A method for the synthesis of heteroaryl trifluoromethyl compounds

Abstract

This invention discloses a method for synthesizing heteroaryl trifluoromethyl compounds. The method involves mixing a heteroaryl iodide, a catalyst, and a trifluoromethylating agent, followed by a trifluoromethylation reaction. This invention proposes a method for generating heteroaryl trifluoromethyl compounds by reacting a heteroaryl iodide with sodium trifluoromethanesulfonate under copper catalysis. The copper powder and sodium trifluoromethanesulfonate used in this method are inexpensive, the reaction system has low moisture requirements, the reaction operation is simple, no byproducts are generated, post-processing is simple, and it exhibits good substrate compatibility, making it suitable for industrial-scale production.

Description

Technical Field

[0001] This invention belongs to the field of organic synthesis, specifically relating to a method for synthesizing heteroaryl trifluoromethyl compounds. Background Technology

[0002] The introduction of fluorine atoms endows organic and inorganic compounds with unique physical, chemical, and physiological properties. Since the advent of Freon in the early 1930s, fluorine chemistry has shown a booming trend. Many cutting-edge technologies (atomic energy industry, rockets, aerospace, etc.), as well as some major industrial projects and pharmaceuticals, have adopted fluorine-containing compounds.

[0003] Common methods for synthesizing organofluorine compounds include: addition of unsaturated C-C bonds, synthesis of fluorine compounds via diazonium salts, nucleophilic fluorination, electrophilic fluorination, and the introduction of trifluoromethyl groups (trifluoromethylation).

[0004] Trifluoromethyl groups possess strong electron-withdrawing inductive effects, lipophilicity, and stable CF bonds, making their introduction into organic molecules highly effective in altering various properties of the target molecule. For example, introducing trifluoromethyl groups into drug molecules can effectively prolong their duration of action in vivo and enhance metabolic stability. Simultaneously, the introduction of trifluoromethyl groups typically increases the lipophilicity of drug molecules, thereby facilitating their absorption, transport, and diffusion within the body. Anticancer drug sorafenib tosylate, antidepressant fluoxetine, novel broad-spectrum plant fungicide trifloxystrobin, and ZLI-2857, a typical material for liquid crystal displays, all contain trifluoromethyl groups. Therefore, how to introduce trifluoromethyl groups into target molecules has become an important topic in fluorine chemistry.

[0005]

[0006] After years of research, many methods for introducing trifluoromethyl groups have been developed, such as using SF4 to convert carboxyl groups into trifluoromethyl groups. According to the reaction mechanism, the introduction of trifluoromethyl groups can be mainly divided into three categories: free radical trifluoromethylation, nucleophilic trifluoromethylation, and electrophilic trifluoromethylation.

[0007] Regarding radical trifluoromethylation, trifluoromethyl radicals can be obtained through various routes. Due to their strong electrophilicity, they can undergo electrophilic addition reactions with electron-rich benzene rings. However, this method suffers from low yields, poor selectivity, and difficulty in controlling the reaction, thus limiting its application in organic synthesis.

[0008] Regarding electrophilic trifluoromethylation, Umemoto reported the synthesis and application of compounds I and II in 1990, which were the first electrophilic trifluoromethylating agents. Subsequently, Umemoto reported the synthesis and application of compounds III and IV. These compounds are stable crystals with good stability. The benzo[a] ring is a good leaving group, easily leaving during substitution, which is beneficial to the reaction. The reaction is easy to handle, especially compound IV; the resulting sulfonic acid is water-soluble and easily removed. In addition, compounds V, VI, and VII are also common electrophilic trifluoromethylating agents.

[0009]

[0010] This trifluoromethylation is not achieved through CF... 3+ It is not S. N Substitution, possibly through a SET mechanism, generates a trifluoromethyl radical, followed by electrophilic addition to a carbanion. This method is highly versatile, allowing the introduction of trifluoromethyl groups onto a variety of nucleophiles. However, the preparation of these reagents is difficult and expensive, limiting its application.

[0011] Regarding nucleophilic trifluoromethylation, another method for introducing trifluoromethyl groups into a compound is through CF3. - Nucleophilic reactions are achieved, mainly including two categories: nucleophilic substitution of halobenzenes with CuCF3 and nucleophilic substitution of carbonyl compounds with TMSCF3.

[0012] The earliest method was based on CuCF3 as CF3. - The method involves nucleophilic substitution of a halobenzene (usually bromobenzene or iodobenzene, the latter being more reactive) to synthesize trifluoromethyl-substituted aryl compounds. This method was first reported by McLoughlin in 1969 and, after many years of development, has become one of the most important methods for trifluoromethylation.

[0013] CuCF3 can be prepared and used immediately in the presence of Cu using various methods.

[0014] Another method is the nucleophilic substitution of carbonyl compounds using TMSCF3 (Prakash reagent). This method was first reported by Ruppert in 1984, and Prakash subsequently conducted extensive research on its application. It is the most convenient method for synthesizing trifluoromethyl compounds from carbonyl compounds, with mild reaction conditions, easy operation, and high yields, and it is widely used in organic synthesis.

[0015] In addition, Dolbier et al. recently used the CF3I / TDAE system to successfully achieve trifluoromethylation of electrophilic species under mild conditions.

[0016] Through years of research, many methods for trifluoromethylation have been developed. However, trifluoromethylation of heteroaryl groups is still relatively difficult to achieve. It is generally achieved through nucleophilic reactions of heteroaryl halides with trifluoromethyl reagents catalyzed by Cu, Ag, Pd, etc., such as Ruppert's reagent, Umemoto's reagent, and Chern's reagent. These reagents all require a strictly anhydrous reaction system, are relatively expensive, and have troublesome byproduct post-processing or may produce harmful gases, making them unsuitable for industrial-scale production. Summary of the Invention

[0017] To address the shortcomings of existing technologies, this invention provides a method for synthesizing heteroaryl trifluoromethyl compounds. This invention is the first to propose a method for the reaction of heteroaryl iodides with sodium trifluoromethanesulfonate under copper catalysis to generate heteroaryl trifluoromethyl compounds. This reaction uses inexpensive copper powder and sodium trifluoromethanesulfonate, has low requirements for the moisture content of the reaction system, produces no byproducts, has simple post-processing, exhibits good substrate compatibility, and is suitable for industrial-scale production.

[0018] The technical solution of the present invention is as follows:

[0019] A method for synthesizing a heteroaryl trifluoromethyl compound, wherein the method comprises mixing a heteroaryl iodide, a catalyst, and a trifluoromethyl reagent, and carrying out a trifluoromethylation reaction to obtain the compound;

[0020] The trifluoromethyl reagent is sodium trifluoromethanesulfonate.

[0021] Furthermore, the catalyst includes one or more of copper, gold, and silver.

[0022] Furthermore, the catalyst is preferably copper.

[0023] Furthermore, the synthesis method follows this route:

[0024]

[0025] in:

[0026] R 1 Including one of the heterocyclic aromatic groups;

[0027] R 2 It includes one or more of the following: hydrogen atom, halogen, C1-C6 alkyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, C1-C6 alkylthio, C1-C6 alkoxycarbonyl, and C1-C3 cyano.

[0028] Furthermore, the R 1 It includes one of five-membered, six-membered, seven-membered heterocyclic compounds and fused heterocyclic aromatic groups.

[0029] Furthermore, the R 2 It includes one or more of the following: hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, methyl ester group, and cyano group.

[0030] Furthermore, the R 1 It includes one of the following: thiazolyl, thiophene, pyridazinyl, pyrazinyl, pyridinyl, and pyrazolopyridinyl.

[0031] Furthermore, the synthesis method specifically includes the following steps:

[0032] (1) Compound 1 was dissolved in organic solvent I, and a catalyst and trifluoromethyl reagent were added. The reaction was carried out under inert gas protection to obtain a reaction solution.

[0033] (2) Add water to the reaction solution, extract with organic solvent II, combine the organic phases, wash, dry, and evaporate under reduced pressure to obtain target compound 2;

[0034] Compound 1 is a heteroaryl iodide.

[0035] Furthermore, the extraction is performed using organic solvent II, the washing is performed using saturated brine, the drying is performed using anhydrous sulfate, and the vacuum drying is performed using low-temperature vacuum drying.

[0036] Furthermore, the anhydrous sulfates include, but are not limited to, anhydrous sodium sulfate and anhydrous magnesium sulfate.

[0037] Further, in step (1), the organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone.

[0038] Further, in step (1), the molar ratio of compound 1, catalyst, and trifluoromethyl reagent is 1.0:(1.0~4.0):(1.0~6.0); the mass-volume ratio of compound 1 to organic solvent I (g / mL) is 1:3~40.

[0039] Further, in step (1), the inert gas is selected from one or more of nitrogen and argon; the reaction temperature is 40-130°C, preferably 30-100°C, and most preferably 70°C; the reaction time is 1-30h, preferably 5-30h, and most preferably 12h.

[0040] Further, in step (2), adding water refers to adding an appropriate amount of water, preferably with a volume ratio of reaction solution to water of 1:1 to 1:20;

[0041] Further, in step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0042] The beneficial technical effects of this invention are as follows:

[0043] This invention uses heteroaryl iodinated compounds as raw materials, copper powder as a catalyst, and sodium trifluoromethanesulfonate as a trifluoromethyl reagent to carry out trifluoromethylation reaction, thereby obtaining heteroaryl trifluoromethyl compounds.

[0044] The copper powder and sodium trifluoromethanesulfonate used in the method of this invention are relatively inexpensive, have low requirements for the moisture content of the reaction system, and the reaction operation is simple, with no byproducts generated and simple post-processing. It also has good substrate compatibility, making it suitable for industrial-scale production. To a certain extent, it overcomes some shortcomings of existing technologies for the trifluoromethylation of heteroaryl groups, such as the high cost of catalysts and trifluoromethylating reagents, strict requirements for an anhydrous reaction system, the generation of byproducts, difficulty in purification, low yield, and difficulty in industrial-scale production. Attached Figure Description

[0045] Figure 1 The 1H NMR spectrum of the target compound (2a) provided in the embodiments of the present invention.

[0046] Figure 2 The 1H NMR spectrum of the target compound (2b) provided in this embodiment of the invention.

[0047] Figure 3 The 1H NMR spectrum of the target compound (2c) provided in the embodiments of the present invention.

[0048] Figure 4 The 1H NMR spectrum of the target compound (2d) provided in the embodiments of the present invention.

[0049] Figure 5 The 1H NMR spectrum of the target compound (2e) provided in the embodiments of the present invention. Detailed Implementation

[0050] The present invention will now be described in detail with reference to the accompanying drawings and embodiments. Obviously, the described embodiments are only some, not all, of the embodiments of the present invention. All other embodiments obtained by those skilled in the art based on the described embodiments of the present invention without inventive effort are within the scope of protection of the present invention. Unless otherwise defined, the technical or scientific terms used herein should have the ordinary meaning understood by those skilled in the art to which this invention pertains.

[0051] Unless otherwise specified, all reagents and materials used in the following examples are commercially available.

[0052] This invention provides a method for synthesizing heteroaryl trifluoromethyl compounds, the synthetic route of which is as follows:

[0053]

[0054] in,

[0055] R 1 It is one of the heterocyclic aromatic groups;

[0056] R 2 It is one or more of the following: hydrogen atom, halogen, C1-C6 alkyl, C1-C6 alkoxy, haloalkyl, haloalkoxy, C1-C6 alkylthio, C1-C6 alkoxycarbonyl, and C1-C3 cyano.

[0057] In one embodiment of the invention, R 1 It is one of the five-membered, six-membered, seven-membered heterocyclic and fused heterocyclic aromatic groups.

[0058] In one embodiment of the present invention, R 1 It is one of thiazolyl, thiophene, pyridazinyl, pyrazinyl, pyridinyl, and pyrazolopyridinyl.

[0059] In one embodiment of the present invention, R 2 It is one or more of the following: hydrogen atom, fluorine, chlorine, bromine, methyl, methoxy, benzyloxy, trifluoromethyl, trifluoromethoxy, methyl ester group, and cyano group.

[0060] In one embodiment of the present invention, R 1 Including one of pyridinyl, pyridinyl, or pyrazolopyridinyl;

[0061] In one embodiment of the present invention, R 2 It includes one or more of the following: chlorine, bromine, methyl, and amino groups.

[0062] The invention will be further described below through examples and other means.

[0063] Example 1

[0064] The synthesis of compound 3,6-dichloro-4-iodadiazine (1a) is as follows:

[0065]

[0066] (I) 2,2,6,6-Tetramethylpiperidine (237.05 g, 1.68 mol, 2.5 eq) was dissolved in THF (1000 mL). Under inert gas protection and with the temperature maintained at -40 °C, n-butyllithium (107.50 g, 1.68 mol, 2.5 eq) was added dropwise. After the addition was complete, the mixture was heated to -10 °C and stirred for 1 hour. Then, while maintaining the temperature at -10 °C, a THF solution of zinc chloride (256.14 g, 1.88 mol, 2.8 eq) was added dropwise. After the addition was complete, the mixture was stirred at room temperature for 1 hour to obtain a mixed solution containing TMPZnCl·LiCl.

[0067] (II) Then, add the THF solution of compound Aa (100.00 g, 671.26 mmol, 1 eq) to the above TMPZnCl·LiCl solution and stir at room temperature for 30 minutes. Then, add the THF solution of iodine (255.56 g, 1.01 mol, 1.5 eq) dropwise to the mixture and stir the reaction solution at room temperature for 12 hours.

[0068] (III) After the reaction was completed, the reaction solution was quenched with a saturated sodium thiosulfate and ammonium chloride aqueous solution, extracted three times with ethyl acetate, the organic phases were combined, dried over anhydrous sodium sulfate, and concentrated to obtain the crude product. The crude product was purified by column chromatography to obtain 128.00 g of pale yellow solid compound 1a with a purity of 96% and a yield of 70%.

[0069] The synthesis of compound 3,6-dichloro-4-(trifluoromethyl)pyridazine (2a) is as follows:

[0070]

[0071] (1) Compound 1a (50.00 g, 181.90 mmol, 1 eq) was dissolved in dry DMF (500 mL), and copper powder (23.12 g, 363.81 mmol, 2 eq) and sodium trifluoromethanesulfonate (220.65 g, 545.71 mmol, 3 eq) were added. The mixture was reacted for 12 h at 70 °C under nitrogen protection.

[0072] (2) After the reaction was complete, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic phases were combined and washed with saturated brine. The mixture was then dried in anhydrous sodium sulfate and evaporated under reduced pressure at low temperature to obtain 34.73 g of white solid 2a with a purity of 98% and a yield of 88%.

[0073] The obtained 1H NMR spectrum of 2a is as follows Figure 1 As shown, the obtained characterization data are as follows:

[0074] 1 H NMR (400MHz, CDCl3) δ7.80 (s, 1H).

[0075] 19 F NMR(377MHz, CDCl3)δ-65.86(s).

[0076] Examples 2-6

[0077] Examples 2-6 are the same as Example 1, except that the catalyst, trifluoromethyl reagent, solvent, and reaction temperature used in the reaction were adjusted, as detailed in Table 1.

[0078] Comparative Examples 1-5

[0079] Comparative Examples 1-5 are the same as Example 1, except that the trifluoromethyl reagent, additives, solvents, etc. used in the reaction were adjusted, as detailed in Table 1.

[0080] The effects of various reaction conditions on the reaction yield in the synthesis of 2a were investigated through Examples 1-6 and Comparative Examples 1-5. The results obtained are shown in Table 1.

[0081] Table 1 Synthesis conditions and results of the examples and comparative examples

[0082]

[0083]

[0084] The structures of the trifluoromethyl reagents used in Table 1 are shown below:

[0085]

[0086] As can be seen from Table 1, compared with Examples 1-3, halving the amount of catalyst and trifluoromethyl reagent resulted in a poorer conversion rate and a lower reaction yield. In addition, the slightly larger molar amount of trifluoromethyl reagent than catalyst was also more conducive to the reaction.

[0087] Comparing Examples 1, 4, 5 and Comparative Example 1, the reaction can hardly proceed in the solvent CH3CN. Solvents DMF, DMSO and toluene all have a promoting effect on the reaction, with DMF being the most effective solvent.

[0088] Comparing Examples 1 and 6, it can be seen that lowering the reaction temperature slows down the reaction rate and reduces the reaction yield; 70°C is more suitable for the reaction.

[0089] Comparative Examples 1 and 2-5 show that the use of copper powder and sodium trifluoromethanesulfonate significantly promotes the reaction.

[0090] Example 7

[0091] The synthesis of compound 3,5-dichloro-4-(trifluoromethyl)pyridine (2b) is as follows:

[0092]

[0093] Following the synthesis of 2a in Example 1, using 3,5-dichloro-4-iodopyridine 1b (28.00 g, 102.23 mmol, 1.0 eq) as the starting material, and maintaining the molar ratio of compound 1:catalyst:trifluoromethyl reagent at 1:2:3, with the remaining conditions the same as in Example 1, 18.99 g of colorless oily compound 2b with a purity of 97% and a yield of 86% was obtained.

[0094] The obtained 1H NMR spectrum of 2b is as follows Figure 2 As shown, the obtained characterization data are as follows:

[0095] 1 H NMR (400MHz, DMSO) δ8.89 (d, J = 0.6Hz, 2H).

[0096] 19 F NMR(377MHz,DMSO)δ-56.95(s).

[0097] Comparative Example 6

[0098] Comparative Example 6 was the same as Example 6, except that the catalyst used in Comparative Example 6 was cuprous iodide, and the trifluoromethyl reagent was methyl fluorosulfonyl difluoroacetate. The yield of target compound 2b was only 54%, and the ratio of it to the byproduct 3,5-dichloro-4-((trifluoromethyl)thio)pyridine was 3:1. It is evident that changing the catalyst and trifluoromethyl reagent reduces the product yield and increases the proportion of byproducts.

[0099] Example 8

[0100] The synthesis of compound 3-bromo-2-methyl-6-(trifluoromethyl)pyridine (2c) is as follows:

[0101]

[0102] Following the synthesis described in Example 1, 2a, 3-bromo-6-iodo-2-methylpyridine 1c (18.50 g, 62.10 mmol, 1.0 eq) was used as the starting material. The molar ratio of compound 1:catalyst:trifluoromethyl reagent was kept at 1:2:3, and the other conditions were the same as in Example 1. 13.56 g of colorless liquid compound 2c with a purity of 96% and a yield of 91% was obtained.

[0103] The obtained 2c 1H NMR spectrum is as follows Figure 3 As shown, the obtained characterization data are as follows:

[0104] 1H NMR (400MHz, CDCl3) δ7.97 (d, J = 8.2 Hz, 1H), 7.38 (d, J = 8.2 Hz, 1H), 2.73 (s, 3H).

[0105] 19 F NMR(377MHz, CDCl3)δ-67.91(s).

[0106] Example 9

[0107] The synthesis of compound 6-(trifluoromethyl)-1H-pyrazolo[4,3-b]pyridine (2d) is as follows:

[0108]

[0109] Following the synthesis described in Example 1, 2a, using 6-iodo-1H-pyrazolo[4,3-b]pyridine 1d (50.00 g, 204.06 mmol, 1.0 eq) as the starting material, and maintaining the molar ratio of organic solvent 1:catalyst:trifluoromethyl reagent at 1:2:3, with the remaining conditions the same as in Example 1, 31.20 g of compound 2d was obtained with a purity of 99% and a yield of 82%.

[0110] The obtained 2d 1H NMR spectrum is as follows Figure 4 As shown, the obtained characterization data are as follows:

[0111] 1 H NMR (600MHz, CDCl3) δ8.89 (d, J = 1.0Hz, 1H), 8.47 (s, 1H), 8.19 (s, 1H).

[0112] Example 10

[0113] The synthesis of compound 2-amino-4-trifluoromethylpyridine (2e) is as follows:

[0114]

[0115] Following the synthesis of 2a in Example 1, using 4-iodo-2-aminopyridine 1e (50.00 g, 227.26 mmol, 1.0 eq) as the starting material, and maintaining the molar ratio of compound 1:catalyst:trifluoromethyl reagent at 1:2:3, with the other conditions being the same as in Example 1, 31.98 g of off-white powder 2e with a purity of 98% and a yield of 87% was obtained.

[0116] The obtained 2e 1H NMR spectrum is as follows Figure 5 As shown, the obtained characterization data are as follows:

[0117] 1H NMR (400MHz, CDCl3) δ8.22(s,1H),6.96–6.52(m,2H),4.57(s,2H).

[0118] The above description is merely a preferred embodiment of the present invention, and the present invention is not limited to the above embodiments. It is understood that other improvements and variations that are directly derived or conceived by those skilled in the art without departing from the spirit and concept of the present invention should be considered to be included within the protection scope of the present invention.

Claims

1. A method for synthesizing a heteroaryltrifluoromethyl compound, characterized in that, The synthesis method involves mixing a heteroaryl iodide, a catalyst, and a trifluoromethyl reagent, and then performing a trifluoromethylation reaction to obtain the product. The trifluoromethyl reagent is sodium trifluoromethanesulfonate, and the catalyst is copper; The synthetic method follows this route: in: R 1 Selected from one of pyridazinyl, pyridinyl, and pyrazolopyridinyl; R 2 Selected from either fluorine or chlorine; The synthesis method specifically includes the following steps: (1) Compound 1 was dissolved in organic solvent I, and a catalyst and trifluoromethyl reagent were added. The reaction was carried out under inert gas protection to obtain a reaction solution; the compound 1 was a heteroaryl iodide derivative. (2) Add water to the reaction solution, extract with organic solvent II, combine the organic phases, wash, dry, and evaporate under reduced pressure to obtain target compound 2; In step (1), the organic solvent I is selected from one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolinone, hexamethylphosphoric triamine, and N-methylpyrrolidone; The molar ratio of compound 1, catalyst, and trifluoromethyl reagent is 1.0:(1.0~4.0):(1.0~6.0); The reaction was carried out at a temperature of 70°C.

2. The synthesis method according to claim 1, characterized in that, In step (1), the mass-to-volume ratio of compound 1 to organic solvent I is 1:3~40 (g / mL); the inert gas is selected from one or more of nitrogen and argon; and the reaction time is 1~30h.

3. The synthesis method according to claim 1, characterized in that, In step (1), the reaction time is 5 to 30 hours.

4. The synthesis method according to claim 1, characterized in that, In step (1), the reaction time is 12 hours.

5. The synthesis method according to claim 1, characterized in that, In step (2), the organic solvent II is selected from one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

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