A method for synthesizing quinoline compounds from 2-aminobenzyl alcohol and phenylethanone derivatives

Abstract

The application belongs to the technical field of organic synthesis chemistry, and relates to a method for synthesizing quinoline compounds by synthesizing 2-amino benzyl alcohol and phenylethanone derivatives. The 2-amino benzyl alcohol, the phenylethanone derivative and the Ru / ETS-10 zeolite catalyst are sequentially added into a reaction tube, mixed in an organic solvent 1,4-dioxane, and reacted at 60-120 DEG C for 2-8 hours. After the reaction is completed, corresponding quinoline derivatives are obtained by separation and purification. Compared with the prior art, the method has the advantages of simple operation, mild reaction conditions, good substrate universality and the like, and has great application potential in the synthesis of pharmaceutical intermediates.

Description

Technical Field

[0001] This invention relates to the field of heterogeneous catalytic organic synthesis, and discloses a method for synthesizing quinoline compounds from 2-aminobenzyl alcohol and acetophenone derivatives using a heterogeneous catalyst. Technical Background

[0002] Quinoline compounds are an important class of nitrogen-containing heterocyclic compounds that are widely found in various natural products, pharmaceuticals, agrochemicals, dyes and materials. Due to their wide application in antibacterial, anti-inflammatory and other fields, many synthetic methods have been developed to construct this N-heterocyclic structure. In recent years, the preparation of quinolines catalyzed by transition metal Ru has attracted considerable attention. For example: (1) RuCl3, SnCl2, and bis(diphenylphosphine) catalyze the reaction of aniline with trialkylamine, with hexene added as an additive to synthesize quinoline compounds (Chem. Commun. 2000, 1885-1886.); (2) RuCl2(DMSO)4 is used as a catalyst, with benzophenone as an additive to catalyze the condensation reaction of 2-aminophenyl ketone derivatives with alcohols (Eur. J. Org. Chem. 2007, 2007, 1599-1605.); (3) Ruthenium complexes catalyze the reaction of amino alcohols with secondary alcohols (Chem. Commun. 2013, 49, 6632-6634.; ACS Catal. 2016, 6, 1247-1253.). However, these methods have many drawbacks, such as high reaction temperature, long reaction time, large catalyst loading, poor catalyst stability, and the need for additional additives. Summary of the Invention

[0003] The purpose of this invention is to overcome the shortcomings of the prior art. By using Ru / ETS-10 zeolite material, quinoline compounds can be synthesized from 2-aminobenzyl alcohol and acetophenone derivatives under mild conditions, avoiding the use of soluble metal salts and additives, and exhibiting excellent conversion rate and selectivity.

[0004] To achieve the above objectives, the technical solution adopted by the present invention is as follows:

[0005] 2-Aminobenzyl alcohol, acetophenone derivative, metal catalyst Ru / ETS-10 and solvent were sequentially added to a glass reaction tube and reacted at 60-120℃ for a period of time. After the reaction was completed, the catalyst was separated by centrifugation, and the liquid product was obtained by low-pressure rotary evaporation. The crude product was purified by column chromatography to obtain the corresponding quinoline derivative.

[0006] Furthermore, the general structural formula of acetophenone derivatives is as follows: R can be located at the ortho, meta, or para position, and R can be H, methyl, butyl, methoxy, fluorine, chlorine, bromine, or a benzene ring.

[0007] Furthermore, the reaction temperature in this invention is 60–120°C, preferably 80°C. Furthermore, the reaction time in this invention is 2–8 hours, preferably 6 hours.

[0008] Furthermore, the solvent in this invention can be one of acetonitrile, toluene, 1,4-dioxane and DMF, preferably 1,4-dioxane.

[0009] Furthermore, the Ru / ETS-10 catalyst is obtained by impregnating ETS-10 zeolite with Ru in equal volumes. For example, water glass, sodium hydroxide, potassium fluoride aqueous solution and titanium trichloride solution are mixed evenly, loaded into a reactor, crystallized at high temperature, filtered, washed, dried and calcined at high temperature to obtain ETS-10 zeolite; a certain amount of RuCl3·3H2O is weighed and added to distilled water, and after obtaining a mixed solution, it is impregnated with ETS-10 zeolite in equal volumes. After standing at room temperature, drying in an oven and calcining in a muffle furnace, the Ru-loaded ETS-10 catalyst is obtained, which is Ru / ETS-10, and the Ru loading is 1 to 3 wt.%.

[0010] Furthermore, the molar composition of each substance in the reaction gel system during the preparation of ETS-10 zeolite is as follows: Na2O:K2O:SiO2:TiO2:H2O=8~15:1~8:3~28:1~3.5:180~360.

[0011] Furthermore, the high-temperature crystallization conditions were 150–200℃ for 2–3 days; the high-temperature calcination temperature was 400–550℃, resulting in the ETS-10 zeolite catalyst, in which the silicon-to-titanium ratio in the zeolite synthesis system was 3–8.

[0012] Compared with the prior art, the present invention has the following technical advantages:

[0013] This invention provides a method for synthesizing quinoline compounds from 2-aminobenzyl alcohol and acetophenone derivatives using alkaline Ru / ETS-10 zeolite as a catalyst. Quinoline compounds can be synthesized using only Ru-containing Ru / ETS-10 zeolite, and the catalyst is simple to prepare, easily separated, recovered, and reused. Attached Figure Description

[0014] Figure 1 The hydrogen spectrum of the cyclization product of acetophenone and 2-aminobenzyl alcohol in Example 1;

[0015] Figure 2 The 1H NMR spectrum of the cyclized product of p-chloroacetophenone and 2-aminobenzyl alcohol in Example 2;

[0016] Figure 3 The 1H NMR spectrum of the cyclized product of p-methoxyacetophenone and 2-aminobenzyl alcohol in Example 3;

[0017] Figure 4The photon spectrum is the proton NMR spectrum of the cyclized product of 4-butylacetophenone and 2-aminobenzyl alcohol in Example 4. Detailed Implementation

[0018] The following examples will help to illustrate the present invention, but are not intended to limit its scope.

[0019] The preparation method of the Ru / ETS-10 zeolite catalyst in the example is as follows:

[0020] 20.8 g of water glass was added dropwise to a 150 mL beaker; 3.0 g of NaOH was weighed and dissolved in 10 mL of distilled water to prepare a NaOH solution, which was then added to the water glass solution; 2.1 g of KF was weighed and dissolved in 20.0 mL of distilled water to prepare a KF solution, which was then added to the water glass mixture; after stirring for 20 min, 13.4 g of TiCl3 hydrochloric acid solution was added dropwise; the mixture was stirred for 120 min; finally, the mixture was placed in a polytetrafluoroethylene-lined reactor and crystallized at 230 °C for 60 h under static conditions. After washing with water to neutralize, the mixture was filtered, dried, and calcined at 500 °C for 5 h to obtain ETS-10. The molar ratio of the reaction gel system was Na2O:K2O:SiO2:TiO2:H2O = 4.2:1.21:6:1:188.4.

[0021] 0.052 g of ruthenium chloride trihydrate was dissolved in 1.2 g of water to obtain a clear and transparent solution. This solution was then mixed thoroughly with 2.0 g of ETS-10 zeolite. The mixture was allowed to stand at room temperature, dried at 120°C, and calcined at 400°C to obtain the target catalyst Ru / ETS-10, wherein the Ru loading was 1 wt.%. This catalyst is designated as 1 wt.%-Ru / ETS-10. It was used in the following examples.

[0022] The above-described method for preparing 1wt.% Ru / ETS-10, under the same conditions, yields Ru / ETS-10 catalysts with Ru loadings of 0.5wt.%, 2wt.%, and 3wt.%, respectively, denoted as 0.5wt.%-Ru / ETS-10, 2wt.%-Ru / ETS-10, and 3wt.%-Ru / ETS-10.

[0023] Example 1:

[0024]

[0025] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate, volume ratio 15:1) to obtain the product. The conversion rate is 97%, the selectivity is 100%, and the product yield can reach 97%.

[0026] The characterization data of the product are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.26-8.11(m,4H),7.84(dd,J=17.8,9.0Hz,2H),7.55-7.50(m,3H),7.49-7.46(m,1H).

[0027] Example 2:

[0028]

[0029] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of p-chloroethyl ketone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate, volume ratio 15:1) to obtain the product. The conversion rate is 93%, the selectivity is 100%, and the product yield can reach 93%.

[0030] The characterization data of the product are as follows: 1 H NMR (400MHz, Chloroform-d) δ8.20-7.98 (m, 4H), 7.72 (dq, J=14.8, 7.7Hz, 3H), 7.46 (dd, J=20.4, 7.9Hz, 3H).

[0031] Example 3:

[0032]

[0033] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of p-methoxyethyl ketone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. The conversion rate is 92%, the selectivity is 100%, and the product yield can reach 92%.

[0034] The characterization data of the product are as follows: 1 HNMR(400MHz,Chloroform-d)δ8.22-8.12(m,4H),7.82(dd,J=12.6,8.3Hz,2H),7.7 2(td,J=6.9,3.4Hz,1H),7.50(t,J=7.5Hz,1H),7.05(d,J=8.7Hz,2H),3.89(s,3H).

[0035] Example 4:

[0036]

[0037] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of 4-butylacetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. The conversion rate is 95%, the selectivity is 100%, and the product yield can reach 95%.

[0038] The characterization data of the product are as follows: 1 H NMR(400MHz,Chloroform-d)δ8.16(d,J=9.5Hz,1H),8.05(d,J=8.4Hz,3H),7.77-7.61(m,3H),7.42(t,J=6. 9Hz,1H),7.32-7.25(m,2H),2.68-2.60(m,2H),1.66-1.55(m,2H),1.40-1.30(m,2H),0.92(t,J=7.4Hz,3H).

[0039] Example 5:

[0040] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 60 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 53%.

[0041] Example 6:

[0042] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 100 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 98%.

[0043] Example 7:

[0044] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 2 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 45%.

[0045] Example 8:

[0046] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 4 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 70%.

[0047] Example 9:

[0048] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 8 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 97%.

[0049] As shown in Examples 5-9, when the reaction time is 6 hours, the product yield gradually increases with increasing temperature. When the temperature is 80°C, the product yield gradually increases with increasing time, and then stabilizes after 6 hours. From the perspective of practical industrial application, we prefer 80°C and 6 hours as the optimal reaction conditions.

[0050] Example 10

[0051] Weigh 20 mg of 0.5 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 50%.

[0052] Example 11

[0053] 20 mg of 2 wt.% Ru / ETS-10 catalyst was weighed into a reaction tube, followed by the addition of 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation was completed, the reaction was carried out in a reactor at 80 °C for 6 h. After the experiment, the mixture was cooled to room temperature and centrifuged. The resulting liquid product was separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) after rotary evaporation. The product was obtained. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 95%.

[0054] Example 12

[0055] 20 mg of 3 wt.% Ru / ETS-10 catalyst was weighed into a reaction tube, followed by the addition of 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation was completed, the reaction was carried out in a reactor at 80 °C for 6 h. After the experiment, the mixture was cooled to room temperature and centrifuged. The resulting liquid product was separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) after rotary evaporation. The product was obtained. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 82%.

[0056] Comparative Example 1

[0057] 20 mg of 1 wt.% Ru / ETS-10 catalyst was weighed into a reaction tube, followed by the addition of 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of acetonitrile. After the operation was completed, the reaction was carried out in a reactor at 80 °C for 6 h. After the experiment, the mixture was cooled to room temperature and centrifuged. The resulting liquid product was separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) after rotary evaporation. The product was obtained. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 57%.

[0058] Comparative Example 2

[0059] 20 mg of 1 wt.% Ru / ETS-10 catalyst was weighed into a reaction tube, followed by the addition of 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of toluene. After the operation was completed, the reaction was carried out in a reactor at 80 °C for 6 h. After the experiment, the mixture was cooled to room temperature and centrifuged. The resulting liquid product was separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) after rotary evaporation. The product was obtained. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 70%.

[0060] Comparative Example 3

[0061] Weigh 20 mg of 1 wt.% Ru / ETS-10 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of DMF. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 50%.

[0062] Comparative Example 4

[0063] The Ru / TS-1 catalyst was applied to this reaction. The catalyst was prepared as follows: 0.052 g of ruthenium chloride trihydrate was dissolved in 1.0 g of water to obtain a clear and transparent solution. The prepared solution was then mixed with 2.0 g of TS-1 zeolite. The mixture was allowed to stand at room temperature, dried at 120 °C, and calcined at 400 °C to obtain the target catalyst Ru / TS-1, wherein the Ru loading was 1 wt.%. This catalyst is denoted as 1 wt.%-Ru / TS-1.

[0064] Weigh 20 mg of 1 wt.% Ru / TS-1 catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 74%.

[0065] Comparative Example 5

[0066] The Ru / Beta catalyst was applied to this reaction. The catalyst was prepared as follows: 0.052 g of ruthenium chloride trihydrate was dissolved in 1.5 g of water to obtain a clear and transparent solution. The prepared solution was then mixed with 2.0 g of Beta zeolite. The mixture was allowed to stand at room temperature, dried at 120 °C, and calcined at 400 °C to obtain the target catalyst Ru / Beta, wherein the Ru loading was 1 wt.%. This catalyst is denoted as 1 wt.%-Ru / Beta.

[0067] Weigh 20 mg of 1 wt.% Ru / Beta catalyst into a reaction tube, then add 0.3 mmol of 2-aminobenzyl alcohol, 0.4 mmol of acetophenone, and 1 mL of 1,4-dioxane. After the operation is complete, react in a reactor at 80 °C for 6 h. After the experiment, cool to room temperature and centrifuge the reaction system. After rotary evaporation, the obtained liquid product is separated by rapid column chromatography (eluting reagents: petroleum ether and ethyl acetate in a volume ratio of 15:1) to obtain the product. GC analysis of the reaction liquid phase was performed to calculate the conversion and selectivity of the reaction. The product yield was 53%.

[0068] The optional embodiments of the present invention have been described above to teach those skilled in the art how to implement and reproduce the invention. Unless otherwise specified, the raw materials and equipment used in this invention are commonly used in the art; the methods used in this invention, unless otherwise specified, are conventional methods in the art. For the purpose of teaching the present invention, some conventional technical aspects have been simplified and omitted. Those skilled in the art should understand that variations derived from these aspects are within the scope of protection of this invention.

Claims

1. A method for synthesizing quinoline compounds from 2-aminobenzyl alcohol and acetophenone derivatives, characterized in that: 2-Aminobenzyl alcohol, acetophenone derivatives, Ru / ETS-10 catalyst, and an organic solvent were mixed and reacted at 80°C for 6–8 h. After the reaction, the catalyst was separated by centrifugation, and the product, namely a quinoline compound, was obtained by purification. The organic solvent was 1,4-dioxane. The Ru loading in the Ru / ETS-10 catalyst was 1–3 wt.%. ； R can be H, methyl, butyl, methoxy, fluorine, chlorine, or bromine.

2. The method for synthesizing quinoline compounds from 2-aminobenzyl alcohol and acetophenone derivatives according to claim 1, characterized in that: The Ru loading in the Ru / ETS-10 catalyst is 1 wt.%.

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