A method for synthesizing 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester

Abstract

The application relates to a synthesis method of a compound 4-bromo-5-(trifluoromethyl) thiophene-2-carboxylic acid methyl ester, characterized in that the synthesis method takes 4,5-dibromothiophene-2-methyl ester as raw material, takes cuprous halide as a catalyst, takes diphenyl(trifluoromethyl)sulfonium triflate as a trifluoromethyl reagent, and reacts at a selected temperature, so that 4-bromo-5-(trifluoromethyl) thiophene-2-carboxylic acid methyl ester is generated with high selectivity. The method is high in atom economy, simple to operate, high in regioselectivity, relatively mild in reaction conditions, and very suitable for industrial scale production.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic synthesis, and particularly relates to a synthesis method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate. BACKGROUND

[0002] The general methods for synthesizing organic fluorides include: synthesizing fluorides through addition of unsaturated C-C bonds, synthesizing fluorides through diazonium salts, nucleophilic fluorination, electrophilic fluorination, and introduction of trifluoromethyl groups (trifluoromethylation reaction), etc. Due to the strong electronegativity, high stability and good liposolubility of the trifluoromethyl group, the introduction of the trifluoromethyl group often causes significant changes in the properties of the compound, especially its physiological activity, which is increasingly concerned in new drug development. Therefore, how to introduce the trifluoromethyl group into the target molecule has become an important topic in fluorine chemistry. Halogenated trifluoromethyl thiophene compounds are an important class of intermediates and have wide applications in the fields of synthesis and medicine. For example, in the patent WO2012 / 124825, they are used for the synthesis of sulfonamide compounds with TRPM8 antagonistic activity; in the patent US9403798, they are used for the synthesis of triazinone compounds with excellent T-type voltage-dependent calcium channel inhibitory activity and are particularly suitable for treating pain; in the patent WO2008 / 074820A1, they are used for the synthesis of novel oxadiazole derivatives with pharmacological activity, which can be used as S1P1 receptor agonists.

[0003] Among these compounds, the compound 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate, as an important molecular building block, is used for the synthesis of pyridin-2-one compounds in the patent WO2020 / 023657A1, which can be used for treating diseases such as cancer or SMARCA2-related diseases and can be used as an antagonist (for example, an inhibitor) of SMARCA2. Therefore, it is of certain significance to study the synthesis method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate.

[0004] In the prior art, for the synthesis of the similar compound 3,4-dibromo-2-(trifluoromethyl)thiophene, there is a literature report that 3,4-dibromothiophene is used as a raw material, mesoporous graphite phase carbon nitride (mpg-CN) is used as a photo-oxidation-reduction catalyst, and a fluoralkylation reaction is carried out to obtain (Chemistry A European Journal, 2015, 21, 526-530). However, this method has a complex synthesis operation and produces toxic and harmful sulfur dioxide, and is generally not suitable for process amplification. Therefore, based on the current process status of the project, it is necessary to develop a simple and applicable preparation method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate with relatively mild reaction conditions. SUMMARY

[0005] The present application aims at the deficiencies of the synthesis method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester, and provides a synthesis method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester, which can selectively generate 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester.

[0006] In order to achieve the above-mentioned purpose, the present application provides the following technical scheme:

[0007] The synthesis method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester is characterized in that: the synthesis method takes 4,5-dibromothiophene-2-carboxylic acid methyl ester as a raw material, takes cuprous halide as a catalyst, takes diphenyl(trifluoromethyl)sulfonium triflate as a trifluoromethyl reagent, and reacts at a selected temperature, so as to selectively generate 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester.

[0008] Further, the synthesis route is as follows:

[0009]

[0010] Further, it includes the following steps:

[0011] (1) Compound 4,5-dibromothiophene-2-carboxylic acid methyl ester is dissolved in dry organic solvent I, then cuprous halide and diphenyl(trifluoromethyl)sulfonium triflate are added, and the reaction is carried out at a selected temperature to obtain a reaction liquid;

[0012] (2) After the raw material is completely reacted, the reaction liquid is poured into water, the solid is filtered out, the liquid is collected, the collected liquid is extracted with organic solvent II, the organic phase is combined, washed, dried, filtered, and concentrated under reduced pressure to obtain a crude product;

[0013] (3) The crude product is purified to obtain compound 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester.

[0014] Further, in step (1), the organic solvent I is one or more of N,N-dimethylformamide, N,N-dimethylacetamide, dimethyl sulfoxide, toluene, acetone, 1,3-dimethyl-2-imidazolidinone, hexamethylphosphoric triamide, and N-methyl pyrrolidone, and more preferably, the organic solvent I is N,N-dimethylformamide.

[0015] Further, in step (1), the cuprous halide CuX is one of cuprous bromide, cuprous iodide, and cuprous chloride.

[0016] Further, in step (1), the molar ratio of the methyl 4,5-dibromothiophene-2-carboxylate, the cuprous halide and the diphenyl(trifluoromethyl)sulfonium triflate is 1.0:(0.2-1.0):(1.0-3.0); further preferably the molar ratio of the methyl 4,5-dibromothiophene-2-carboxylate, the cuprous halide and the diphenyl(trifluoromethyl)sulfonium triflate is 1.0:0.5:1.5.

[0017] Further, in step (1), the mass-volume ratio g / mL of the compound methyl 4,5-dibromothiophene-2-carboxylate and the organic solvent I is 1:(5-40).

[0018] Further, in step (1), the reaction temperature is 30-70℃; further preferably the reaction temperature is 60℃.

[0019] Further, in step (1), the reaction time is 2-40h; further preferably the reaction time is 5-30h, most preferably 12h.

[0020] Further, in step (2), the organic solvent II is selected from one or more of ethyl acetate or butyl acetate, chloroform, toluene, dichloromethane, dichloroethane.

[0021] Further, in step (3), the purification method comprises one or more of column chromatography, recrystallization, distillation.

[0022] The present application has the beneficial technical effects in that:

[0023] The present application provides a preparation method of methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate, which uses methyl 4,5-dibromothiophene-2-carboxylate as raw material, cuprous halide as catalyst and diphenyl(trifluoromethyl)sulfonium triflate as trifluoromethyl reagent to react at a selected temperature, thereby realizing high selectivity of methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate. The method has high atom economy, is simple and easy to operate, has high regioselectivity, and has relatively mild reaction conditions, and is very suitable for industrial scale production. BRIEF DESCRIPTION OF DRAWINGS

[0024] Figure 1 The reaction formula for synthesizing the target compound methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate in Example 1 of the present application;

[0025] Figure 2 The nuclear magnetic hydrogen spectrum of the target compound methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate in Examples 1-10 of the present application; DETAILED DESCRIPTION

[0026] In order to make the technical solutions and advantages of the embodiments of the present application clearer, the technical solutions of the embodiments of the present application will be described clearly and completely below with reference to the drawings of the embodiments of the present application. Obviously, the described embodiments are some but not all of the embodiments of the present application. Based on the described embodiments of the present application, all other embodiments obtained by those of ordinary skill in the art without creative effort are within the scope of the present application. Unless otherwise defined, the technical terms or scientific terms used herein should be understood as their common meanings to those having ordinary skill in the art to which the present application pertains.

[0027] Unless otherwise specified, the reagents and materials used in the following examples are commercially available.

[0028] The synthesis method of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester provided in the embodiment takes 4,5-dibromothiophene-2-carboxylic acid methyl ester as a raw material, takes cuprous halide as a catalyst, takes diphenyl(trifluoromethyl)sulfonium triflate as a trifluoromethyl reagent, and reacts at a certain temperature to selectively generate 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester.

[0029] As shown in the attached Figure 1 synthesis route as follows:

[0030]

[0031] The application will be further described below through examples.

[0032] Example 1

[0033] The synthesis of compound 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester is as follows:

[0034]

[0035] (1) At room temperature, compound 4,5-dibromothiophene-2-carboxylic acid methyl ester (200.00 g, 666.75 mmol, 1.0 eq) was dissolved in N,N-dimethylformamide (1200 mL), and then CuBr (47.82 g, 133.35 mmol, 0.5 eq) and diphenyl(trifluoromethyl)sulfonium triflate (404.39 g, 1.00 mol, 1.5 eq) were added. The reaction liquid was obtained by stirring the reaction at 60°C for 12 hours.

[0036] (2) After the raw materials were completely reacted, the reaction solution was cooled to room temperature, then poured into water (1200 mL), and the solid was filtered out using diatomite and the filter cake was washed with ethyl acetate (100 mL*2), and the liquid was collected. The collected liquid was extracted with ethyl acetate three times (300 mL*2), the organic phase was combined, washed with water three times (300 mL*3), washed with saturated brine (300 mL), dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure to obtain a crude product.

[0037] (3) The crude product was purified to obtain 181.00 g of colorless liquid compound 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester with a purity of 97% and a yield of 91%.

[0038] The nuclear magnetic hydrogen spectrum of the obtained compound 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester is shown in Figure 2 The obtained characterization data are as follows:

[0039] 1 H NMR (400 MHz, CDCl3) δ 8.44 (d, J = 1.1 Hz, 1H), 4.39 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.2 Hz, 3H).

[0040] Example 2-10

[0041] Example 2-10 is the same as Example 1, except that the catalyst used in the reaction, the trifluoromethyl reagent, the solvent, the reaction temperature, the solvent, etc. are adjusted, as shown in Table 1.

[0042] Comparative Example 1

[0043] Comparative Example 1 is the same as Example 1, except that the solvent used in the reaction is adjusted, as shown in Table 1.

[0044] Through Examples 1-10 and Comparative Example 1, the effects of various reaction conditions on the yield of the synthesis of 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid methyl ester were explored, and the results of the reaction are shown in Table 1.

[0045] Table 1: Synthesis conditions and results of examples and comparative examples

[0046]

[0047] Based on the above chart, it can be seen that

[0048] Comparative Examples 1, 9, 10 and Comparative Example 1, the reaction cannot be carried out in the solvent CH3CN, the solvents DMF, DMSO, toluene have a promoting effect on the reaction, and DMF as the solvent has the best effect.

[0049] Comparative Examples 1, 4, 5, when cuprous bromide is used as catalyst, the yield of target compound is slightly improved.

[0050] Comparative Examples 1, 6, 7, 8, when the reaction temperature is reduced from 60℃ to 40℃, the reaction rate is slowed down, and the reaction yield is decreased; when the reaction temperature is increased from 60℃ to 70℃, the reaction yield is also decreased, and 60℃ is more suitable for the reaction.

[0051] Comparative Examples 1-3, when the amount of catalyst and trifluoromethyl reagent is reduced, the conversion rate is poor, and the reaction yield is decreased.

Claims

1. A method for synthesizing methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid, characterized in that, The synthesis method uses methyl 4,5-dibromothiophene-2-carboxylate as a raw material, cuprous halide as a catalyst, and diphenyl(trifluoromethyl)sulfonate trifluoromethanesulfonate as a trifluoromethyl reagent. The reaction is carried out at a selected temperature to achieve highly selective generation of methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylate. Its synthetic route is as follows: ； It includes the following steps: (1) Dissolve methyl 4,5-dibromothiophene-2-carboxylate in dry organic solvent I, then add cuprous halide and diphenyl(trifluoromethyl)sulfonate trifluoromethanesulfonate, and react at a selected temperature to obtain a reaction solution; (2) After the raw materials have reacted completely, the reaction solution is poured into water, the solid is filtered out, the liquid is collected, the collected liquid is extracted with organic solvent II, the organic phases are combined, washed, dried, filtered, and concentrated under reduced pressure to obtain crude product. (3) The crude product was purified to obtain methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid; In step (1), the organic solvent I is one or more of N,N-dimethylformamide, dimethyl sulfoxide, or toluene; The molar ratio of methyl 4,5-dibromothiophene-2-carboxylate, cuprous halide, and diphenyl(trifluoromethyl)sulfonium trifluoromethanesulfonate is 1.0:(0.2-1.0):(1.0-3.0). The mass-to-volume ratio of the compound methyl 4,5-dibromothiophene-2-carboxylate to organic solvent I is 1:(5-40) g / mL; The reaction temperature is (30-70)℃; The reaction time is (2-40) h.

2. The method for synthesizing methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid according to claim 1, characterized in that: In step (1), the cuprous halide CuX is one of cuprous bromide, cuprous iodide, or cuprous chloride.

3. The method for synthesizing methyl 4-bromo-5-(trifluoromethyl)thiophene-2-carboxylic acid according to claim 1, characterized in that: In step (2), the organic solvent II is one or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, or dichloroethane.

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