A method for synthesizing 2-trifluoromethyl-4-benzyl quinoline compounds

Abstract

The present application relates to the technical fields of medical and pharmaceutical chemical synthesis, and particularly relates to a synthesis method of 2-trifluoromethyl-4-benzyl quinoline compound, which comprises the following steps: adding compound 1, compound 2, an additive, a catalyst and an appropriate amount of solvent into a reactor, stirring under the condition of nitrogen at 80 DEG C for 5 hours, cooling to room temperature after the reaction is completed, diluting the reaction solution, filtering, and reducing pressure distillation to obtain a crude product, and then purifying the crude product through column chromatography to obtain the 2-trifluoromethyl quinoline compound. The present application uses trifluoromethyl imine ylide compound and phenylacetylene as raw materials, and synthesizes the 2-trifluoromethyl quinoline compound through one-pot method. The present application has the advantages of simple synthesis steps, easily available raw materials, safe synthesis operation, good functional group compatibility, high catalyst efficiency, low cost and the like, and is conducive to industrialized production.

Description

TECHNICAL FIELD

[0001] The present application relates to the technical field of medical and chemical synthesis, and particularly relates to a synthesis method of 2-trifluoromethyl-4-benzyl quinoline compound. BACKGROUND

[0002] Quinoline is an important six-membered nitrogen heterocyclic structure, and quinoline and its derivatives are the most important six-membered nitrogen heterocyclic compounds, which have a wide range of applications in the fields of medicinal chemistry, organic chemistry and natural products. In particular, the nitrogen heterocyclic ring of trifluoromethyl is an important structural part in biologically and pharmaceutically active compounds, which has the effects of antioxidant, anti-inflammatory, antitumor, antihyperlipidemia, antimicrobial and the like. It is well known that the introduction of trifluoromethyl into the parent molecule can greatly change its physicochemical properties, such as dissociation constant, lipophilicity and metabolic stability. Therefore, it is of great significance to develop an efficient and practical strategy to synthesize 2-trifluoromethyl quinoline in the fields of organic chemistry and medicinal chemistry.

[0003] Some efficient synthetic methods have been established for the synthesis of trifluoromethyl quinoline compounds. In 2001, Uneyama and co-workers successfully disclosed a method for the synthesis of 2-trifluoromethyl quinoline derivatives through Rh-catalyzed N-aryl trifluoroacetimidoyl chlorides with alkynes. (Amii, H.; Kishikawa, Y.; Uneyama, K., Rh(I)-Catalyzed Coupling Cyclization of N-Aryl Trifluoroacetimidoyl Chlorides with Alkynes: One-Pot Synthesis of Fluorinated Quinolines. Org. Lett. 2001, 3(8), 1109-1112). Zhou and co-workers reported in 2013 the [4+2] reaction of trifluoroacetimidoyl chlorides and alkynes in the presence of visible light to synthesize quinoline (Dong, X.; Xu, Y.; Liu, J. J.; Hu, Y.; Xiao, T.; Zhou, L., Visible-Light-Induced Radical Cyclization of Trifluoroacetimidoyl Chlorides with Alkynes: Catalytic Synthesis of 2-Trifluoromethyl Quinolines. Chemistry - A European Journal 2013, 19(50), 16928-16933). In 2019, Zhang and co-workers disclosed the synthesis of quinoline through [4+2] cyclization of o-azido benzaldehyde and fluorinated 1,3-diketones (Zhang, X.; Ma, X.; Qiu, W.; Evans, J.; Zhang, W., Cascade Knoevenagel and aza-Wittig reactions for the synthesis of substituted quinolines and quinolin-4-ols. Green Chemistry 2019, 21(2), 349-354.). Despite these achievements, the further use of these methods is limited by complex starting materials, multiple synthetic steps, harsh reaction conditions, toxic or hazardous reagents and solvents, lower atomic and step economy, and poor regioselectivity. Therefore, from the scientific and practical point of view, it is still extremely challenging and attractive to develop new efficient methods for the synthesis of 2-trifluoromethyl-4-benzyl quinoline from readily available materials under environmentally friendly conditions. SUMMARY

[0004] In order to solve the above problems, the application provides a synthesis method of 2-trifluoromethyl-4-benzyl quinoline compounds, which is safe and simple to operate, raw materials are easy to obtain, the catalyst is efficient, recyclable and low in cost, and is conducive to industrial production.

[0005] In order to achieve the above object, the technical scheme adopted by the application is as follows:

[0006] A synthesis method of 2-trifluoromethyl-4-benzyl quinoline compounds comprises the following synthesis steps:

[0007] In the reactor, compound 1, compound 2, a metal catalyst and an appropriate amount of solvent are added, stirred at 80 DEG C under air for 5 hours, cooled to room temperature after the reaction is completed, the reaction solution is diluted, filtered, and the crude product is obtained by reduced pressure distillation, and 2-trifluoromethyl-4-benzyl quinoline compounds are obtained by column chromatography purification, and the reaction equation is as follows:

[0008]

[0009] The compound 1 refers to a compound with the structure of formula (1): trifluoromethyl imine ylide; the compound 2 refers to a compound with the structure of formula (2): phenylacetylene.

[0010]

[0011] Among them, R 1 4-cyano, 4-methyl, 3-nitro, 4-chloro, 4-bromo; R 2 is phenyl.

[0012] Preferably, the molar ratio of the compound 1 to the compound 2 is 1:1-3, and here the molar ratio of the compound 1 to the compound 2 is 1:2.

[0013] Preferably, the solvent refers to any one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane and toluene; here the solvent is preferably acetonitrile; the ratio of the solvent to the compound 1 is 1-3 mL:0.2 mmol, and here the ratio of the solvent to the compound 1 is preferably 1 mL:0.2 mmol.

[0014] Preferably, the catalyst refers to any one of dichloro(pentamethylcyclopentadienyl) iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, dichloro(p-methylisopropylbenzene) ruthenium dimer and dichloro(pentamethylcyclopentadienyl) rhodium dimer; here the catalyst is preferably dichloro(pentamethylcyclopentadienyl) iridium dimer; the molar ratio of the catalyst to the compound 1 is 0.05-0.1:1, and here the molar ratio of the catalyst to the compound 1 is preferably 0.05:1.

[0015] Preferably, the eluent used in the column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1 to 2; preferably, the eluent used in the column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1.

[0016] Preferably, the temperature is 80-120 DEG C, and preferably, the temperature is 80 DEG C.

[0017] Preferably, the reactor is a schlenk tube.

[0018] Compared with the prior art, the present application has the following beneficial effects:

[0019] 1. The present application uses trifluoromethyl imine ylide compounds and phenylacetylene as raw materials to synthesize 2-trifluoromethyl quinoline compounds by one-pot method, which is a method for quickly constructing trifluoromethyl substituted quinoline. It has the advantages of high flexibility, easy availability of raw materials, simple operation, wide substrate range, etc., and the intermediates do not need to be separated, the cost is low, and it is conducive to industrialized production.

[0020] 2. The present application does not need to use traditional diazo compounds as metal carbene precursors, which avoids the danger of releasing a large amount of nitrogen; secondly, the present application uses trifluoromethyl synthons to efficiently synthesize fluorinated quinoline compounds, which avoids the use of expensive fluorinated reagents, and has good selectivity. BRIEF DESCRIPTION OF DRAWINGS

[0021] Figure 1 The hydrogen spectrum of the product 3a obtained in Example 1 of the present application is shown in the figure;

[0022] Figure 2 The carbon spectrum of the product 3a obtained in Example 1 of the present application is shown in the figure;

[0023] Figure 3 The hydrogen spectrum of the product 3b obtained in Example 2 of the present application is shown in the figure;

[0024] Figure 4 The carbon spectrum of the product 3b obtained in Example 2 of the present application is shown in the figure;

[0025] Figure 5 The hydrogen spectrum of the product 3c obtained in Example 3 of the present application is shown in the figure;

[0026] Figure 6 The carbon spectrum of the product 3c obtained in Example 3 of the present application is shown in the figure;

[0027] Figure 7 The hydrogen spectrum of the product 3d obtained in Example 4 of the present application is shown in the figure;

[0028] Figure 8 The carbon spectrum of the product 3d obtained in Example 4 of the present application is shown in the figure.

[0029] Figure 9 The hydrogen spectrum of the product 3e obtained in Example 5 of the present application;

[0030] Figure 10 The carbon spectrum of the product 3e obtained in Example 5 of the present application. DETAILED DESCRIPTION

[0031] The present application will be further described in conjunction with the examples and the accompanying drawings, but the embodiments of the present application are not limited thereto.

[0032] Example 1

[0033] In a schlenk tube, 1.0 mmol of N-(4-cyanophenyl)trifluoroacetimidate, 2.0 mmol of phenylacetylene, 0.05 mmol of dichloro(pentamethylcyclopentadienyl)iridium dimer and 5.0 ml of acetonitrile were added, and the reaction was carried out at 80°C for 5 hours under the condition of nitrogen. After the system was cooled to room temperature, the solvent was removed by distillation under reduced pressure. Column chromatography was used for separation and purification, and the target product 3a was obtained with a yield of 81%, using petroleum ether as the eluent for column chromatography.

[0034] The hydrogen spectrum and carbon spectrum of the obtained product 3a are shown in Figure 1 and Figure 2 The structure characterization data are as follows:

[0035] 1 H NMR (400 MHz, CDCl3) δ 8.51 (s, 1H), 8.33 (d, J = 8.8 Hz, 1H), 7.93 (d, J = 8.8 Hz, 1H), 7.60 (s, 1H), 7.39-7.31 (m, 3H), 7.19 (d, J = 7.2 Hz, 2H), 4.54 (s, 2H).

[0036] 13 C NMR (101 MHz, CDCl3) δ 150.64, 150.50 (q, J = 35.3 Hz), 148.34, 136.69, 132.45, 131.05, 130.39, 129.29, 128.80, 127.73, 127.50, 121.10 (q, J = 276.7 Hz), 118.93 (q, J = 2.0 Hz), 118.22, 112.38, 38.40. C-F C-F C-F = 276.7 Hz), 118.93 (q, J = 2.0 Hz), 118.22, 112.38, 38.40.

[0037] MS (EI, m / z): 312 [M]+.

[0038] HRMS (ESI): Calcd. for C 18 H​​14 F3N[M+H] + :313.0941; found:313.0947.

[0039] The structure of the product obtained according to the above data is as shown in the following formula:

[0040]

[0041] Example 2:

[0042] In a schlenk tube, 1.0 mmol of N-(4-methylphenyl)trifluoroacetimidate, 2.0 mmol of phenylacetylene, 0.05 mmol of dichloro(pentamethylcyclopentadienyl)iridium dimer and 5.0 ml of acetonitrile were added, and the reaction was carried out at 80°C for 5 hours under the condition of nitrogen. After the system was cooled to room temperature, the solvent was removed by distillation under reduced pressure. Column chromatography was used for separation and purification, and the target product 3b was obtained with a yield of 76%, using petroleum ether as the eluent.

[0043] The hydrogen spectrum and carbon spectrum of the obtained product 3b are shown in Figure 3 and Figure 4 , and the structure characterization data are as follows:

[0044] 1 H NMR (400 MHz, CDCl3) δ 8.13 (d, J = 8.4 Hz, 1H), 7.85 (s, 1H), 7.62 (d, J = 8.8 Hz, 1H), 7.42 (s, 1H), 7.35-7.26 (m, 3H), 7.19 (d, J = 7.6 Hz, 2H), 4.47 (s, 2H), 2.55 (s, 3H).

[0045] 13 C NMR (101 MHz, CDCl3) δ 148.44, 146.88 (q, J C-F = 33.3 Hz), 145.94, 138.87, 137.87, 132.76, 130.54, 128.94, 128.89, 128.25, 126.95, 122.72, 121.72 (q, J C-F = 275.7 Hz), 117.35 (q, J C-F = 2.0 Hz), 38.33, 22.16

[0046] MS (EI, m / z): 301 [M] + .

[0047] HRMS (ESI): Calcd. for C 17 H 11 BrF3N[M+H]+ 302.1155; found: 302.1150.

[0048] The structure of the product obtained according to the above data is as shown in the following formula:

[0049]

[0050] Example 3:

[0051] In a schlenk tube, 1.0 mmol of N-(3-nitrophenyl)trifluoroacetimidate, 2.0 mmol of phenylacetylene, 0.05 mmol of 1,5-cyclooctadiene iridium chloride dimer and 5.0 mL of acetonitrile were added, and the reaction was carried out at 80°C for 5 hours under the condition of nitrogen. After the system was cooled to room temperature, the solvent was removed by distillation under reduced pressure. Column chromatography was used for separation and purification, and the target product 3c was obtained with a yield of 85%, using petroleum ether as the eluent.

[0052] The hydrogen spectrum and carbon spectrum of the obtained product 3c are shown in Figure 5 and Figure 6 , and the structure characterization data are as follows:

[0053] 1 H NMR (400 MHz, CDCl3) δ 8.47-8.45 (m, 1H), 7.94-7.89 (m, 1H), 7.87-7.82 (m, 1H), 7.43-7.40 (m, 1H), 7.38-7.26 (m, 3H), 7.09-7.07 (m, 2H), 4.33 (s, 2H).

[0054] 13 C NMR (101 MHz, CDCl3) δ 148.21, 139.76 (q, J C-F = 2.3 Hz), 138.85, 134.83, 130.81, 129.77, 128.98, 128.49, 127.94, 123.94, 123.89 (q, J C-F = 38.4 Hz), 123.63, 120.93 (q, J C-F = 267.7 Hz), 113.09 (q, J C-F = 4.0 Hz), 109.30.

[0055] MS (EI, m / z): 332 [M] + .

[0056] HRMS (ESI): Calcd. for C 17 H 11 F3N2O2 [M+H] +: 333.0845; found: 333.0841.

[0057] The structure of the product obtained from the above data is deduced as shown in the following formula:

[0058]

[0059] Example 4:

[0060] In a schlenk tube, 1.0 mmol of N-(4-chlorophenyl)-trifluoroacetimidate, 2.0 mmol of phenylacetylene, 0.05 mmol of dichloro(p-methylisopropylbenzene) ruthenium dimer and 5.0 ml of acetonitrile were added, and the reaction was carried out at 80°C for 5 hours under the condition of nitrogen. After the system was cooled to room temperature, the solvent was removed by reduced pressure distillation. Column chromatography was used for separation and purification, and the target product 3d was obtained with a yield of 77%, using petroleum ether as the column chromatography eluent.

[0061] The hydrogen spectrum and carbon spectrum of the obtained product 3d are shown in Figure 7 and Figure 8 respectively, and the structure characterization data are as follows:

[0062] 1 H NMR (400 MHz, CDCl3) δ 8.25 (d, J = 8.5 Hz, 1H), 8.04 (d, J = 8.4 Hz, 1H), 7.82-7.79 (m, 1H), 7.67-7.63 (m, 1H), 7.47 (s, 1H), 7.29 (d, J = 8.1 Hz, 2H), 7.12 (d, J = 8.0 Hz, 2H), 4.48 (s, 2H).

[0063] 13 C NMR (101 MHz, CDCl3) δ 148.69, 147.81 (q, J = 34.3 Hz), 147.38, 136.25, 132.88, 130.99, 130.58, 130.14, 129.11, 128.76, 128.03, 123.74, 121.54 (q, J = 275.5 Hz), 117.34 (q, J = 2.0 Hz), 37.86. C-F C-F C-F

[0064] MS (EI, m / z): 321 [M]+.

[0065] HRMS (ESI): Calcd. for C17H11ClF3N [M+H]+: 322.0605; found: 322.0601.

[0066] ​​​Based on the above data, the structure of the product is inferred as follows:

[0067]

[0068] Example 5

[0069] 1.0 mmol N-(4-bromophenyl)-trifluoroacetylimide ylide, 2.0 mmol phenylacetylene, 0.05 mmol dichloro(pentamethylcyclopentadienyl)iridium dimer, and 5.0 mL acetonitrile were added to a Schlenk tube, and the reaction was carried out at 80 °C for 5 hours under nitrogen atmosphere. After cooling to room temperature, the solvent was removed by vacuum distillation. The target product 3e was obtained by column chromatography separation and purification, with petroleum ether as the eluent, and a yield of 75%.

[0070] The proton and carbon spectra of the obtained product 3e are as follows: Figure 9 and Figure 10 As shown, the structural characterization data are as follows:

[0071] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=8.4Hz,1H),8.03(d,J=8.4Hz,1H),7.80(t,J=8.0Hz ,1H),7.65(t,J=7.6Hz,1H),7.47–7.43(m,3H),7.06(d,J=8.0Hz,2H),4.46(s,2H).

[0072] 13 C NMR(101MHz,CDCl3)δ148.58,147.38,147.80(q,J C-F =34.3Hz),136.78,132.06,130.99,130.58,130.50,128.78,128.01,123.74,121.54(q,J C-F =275.5Hz), 120.93, 117.35(q,J) C-F =2.0Hz), 37.93.

[0073] MS(EI,m / z):365[M] + .

[0074] HRMS(ESI):Calcd.for C 17 H 11 BrF3N[M+H] + :366.0100; found:366.0095.

[0075] Based on the above data, the structure of the product is inferred as follows:

[0076]

[0077] In summary, the application synthesizes 2-trifluoromethyl-4-benzyl quinoline compounds by one-pot method with trifluoromethyl imine ylide and terminal alkyne as raw materials. The application has the advantages of simple synthesis steps, easy-to-obtain raw materials, safe synthesis operation, etc. Without catalyst, the application has high reaction conversion rate and low cost, which is conducive to industrial production.

[0078] While embodiments of the application have been shown and described, it is to be understood that the embodiments described are merely exemplary of the principles and application of the present application. Numerous modifications and adaptions can be effected without departing from the spirit and scope of the present application, which is not limited to the embodiments disclosed herein, but is only defined by the claims and their equivalents.

Claims

1. A method for synthesizing a 2-trifluoromethyl-4-benzylquinoline compound, characterized in that, The synthesis includes the following steps: In a reactor, compound 1, compound 2, catalyst, and an appropriate amount of solvent are added, and the temperature is raised to 80°C for 5 hours. After the reaction is completed, the mixture is cooled to room temperature, the reaction solution is diluted, filtered, and distilled under reduced pressure to obtain the crude product. The crude product is then purified by column chromatography to obtain 2-trifluoromethyl-4-benzylquinoline compounds. The reaction equation is as follows: ； Compound 1 refers to a compound having the structure of formula (1): trifluoromethylimine ylide; Compound 2 refers to a compound having the structure of formula (2): phenylacetylene; ； Among them, R 1 It is 4-cyano, 4-methyl, 3-nitro, 4-chloro, 4-bromo; R 2 It is phenyl; The catalyst refers to dichloro(pentamethylcyclopentadienyl)iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, and dichloro( p Any one of the 1,3-methylisopropylbenzene (M2M)ruthenium dimers.

2. The method for synthesizing a 2-trifluoromethyl-4-benzylquinoline compound according to claim 1, characterized in that, The molar ratio of compound 1 to compound 2 is 1:1~3.

3. The method for synthesizing a 2-trifluoromethyl-4-benzylquinoline compound according to claim 1, characterized in that, The solvent is any one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane, and toluene; the ratio of solvent to compound 1 is 1~3 mL: 0.2 mmol.

4. The method for synthesizing a 2-trifluoromethyl-4-benzylquinoline compound according to claim 1, characterized in that, The molar ratio of catalyst to compound 1 is 0.05~0.1:

1.

5. The method for synthesizing a 2-trifluoromethyl-4-benzylquinoline compound according to claim 1, characterized in that, The eluent used for column chromatography purification is a mixed solvent of petroleum ether and ethyl acetate in a volume ratio of 10:1~2.

6. The method for synthesizing a 2-trifluoromethyl-4-benzylquinoline compound according to claim 1, characterized in that, The reactor refers to a Schlenk tube.

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