b, with an isolated yield of 53 %.

NMR (NuclearMagnetic Resonance Spectroscopy, nuclear magnetic resonance spectrum) is carried out to the quinoline compound 3b that the substituted 4-cyano-2-difluoromethyl that prepares obtains, obtain the H spectrogram shown in accompanying drawing 7, shown in accompanying drawing 8 The C spectrogram, the F spectrogram shown in accompanying drawing 9 and the following data:

¹ H NMR (400MHz, CDCl ₃ ) δ8.35 (d, J = 8.4Hz, 1H), 8.28 (dd, J = 0.8, 8.4Hz, 1H), 7.97-7.92 (m, 1H), 7.89-7.85 ( m,1H),7.48-7.44(m,1H),7.39-7.37(m,1H),7.27-7.25(m,2H),6.68(t,J＝54.0Hz,1H),2.47(s,3H) ;

¹³ C NMR (100MHz, CDCl ₃ ) δ149.9 (t, J=23.0Hz), 146.3, 138.7, 137.8, 132.8, 131.7, 131.0, 130.8, 130.6, 130.2, 128.7, 126.8, 126.4, 125.2, 120.5, 114.4 ,112.2(t,J=241.0Hz),21.5;

¹⁹ F NMR (377MHz, CDCl ₃ ) δ-113.0 (s, 2F);

HRMS (ESI): calcd for C ₁₈ H ₁₂ F ₂ N ₂ ([M+H] ⁺ ) 295.1041, found. 295.1044.

Example 3

The embodiment of the present invention provides a 4-cyano-2-difluoromethyl-substituted quinoline compound 3c, the 4-cyano-2-difluoromethyl-substituted quinoline compound 3c has the following structural formula:

The embodiment of the present invention also provides a synthesis method of 4-cyano-2-difluoromethyl-substituted quinoline compound 3c, which specifically includes:

S301: Add 0.2mmol (47.2mg) ortho alkenyl aryl isonitrile 1c, 0.3mmol (117.8mg) difluoromethyltriphenylphosphonium bromide 2, 2mol% (2.6mg) fac- Ir(ppy) ₃ , 1 mL N,N-dimethylformamide (DMAc);

S302: Under the conditions of blue light LED irradiation with a power of 10W and a nitrogen atmosphere, stir at room temperature for 12 hours to obtain the product; wherein, the formation reaction formula of the product is:

S303: After the reaction is completed, use a rotary evaporator to remove the solvent in the product to obtain a crude product;

S304: Using a mixed solvent of petroleum ether and ethyl acetate as the eluent, the crude product was subjected to column chromatography to obtain 13.2 mg of 4-cyano-2-difluoromethyl-substituted quinoline compound 3c with an isolated yield of 23 %.

NMR (NuclearMagnetic Resonance Spectroscopy, nuclear magnetic resonance spectrum) is carried out to the quinoline compound 3c that the substituted 4-cyano-2-difluoromethyl that prepares obtains, obtain the H spectrogram shown in accompanying drawing 10, shown in accompanying drawing 11 The C spectrogram, the F spectrogram shown in accompanying drawing 12 and following data:

¹ H NMR (400MHz, CDCl ₃ ) δ8.35 (d, J = 8.4Hz, 1H), 8.28 (dd, J = 0.8, 8.0Hz, 1H), 7.99-7.95 (m, 1H), 7.91-7.87 ( m,1H),7.66(dd,J=1.2,5.2Hz,1H),7.35-7.33(m,1H),7.27-7.25(m,1H),6.79(t,J=54.0Hz,1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ150.3(t, J=22.8Hz), 146.5, 132.2, 131.8, 131.2, 131.1, 130.8, 130.6, 129.3, 127.8, 126.4, 125.3, 122.1, 114.1, 112.2(t ,J=241.5Hz);

¹⁹ F NMR (377MHz, CDCl ₃ ) δ-113.1 (s, 2F);

HRMS (ESI): calcd for C ₁₅ H ₈ F ₂ N ₂ S ([M+H] ⁺ ) 287.0449, found. 287.0453.

Example 4

The embodiment of the present invention provides a 4-cyano-2-difluoromethyl-substituted quinoline compound 3d, the 4-cyano-2-difluoromethyl-substituted quinoline compound 3d has the following structural formula:

The embodiment of the present invention also provides a synthesis method of 4-cyano-2-difluoromethyl-substituted quinoline compound 3d, which specifically includes:

S401: Add 0.2mmol (47.2mg) o-alkenyl aryl isonitrile 1d, 0.3mmol (117.8mg) difluoromethyltriphenylphosphine bromide 2, 2mol% (2.6mg) fac- Ir(ppy) ₃ , 1 mL N,N-dimethylformamide (DMAc);

S402: Under the conditions of blue light LED irradiation with a power of 10W and a nitrogen atmosphere, stir at room temperature for 12 hours to obtain the product; wherein, the formation reaction formula of the product is:

S403: After the reaction is completed, use a rotary evaporator to remove the solvent in the product to obtain a crude product;

S404: Using a mixed solvent of petroleum ether and ethyl acetate as the eluent, the crude product was subjected to column chromatography to obtain 22.5 mg of 4-cyano-2-difluoromethyl-substituted quinoline compound 3d with an isolated yield of 39 %.

NMR (NuclearMagnetic Resonance Spectroscopy, nuclear magnetic resonance spectrum) is carried out to the quinoline compound 3d that the substituted 4-cyano-2-difluoromethyl that prepares obtains, obtain the H spectrogram shown in accompanying drawing 13, shown in accompanying drawing 14 The C spectrogram, the F spectrogram shown in accompanying drawing 15 and the following data:

¹ H NMR (400MHz, CDCl ₃ ) δ8.29-8.26 (m, 1H), 8.18-8.16 (m, 1H), 7.86-7.82 (m, 2H), 6.91 (t, J = 54.4Hz, 1H), 3.55-3.47(m,1H),2.38-2.32(m,2H),1.99-1.93(m,2H),1.91-1.85(m,2H),1.84-1.81(m,1H),1.55-1.44(m ,3H);

¹³ C NMR (100MHz, CDCl ₃ ) δ150.8(t, J=25.4Hz), 144.5(t, J=1.8Hz), 143.3, 130.8, 130.5, 130.3, 127.6, 124.6, 118.4, 117.9(t, J =238.4Hz), 115.6, 38.7, 30.8, 26.9, 25.4;

¹⁹ F NMR (377MHz, CDCl ₃ ) δ-110.5 (s, 2F);

HRMS (ESI): calcd for C ₁₇ H ₁₆ F ₂ N ₂ ([M+H] ⁺ ) 287.1354, found. 287.1359.

Example 5

The embodiment of the present invention provides a 4-cyano-2-difluoromethyl-substituted quinoline compound 3e, the 4-cyano-2-difluoromethyl-substituted quinoline compound 3e has the following structural formula:

The embodiment of the present invention also provides a synthesis method of 4-cyano-2-difluoromethyl-substituted quinoline compound 3e, which specifically includes:

S501: Add 0.2mmol (49.6mg) ortho alkenyl aryl isonitrile 1e, 0.3mmol (117.8mg) difluoromethyl triphenylphosphine bromide 2, 2mol% (2.6mg) fac- Ir(ppy) ₃ , 1 mL N,N-dimethylformamide (DMAc);

S502: Under the condition of blue light LED irradiation with a power of 10W and a nitrogen atmosphere, stir at room temperature for 12 hours to obtain the product; wherein, the formation reaction formula of the product is:

S503: After the reaction is completed, use a rotary evaporator to remove the solvent in the product to obtain a crude product;

S504: Using a mixed solvent of petroleum ether and ethyl acetate as the eluent, the crude product was subjected to column chromatography to obtain 25.1 mg of 4-cyano-2-difluoromethyl-substituted quinoline compound 3e, with an isolated yield of 42 %.

NMR (NuclearMagnetic Resonance Spectroscopy, nuclear magnetic resonance spectrum) is carried out to the quinoline compound 3e that the substituted 4-cyano-2-difluoromethyl that prepares obtains, obtain the H spectrogram shown in accompanying drawing 16, shown in accompanying drawing 17 The C spectrogram, the F spectrogram shown in accompanying drawing 18 and the following data:

¹ H NMR (400MHz, CDCl ₃ ) δ8.31(dd, J=5.6, 9.2Hz, 1H), 7.98(dd, J=2.8, 9.2Hz, 1H), 7.70-7.65(m, 1H), 7.59- 7.57(m,3H),7.47-7.45(m,2H),6.67(t,J=54.0Hz,1H);

¹³ C NMR (100MHz, CDCl ₃ ) δ164.1(d, J=254.0Hz), 151.1(t, J=23.3Hz), 147.4(d, J=13.0Hz), 137.0, 132.6, 130.0, 129.7, 128.9 ,127.6(d,J=9.8Hz),123.5,121.7(d,J=25.8Hz),120.7(d,J=1.4Hz),114.6(d,J=20.9Hz),114.1,112.4(t,J = 241.6Hz);

¹⁹ F NMR (377MHz, CDCl ₃ ) δ-104.7(s, 1F), -112.9(s, 2F);

HRMS (ESI): calcd for C ₁₇ H ₉ F ₃ N ₂ ([M+H] ⁺ ) 299.0791, found. 299.0794.

Other embodiments of the invention will be readily apparent to those skilled in the art from consideration of the specification and practice of the invention disclosure herein. This application is intended to cover any modification, use or adaptation of the present invention, these modifications, uses or adaptations follow the general principles of the present invention and include common knowledge or conventional technical means in the technical field not disclosed in the present invention . The specification and examples are to be considered exemplary only, with a true scope and spirit of the invention being indicated by the following claims.

It should be understood that relational terms such as "first" and "second", etc., are only used to distinguish one entity or operation from another and do not necessarily require or imply a relationship between these entities or operations. There is no such actual relationship or order between them. The present invention is not limited to the precise constructions which have been described above and shown in the drawings, and various modifications and changes may be made without departing from the scope thereof. The scope of the invention is limited only by the appended claims.

Claims (7)

1. a kind of synthetic method of the quinoline compound that 4-cyano group-2-difluoromethyl replaces, it is characterized in that, described method comprises: In the reactor, add ortho alkenyl aryl isocyanide, difluoromethyltriphenylphosphorus bromide, photocatalyst and solvent successively; Wherein, the structural formula of the ortho alkenyl aryl isocyanide is

R ¹ is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, and the heteroaryl is one of pyridyl, thienyl, and furyl; the substituent on the phenyl is C1- One, two or three of C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I; R2 is selected from ^hydrogen , C1-C5 alkyl, alkane One of oxygen, trifluoromethyl, cyano, nitro, F, Cl, Br, I; the structural formula of the difluoromethyl triphenylphosphonium bromide is

The photocatalyst is selected from fac-Ir(ppy) ₃ ; the solvent is selected from one of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, and acetonitrile or both; Under the conditions of visible light irradiation and nitrogen atmosphere, the reaction was stirred at room temperature to obtain the product; A rotary evaporator was used to remove the solvent in the product to obtain a crude product; The crude product was subjected to column chromatography to obtain 4-cyano-2-difluoromethyl-substituted quinolines. 2. synthetic method according to claim 1, is characterized in that, the generating reaction formula of described product is:

3. synthetic method according to claim 1, is characterized in that, the mol ratio of described ortho alkenyl aryl isocyanide and described difluoromethyltriphenylphosphorus bromide is 1:1.1-2. 4. The synthesis method according to claim 1, characterized in that, the amount of the photocatalyst is 2mol% of the amount of the ortho alkenyl aryl isonitrile. 5. The synthetic method according to claim 1, characterized in that, the amount of solvent used is 0.5-10 mL of solvent per millimole of ortho alkenyl aryl isonitrile. 6. synthetic method according to claim 1, is characterized in that, the synthetic reaction formula of described ortho alkenyl aryl isocyanide is:

Wherein, R is selected from cycloalkyl, phenyl, heteroaryl or substituted phenyl, and the heteroaryl is ^a kind of pyridyl, thienyl, or furyl; the substituent on the phenyl is C1 -One, two or three of C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I; R ² is selected from one of hydrogen, C1-C5 alkyl, alkoxy, trifluoromethyl, cyano, nitro, F, Cl, Br, I. 7. synthetic method according to claim 1, is characterized in that, the eluent of described column chromatography is the mixed solvent of sherwood oil and ethyl acetate.

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