A method for green synthesis of benzimidazole and its derivatives using o-phenylenediamine and supercritical CO2 as raw materials

Abstract

The present application relates to a kind of method for green synthesis benzimidazole derivatives using o-phenylenediamine and supercritical CO2 as raw material, belong to medicine, pesticide and material field.This method uses o-phenylenediamine compound and supercritical carbon dioxide as reactant, with borohydride as reducing agent, and carries out reaction.Supercritical carbon dioxide is used as solvent and reactant, borohydride compound is used as reducing agent to activate CO2, o-phenylenediamine compound and CO2 are converted into benzimidazole compound under certain CO2 pressure and certain reaction temperature.Supercritical carbon dioxide is used as raw material and solvent, and the use of toxic solvent is abandoned, which solves the technical problems of high toxicity, high boiling point, large solvent residue and complex separation process of the solvent used in existing method;It provides a simple and green method for carbon dioxide as carbon source to synthesize benzimidazole derivatives.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of medicine, pesticide and material, and further relates to a method for green synthesis of benzimidazole and its derivatives using o-phenylenediamine and supercritical CO2 as raw materials. BACKGROUND

[0002] With the development of industry, the combustion of fossil fuels has caused a significant increase in the concentration of carbon dioxide in the atmosphere. Excessive carbon dioxide has caused the earth's heat cycle to be out of balance, and extreme weather has become more frequent. However, carbon dioxide is also a rich and renewable C1 resource, so converting carbon dioxide into valuable chemicals not only can alleviate the dependence of the chemical industry on fossil resources, but also can effectively reduce carbon dioxide emissions.

[0003] Benzimidazole is a benzoheterocyclic compound containing two C-N bonds, and is one of the important advantage skeleton structures. Benzimidazole derivatives containing imidazole rings have important values in anticancer, anti-rheumatism, antifungal, anti-inflammatory analgesic, etc. Therefore, in recent years, the development of benzimidazole compounds has been valued by the relevant industry. Commercial products with such compounds as bioactive components are emerging in an endless stream, such as liarazole, lansoprazole, fluorobenzimidazole, and bendamustine hydrochloride, etc.

[0004] Generally, benzimidazole is synthesized by o-phenylenediamine and formic acid, formaldehyde, methanol or DMF under the action of a catalyst. This synthesis method has high toxicity, high boiling point, large amount of residual solvent and complex separation process, which limits the promotion and application of the corresponding method. SUMMARY

[0005] In view of the shortcomings of the prior art, the purpose of the present application is to provide a non-toxic and environmentally friendly synthesis method of benzimidazole and its derivatives.

[0006] The synthesis method of the present application uses supercritical carbon dioxide as both a solvent and a reactant to react with o-phenylenediamine compounds to greenly synthesize benzimidazole and its derivatives. This synthesis method avoids the use of high-boiling organic solvents, and provides a simple and green method for synthesizing benzimidazole derivatives using carbon dioxide as a carbon source.

[0007] A method for green synthesis of benzimidazole and its derivatives using o-phenylenediamine and supercritical CO2 as raw materials, the method comprising using o-phenylenediamine compounds and supercritical carbon dioxide as reactants, and using borohydride as a reducing agent to carry out a reaction; wherein the supercritical carbon dioxide acts as a solvent.

[0008] The synthesis method utilizes supercritical CO2 as both a solvent and a reactant, utilizes a borohydride compound as a reducing agent to activate CO2, and converts an o-phenylenediamine compound and CO2 into a benzimidazole compound under a certain CO2 pressure and a certain reaction temperature. The reaction equation is as follows:

[0009]

[0010] The benzimidazole and its derivatives have a chemical formula of: R is selected from at least one of H, F, Cl, Br, CF3, OCH3, CH3, C(CH3)3, C 1-8 alkyl, and C 1-8 alkoxy.

[0011] The o-phenylenediamine compound includes o-phenylenediamine and any substituted o-phenylenediamine. The o-phenylenediamine compound has a chemical formula of: wherein R is selected from at least one of H, F, Cl, Br, CF3, OCH3, CH3, C(CH3)3, C 1-8 alkyl, and C 1-8 alkoxy.

[0012] In some embodiments, the o-phenylenediamine compound is

[0013] Their corresponding products (benzimidazole and its derivatives) are, in turn, benzimidazole,

[0014] The borohydride is selected from at least one of BH3NH3, NaBH4, and BH3N(C2H5)3. In some embodiments, BH3NH3 is used as a reducing agent, and the highest yield of benzimidazole and its derivatives can reach 97%. In some embodiments, NaBH4 is used as a reducing agent, and the highest yield of benzimidazole and its derivatives can reach 97%. In some embodiments, triethylamine borane is used as a reducing agent, and the highest yield of benzimidazole and its derivatives can reach 95%.

[0015] The molar ratio of the o-phenylenediamine compound to borohydride has a significant effect on the yield of the benzimidazole and its derivatives. In some embodiments, when the molar ratio of the o-phenylenediamine compound to borohydride is 1:0.5-5, the yield of the benzimidazole and its derivatives is 38-97%; when the molar ratio of the o-phenylenediamine compound to borohydride is 1:1-2, the yield of the benzimidazole and its derivatives is 78-97%. When the molar ratio of the o-phenylenediamine compound to borohydride is about 1:1, the yield of the benzimidazole and its derivatives is 95-97%. Therefore, in the present application, the molar ratio of the o-phenylenediamine compound to borohydride is 1:0.5-5, preferably 1:1-2. Alternatively, the molar ratio of the o-phenylenediamine compound to borohydride is 1:0.5-1, 1:1-1.5, 1:1-3, 1:1.5-2, 1:1.5-3, or 1:2-3.

[0016] The pressure of the supercritical carbon dioxide has a significant effect on the yield of the benzimidazole and its derivatives. In some embodiments, as the pressure of the supercritical carbon dioxide increases, the yield of the benzimidazole and its derivatives increases; when the pressure of the supercritical carbon dioxide increases to about 9 MPa, further increasing the pressure of the supercritical carbon dioxide will result in a decrease in the yield of the benzimidazole and its derivatives. Therefore, in order to obtain a higher yield, the pressure of the supercritical carbon dioxide can be limited to 7.5-13 MPa. In some embodiments, when the pressure of the supercritical carbon dioxide is 8-9 MPa, the yield of the benzimidazole and its derivatives is 86-97%. Therefore, in the present application, the pressure of the supercritical carbon dioxide is 7.5-13 MPa, preferably 8-9 MPa.

[0017] The reaction temperature has a significant effect on the yield of the benzimidazole and its derivatives. In some embodiments, as the reaction temperature increases, the yield of the benzimidazole and its derivatives increases; when the reaction temperature increases to about 50°C, further increasing the reaction temperature will result in a decrease in the yield of the benzimidazole and its derivatives. Therefore, in order to obtain a higher yield, the reaction temperature can be limited to 40-90°C. In some embodiments, when the reaction temperature is 50-60°C, the yield of the benzimidazole and its derivatives is 90-95%. Therefore, in the present application, the reaction temperature is 40-90°C, preferably 50-60°C.

[0018] The reaction time can be determined by monitoring the reaction condition. Generally, the reaction time is more than 6 hours. Generally, the reaction time is prolonged to improve the yield of the product. In the present application, when the reaction time is prolonged to a certain time, the yield of the benzimidazole and its derivatives will decrease with the further prolongation of the reaction time. In some embodiments, the reaction time is 6 hours, and the yield of the benzimidazole and its derivatives can reach 52%; the reaction time is prolonged to 10 hours, and the yield of the benzimidazole and its derivatives can reach 78%; the reaction time is prolonged to 12 hours, and the yield of the benzimidazole and its derivatives can reach 95%; the reaction time is prolonged to 24 hours, and the yield of the benzimidazole and its derivatives can reach 97%; the reaction time is prolonged to 36 hours, and the yield of the benzimidazole and its derivatives will decrease to 96%. Therefore, in the present application, the reaction time is more than 6 hours, preferably 10-36 hours, and more preferably 12-24 hours.

[0019] The specific process of the above method is as follows: the o-phenylenediamine compound and the reducing agent borohydride are added into a high-pressure reaction kettle, which is tightly screwed and is connected with 7.5-13 MPa CO2, and the reaction is carried out at 40-90℃ for more than 6 hours. The reaction liquid is concentrated and purified to obtain the benzimidazole and its derivatives.

[0020] After the reaction is completed, the reaction liquid is concentrated and purified to obtain the benzimidazole and its derivatives. The concentration is carried out by atmospheric or reduced pressure distillation, for example, vacuum concentration by a rotary evaporator. The purification is carried out by column chromatography or recrystallization for separation and purification.

[0021] Compared with the prior art, the present application has the following advantages:

[0022] The present application utilizes the reaction of the o-phenylenediamine compound and the supercritical carbon dioxide to quickly and efficiently synthesize the benzimidazole and its derivatives. The supercritical carbon dioxide is used as the raw material and the solvent at the same time, which avoids the use of toxic solvents, and solves the technical problems of the high toxicity, high boiling point, large residual amount of the solvent and complex separation process of the solvents used in the prior art. The method of the present application has the advantages of low reaction temperature, simple operation, easy post-treatment, high reaction rate, easy purification of the product, environmental friendliness and high product yield. The present application provides a simple and green method for synthesizing the benzimidazole and its derivatives by using CO2 as the carbon source. In addition, the method of the present application has the following advantages:

[0023] 1. The activator of carbon dioxide is borohydride, which reduces the temperature required for activating the carbon dioxide and reduces the energy consumption of the reaction;

[0024] 2. The reaction system is relatively simple, and no other catalysts and solvents are added except the reactants and the reducing agent;

[0025] 3. Direct dehydration during the reaction, without adding other dehydrating agents, improves atomic economy.

[0026] In the present application, "about" means floating 10% up and down. DETAILED DESCRIPTION

[0027] The present application will be described in detail below with specific examples. It is necessary to point out that the following examples are only used to further illustrate the present application and cannot be understood as limiting the scope of protection of the present application. Some non-essential improvements and adjustments made by those skilled in the art based on the content of the present application still fall within the scope of protection of the present application.

[0028] The reaction reagents involved in the examples are all commonly used commercially available products. The nuclear magnetic resonance spectrometer used in the examples is Agilent 500MHz DD2.

[0029] Example 1

[0030] Benzimidazole is synthesized by reacting o-phenylenediamine with supercritical carbon dioxide as a reactant, a solvent and ammonia borane as a reducing agent.

[0031]

[0032] Into a 15 mL polytetrafluoroethylene lined stainless steel reactor, 108 mg (1 mmol) of o-phenylenediamine and a certain amount of ammonia borane (ammonia borane dosage is 0.5-5 mmol, as shown in Table 1) were added, a magnetic stirrer was placed, the reactor was tightly closed, and the reactor was preheated to a certain temperature (temperature is 40-90℃, as shown in Table 1). A certain amount of carbon dioxide was charged under constant temperature conditions to make the carbon dioxide in the reactor reach a certain pressure (carbon dioxide pressure is 7.5 MPa-13 MPa, as shown in Table 1), and the reaction was stirred for a certain time (reaction time is more than 6 hours, as shown in Table 1). The reactor was cooled to room temperature, the obtained solid was dissolved with ethyl acetate, then silica gel was added, and then ethyl acetate was removed under reduced pressure to obtain the crude product; the crude product was separated by column chromatography (200-300 mesh silica gel, dichloromethane and methanol as eluent, volume ratio of dichloromethane to methanol is 20:1), and the first eluted layer was collected to obtain yellow solid benzimidazole with a purity of more than 99%. The nuclear magnetic characterization data are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.20 (s, 1H), 7.59 (s, 2H), 7.19 (dd, J = 6.0, 3.1 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 142.37, 122.14, 115.75.

[0033] The yield of benzimidazole is different under different conditions of the amount of ammonia borane, reaction temperature T, carbon dioxide pressure (reaction pressure) and reaction time t, as shown in Table 1.

[0034] Table 1

[0035]

[0036] According to the data in Table 1, the optimal conditions are as follows: the molar ratio of o-phenylenediamine to BH3NH3 is 1:1, the temperature is 50°C, the pressure is 9 MPa, the reaction time is 12-24 h, and the yield is 97%.

[0037] Example 2

[0038] Benzimidazole is synthesized by reacting o-phenylenediamine with sodium borohydride as a reducing agent, supercritical carbon dioxide as a reactant, a solvent and o-phenylenediamine.

[0039]

[0040] In a 15 ml polytetrafluoroethylene-lined reaction kettle, 108 mg (1 mmol) of o-phenylenediamine and a certain amount of NaBH4 (the molar ratio of o-phenylenediamine to NaBH4 is 1:0.5-5, as shown in Table 2) were added, a magnetic stirrer was placed, the reaction kettle was tightly closed, and the reaction kettle was preheated to a certain temperature (the temperature is 40-90°C, as shown in Table 2). A certain amount of carbon dioxide was charged under constant temperature conditions to make the carbon dioxide in the reaction kettle reach a certain pressure (the carbon dioxide pressure is 7.5 MPa-13 MPa, as shown in Table 2), and the reaction was stirred for a certain time (the reaction time is more than 6 hours, as shown in Table 2). The reaction kettle was cooled to room temperature, and the obtained solid was dissolved in ethyl acetate, then silica gel was added, and then the ethyl acetate was removed under reduced pressure to obtain the crude product; the crude product was separated by column chromatography (200-300 mesh silica gel, dichloromethane and methanol as eluent, the volume ratio of dichloromethane to methanol is 20:1), and the first eluted layer was collected to obtain yellow solid benzimidazole with a purity of more than 99%. The nuclear magnetic resonance characterization data are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.20 (s, 1H), 7.59 (s, 2H), 7.19 (dd, J = 6.0, 3.1 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 142.37, 122.14, 115.75.

[0041] The yield of benzimidazole is different under different conditions of the amount of ammonia borane, reaction temperature T, carbon dioxide pressure (reaction pressure) and reaction time t, as shown in Table 2.

[0042] Table 2

[0043]

[0044]

[0045] From the data in Table 2, it can be concluded that the optimum conditions are: the molar ratio of o-phenylenediamine to NaBH4 is 1:1, the temperature is 50°C, the pressure is 9 MPa, the reaction time is 12 h, and the yield is 97%.

[0046] Example 3

[0047] The reaction of o-phenylenediamine with triethylborane as the reducing agent and supercritical carbon dioxide as the reactant, solvent and reagent was used to synthesize benzimidazole.

[0048]

[0049] In a 15 ml Teflon-lined autoclave, 108 mg (1 mmol) of o-phenylenediamine and a certain amount of BH3N(C2H5)3 (the molar ratio of o-phenylenediamine to BH3N(C2H5)3 is 1:0.5-5, as shown in Table 3) were added, a magnetic stirrer was placed, the autoclave was tightly closed, and the autoclave was preheated to a certain temperature (the temperature is 40-90°C, as shown in Table 3). Under constant temperature, a certain amount of carbon dioxide was filled into the autoclave until the carbon dioxide reached a certain pressure (the carbon dioxide pressure is 7.5 MPa-13 MPa, as shown in Table 3), and the reaction was stirred for a certain time (the reaction time is more than 6 hours, as shown in Table 3). The autoclave was cooled to room temperature, and the obtained solid was dissolved in ethyl acetate, then silica gel was added, and then the ethyl acetate was removed under reduced pressure to obtain the crude product; the crude product was separated by column chromatography (200-300 mesh silica gel, dichloromethane and methanol as eluents, the volume ratio of dichloromethane to methanol is 20:1), and the first eluted layer was collected to obtain yellow solid benzimidazole with a purity of more than 99%. The nuclear magnetic resonance characterization data are as follows: 1 H NMR (500 MHz, DMSO-d6) δ 12.43 (s, 1H), 8.20 (s, 1H), 7.59 (s, 2H), 7.19 (dd, J = 6.0, 3.1 Hz, 2H). 13 C NMR (125 MHz, DMSO-d6) δ 142.37, 122.14, 115.75.

[0050] Among them, under the conditions of different amounts of borane amine, reaction temperature T, carbon dioxide pressure (reaction pressure) and reaction time t, the yield of benzimidazole is different, as shown in Table 3.

[0051] Table 3

[0052]

[0053]

[0054] From the data in Table 3, it can be concluded that the optimum conditions are: the molar ratio of o-phenylenediamine compound to BH3N(C2H5)3 is 1:1, the temperature is 50°C, the pressure is 9 MPa, and the reaction time is 24 h; under these conditions, the yield is 95%.

[0055] Examples 4-12

[0056] Benzimidazole derivatives were synthesized by reacting o-phenylenediamine compounds with borohydride as the reducing agent and supercritical carbon dioxide as both the reactant and the solvent. The structures of the o-phenylenediamine compounds used are listed in Table 4; the selection of borohydride and the synthesis conditions refer to the optimum conditions in the synthesis method of benzimidazole, and the relevant data are listed in Table 4; the structures of the synthesized products, benzimidazole derivatives, and their NMR characterization data are listed in Table 4.

[0057] Table 4: Synthesis of benzimidazole derivatives

[0058]

[0059]

[0060]

Claims

1. A method for the green synthesis of benzimidazole and its derivatives using o-phenylenediamine and supercritical CO2 as raw materials, characterized in that: The method uses o-phenylenediamine compounds and supercritical carbon dioxide as reactants, and borohydride as a reducing agent to carry out the reaction; wherein the supercritical carbon dioxide simultaneously acts as a solvent; The chemical formula of the benzimidazole and its derivatives is: ; R is selected from H, F, Cl, Br, CF3, C 1-8 alkyl and C 1-8 alkoxy; The chemical formula of the ortho-phenylenediamine compound is: ; wherein R is selected from at least one of H, F, Cl, Br, CF3, C 1-8 alkyl, and C 1-8 alkoxy. The borohydride is selected from at least one of BH3NH3, NaBH4 and BH3N(C2H5)3; The pressure of the supercritical carbon dioxide is 8-13 MPa.

2. The method of claim 1, wherein: The molar ratio of the o-phenylenediamine compound to the borohydride is 1:0.5-5.

3. The method of claim 2, wherein: The molar ratio of the o-phenylenediamine compound to the borohydride is 1:1-2.

4. The method of claim 1, wherein: The pressure of the supercritical carbon dioxide is 8-9 MPa.

5. The method of claim 1, wherein: The reaction temperature is 40-90℃.

6. The method of claim 5, wherein: The reaction temperature is 50-60℃.

7. The method of claim 1, wherein: The reaction time is more than 6 hours.

8. The method of claim 7, wherein: The reaction time is 10-36 hours.

9. The method of claim 7, wherein: The reaction time is 12-24 hours.

10. The method of claim 1, wherein: After the reaction is completed, the reaction liquid is concentrated and purified to obtain benzimidazole and its derivatives.

11. The method of claim 10, wherein: The concentration uses atmospheric or reduced pressure distillation; or / and, the purification uses column chromatography or recrystallization to separate and purify.

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