A process for the preparation of a 2-trifluoromethyl substituted quinoline compound with heating acceleration
By heating the reaction of trifluoroacetimide sulfur ylide and amine, combined with triphenylphosphine difluoroacetate, the problems of heavy metal catalysis and violent reaction in the existing technology are solved, and a cheap and easy-to-operate 2-trifluoromethylquinoline compound is efficiently synthesized, which is suitable for large-scale application.
Patent Information
- Application Number
- CN202310738490.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Patents(China)
- Current Assignee / Owner
- Filing Date
- 2023-06-21
- Publication Date
- 2025-10-24
- Estimated Expiration
- 2043-06-21
AI Technical Summary
The existing methods for synthesizing 2-trifluoromethyl-substituted quinoline compounds have the problems of using heavy metal catalysts, severe reaction conditions and poor substrate compatibility, making it difficult to achieve green, easy-to-operate and efficient synthesis.
The invention adopts cheap and readily available trifluoroacetimidosulfur ylide and amine as starting materials, combines triphenylphosphine difluoroacetate through a simple heating reaction, and performs a heat-promoted synthesis method without the need for metal catalysts and additives.
A simple and environmentally friendly synthesis of 2-trifluoromethyl-substituted quinoline compounds has been achieved. The reaction conditions are mild, the applicability is wide, it conforms to the concept of green chemistry, and is suitable for large-scale operation.
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Abstract
Description
TECHNICAL FIELD
[0001] The present application belongs to the field of organic synthesis, and particularly relates to a method for efficiently synthesizing 2-trifluoromethyl-substituted quinoline compounds in the presence of a metal-free catalyst, an oxidant and an additive. BACKGROUND
[0002] Quinoline compounds are an important class of nitrogen-containing heterocyclic molecular skeletons, and are widely present in various biologically active and drug molecules (Curr. Med. Chem. 2011, 18, 1488-1508). 2-Trifluoromethyl-substituted quinolines have significantly enhanced biological activity due to the presence of trifluoromethyl groups, and are widely used in various drugs and inhibitors. For example, mefloquine is a landmark antiprotozoal drug for treating malaria (J. Med. Chem. 1971, 14, 926-928). At the same time, 2-fluoroalkyl-substituted quinoline molecules are also used as antituberculosis drugs, PDE4 inhibitors and 5-HT5A receptor serotonins.
[0003]
[0004] The mainstream method for synthesizing 2-trifluoromethyl-substituted quinoline compounds is a transition metal-catalyzed tandem cycloaddition reaction of trifluoroacetimidoyl chloride with various alkynes. Although a number of different metal-catalyzed cyclization reactions for synthesizing 2-trifluoromethyl-substituted quinolines have been reported in recent years, there are generally the following disadvantages, such as the use of heavy metal catalysts, severe reaction conditions and poor substrate compatibility. Based on the concepts of green chemistry and atom economy, it is of important theoretical research significance and practical application value to develop a simple, green and easy-to-operate synthetic method for constructing 2-trifluoromethyl-substituted quinolines.
[0005] Based on this, we have developed a simple and efficient synthetic method for 2-trifluoromethyl-substituted quinolines, which uses cheap and readily available trifluoroacetimidoyl sulfonium ylide and amine as starting materials, does not require the presence of any metal catalyst, oxidant or additive, and only needs simple heating promotion. SUMMARY
[0006] The present application provides a preparation method for 2-trifluoromethyl-substituted quinoline compounds, which has simple steps, cheap and readily available starting materials, extremely simple reaction conditions, only needs ordinary heating, does not require the addition of any catalyst and additive, does not require inert gas protection, can be operated in an air atmosphere, and is convenient for large-scale operation and later application.
[0007] A preparation method of a 2-trifluoromethyl substituted quinoline compound, comprising the following steps: adding trifluoroacetimidoyl sulfonium leaflet, an amine and triphenyl phosphine difluoroacetate (PDFA) into an organic solvent, reacting at 70-90 DEG C for 20-30 hours, and after the reaction is completed, post-treatment to obtain the 2-trifluoromethyl substituted quinoline compound;
[0008] The structure of the trifluoroacetimidoyl sulfonium leaflet is shown in formula (II):
[0009]
[0010] The structure of the amine is shown in formula (III):
[0011] R 2 -NH2 (III);
[0012] The structure of the 2-trifluoromethyl substituted quinoline compound is shown in formula (I):
[0013]
[0014] In formula (I)-(III), R 1 is H, C1-C4 alkyl, C1-C4 alkoxy, halogen or trifluoromethyl; R 2 is C1-C 10 alkyl, substituted or unsubstituted aryl;
[0015] In R 2 , the substituent of the aryl is selected from C1-C4 alkyl, C1-C4 alkoxy, halogen or trifluoromethyl.
[0016] R 1 and R 2 The substituent position of the phenyl can be ortho, para or meta.
[0017] The reaction formula is as follows:
[0018]
[0019] In the reaction, the trifluoroacetimidoyl sulfonium leaflet and the triphenyl phosphine difluoroacetate can be coupled to obtain a difluoro olefin compound under heating, then the amine and the difluoro olefin compound can be added to generate an addition / elimination reaction to obtain an enone imine intermediate, and then intramolecular Friedel-Crafts cyclization and isomerization are generated to obtain the final 2-trifluoromethyl substituted quinoline compound.
[0020] In the present application, the optional post-treatment process comprises: filtration, silica gel sample mixing, and finally column chromatography purification to obtain the corresponding 2-trifluoromethyl substituted quinoline compound, and the column chromatography purification is a common technical means in the field.
[0021] As preferred, R 1 is H, methyl, methoxy, fluorine, bromine or trifluoromethyl; R 2 is alkyl, substituted or unsubstituted phenyl or naphthyl; the substituent on the phenyl is selected from methyl, methoxy, chlorine, bromine or trifluoromethyl, at this time, the aromatic amine and trifluoroacetimidoyl sulfonium ylide are easy to obtain and the reaction yield is high.
[0022] The amine and triphenylphosphine difluoroacetate are relatively easy to obtain and cheap, and the amount of the trifluoroacetimidoyl sulfonium ylide is excessive relative to the amount of the amine and triphenylphosphine difluoroacetate, as preferred, the molar ratio of trifluoroacetimidoyl sulfonium ylide: amine: triphenylphosphine difluoroacetate is 1:1-2:1-2, and as further preferred, the molar ratio of trifluoroacetimidoyl sulfonium ylide: amine: triphenylphosphine difluoroacetate is 1:1.5:1.5.
[0023] In the present application, any organic solvent that can dissolve the raw materials sufficiently can make the reaction occur, but the reaction efficiency differs greatly, and the non-protic solvent is preferred, which can effectively promote the reaction; as preferred, the organic solvent is tetrahydrofuran, acetonitrile or 1,4-dioxane; as further preferred, the organic solvent is 1,4-dioxane, which is the most suitable, at this time, various raw materials can be converted into products with high conversion rate.
[0024] The amount of the organic solvent can dissolve the raw materials well, and the amount of the organic solvent used for 1 mmol of trifluoroacetimidoyl sulfonium ylide is about 5-10 mL.
[0025] As preferred, the reaction condition is only ordinary heating, and ordinary heating condition is enough to make the reaction completely convert.
[0026] As further preferred, the 2-trifluoromethyl-substituted quinoline compound is one of the compounds shown in formula (I-1) to formula (I-5):
[0027]
[0028] In the above preparation method, the aromatic amine and amine are generally commercially available products, which can be conveniently obtained from the market, the trifluoroacetimidoyl sulfonium ylide can be obtained from trifluoroacetimidoyl chloride and methyl-substituted iodo sulfoxide with high yield, and the trifluoroacetimidoyl chloride can be quickly synthesized from the corresponding aromatic amine, triphenylphosphine, carbon tetrachloride and trifluoroacetic acid. The triphenylphosphine difluoroacetate can be prepared from triphenylphosphine and potassium difluoro(bromo)acetate.
[0029] Compared with the prior art, the preparation method has the advantages that: the preparation method is easy to operate, and post-treatment is simple; the reaction starting materials are cheap and easy to obtain, and any catalyst and additive is not needed, the reaction substrate has strong designability, the functional group tolerance range of the substrate is wide, different substituted quinoline compounds with trifluoromethyl and amino groups can be designed and synthesized according to actual needs, practicality and atom economy are strong, and the preparation method meets the concept of green chemistry. DETAILED DESCRIPTION
[0030] The application will be further described below in combination with specific examples.
[0031] According to the raw material ratio in Table 1, trifluoroacetylimidoyl sulfonium leaflet (II), amine (III), triphenyl phosphine difluoroacetate and 2 mL of an organic solvent are added into a 35 mL Schlenk tube, uniformly mixed and stirred, reacted for 20-30 hours according to the reaction conditions in Table 2, filtered, mixed with silica gel, and purified by column chromatography to obtain the corresponding 2-trifluoromethyl-substituted quinoline compound (I). The reaction process is shown in the following formula:
[0032]
[0033] Table 1: raw material addition amount of examples 1-15
[0034]
[0035] Table 2
[0036]
[0037]
[0038] In Table 1 and Table 2, T is the reaction temperature, t is the reaction time, Ph is phenyl, Me is methyl, OMe is methoxy, t-Bu is tert-butyl, n-Bu is n-butyl, CF3 is trifluoromethyl, and 1,4-dioxane is 1,4-dioxane.
[0039] The structure confirmation data of the compound prepared in examples 1-5 are as follows:
[0040] The nuclear magnetic resonance (H NMR, C NMR and F NMR) detection data of the 2-trifluoromethyl-substituted quinoline compound (I-1) prepared in example 1 are as follows: 1 H NMR, 13 C NMR and 19 F NMR
[0041]
[0042] 1H NMR (400 MHz, CDC13) δ 8.16 (d, J = 8.4 Hz, 1H), 7.97 (d, J = 8.4 Hz, 1H), 7.78 (t, J = 7.3 Hz, 1H), 7.62 (t, J = 7.6 Hz, 1H), 7.52 - 7.42 (m, 2H), 7.34 (d, J = 7.6 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.24 (s, 1H), 6.91 (s, 1H).
[0043] 13 C NMR (101 MHz, CDC13) δ 149.6, 148.9 (C-F, q, J = 33.7 Hz), 148.3, 138.86, 131.0, 130.7, 130.2, 127.2, 126.1, 125.9, 121.8 (C-F, q, J = 275.7 Hz), 97.5.
[0044] 19 F NMR (377 MHz, CDC13) δ -67.9.
[0045] M.p. 144.2 - 145.0 °C
[0046] HRMS (ESI): [M + H] + calcd. for C 21 H 16 F3N4 + 287.0791, found 287.0797.
[0047] The 2-trifluoromethyl substituted quinoline compound (1-2) prepared from Example 2 was tested for its NMR (400 MHz, CDC13) δ 8.03 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 19.3 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.16 (s, 1H). 1 H NMR、 13 C NMR and 19 F NMR) detection data:
[0048]
[0049] 1 H NMR (400 MHz, CDC13) δ 8.03 (d, J = 8.6 Hz, 1H), 7.82 (d, J = 19.3 Hz, 1H), 7.54 (d, J = 7.9 Hz, 1H), 7.47 (t, J = 7.8 Hz, 2H), 7.35 (d, J = 7.5 Hz, 2H), 7.29 (d, J = 7.4 Hz, 1H), 7.26 (s, 1H), 7.16 (s, 1H).
[0050] 13C NMR (101 MHz, CDC13) δ 149.9, 148.7 (C-F, q, J = 34.3 Hz), 138.7, 137.7, 133.4, 130.1, 129.0, 126.1, 123.5, 121.5 (C-F, d, J = 275.3 Hz), 119.4, 119.3, 97.4, 22.0.
[0051] 19 F NMR (377 MHz, CDC13) δ -67.4, -75.7.
[0052] M.p. 109.7-110.3 °C
[0053] HRMS (ESI): [M + H] + calcd. for C 22 H 18 F3N4 + 301.0947, found 301.0950.
[0054] The 2-trifluoromethyl substituted quinoline compound (1-3) prepared from Example 3 was tested for its NMR (1H, 13C and 19F) data: 1 H NMR、 13 C NMR and 19 F NMR) detection data:
[0055]
[0056] 1 H NMR (400 MHz, CDC13) δ 8.13 (d, J = 1.7 Hz, 1H), 8.00 (d, J = 9.0 Hz, 1H), 7.85 - 7.78 (m, 1H), 7.48 (t, J = 7.8 Hz, 2H), 7.37 - 7.27 (m, 3H), 7.22 (s, 1H), 6.88 (s, 1H).
[0057] 13 C NMR (101 MHz, CDC13) δ 149.3 (C-F, q, J = 33.8 Hz), 148.9, 147.0, 138.5, 134.1, 132.6, 130.2, 126.2, 123.6, 122.5, 121.7 (C-F, q, J = 275.6 Hz). 121.3, 120.9, 98.2.
[0058] 19 F NMR (377 MHz, CDC13) δ -68.1.
[0059] HRMS (ESI): [M + H]+ C 21 H 15 F4N4 + 364.9896, found 364.9893.
[0060] The nuclear magnetic resonance (1H NMR, 13C NMR and 19F NMR) detection data of the 2-trifluoromethyl substituted quinoline compound (I-4) prepared from Example 4 are as follows: 1 H NMR, 13 C NMR and 19 F NMR) detection data of the 2-trifluoromethyl substituted quinoline compound (I-4) prepared from Example 4 are as follows:
[0061]
[0062] 1 H NMR (400 MHz, CDC13) δ 8.01 (t, J = 8.5 Hz, 1H), 7.44-7.34 (m, 1H), 7.24-7.17 (m, 3H), 7.02-6.92 (m, 3H), 6.88 (s, 1H), 3.89 (s, 3H), 3.85 (s, 3H).
[0063] 13 C NMR (101 MHz, CDC13) δ 158.5, 157.9, 149.8, 146.5 (C-F, q, J = 33.5 Hz), 143.8, 132.1, 131.6, 126.4, 122.6, 122.1 (C-F, q, J = 275.2 Hz), 120.1, 115.3, 98.6, 97.1, 55.7, 55.6.
[0064] 19 F NMR (377 MHz, CDC13) δ -67.5.
[0065] HRMS (ESI): [M+H] + calcd. for C 22 H 16 F5N4 + 347.1002, found 347.1007.
[0066] The nuclear magnetic resonance (1H NMR, 13C NMR and 19F NMR) detection data of the 2-trifluoromethyl substituted quinoline compound (I-4) prepared from Example 4 are as follows: 1 H NMR, 13 C NMR and 19 F NMR) detection data of the 2-trifluoromethyl substituted quinoline compound (I-4) prepared from Example 4 are as follows:
[0067]
[0068] 1H NMR (400 MHz, CDC13) δ 8.01 (d, J = 9.2 Hz, 1H), 7.38 - 7.35 (m, 1H), 6.95 (s, 1H), 6.71 (s, 1H), 4.98 (s, 1H), 3.94 (s, 3H), 3.38 - 3.33 (m, 2H), 1.84 - 1.77 (m, 2H), 1.49 - 1.40 (m, 4H), 0.96 (t, J = 7.0 Hz, 3H).
[0069] 13 C NMR (101 MHz, CDC13) δ 158.2, 150.3, 146.9 (C-F, q, J = 34.5 Hz), 143.2, 132.4, 122.3 (C-F, q, J = 274.6 Hz), 121.5, 119.6, 98.8, 94.7, 55.8, 43.6, 29.4, 28.7, 22.6, 14.1.
[0070] 19 F NMR (377 MHz, CDC13) δ -68.2.
[0071] HRMS (ESI): [M + H] + calcd. for C 16 H 20 F3N2O + 313.1522, found 313.1530.
Claims
1. A method for the synthesis of a 2-trifluoromethyl substituted quinoline compound with heating acceleration, characterized in that, comprising the steps of: adding trifluoroacetimidate sulfonium leaflet, amine and triphenylphosphine difluoroacetate into an organic solvent, and stirring at 70~90 o C reacts for 20~30 hours, after the reaction is completed, the post-processing obtains the 2-trifluoromethyl substituted quinoline compound; The structure of the trifluoroacetylimine sulfonium ylide is shown in formula (II): ； The structure of the amine is shown in formula (III): ； The structure of the 2-trifluoromethyl substituted quinoline compound is shown in formula (I): ； In the formulae (I) to (III), R 1 is H, C1-C4 alkyl, C1-C4 alkoxy, halogen or trifluoromethyl; R 2 C1~C 10 Alkyl, substituted or unsubstituted phenyl or naphthyl; The substituent on the phenyl group is selected from methyl, methoxy, chlorine, bromine or trifluoromethyl; The organic solvent is 1,4-dioxane; The molar ratio of trifluoroacetylimine sulfonium ylide: amine: triphenylphosphine difluoroacetate is 1:1~2:1~2; No other catalyst or additive is added during the reaction.
2. The process for preparing a 2-trifluoromethyl substituted quinoline compound according to claim 1, characterized by, R 1 is H, methyl, tert-butyl, methoxy, fluorine, bromine or trifluoromethyl.
3. The method for preparing a 2-trifluoromethyl-substituted quinoline compound according to claim 1, wherein The 2-trifluoromethyl substituted quinoline compound is one of the compounds shown in formula (I-1)~formula (I-5): （I-1） （I-2） （I-3） （I-4） （I-5）。