RU2831364C1 - Method of producing 2,4-dimethylquinoline - Google Patents

Abstract

FIELD: organic chemistry.

SUBSTANCE: invention relates to organic chemistry, specifically to a method of producing 2,4-dimethylquinoline, which is used in medicine, optical materials and methods of analysis. Method of production involves catalytic cyclocondensation of 2-aminoacetophenone with acetone and is characterized by that the catalyst used is granular Y_h or ZSM-5_h zeolites in H-form with a hierarchical porous structure, with catalyst content of 5-40 wt.% with respect to 2-aminoacetophenone. Process is carried out in an autoclave at autogenous pressure of 180 °C, molar ratio of 2-aminoacetophenone : acetone 1:1-3, for 1-5 hours.

EFFECT: providing a simplified method of synthesis of the end product, reducing energy and material consumption of the heterocyclisation process.

1 cl, 1 tbl, 8 ex

Description

The invention relates to the field of organic chemistry, in particular to a method for producing 2,4-dimethylquinoline ( 1 ).

2,4-Dimethylquinoline ( 1 ) is used as a scaffold of biologically active compounds in the pharmaceutical industry. For example, substituted 2,4-dimethylquinolines possess antioxidant, antibacterial, antifungal, antimalarial, and anticancer activities [ M. Brahmayya, B. Venkateswara Rao, U. Viplavaprasad, MV Basaveswara Rao, K. Raghu Babu, B. Kishore Babu, K. Rajkumara, Ch. Praveen, N. Giribabud, M. Vijaya, Ch. V. Padmarao, N. Srinivasa Rao (2012). J. of Appl. Pharm. Sci., 2 (10), 041–044; Patel, DB, Darji, DG, Patel, KR, Rajani, DP, Rajani, SD, & Patel, HD (2020). Journal of Heterocyclic Chemistry, 57(3), 1183-1200; Kidwai, M., Bhushan, K. R., Sapra, P., Saxena, R. K., & Gupta, R. (2000). Bioorganic & Medicinal Chemistry, 8(1), 69-72; Temple, K. J., Engers, J. L., Long, M. F., Gregro, A. R., Watson, K. J., Chang, S., Lindsley, C. W. (2019). Bioorganic & Medicinal Chemistry Letters, 126678; US2022291237A1 ].

In addition to medicine, compound ( 1 ) is used in the composition of a light-absorbing layer for optical materials [ JP2022150261A; JP2022077664A; WO2021107038A1; JP6658942B1; WO2022196615A1 ] and for the detection of various compounds by liquid chromatography-mass spectrometry [ CN109187805A; CN109212087A; CN109212088B ].

Of interest is the possibility of using 2,4-dimethylquinoline ( 1 ) to determine the concentration of acid sites on the outer surface of zeolites [ Kim, JH., Ishida, A. & Niwa, M. (1999). React Kinet Catal Lett, 67, 281-287 ].

One of the most important and effective synthetic methods for the synthesis of compounds containing a quinoline framework is the Friedlander reaction. According to this method, 2,4-dimethylquinoline ( 1 ) is obtained by the reaction of 2-aminoacetophenone with acetone:

Propylphosphoric anhydride is known as a catalyst for this reaction, which allows the synthesis of 2,4-dimethylquinoline ( 1 ) with a yield of up to 96% [ Augustine JK (2011). Tetrahedron Letters, 52(50), 6814-6818 ]. The reaction was carried out under the following conditions: 20 mol. % T3P, dimethylformamide DMF, 90°C, 4-6 h.

The disadvantage of this method is the use of DMF solvent; the use of a homogeneous catalyst, which leads to a multi-stage process, complex separation of products from catalysts, and the impossibility of their reuse. Heterogeneous catalysts are free of such disadvantages.

The authors [ Heravi, Majid M.; et al (2010). E-Journal of Chemistry, 7(3), 875-881 ] used phosphotungstic acid H ₆ [P ₂ W ₁₈ O ₆₂ ] as a catalyst to obtain 2,4-dimethylquinoline ( 1 ) via the Friedlander reaction. The reaction was carried out at 70°C, with a molar ratio of 2-aminoacetophenone:acetone = 1:1.2, for 5 h. The yield of 2,4-dimethylquinoline ( 1 ) was 90%. Despite the high acidity of heteropoly acids, a disadvantage of their use as heterogeneous catalysts without a support is the low specific surface area (<5 m ² /g) [ da Silva MJ, Rodrigues AA, Lopes NPG (2023). Chemistry, 5(1), 662–690 ].

Among other heterogeneous catalysts, zeolite catalysts have found wide application; they possess not only high acidity and specific surface area, but also regular geometry of channels and cavities, good thermal stability, and other properties necessary for catalysis.

The objective of the present invention is to develop an efficient heterogeneous catalytic method for producing 2,4-dimethylquinoline ( 1 ).

The solution to the problem is achieved by the fact that the method for obtaining 2,4-dimethylquinoline ( 1 ) is carried out by the condensation reaction of 2-aminoacetophenone and acetone in the presence of granulated zeolites ZSM-5 _h and Y _h in the H-form with a hierarchical (micro-meso-macro) porous structure. The reaction is carried out in an autoclave, at a molar ratio of ketoamine: acetone = 1:1-3, at 180 °C for 1-5 hours. The amount of catalyst is 5-40% by weight based on 2-aminoacetophenone.

Zeolites ZSM-5 _h and Y _h are synthesized in the form of granules without binders. The resulting granules are single intergrowths of zeolite crystals and have a degree of crystallinity close to 100%. The porous structure of the granules consists of the microporous structure of the zeolite itself and the secondary meso/macroporous structure formed between the intergrowths of crystals. A significant advantage of granulated zeolites H-ZSM-5 _h and HY _h over highly dispersed zeolites is that they are synthesized in granules. The granulated catalyst has better physical properties: it does not dust, does not cake, is easily dispersed and is easily separated from the reaction mass by filtration (unlike the highly dispersed catalyst, which quickly clogs the filter or passes through the filter cloth). The use of zeolites in the synthesis of 2,4-dimethylquinoline ( 1 ) is unknown.

Traditionally, granulated zeolites are synthesized as follows: highly dispersed zeolite is mixed with a binder, and then the resulting mixture is formed into granules [ Mukhlenov I.P., Dobkina E.I., Deryuzhkina V.I., Soroko V.E. / Ed. by Doctor of Technical Sciences, Professor Mukhlenov I.P. Catalyst Technology. Industrial Edition. Leningrad Chemistry. 1989. 137 p .]. The introduction of a binder into the granules reduces the adsorption capacity and catalytic activity of zeolites compared to highly dispersed zeolites, and in some cases it is not possible to ensure the mechanical strength of the granulated materials obtained in this way. The granules of the H-ZSM-5 _h and HY _h catalysts are 100% zeolite and do not contain a binder.

Zeolites H-ZSM-5 _h and HY _h have a combined micro-meso-macroporous crystalline structure, which is highly stable and does not deteriorate during the ion exchange of Na ⁺ cations for H ⁺ .

The use of the proposed method has the following advantages:

1) A known catalyst, for example, a heteropoly acid, has a low specific surface area, while the granulated zeolites we used are characterized by a developed specific surface area [ Travkina OS, Agliullin MR, Filippova NA, Khazipova AN, Danilova IG, Grigor'eva NG, Narender N, Pavlov ML, Kutepov BI // RSC Advances. 7 (2017) 32581-32590; NG Grigorieva, OS Travkina, SV Bubennov, NA Filippova, AS Artem'eva, AV Bayburtli, , RZ Kuvatova, BI Kutepov // Kinetics and Catalysis. 63( 2022) 781-792].

2) Granulated zeolites in the proposed method have improved mechanical properties.

3) The use of granulated catalysts is much more technologically advanced than the use of highly dispersed materials.

4) Zeolite catalysts are environmentally friendly materials.

5) Granular zeolite catalysts are easily removed by filtration and can be used repeatedly.

The granulated hierarchical zeolite catalyst HY _h is synthesized in the Na form using the method described in [ Travkina OS, Agliullin MR, Filippova NA, Khazipova AN, Danilova IG, Grigor'eva NG, Narender N, Pavlov ML, Kutepov BI // RSC Advances. 7 (2017) 32581-32590; Russian Federation Patents No. 2540086, No. 2553876 ], and the zeolite catalyst H-ZSM-5 _h is synthesized using the method described in the patent [ Russian Federation Patent No. 2739350 ]. By ion exchange from a NH ₄ NO ₃ solution, the zeolite Na-Y _h is converted into the NH ₄ form; subsequent calcination at 540°C for 4 hours converts it into the H form.

The reaction of 2-aminoacetophenone with acetone is carried out in an autoclave at autogenous pressure, 180°C, with a molar ratio of 2-aminoacetophenone: acetone = 1: 1-3, in the presence of 5-40% catalyst (based on 2-aminoacetophenone), for 1-5 hours.

The reaction products after separation of the catalyst are extracted with methylene chloride and analyzed using GLC on a Crystalux 4000M chromatograph (thermal conductivity detector, Agilent glass capillary column with DB-5 phase (50 m x 0.32 mm; layer thickness 0.52 μm), programmed heating 100 - 250 °C at a rate of 8 °C/min, carrier gas helium). The degree of conversion of the initial 2-aminoacetophenone is determined relative to the internal standard - toluene.

The invention is illustrated by the following examples.

EXAMPLE 1. 0.15 g of 2-aminoacetophenone (0.0011 mol), 0.19 g of acetone (0.0033 mol) and 0.015 g of zeolite H-Y _h (10% by weight based on 2-aminoacetophenone) are loaded into an autoclave. The autoclave is hermetically sealed and placed in a thermostatted cabinet. The reaction is carried out at 180°C for 5 hours with stirring. After completion of the synthesis, the autoclave is cooled, the reaction mass is separated from the catalyst by filtration and extracted with dichloromethane. 2,4-Dimethylquinoline ( 1 ) is isolated using column chromatography. The selectivity for the formation of dimethylquinoline ( 1 ) is 99%, the conversion of 2-aminoacetophenone is 74%.

EXAMPLES 2-8. Similar to example 1. The conditions and results of the examples are presented in the table.

Table. Synthesis of 2,4-dimethylquinoline ( 1 ) in the presence of granulated zeolite catalysts HY _h and H-ZSM-5 _h

Rolled-
congestion T, °C Quantity
catalyst,
% wt. Time,
h Ratio
2-aminoacetophenone:acetone, mol/mol Conversion
2-aminoacetophenone,% Selectivity, % ( 1 ) Other 1 H-Y _h 180 10 5 1:3 74 99 1 2 H-Y _h 180 10 1 1:3 37 100 0 3 H-Y _h 180 5 5 1:3 63 89 11 4 H-Y _h 180 25 5 1:3 64 95 5 5 H-Y _h 180 40 5 1:3 73 96 4 6 H-ZSM-5 _h 180 25 5 1:3 64 95 5 7 H-ZSM-5 _h 180 25 5 1:2 62 84 16 8 H-ZSM-5 _h 180 25 5 1:1 61 74 26

(1) - 2,4-dimethylquinoline

Claims (1)

A method for producing 2,4-dimethylquinoline by catalytic cyclocondensation of 2-aminoacetophenone with acetone, characterized in that granulated zeolites Y _h or ZSM-5 _h in the H-form with a hierarchical porous structure are used as a catalyst, the reaction is carried out in the presence of 5-40 wt.% of the catalyst based on 2-aminoacetophenone, in an autoclave at autogenous pressure, 180°C, a molar ratio of 2-aminoacetophenone: acetone of 1:1-3, for 1-5 hours.