A process for the preparation of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid

Abstract

The application discloses a preparation method of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. The preparation method comprises the following steps: dissolving compound I in an organic solvent I, then adding sodium hyposulfite and a bromination reagent in sequence, and performing a reaction under temperature rising to obtain a 4,5-dibromo-3-chlorothiophene-2-carboxylic acid crude product solution; pouring into ice water, adding an organic solvent II for extraction, washing and separating an organic phase, drying the obtained organic phase, filtering, concentrating, adding an organic solvent III for beating, filtering, and drying to obtain 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. The application realizes the preparation of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid in one step by adopting sodium hyposulfite to participate in the bromination reaction, the reagent used in the preparation is cheap and easy to obtain, the production cost of the target compound is reduced, the reaction time is shortened, the reaction yield is improved, and reliable reference is provided for the bromination of similar compounds.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis, and more particularly to a method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. Background Technology

[0002] In recent years, with the excellent reactivity of heterocyclic compounds in the fields of medicine and pesticides, the preparation methods of heterocyclic compounds have received unprecedented attention. Among them, 4,5-dibromo-3-chlorothiophene-2-carboxylic acid is a key intermediate in the synthesis of novel 3-(2,6-disubstituted phenyl)-5-(4- or 5-arylthiophene-2- or -3-yl)-1,2,4-triazole insecticides that show high activity against lepidopteran, coleopteran, mites and other sucking pests. The exploration of its preparation methods has a particularly important impact on the development of this type of novel insecticide in the pesticide field.

[0003] In the prior art, ethyl 2-thiophenecarboxylate is reacted with N-chlorosuccinimide in the presence of trifluoromethanesulfonic acid and palladium acetate to obtain ethyl 3-chlorothiophene-2-carboxylate, which is then reacted with sodium acetate and bromine in acetic acid to obtain methyl 4,5-dibromo-3-chlorothiophene-2-carboxylate, which is then hydrolyzed to obtain the target compound 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0004]

[0005] The preparation of similar compound II 5-bromo-2-carboxythiophene typically involves using 5-bromo-2-carboxythiophene as a raw material, heating it to 90-100°C in acetic acid, and reacting it with bromine to obtain the target compound II 5-bromo-2-carboxythiophene.

[0006]

[0007] The synthesis of the target compound 4,5-dibromo-3-chlorothiophene-2-carboxylic acid in the aforementioned prior art has certain drawbacks, hindering its application. Firstly, this synthetic route requires multiple reaction steps, which are lengthy and complex. Secondly, step 1 requires an expensive palladium catalyst, significantly increasing reaction costs. Thirdly, step 2 involves a lengthy reaction time, requiring 136 hours to obtain the target compound, increasing energy consumption and prolonging the preparation cycle of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, thus hindering its application in related fields. Furthermore, the preparation of similar compound II, 5-bromo-2-carboxythiophene, not only requires high-temperature reactions but also has a low yield of only 8%. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. The reagents used in this method are inexpensive and readily available, exhibiting high reactivity, and the method can achieve the preparation of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid in one step.

[0009] The technical solution of the present invention is as follows:

[0010] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, characterized in that the preparation method comprises the following steps:

[0011] (1) After dissolving compound I in organic solvent I, sodium dithionite and brominating reagent were added in sequence, and the reaction was heated to obtain crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid;

[0012] (2) Pour the crude solution obtained in step (1) into ice water, extract with organic solvent II, wash and separate the organic phase, dry, filter and concentrate the obtained organic phase, add organic solvent III to pulp, filter and dry to obtain 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0013] Further, in step (1), compound I is 3-chlorothiophene-2-carboxylic acid, purchased from Leyen or Sigma-Aldrich.

[0014] Further, in step (1), the organic solvent I is one or more of formic acid, acetic acid, and propionic acid; the organic solvent I is preferably formic acid.

[0015] Further, in step (1), the brominating agent is one or more of bromine, N-bromosuccinimide, and dibromohydantoin; preferably, the brominating agent is bromine.

[0016] Further, in step (1), the solid-liquid ratio of compound I to organic solvent I is 1:5 to 15 g / mL.

[0017] Further, in step (1), the molar ratio of compound I to sodium dithionite and the brominizing agent is 1:0.3 to 1:1.5 to 2.5; preferably, the molar ratio of compound I to sodium dithionite and the brominizing agent is 1:0.5:2.2.

[0018] Further, in step (1), the temperature of the heating reaction is 30-80°C and the time is 5-18h; the temperature of the heating reaction is preferably 50°C and the time is preferably 12h.

[0019] Further, in step (2), the ice water is an ice-water mixture, and the volume ratio of ice to water is 2 to 6:1; the mass-volume ratio of the brominating reagent to the ice water is 1:1 to 5 g / mL; the volume ratio of organic solvent II to ice water is 1 to 5:1; and the organic solvent II is one or more of ethyl acetate, isopropyl acetate, and dichloromethane.

[0020] Further, in step (2), organic solvent III is one or more of petroleum ether, n-hexane, heptane, cyclohexane, ethyl acetate, isopropyl acetate, and dichloromethane; the organic solvent III is preferably a mixture of dichloromethane and petroleum ether, wherein the volume ratio of dichloromethane to petroleum ether in the mixture is 1:4 to 6.

[0021] Further, in step (2), the solid-liquid ratio of compound I to organic solvent III is 1:0.5-3.5 g / mL; preferably, the solid-liquid ratio of compound I to organic solvent III is 1:2.5 g / mL.

[0022] The beneficial technical effects of this invention are as follows:

[0023] This invention utilizes sodium dithionite in a bromination reaction to achieve the preparation of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. The reagents used in the preparation are inexpensive and readily available, avoiding the use of expensive catalysts, reducing the production cost of the target compound, shortening the reaction time from 136 hours to 12 hours, and improving the reaction yield. This provides a reliable reference for the bromination of similar compounds.

[0024] In the technical solution described in this invention, sodium dithionite is homolytically cleaved under heating conditions to generate free radicals, which initiate a reaction. The generated free radicals further undergo free radical chain transfer with a brominating reagent to obtain bromine free radicals. These free radicals then undergo disubstituted bromination with the substrate to obtain the target compound 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. The reaction exhibits high reactivity and a short reaction time, making it an ideal bromination preparation method. Attached Figure Description

[0025] Figure 1 The 1H NMR spectrum of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid of this invention is shown below. Detailed Implementation

[0026] The present invention will now be described in detail with reference to the accompanying drawings and embodiments.

[0027] The reaction process for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid according to the present invention is as follows (1 is compound I, 2 is the prepared product):

[0028]

[0029] The specific preparation method is as follows: 3-chlorothiophene-2-carboxylic acid is dissolved in organic solvent I, and sodium dithionite and brominating reagent are added sequentially. The mixture is heated to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. Then, the solution is purified by pouring the crude solution into an ice-water mixture, extracting it with organic solvent II, washing and separating the organic phase, drying, filtering and concentrating the obtained organic phase, adding organic solvent III to slurry, filtering and drying to obtain 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0030] In one embodiment of the present invention, the organic solvent I is formic acid, acetic acid or propionic acid, and the formic acid, acetic acid or propionic acid is of AR purity.

[0031] In one embodiment of the present invention, the solid-liquid ratio of compound I to organic solvent I is 1:5 g / mL, 1:15 g / mL, 1:8 g / mL, or 1:12 g / mL.

[0032] In one embodiment of the present invention, the molar ratio of compound I to sodium dithionite and the brominizing agent is 1:0.3:1.5, 1:1:2.5, 1:1:1.5 or 1:0.3:2.5.

[0033] In one embodiment of the present invention, the temperature of the heating reaction is 30, 40, 60, 70 or 80°C, and the time is 5h, 6h, 8h, 12h, 14h, 16h or 18h.

[0034] In one embodiment of the present invention, the mass-to-volume ratio of the brominated reagent to ice water is 1:1 g / mL, 1:5 g / mL, 1:2 g / mL, 1:3 g / mL, or 1:4 g / mL; and the volume ratio of the organic solvent II to ice water is 1:1, 5:1, 2:1, 3:1, or 4:1.

[0035] In one embodiment of the present invention, the solid-liquid ratio of compound I to organic solvent III is 1:0.5 g / mL, 1:3.5 g / mL, 1:2.5 g / mL, 1:1.5 g / mL, or 1:2 g / mL.

[0036] The present invention will be further illustrated and explained below through specific embodiments and comparative examples.

[0037] Example 1

[0038] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid includes the following steps:

[0039] 320g of 3-chlorothiophene-2-carboxylic acid was added to 2.5L of formic acid, cooled to 0℃, and then 173.09g of sodium dithionite and 681.54g of liquid bromine were added. After the addition was complete, the temperature was raised to 50℃ and reacted for 12h to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0040] The above crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid was poured into 2 L of ice water, extracted with 8 L of DCM, washed with 4 L of sodium thiosulfate solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was slurried with 800 mL of a (1:5) mixture of dichloromethane and petroleum ether, filtered, and dried to obtain 533.29 g of off-white solid 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, yield: 86.3%, purity: 97.3%.

[0041] Examples 2-9

[0042] To further determine the optimal type of brominating reagent, optimal reaction temperature, and optimal material ratio, Examples 2-9 of this invention investigated the influence of various reaction conditions on the reaction results.

[0043] Examples 2-9 were prepared under the same conditions as Example 1, except that in Example 2, NBS was used as the bromine reagent, dibromohydantoin was used in Example 3, the reaction temperature was adjusted to 80°C in Example 4, and the reaction temperature was adjusted to 30°C in Example 5. Examples 6-9 specified the molar ratios of Compound I, sodium dithionite, and the brominating reagent. In Example 6, n(Compound I) / n(Sodium dithionite) / n(Brominated reagent) was 1:0.3:2.2; in Example 7, n(Compound I) / n(Sodium dithionite) / n(Brominated reagent) was 1:1:2.2; in Example 8, n(Compound I) / n(Sodium dithionite) / n(Brominated reagent) was 1:0.5:1.5; and in Example 9, n(Compound I) / n(Sodium dithionite) / n(Brominated reagent) was 1:0.5:2.5.

[0044] Comparative Example 1

[0045] The preparation method is the same as in the example, except that sodium dithionite is not added, i.e., n(compound I) / n(sodium dithionite) / n(brominating reagent) is 1:0:2.5, and the other preparation conditions are the same as in Example 1.

[0046] The yields of Examples 1-9 and Comparative Example 1 were determined, and the results are shown in Table 1.

[0047] Table 1. Core parameters and yields of reactions in Examples 1-9 and comparative examples.

[0048]

[0049] Table 1 shows that, comparing Examples 1-3, bromine exhibits better reaction performance than NBS and dibromohydantoin. Furthermore, comparing Examples 1, 8, and 9, a dosage of 2.2 eq is optimal; increasing or decreasing the dosage below this level reduces the yield. Comparing Examples 1, 4, and 5, a reaction temperature of 50°C is optimal. Increasing the reaction temperature promotes side reactions, while decreasing it slows down the reaction rate, resulting in a lower yield. Comparing Examples 1, 6, and 7, the dosage of sodium dithionite is also crucial in this reaction; a dosage of 2.2 eq is suitable. Meanwhile, Comparative Example 1 shows that the reaction yield is only 14.2% when sodium dithionite is used.

[0050] Example 10

[0051] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid includes the following steps:

[0052] 32g of 3-chlorothiophene-2-carboxylic acid was added to 250mL of acetic acid, cooled to 0℃, and then 17.3g of sodium dithionite and 68.15g of liquid bromine were added. After the addition was complete, the temperature was raised to 50℃ and reacted for 12h to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0053] The crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid was poured into 200 mL of ice water, extracted with 800 mL of DCM, washed with 400 mL of sodium thiosulfate solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was slurried with 60 mL of a 1:5 mixture of dichloromethane and petroleum ether to give 46.06 g of off-white solid 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, yield: 72.3%, purity: 97.0%.

[0054] Example 11

[0055] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid includes the following steps:

[0056] 33 g of 3-chlorothiophene-2-carboxylic acid was added to 250 mL of propionic acid, cooled to 0 °C, and then 17.9 g of sodium dithionite and 70.3 g of liquid bromine were added. After the addition was complete, the mixture was heated to 50 °C and reacted for 12 h to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0057] The crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid was poured into 200 mL of ice water, extracted with 800 mL of DCM, washed with 400 mL of sodium thiosulfate solution, and the organic phase was dried over anhydrous sodium sulfate. The mixture was filtered, evaporated to dryness, and the residue was slurried with 80 mL of a 1:5 mixture of dichloromethane and petroleum ether to give 43.1 g of off-white solid 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, yield: 65.4%, purity: 96.7%.

[0058] Example 12

[0059] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid includes the following steps:

[0060] 30 g of 3-chlorothiophene-2-carboxylic acid was added to 250 mL of formic acid, cooled to 0 °C, and then 13.0 g of sodium dithionite and 63.89 g of liquid bromine were added. After the addition was complete, the mixture was heated to 50 °C and reacted for 12 h to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0061] The above crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid was poured into 200 mL of ice water, extracted with 800 mL of DCM, washed with 400 mL of sodium thiosulfate solution, and the organic phase was dried over anhydrous sodium sulfate. After filtration and evaporation, the residue was slurried with 60 mL of a 1:5 mixture of dichloromethane and petroleum ether to obtain 41.2 g of off-white solid 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, with a yield of 68.89% and a purity of 96.8%.

[0062] As can be seen from Examples 10-12, the present invention has a high reproducibility rate and can obtain the target compound with ideal reaction yield under various reaction conditions.

[0063] Example 13

[0064] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid includes the following steps:

[0065] 320g of 3-chlorothiophene-2-carboxylic acid was added to 1.6L of acetic acid, cooled to 0℃, and then 173.1g of sodium dithionite and 681.6g of liquid bromine were added. After the addition was complete, the temperature was raised to 30℃ and reacted for 18h to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0066] The above crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid was poured into 680 mL of ice water, extracted with 680 mL of ethyl acetate, washed with 4 L of sodium thiosulfate solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was slurried with 800 mL of a (1:4) mixture of ethyl acetate and petroleum ether, filtered, and dried to give 453.59 g of off-white solid 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, with a yield of 71.2% and a purity of 97%.

[0067] Example 14

[0068] A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid includes the following steps:

[0069] 320g of 3-chlorothiophene-2-carboxylic acid was added to 4.8L of propionic acid, cooled to 0℃, and then 172.93g of sodium dithionite and 681.44g of liquid bromine were added. After the addition was complete, the temperature was raised to 80℃ and reacted for 5h to obtain a crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid.

[0070] The above crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid was poured into 3400 mL of ice water, extracted with 3400 mL of isopropyl acetate, washed with 4 L of sodium thiosulfate solution, the organic phase was separated, dried with anhydrous sodium sulfate, filtered, and evaporated to dryness. The residue was treated with 800 mL of a (1:6) mixture of ethyl acetate and petroleum ether, filtered, and dried to give 485.39 g of off-white solid 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, with a yield of 75.8% and a purity of 96.5%.

[0071] This invention improves the reaction activity by adding sodium dithionite, resulting in a significant increase in product yield. Therefore, compared with the existing synthesis method of bromination of ester groups, this invention achieves the synthesis of the target compound in one step.

[0072] The foregoing has shown and described the basic principles, main features, and advantages of the present invention. Those skilled in the art should understand that the present invention is not limited to the above embodiments. The embodiments and descriptions in the specification are merely illustrative of the principles of the invention. Various changes and modifications can be made to the invention without departing from its spirit and scope, and all such changes and modifications fall within the scope of the claimed invention.

Claims

1. A method for preparing 4,5-dibromo-3-chlorothiophene-2-carboxylic acid, characterized in that, The preparation method includes the following steps: (1) After dissolving compound I in organic solvent I, sodium dithionite and brominating reagent were added in sequence, and the reaction was heated to obtain crude solution of 4,5-dibromo-3-chlorothiophene-2-carboxylic acid; (2) Pour the crude solution obtained in step (1) into ice water, extract with organic solvent II, wash and separate the organic phase, dry, filter and concentrate the obtained organic phase, add organic solvent III to slurry, filter and dry to obtain 4,5-dibromo-3-chlorothiophene-2-carboxylic acid. In step (1), compound I is 3-chlorothiophene-2-carboxylic acid.

2. The preparation method according to claim 1, characterized in that, In step (1), the organic solvent I is one or more of formic acid, acetic acid, and propionic acid.

3. The preparation method according to claim 1, characterized in that, In step (1), the organic solvent I is formic acid.

4. The preparation method according to claim 1, characterized in that, In step (1), the brominating agent is one or more of bromine, N-bromosuccinimide, and dibromohydantoin.

5. The preparation method according to claim 1, characterized in that, In step (1), the brominating agent is bromine.

6. The preparation method according to claim 1, characterized in that, In step (1), the solid-liquid ratio of compound I to organic solvent I is 1:5-15 g / mL.

7. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound I to sodium dithionite and brominating reagent is 1:0.3 to 1:1.5 to 2.

5.

8. The preparation method according to claim 1, characterized in that, In step (1), the molar ratio of compound I to sodium dithionite and brominating reagent is 1:0.5:2.

2.

9. The preparation method according to claim 1, characterized in that, In step (1), the temperature of the heating reaction is 30-80°C and the time is 5-18h.

10. The preparation method according to claim 1, characterized in that, In step (1), the temperature of the heating reaction is 50°C and the time is 12h.

11. The preparation method according to claim 1, characterized in that, In step (2), the mass-to-volume ratio of the brominated reagent to ice water is 1:1 to 5 g / mL; the volume ratio of the organic solvent II to ice water is 1 to 5:1; and the organic solvent II is one or more of ethyl acetate, isopropyl acetate, and dichloromethane.

12. The preparation method according to claim 1, characterized in that, In step (2), organic solvent III is one or more of petroleum ether, n-hexane, heptane, cyclohexane, ethyl acetate, isopropyl acetate, and dichloromethane.

13. The preparation method according to claim 1, characterized in that, In step (2), the organic solvent III is preferably a mixture of dichloromethane and petroleum ether, wherein the volume ratio of dichloromethane to petroleum ether in the mixture is 1:4 to 6.

14. The preparation method according to claim 1, characterized in that, In step (2), the solid-liquid ratio of compound I to organic solvent III is 1:0.5-3.5 g / mL.

15. The preparation method according to claim 1, characterized in that, In step (2), the solid-liquid ratio of compound I to organic solvent III is preferably 1:2.5 g / mL.

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