A method for synthesizing an N-methyl-4-((2-phenylbenzo[d]imidazo[2,1-b]thiazol-3-yl)methyl)aniline compound

Abstract

The application relates to the technical field of organic synthesis, in particular to a synthesis method of an N-methyl-4-((2-phenylbenzo[d]imidazo[2,1-b]thiazol-3-yl)methyl) aniline compound. The synthesis method comprises the following steps: taking substituted or unsubstituted alpha-bromoacetophenone, 2-amino benzothiazole and N,N-dimethylaniline as raw materials, and reacting in an organic solvent to obtain the product. The application provides a new synthesis route, the operation is simpler, the atomic economy of the reaction is increased, the yield of the reaction is improved, the route of industrial production is explored, and the reaction is more suitable for industrial amplification production.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and in particular to a method for synthesizing N-methyl-4-((2-phenylbenzi[d]imidazol[2,1-b]thiazolyl-3-yl)methyl)aniline compounds. Background Technology

[0002] 2-Phenylen[d]imidazo[2,1-b]thiazoles are an important class of active molecular skeletons, widely found in antibacterial, anti-inflammatory, and antiviral drugs, and also have broad application prospects in pesticides and materials science. Existing synthetic methods for this class of compounds suffer from problems such as high reaction costs, low atom utilization, cumbersome synthetic steps, and low yields.

[0003] Existing technologies report the preparation of N-methyl-4-((2-phenylimidazo[1,2-a]pyridine, formaldehyde, and N-methylaniline as starting materials, reacting them under the catalysis of acetic acid.

[0004] Using formaldehyde as the methylene source and acetic acid as an additive, these additional reagents will increase the cost of the reaction. At the same time, the use of waste acid will increase the cost of treating waste acid water in the later stage. From the perspective of industrial production, the reaction cost is high. Moreover, the starting material 2-phenylimidazo[1,2-a]pyridine needs to be synthesized in advance, which adds an extra reaction step. Summary of the Invention

[0005] In view of this, the present invention provides a method for synthesizing N-methyl-4-((2-phenylbenzi[d]imidazol[2,1-b]thiazolyl-3-yl)methyl)aniline compounds.

[0006] To achieve the above objectives, the present invention is implemented through the following technical solution: This invention provides a method for synthesizing N-methyl-4-((2-phenylbenzi[d]imidazol[2,1-b]thiazolyl-3-yl)methyl)aniline compounds, comprising the following steps: The product is obtained by reacting substituted or unsubstituted α-bromoacetophenone, 2-aminobenzothiazole, and N,N-dimethylaniline in an organic solvent; the specific reaction formula is as follows: .

[0007] Furthermore, the substituents in the substituted α-bromoacetophenone are methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, and bromine.

[0008] Furthermore, substituted or unsubstituted α-bromonaphthone or α-bromocyclopropane ketone are used instead of substituted or unsubstituted α-bromoacetophenone, with substituents being methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, or bromine.

[0009] Furthermore, the reaction temperature is 40-140℃; preferably 90-130℃.

[0010] Furthermore, the reaction time is 1-36 hours; preferably 12-36 hours.

[0011] Further, the organic solvent is methanol, acetonitrile, tetrahydrofuran, dioxane, 1,2-dichloroethane, toluene, acetone, ethyl acetate, N,N-dimethylformamide, or dimethyl sulfoxide.

[0012] Furthermore, the molar ratio of substituted or unsubstituted α-bromoacetophenone to 2-aminobenzothiazole is 1:1-1.1.

[0013] Furthermore, the molar ratio of substituted or unsubstituted α-bromoacetophenone to N,N-dimethylaniline is 1:1-1.1.

[0014] Furthermore, the ratio of substituted or unsubstituted α-bromoacetophenone to organic solvent is 1 mmol: 1-2 mL.

[0015] Furthermore, the reaction also includes a post-processing step, specifically: after the reaction is completed, the organic phase is extracted with a mixture of water and dichloromethane, dried, filtered, and the solvent is removed under reduced pressure, and then the target compound is obtained by column chromatography.

[0016] Furthermore, the volume ratio of water to dichloromethane is 1:8-12, preferably 1:10.

[0017] Compared with the prior art, the present invention has achieved the following beneficial effects: This invention provides a novel synthetic route that simplifies the operation, increases atom economy, improves yield, and explores routes for industrial production, making the reaction more suitable for large-scale industrial production. This invention develops a novel methyl source, using N,N-dimethylaniline to provide the methyl group, offering a new methylating agent for subsequent methylation experiments. Compared to existing methods, this reaction exhibits higher atom and step economy. No additives / catalysts are used in the reaction, significantly reducing costs. The target compound is synthesized directly from commercially available raw materials through a one-pot tandem reaction, avoiding additional reaction steps. Attached Figure Description

[0018] The accompanying drawings, which form part of this invention, are used to provide a further understanding of the invention. The illustrative embodiments of the invention and their descriptions are used to explain the invention and do not constitute an improper limitation of the invention.

[0019] Figure 1 This is the 1H NMR spectrum of the synthesized product in Example 1 of this invention; Figure 2 This is the carbon NMR spectrum of the synthesized product in Example 1 of this invention. Detailed Implementation

[0020] It should be noted that the following detailed descriptions are exemplary and intended to provide further illustration of the invention. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention pertains.

[0021] 2-Phenylated benzo[d]imidazo[2,1-b]thiazoles are an important class of bioactive molecular skeletons, widely found in antibacterial, anti-inflammatory, and antiviral drugs, and also have broad application prospects in pesticides and materials science. In particular, the functionalization of the C-3 position of these compounds can significantly improve their biological activity. Benzo[d]imidazo[2,1-b]thiazole skeletons are a class of advantageous drug skeletons with broad application prospects in both biological activity and drug scaffolding. For example, in antitumor activity, they can inhibit topoisomerases, EGFR, VEGF, etc., blocking DNA replication and tumor angiogenesis; in antibacterial / antituberculosis activity, they exhibit strong activity against Staphylococcus aureus and Mycobacterium tuberculosis (H37Rv); in anti-inflammatory activity, they can inhibit COX-2 and TNF-α, facilitating the development of novel anti-inflammatory drugs. Given the significant research value of these compounds, developing simple and efficient methods for their synthesis is particularly important.

[0022] This invention provides a method for synthesizing N-methyl-4-((2-phenylbenzi[d]imidazol[2,1-b]thiazolyl-3-yl)methyl)aniline compounds, comprising the following steps: The product is obtained by reacting substituted or unsubstituted α-bromoacetophenone, 2-aminobenzothiazole, and N,N-dimethylaniline in an organic solvent; the specific reaction formula is as follows: .

[0023] The preparation method provided by this invention has high atom economy and step economy. No additives / catalysts are used in the reaction process, greatly reducing the reaction cost. The target compound is synthesized directly from commercially available raw materials through a one-pot tandem reaction, avoiding additional reaction steps. Furthermore, the synthesis method provided by this invention is simpler to operate, increases the atom economy of the reaction, improves the reaction yield, explores routes for industrial production, and makes the reaction more suitable for industrial scale-up.

[0024] Furthermore, the substituents in the substituted α-bromoacetophenone are methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, and bromine.

[0025] Furthermore, substituted or unsubstituted α-bromonaphthone or α-bromocyclopropane ketone are used instead of substituted or unsubstituted α-bromoacetophenone, with substituents being methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, or bromine.

[0026] Furthermore, the reaction temperature is 40-140℃; the reaction temperature can be any value between 40-140℃, such as 50℃, 60℃, 70℃, 80℃, 90℃, 100℃, 110℃, 120℃, 130℃, etc.; preferably 90-130℃. The reaction involves the breaking of chemical bonds. Since no additives / catalysts are added during the reaction process of this invention, the reaction temperature is crucial to the reaction. When the reaction temperature is controlled within 40-140℃, the reaction can proceed smoothly.

[0027] Furthermore, the reaction time is 1-36 hours; the reaction time can be any value between 1 and 36 hours, such as 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, ..., 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, ..., 20 hours, 21 hours, 22 hours, 23 hours, 24 hours, 25 hours, ..., 30 hours, 31 hours, 32 hours, 33 hours, 34 hours, 35 hours, 36 hours, etc.; preferably 12-36 hours. For a reaction, the reaction time plays a crucial role. A short time may result in incomplete reaction, and the process may also produce byproducts. Therefore, selecting an optimal reaction time is beneficial to improving the conversion rate of the reaction.

[0028] Further, the organic solvent is methanol, acetonitrile, tetrahydrofuran, dioxane, 1,2-dichloroethane, toluene, acetone, ethyl acetate, N,N-dimethylformamide, or dimethyl sulfoxide.

[0029] Further, the molar ratio of substituted or unsubstituted α-bromoacetophenone to 2-aminobenzothiazole is 1:1-1.1. The molar ratio of substituted or unsubstituted α-bromoacetophenone to 2-aminobenzothiazole can be any value between 1:1 and 1.1, such as 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, etc.; preferably 1:1.05.

[0030] Further, the molar ratio of substituted or unsubstituted α-bromoacetophenone to N,N-dimethylaniline is 1:1-1.1. The molar ratio of substituted or unsubstituted α-bromoacetophenone to N,N-dimethylaniline can be any value between 1:1 and 1.1, such as 1:1.01, 1:1.02, 1:1.03, 1:1.04, 1:1.05, 1:1.06, 1:1.07, 1:1.08, 1:1.09, etc.; preferably 1:1.05.

[0031] Furthermore, the ratio of substituted or unsubstituted α-bromoacetophenone to organic solvent is 1 mmol: 1-2 mL; where 1-2 mL can represent any value between 1 and 2 mL, such as 1.1 mL, 1.2 mL, 1.3 mL, 1.4 mL, 1.5 mL, 1.6 mL, 1.7 mL, 1.8 mL, 1.9 mL, etc.

[0032] Furthermore, the reaction also includes a post-processing step, specifically: after the reaction is completed, the organic phase is extracted with a mixture of water and dichloromethane, dried, filtered, and the solvent is removed under reduced pressure, and then the target compound is obtained by column chromatography.

[0033] Furthermore, the volume ratio of water to dichloromethane is 1:8-12; the volume ratio of water to dichloromethane can be any value between 1:8 and 12, such as 1:9, 1:10, 1:11, etc.; preferably 1:10.

[0034] The technical solution of the present invention will be further described below with reference to specific embodiments.

[0035] Example 1 Add sequentially to the thick-walled glass tube α - Bromoacetylphenyl ketone (0.2 mmol, 1.0 equivalent), 2-aminobenzothiazole (0.21 mmol, 1.05 equivalent) and N,N0.21 mmol of dimethylaniline (1.05 equivalences) was added, followed by the addition of 2 mL of 1,2-dichloroethane. The mixture was stirred at 100 °C for 24 hours. After the reaction was complete, the reaction was monitored by thin-layer chromatography. Once complete, 10 mL of water and 10 mL of dichloromethane solution were added to the reaction flask, and the reaction mixture was extracted. The organic phase was collected and extracted three times. The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the solvent was removed under reduced pressure. The target compound was then obtained by column chromatography in 90% yield.

[0036]

[0037] N -methyl-4-((2-phenylbenzo[ d ]imidazo[2,1- b ]thiazol-3-yl)methyl)aniline: 1 H NMR (400 MHz, DMSO) δ 8.08 – 7.92 (m, 1H), 7.65 (d, J = 7.4 Hz, 2H),7.59 – 7.52 (m, 1H), 7.42 (t, J = 7.6 Hz, 2H), 7.39 – 7.28 (m, 3H), 6.95 (d, J =8.3 Hz, 2H), 6.50 (d, J = 8.4 Hz, 2H), 5.55 (d, J = 4.5 Hz, 1H), 4.51 (s, 2H), 2.61 (d, J = 3.9 Hz, 3H). 13 C NMR (151 MHz, DMSO) δ 149.15, 146.41, 144.24,134.79, 132.80, 129.84, 129.08, 128.42, 127.60, 127.30, 126.86, 125.37,125.13, 124.21, 123.56, 113.98, 112.71, 30.21, 29.57.

[0038] Example 2 Compared with Example 1, the difference is that the solvent is methanol, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 35%.

[0039] Example 3 Compared with Example 1, the difference is that the solvent is acetonitrile, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 15%.

[0040] Example 4 Compared with Example 1, the difference is that the solvent is tetrahydrofuran, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 20%.

[0041] Example 5 Compared with Example 1, the difference is that the solvent is dioxane, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 26%.

[0042] Example 6 Compared with Example 1, the difference is that the reaction time is 12 hours, while the other steps are the same as in Example 1, and the yield is 82%.

[0043] Example 7 Compared with Example 1, the difference is that the solvent is toluene, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 48%.

[0044] Example 8 Compared with Example 1, the difference is that the solvent is acetone, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 59%.

[0045] Example 9 Compared with Example 1, the difference is that the solvent is ethyl acetate, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 25%.

[0046] Example 10 Compared with Example 1, the difference is that the solvent is N,N-dimethylformamide, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 65%.

[0047] Example 11 Compared with Example 1, the difference is that the solvent is N-methylpyrrolidone, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1. Only the production of trace amounts of the target compound was observed.

[0048] Example 12 Compared with Example 1, the difference is that the solvent is DMSO, the reaction time is 12 hours, and the rest of the steps are the same as in Example 1, with a yield of 68%.

[0049] Example 13 Compared with Example 11, the difference is that the reaction temperature was room temperature, while the rest of the steps were the same as in Example 11, and the expected compound was not obtained.

[0050] Example 14 Compared with Example 11, the difference is that the reaction temperature is 60°C, the rest of the steps are the same as in Example 11, and the yield is 28%.

[0051] Example 15 Compared with Example 11, the difference is that the reaction temperature is 80°C, the rest of the steps are the same as in Example 11, and the yield is 55%.

[0052] Example 16 Compared with Example 11, the difference is that the reaction temperature is 90°C, the other steps are the same as in Example 11, and the yield is 70%.

[0053] Example 17 Compared with Example 11, the difference is that the reaction temperature is 110°C, the rest of the steps are the same as in Example 11, and the yield is 80%.

[0054] Example 18 Compared with Example 11, the difference is that the reaction temperature is 120°C, the rest of the steps are the same as in Example 11, and the yield is 76%.

[0055] Example 19 Compared with Example 11, the difference is that the reaction temperature is 130°C, the rest of the steps are the same as in Example 11, and the yield is 73%.

[0056] Example 20 Compared with Example 11, the difference is that the reaction time is 1 hour, the rest of the steps are the same as in Example 11, and the yield is 24%.

[0057] Example 21 Compared with Example 11, the difference is that the reaction time is 6 hours, the rest of the steps are the same as in Example 11, and the yield is 53%.

[0058] Example 22 Compared with Example 11, the difference is that the reaction time is 24 hours, the rest of the steps are the same as in Example 11, and the yield is 81%.

[0059] Example 23 Compared with Example 11, the difference is that the reaction time is 36 hours, the rest of the steps are the same as in Example 11, and the yield is 80%.

[0060] The above description is merely a preferred embodiment of the present invention and is not intended to limit the invention. Various modifications and variations can be made to the present invention by those skilled in the art. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the scope of protection of the present invention.

Claims

1. A method for synthesizing N-methyl-4-((2-phenylbenzi[d]imidazol[2,1-b]thiazolyl-3-yl)methyl)aniline compounds, characterized in that, Includes the following steps: The product is obtained by reacting substituted or unsubstituted α-bromoacetophenone, 2-aminobenzothiazole and N,N-dimethylaniline in an organic solvent. The reaction temperature is 40-140℃, and the reaction time is 1-36 hours.

2. The synthesis method according to claim 1, characterized in that, The substituents in substituted α-bromoacetophenone are methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, and bromine.

3. The synthesis method as described in claim 1, characterized in that, Use substituted or unsubstituted α-bromonaphthone or α-bromocyclopropaneone instead of substituted or unsubstituted α-bromoacetophenone, with substituents being methyl, methoxy, trifluoromethyl, nitro, fluorine, chlorine, or bromine.

4. The synthesis method according to claim 1, characterized in that, The reaction temperature is 90-130℃, and the reaction time is 12-36 hours.

5. The synthesis method according to claim 1, characterized in that, The organic solvent is methanol, acetonitrile, tetrahydrofuran, dioxane, 1,2-dichloroethane, toluene, acetone, ethyl acetate, N,N-dimethylformamide, or dimethyl sulfoxide; preferably 1,2-dichloroethane, toluene, acetone, N,N-dimethylformamide, or dimethyl sulfoxide.

6. The synthesis method according to claim 1, characterized in that, The molar ratio of substituted or unsubstituted α-bromoacetophenone to 2-aminobenzothiazole is 1:1-1.1; preferably 1:1.

05.

7. The synthesis method according to claim 1, characterized in that, The molar ratio of substituted or unsubstituted α-bromoacetophenone to N,N-dimethylaniline is 1:1-1.1; preferably 1:1.

05.

8. The synthesis method according to claim 1, characterized in that, The ratio of substituted or unsubstituted α-bromoacetophenone to organic solvent is 1 mmol: 1-2 mL.

9. The synthesis method according to claim 1, characterized in that, The reaction also includes a post-processing step, specifically: after the reaction is completed, the organic phase is extracted with a mixture of water and dichloromethane, dried, filtered, and the solvent is removed under reduced pressure, and then the target compound is obtained by column chromatography.

10. The synthesis method according to claim 9, characterized in that, The volume ratio of water to dichloromethane is 1:8-12, preferably 1:10.

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