Synthesis method of 2-trifluoromethyl-4-benzylquinoline compound

Abstract

The invention relates to the technical field of pharmaceutical and chemical synthesis, in particular to a synthesis method of a 2-trifluoromethyl-4-benzylquinoline compound, which comprises the following steps: adding a compound 1, a compound 2, an additive, a catalyst and a proper amount of solvent into a reactor, stirring for 5 hours under the condition of nitrogen at 80 DEG C, cooling to room temperature after the reaction is finished, diluting reaction liquid, and filtering to obtain the 2-trifluoromethyl-4-benzylquinoline compound. And carrying out reduced pressure distillation to obtain a crude product, and carrying out column chromatography purification to obtain the 2-trifluoromethyl quinoline compound. According to the invention, a trifluoromethyl imine ylide compound and phenylacetylene are taken as raw materials, and the 2-trifluoromethyl quinoline compound is synthesized by a one-pot method. The method has the advantages of simple synthesis steps, easily available raw materials, safe synthesis operation, good functional group compatibility and the like; the catalyst is high in efficiency, low in cost and beneficial to industrial production.

Description

Technical Field

[0001] The invention relates to the technical field of pharmaceutical chemical synthesis, and in particular to a method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds. Background Art

[0002] Quinoline is an important benzoic six-membered nitrogen heterocyclic structure. Quinoline and its derivatives are the most important six-membered nitrogen heterocyclic compounds, which are widely used in the fields of medicinal chemistry, organic chemistry and natural products. In particular, trifluoromethyl nitrogen heterocyclic rings are important structural parts in biological and pharmaceutically active compounds, with antioxidant, anti-inflammatory, anti-tumor, anti-hyperlipidemic and anti-microbial effects. It is well known that the introduction of trifluoromethyl groups into the parent molecule can greatly change its physicochemical properties, such as dissociation constant, lipophilicity and metabolic stability. Therefore, the development of efficient and practical strategies to synthesize 2-trifluoromethylquinoline is of great significance in the fields of organic chemistry and medicinal chemistry.

[0003] Some effective synthesis methods have been established for the synthesis of trifluoromethylquinoline compounds. In 2001, Uneyama and his colleagues successfully disclosed a method for synthesizing 2-trifluoromethylquinoline derivatives by Rh-catalyzed N-aryl trifluoroacetimidoyl chloride and 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). In 2013, Zhou and his colleagues reported the [4+2] reaction of trifluoroacetimidoyl chloride 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 colleagues disclosed the synthesis of quinoline from o-azidobenzaldehyde and fluorinated 1,3-diketone via [4+2] cyclization (Zhang, X.; Ma, X.; Qiu, W.; Evans, J.; Zhang, W., Cascade Knoevenageland 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, low atom and step economy, and poor regioselectivity. Therefore, from a scientific and practical point of view, the development of new and efficient methods to synthesize 2-trifluoromethyl-4-benzylquinoline from readily available materials under environmentally friendly conditions remains extremely challenging and attractive. Summary of the invention

[0004] In view of the above problems, the present invention provides a method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds. The method is safe and simple to operate, the raw materials are readily available, the catalyst is highly efficient, recyclable, and low in cost, and is conducive to industrial production.

[0005] In order to achieve the above object, the technical solution adopted by the present invention is as follows:

[0006] A method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds comprises the following synthesis steps:

[0007] In a reactor, compound 1, compound 2, a metal catalyst and an appropriate amount of solvent were added, and stirred for 5 hours under air conditions at 80°C. After the reaction was completed, the mixture was cooled to room temperature, the reaction solution was diluted, filtered, and distilled under reduced pressure to obtain a crude product, which was purified by column chromatography to obtain a 2-trifluoromethyl-4-benzylquinoline compound, the reaction equation of which is as follows:

[0008]

[0009] The compound 1 is a compound having a structure of formula (1): trifluoromethylimine ylide; the compound 2 is a compound having a structure of formula (2): phenylacetylene.

[0010]

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

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

[0013] Preferably, the solvent refers to any one of acetonitrile, tetrahydrofuran, N,N-dimethylformamide, dioxane and toluene; the solvent is preferably acetonitrile; the ratio of the solvent to compound 1 is 1 to 3 mL: 0.2 mmol, and the ratio of the solvent to 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; the catalyst here preferably refers to: dichloro(pentamethylcyclopentadienyl)iridium dimer; the molar ratio of the catalyst to compound 1 is 0.05-0.1:1, and the molar ratio of the catalyst to compound 1 here is preferably 0.05:1.

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

[0016] Preferably, the temperature is 80°C to 120°C, and the temperature preferably is 80°C.

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

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

[0019] 1. The present invention uses trifluoromethylimine ylide compounds and phenylacetylene as raw materials to synthesize 2-trifluoromethylquinoline compounds through a 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 industrial production.

[0020] 2. The present invention does not need to use traditional diazo compounds as metal carbene precursors, thus avoiding the release of a large amount of nitrogen and causing danger; secondly, the present invention utilizes trifluoromethyl synthons to efficiently synthesize fluoroquinoline compounds, thus avoiding the use of expensive fluorination reagents and having good selectivity. BRIEF DESCRIPTION OF THE DRAWINGS

[0021] Figure 1 is the hydrogen spectrum of the product 3a obtained in Example 1 of the present invention;

[0022] Figure 2 This is the carbon spectrum of the product 3a obtained in Example 1 of the present invention;

[0023] Figure 3 is the hydrogen spectrum of the product 3b obtained in Example 2 of the present invention;

[0024] Figure 4 This is the carbon spectrum of the product 3b obtained in Example 2 of the present invention;

[0025] Figure 5 is the hydrogen spectrum of the product 3c obtained in Example 3 of the present invention;

[0026] Figure 6 This is the carbon spectrum of the product 3c obtained in Example 3 of the present invention;

[0027] Figure 7 This is the hydrogen spectrum of the product 3d obtained in Example 4 of the present invention;

[0028] Figure 8 This is the carbon spectrum of product 3d obtained in Example 4 of the present invention.

[0029] Fig. 9 This is the hydrogen spectrum of the product 3e obtained in Example 5 of the present invention;

[0030] Fig.10 This is the carbon spectrum of the product 3e obtained in Example 5 of the present invention. DETAILED DESCRIPTION

[0031] The present invention is further described in detail below in conjunction with embodiments and drawings, but the embodiments of the present invention are not limited thereto.

[0032] Example 1

[0033] 1.0 mmol N-(4-cyanophenyl) trifluoroacetimide ylide, 2.0 mmol phenylacetylene, 0.05 mmol dichloro(pentamethylcyclopentadienyl)iridium dimer and 5.0 ml acetonitrile were added to a schlenk tube and reacted at 80°C for 5 hours under nitrogen. After the system was cooled to room temperature, the solvent was removed by vacuum distillation. The target product 3a was obtained by column chromatography separation and purification. The column chromatography eluent used was petroleum ether solvent, and the yield was 81%.

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

[0035] 1 H NMR (400MHz, CDCl3) δ8.51(s,1H),8.33(d,J=8.8Hz,1H),7.93Z(d,J=8.8Hz,1H),7.60(s,1H),7.39–7.31(m,3H),7.19(d,J=7.2Hz,2H),4.54(s,2H).

[0036] 13 C NMR(101MHz,CDCl3)δ150.64,150.50(q,J C-F =35.3Hz),148.34,136.69,132.45,131.05,130.39,129.29,128.80,127.73,127.50,121.10(q,J C-F =276.7Hz),118.93(q,J C-F =2.0Hz),118.22,112.38,38.40.

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

[0038] HRMS(ESI):Calcd.for C 18 H14 F3N[M+H] + :313.0941; found:313.0947.

[0039] According to the above data, the structure of the obtained product is as follows:

[0040]

[0041] Embodiment 2:

[0042] 1.0 mmol N-(4-methylphenyl) trifluoroacetimide ylide, 2.0 mmol phenylacetylene, 0.05 mmol dichloro(pentamethylcyclopentadienyl)iridium dimer and 5.0 ml acetonitrile were added to a schlenk tube and reacted at 80°C for 5 hours under nitrogen. After the system was cooled to room temperature, the solvent was removed by vacuum distillation. The target product 3b was obtained by column chromatography separation and purification. The column chromatography eluent used was petroleum ether solvent, and the yield was 76%.

[0043] The hydrogen and carbon spectra of the obtained product 3b are shown as follows: Figure 3 and Figure 4 The structural characterization data are as follows:

[0044] 1 H NMR(400MHz, CDCl3)δ8.13(d,J=8.4Hz,1H),7.85(s,1H),7.62(d,J=8.8Hz,1H), 7.42(s,1H),7.35–7.26(m,3H),7.19(d,J=7.6Hz,2H),4.47(s,2H),2.55(s,3H).

[0045] 13 C NMR(101MHz,CDCl3)δ148.44,146.88(q,J C-F =33.3Hz),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 =275.7Hz),117.35(q,J C-F =2.0Hz),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] According to the above data, the structure of the obtained product is as follows:

[0049]

[0050] Embodiment 3:

[0051] 1.0 mmol N-(3-nitrophenyl) trifluoroacetimide ylide, 2.0 mmol phenylacetylene, 0.05 mmol 1,5-cyclooctadiene iridium chloride dimer and 5.0 ml acetonitrile were added to the schlenk tube and reacted at 80°C for 5 hours under nitrogen. After the system was cooled to room temperature, the solvent was removed by vacuum distillation. The target product 3c was separated and purified by column chromatography. The column chromatography eluent used was petroleum ether solvent, and the yield was 85%.

[0052] The hydrogen and carbon spectra of the obtained product 3c are shown as follows: Figure 5 and Figure 6 The structural characterization data are as follows:

[0053] 1 H NMR (400MHz, CDCl3) δ8.47–8.45(m,1H),7.94–7.89(m,1H),7.87–7.82(m,1 H),7.43–7.40(m,1H),7.38–7.26(m,3H),7.09–7.07ZZ(m,2H),4.33(s,2H).

[0054] 13 C NMR(101MHz,CDCl3)δ148.21,139.76(q,J C-F =2.3Hz),138.85,134.83,130.81,129.77,128.98,128.49,127.94,123.94,123.89(q,J C-F =38.4Hz),123.63,120.93(q,J C-F =267.7Hz),113.09(q,J C-F =4.0Hz),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] According to the above data, the structure of the obtained product is as follows:

[0058]

[0059] Embodiment 4:

[0060] 1.0 mmol N-(4-chlorophenyl)-trifluoroacetimide ylide, 2.0 mmol phenylacetylene, 0.05 mmol dichloro(p-methylisopropylbenzene)ruthenium dimer and 5.0 ml acetonitrile were added to the schlenk tube and reacted at 80°C for 5 hours under nitrogen. After the system was cooled to room temperature, the solvent was removed by vacuum distillation. The target product 3d was obtained by column chromatography separation and purification. The column chromatography eluent used was petroleum ether solvent, and the yield was 77%.

[0061] The hydrogen and carbon spectra of the obtained product 3d are as follows: Figure 7 and Figure 8 The structural characterization data are as follows:

[0062] 1 H NMR (400MHz, CDCl3) δ8.25(d,J=8.5Hz,1H),8.04(d,J=8.4Hz,1H),7.82–7.79(m,1H),7. 67–7.63(m,1H),7.47(s,1H),7.29(d,J=8.1Hz,2H),7.12(d,J=8.0Hz,2H),4.48(s,2H).

[0063] 13 C NMR(101MHz,CDCl3)δ148.69,147.81(q,J C-F =34.3Hz),147.38,136.25,132.88,130.99,130.58,130.14,129.11,128.76,128.03,123.74,121.54(q,J C-F =275.5Hz),117.34(q,J C-F =2.0Hz),37.86.

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

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

[0066] According to the above data, the structure of the obtained product is as follows:

[0067]

[0068] Example 5

[0069] 1.0 mmol N-(4-bromophenyl)-trifluoroacetimide ylide, 2.0 mmol phenylacetylene, 0.05 mmol dichloro(pentamethylcyclopentadienyl)iridium dimer and 5.0 ml acetonitrile were added to a schlenk tube and reacted at 80°C for 5 hours under nitrogen. After the system was cooled to room temperature, the solvent was removed by vacuum distillation. The target product 3e was obtained by column chromatography separation and purification. The column chromatography eluent used was petroleum ether solvent, and the yield was 75%.

[0070] The hydrogen and carbon spectra of the obtained product 3e are shown as follows: Fig. 9 and Fig.10 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] According to the above data, the structure of the obtained product is as follows:

[0076]

[0077] In summary, the present invention uses trifluoromethylimine ylide and terminal alkyne as raw materials to synthesize 2-trifluoromethyl-4-benzylquinoline compounds through a one-pot method. The present invention has the advantages of simple synthesis steps, easy availability of raw materials, safe synthesis operation, etc., and does not require a catalyst, has a high reaction conversion rate, and low cost, which is conducive to industrial production.

[0078] Although embodiments of the present invention have been shown and described, it will be appreciated by those skilled in the art that various changes, modifications, substitutions and variations may be made to the embodiments without departing from the principles and spirit of the present invention, and that the scope of the present invention is defined by the appended claims and their equivalents.

Claims

1. A method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds, characterized in that: The method comprises the following steps: adding compound 1, compound 2, a catalyst and an appropriate amount of solvent into a reactor and heating the reactor to 80° C. for reaction for 5 hours; cooling the reactor to room temperature after the reaction is completed; diluting the reaction solution, filtering the solution, and performing vacuum distillation to obtain a crude product; and purifying the crude product by column chromatography to obtain a 2-trifluoromethyl-4-benzylquinoline compound. The reaction equation is as follows: The compound 1 is a compound having a structure of formula (1): trifluoromethylimide ylide; the compound 2 is a compound having a structure of formula (2): phenylacetylene; Among them, R 1 is 4-cyano, 4-methyl, 3-nitro, 4-chloro, 4-bromo; R 2 It is phenyl.

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

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

4. A method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds according to claim 1, characterized in that: The catalyst is any one of dichloro(pentamethylcyclopentadienyl)iridium dimer, 1,5-cyclooctadiene iridium chloride dimer, dichloro(p-methylisopropylbenzene)ruthenium dimer and dichloro(pentamethylcyclopentadienyl)rhodium dimer; the molar ratio of the catalyst to compound 1 is 0.05-0.1:

1.

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

6. The method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds according to claim 1, characterized in that: The temperature is 80°C to 120°C.

7. The method for synthesizing 2-trifluoromethyl-4-benzylquinoline compounds according to claim 1, characterized in that: The reactor is referred to as a schlenk tube.

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