Preparation method of 2-hydroxybenzimidazole

Abstract

The invention discloses a preparation method of 2-hydroxybenzimidazole, which comprises the following steps of: introducing carbonyl fluoride gas into a reactor filled with o-phenylenediamine dissolved by a solvent in a bubbling form for stirring reaction, introducing the carbonyl fluoride gas into the reactor, stirring for 4-48 hours, purging reaction liquid by using gas, removing carbonyl fluoride in the reaction liquid, filtering, washing, and drying to obtain the 2-hydroxybenzimidazole. And carrying out reduced pressure distillation to remove the solvent so as to obtain the 2-hydroxybenzimidazole. The method has the advantages of environment-friendly and simple reaction process, no generation of three wastes, low cost, easy obtaining, simple reaction process, mild reaction, no need of nitrogen protection, no generation of waste gas pollution, easy operation, and suitableness for industrial production.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals, and specifically relates to a method for preparing 2-hydroxybenzimidazole. Background Art

[0002] 2-Hydroxybenzimidazole is an important fine chemical intermediate and an important upstream raw material for drugs such as the antihypertensive drug candesartan cilexetil and the anticancer drug domperidone maleate, as shown in Scheme 1 and Scheme 2. In addition, the product can also be used as a pharmaceutical and pesticide intermediate and is widely used in pesticides, pharmaceutical intermediates, and organic materials.

[0003] Scheme 1:

[0004]

[0005] Scheme 2:

[0006]

[0007] At present, there are few patents for the preparation of 2-hydroxybenzimidazole. Chinese patent 2012102880257 reports a preparation method of 2-hydroxybenzimidazole, which is to react urea with o-phenylenediamine to prepare 2-hydroxybenzimidazole (Scheme 3), and another is to react CDI (N, N'-carbonyldiimidazole) with o-phenylenediamine to prepare 2-hydroxybenzimidazole (Scheme 4). The first method uses hydrochloric acid or acyl chloride, and the reaction will produce three wastes such as organic ammonium salts. The second method will also produce organic by-products such as imidazole salts, which brings great trouble to the purification of 2-hydroxybenzimidazole.

[0008] Scheme 3:

[0009] Summary of the invention

[0010] The invention provides a preparation method for synthesizing 2-hydroxybenzimidazole, which can avoid the problem of by-product generation and has relatively less three wastes.

[0011] The technical solution of the present invention is:

[0012] A method for preparing 2-hydroxybenzimidazole comprises the following steps: introducing carbonyl fluoride gas in the form of bubbling into a reactor containing o-phenylenediamine dissolved in a solvent for stirring and reacting, and removing the solvent by reduced pressure distillation to obtain 2-hydroxybenzimidazole.

[0013] Reaction equation of the present invention is:

[0014]

[0015] Preferably, the specific steps are as follows:

[0016] Step 1, dissolving o-phenylenediamine in a solvent and maintaining a certain temperature;

[0017] Step 2: introducing carbonyl fluoride gas into the reactor, stirring for 4 to 48 hours, and purging the reaction solution with gas to remove carbonyl fluoride in the reaction solution to prepare a crude 2-hydroxybenzimidazole;

[0018] Step 3, removing the solvent by distillation under reduced pressure, washing with alcohols, and obtaining the fine product of 2-hydroxybenzimidazole.

[0019] Preferably, in step 1, the volume ratio of o-phenylenediamine to the solvent is 1:10 to 100;

[0020] Keep the solvent temperature at -15℃~10℃ 。

[0021] Preferably, the solvent is one or more of acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide and dichloromethane.

[0022] Preferably, the solvent is one or more of acetonitrile, tetrahydrofuran and 1,4-dioxane.

[0023] Preferably, the solvent is acetonitrile.

[0024] Preferably, in step 2, the molar ratio of carbonyl fluoride to o-phenylenediamine is 2 to 10:1;

[0025] The ventilation flow rate of carbonyl fluoride is 20 to 500 mL / min;

[0026] The reaction temperature is -15°C to 10°C;

[0027] The gas used for purging is nitrogen, helium or argon, and the purging time is not less than 15 minutes.

[0028] Preferably, in step 3, the pressure of the reduced pressure distillation is -1.0 to -0.90 MPa;

[0029] After the vacuum distillation is completed, recrystallization is carried out using alcohols;

[0030] After recrystallization, washing is performed with alcohol, and the alcohol used in the washing process is the same as the alcohol used in the recrystallization;

[0031] The recrystallization process is as follows: alcohol is added to the crude 2-hydroxybenzimidazole product from which the solvent has been removed by vacuum distillation, heated to the boiling point of the alcohol until the crude product is completely dissolved, and cooled to room temperature to crystallize a solid;

[0032] During the recrystallization process, the mass ratio of crude 2-hydroxybenzimidazole to alcohol is 1:1 to 10;

[0033] During the washing process, the mass ratio of the crude 2-hydroxybenzimidazole to the alcohol is 1:1-10.

[0034] Preferably, the alcohol is one or a mixture of ethanol, methanol and isopropanol.

[0035] Preferably, the alcohol is ethanol.

[0036] The room temperature of the present invention is 4-38°C.

[0037] Beneficial effects of the present invention:

[0038] The process of the invention has low production cost, less three reaction wastes, mild reaction conditions, and the reaction solvent can be recycled. The reaction can be carried out under normal pressure and has a high reaction yield.

[0039] In the present invention, the reactants react fully, the waste is easily discharged after the reaction is completed, the post-treatment is simple, the solvent can be recycled, and the pollution in the synthesis process is reduced, which belongs to a green synthesis process.

[0040] The invention has low cost and high raw material utilization rate. Compared with other acylation reactions, the reaction does not need triethylamine or DIPEA as an acidifying agent, and the reaction does not generate a large amount of organic amine salt byproducts. The method adopts a one-step ring-closing method, and the reaction process is environmentally friendly and simple, and basically no three wastes are generated. The method of the invention uses carbonyl fluoride and o-phenylenediamine as raw materials, which are common chemical raw materials, cheap and easy to obtain. The reaction process is simple, the reaction is mild, no nitrogen protection is required, and no waste gas pollution is generated. The method is easy to operate and is suitable for industrial production. DETAILED DESCRIPTION

[0041] Example 1

[0042] Step 1: Add 40 g of acetonitrile and 2 g of o-phenylenediamine into the reactor, and cool the stainless steel reactor to 0° C. by circulating the cooling liquid.

[0043] Step 2: Bubble carbonyl fluoride into the acetonitrile in the reactor at a flow rate of 20 mL / min. The reaction is stirred at normal pressure and 0°C for 48 hours. After the reaction is completed, stop adding carbonyl fluoride and purge the reaction solution with nitrogen for 30 minutes to remove carbonyl fluoride in the reaction solution.

[0044] Step 3, take out the reaction solution, remove the solvent acetonitrile by vacuum distillation, place 2.8 g of the residual 2-hydroxybenzimidazole crude product in a single-mouth round-bottom flask, add 2.8 g of ethanol to the round-bottom flask, heat to the boiling point of ethanol 78°C, slowly cool to room temperature, filter, wash twice with 2.8 g of ethanol, dry at room temperature and take out, the purity is 92.5%, and the yield is 95.9%.

[0045] Vacuum distillation steps:

[0046] The reaction solution was transferred to a 500 mL eggplant-shaped flask and installed on a rotary evaporator (brand model: Tokyo Rika N-1300D-WB). The system was evacuated to a negative pressure of -0.95 MPa using a vacuum pump (brand model: Gongyi Yuhua SHZ-DIII). The heating temperature of the rotary evaporation water bath was set to 47°C. The rotary evaporation was turned on to slowly evaporate the solvent acetonitrile.

[0047] Example 2

[0048] Step 1: Add 100 g of tetrahydrofuran and 10 g of o-phenylenediamine into the reactor, and cool the stainless steel reactor to -15°C by circulating the cooling liquid.

[0049] Step 2: Bubble carbonyl fluoride into tetrahydrofuran in the reactor at a flow rate of 500 mL / min, and stir the reaction at normal pressure at -15°C for 8 hours. After the reaction is completed, stop adding carbonyl fluoride, and purge the reaction solution with helium for 30 minutes to remove carbonyl fluoride in the reaction solution.

[0050] Step 3, take out the reaction solution, distill under reduced pressure to remove the solvent tetrahydrofuran, place 12g of the residual 2-hydroxybenzimidazole crude product in a single-necked round-bottom flask, add 120g of methanol to the round-bottom flask, heat to 78°C, the boiling point of methanol, slowly cool to room temperature, filter, wash twice with 12g of methanol, dry at room temperature and take out, the purity is 94.7%, and the yield is 91.0%.

[0051] Vacuum distillation steps:

[0052] The reaction solution was transferred to a 500 mL eggplant-shaped flask and installed on a rotary evaporator (brand model: Tokyo Rika N-1300D-WB). The system was evacuated to a negative pressure of -1.00 MPa using a vacuum pump (brand model: Gongyi Yuhua SHZ-DIII). The heating temperature of the rotary evaporation water bath was set to 40°C. The rotary evaporation was turned on to slowly evaporate the solvent tetrahydrofuran.

[0053] Example 3

[0054] Step 1: add 300 g of dioxane and 3 g of o-phenylenediamine into the reactor, and cool the stainless steel reactor to 10° C. by circulating the cooling liquid.

[0055] Step 2: Bubble carbonyl fluoride into 1,4-dioxane in the reactor at a flow rate of 100 mL / min. The reaction is stirred at normal pressure and 10°C for 16 hours. After the reaction is completed, stop adding carbonyl fluoride and purge the reaction solution with argon for 15 minutes to remove carbonyl fluoride from the reaction solution.

[0056] Step three, take out the reaction solution, distill under reduced pressure to remove the solvent 1,4-dioxane, place 4.6 g of the residual crude 2-hydroxybenzimidazole in a single-necked round-bottom flask, add 46 g of a mixed solution of methanol and isopropanol (methanol: 23 g; isopropanol: 23 g) into the round-bottom flask, heat to the azeotropic point of 78 ° C, slowly cool to room temperature, filter, wash twice with 4.6 g of methanol and isopropanol (methanol: 2.3 g; isopropanol: 2.3 g), dry at room temperature and take out, with a purity of 91.2% and a yield of 92.0%.

[0057] Vacuum distillation steps:

[0058] The reaction solution was transferred to a 500 mL eggplant-shaped flask and installed on a rotary evaporator (brand model: Tokyo Rika N-1300D-WB). The system was evacuated to a negative pressure of -0.90 MPa using a vacuum pump (brand model: Gongyi Yuhua SHZ-DIII). The heating temperature of the rotary evaporation water bath was set to 55°C. The rotary evaporation was turned on to slowly evaporate the solvent 1,4-dioxane.

[0059] Comparative Example 1

[0060] The difference between the present invention and Example 1 is that: in step 2, the introduction of carbonyl fluoride is stopped, and the reaction solution is not purged with nitrogen, and the other processes used are the same;

[0061] This comparative example obtained 2.82 g of product with a purity of 91.84% and a yield of 96.59%.

[0062] Comparative Example 2

[0063] The difference between the present invention and Example 1 is that: in step 2, the reaction is stirred at 20° C. under normal pressure for 48 hours, and the other processes used are the same;

[0064] This comparative example obtained 11.57 g of product with a purity of 95.1% and a yield of 93.3%.

[0065] Comparative Example 3

[0066] The difference between the present invention and Example 1 is that: in step 2, there is no recrystallization and washing process, and the other processes used are the same;

[0067] This comparative example obtained 2.91 g of product with a purity of 78.4%. Since it was a crude product and contained by-products, it was already greater than the theoretical yield and the yield could not be calculated.

[0068] Comparative Example 4

[0069] The difference between the present invention and Example 1 is that: in step 1, the solvent used is a mixture of dimethyl sulfoxide and dichloromethane in a mass ratio of 1:1, and the other processes used are the same;

[0070] This comparative example obtained 2.04 g of product with a purity of 90.5% and a yield of 82.2%.

[0071] In summary, the above are only preferred embodiments of the present invention and are not intended to limit the protection scope of the present invention. Any modifications, equivalent substitutions, improvements, etc. made within the spirit and principles of the present invention should be included in the protection scope of the present invention.

Claims

1. A method for preparing 2-hydroxybenzimidazole, characterized in that: Carbonyl fluoride gas is introduced into a reactor containing o-phenylenediamine dissolved in a solvent in the form of bubbling to carry out stirring reaction, and the solvent is removed by distillation under reduced pressure to obtain 2-hydroxybenzimidazole.

2. A method for preparing 2-hydroxybenzimidazole according to claim 1, characterized in that: The specific steps are as follows: Step 1, dissolving o-phenylenediamine in a solvent and maintaining a certain temperature; Step 2: introducing carbonyl fluoride gas into the reactor, stirring for 4 to 48 hours, and purging the reaction solution with gas to remove carbonyl fluoride in the reaction solution to prepare a crude 2-hydroxybenzimidazole; Step 3, removing the solvent by distillation under reduced pressure to obtain the refined 2-hydroxybenzimidazole.

3. A method for preparing 2-hydroxybenzimidazole according to claim 2, characterized in that: In step 1, the volume ratio of o-phenylenediamine to the solvent is 1:10-100; Keep the solvent temperature at -15℃~10℃ 。 4. A method for preparing 2-hydroxybenzimidazole according to any one of claims 1 to 3, characterized in that: The solvent is one or more of acetonitrile, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, dimethyl sulfoxide and dichloromethane.

5. A method for preparing 2-hydroxybenzimidazole according to claim 4, characterized in that: The solvent is one or more of acetonitrile, tetrahydrofuran and 1,4-dioxane.

6. A method for preparing 2-hydroxybenzimidazole according to claim 5, characterized in that: The solvent is acetonitrile.

7. A method for preparing 2-hydroxybenzimidazole according to claim 2, characterized in that: In step 2, the molar ratio of carbonyl fluoride to o-phenylenediamine is 2 to 10:1; The ventilation flow rate of carbonyl fluoride is 20 to 500 mL / min; The reaction temperature is -15°C to 10°C; The gas used for purging is nitrogen, helium or argon, and the purging time is not less than 15 minutes.

8. A method for preparing 2-hydroxybenzimidazole according to claim 2, characterized in that: In step 3, the pressure of the reduced pressure distillation is -1.0 to -0.90 MPa; After the vacuum distillation is completed, recrystallization is carried out using alcohols; After recrystallization, washing is performed with alcohol, and the alcohol used in the washing process is the same as the alcohol used in the recrystallization; The recrystallization process is as follows: alcohol is added to the crude 2-hydroxybenzimidazole product from which the solvent has been removed by vacuum distillation, heated to the boiling point of the alcohol until the crude product is completely dissolved, and cooled to room temperature to crystallize a solid; During the recrystallization process, the mass ratio of crude 2-hydroxybenzimidazole to alcohol is 1:1 to 10; During the washing process, the mass ratio of the crude 2-hydroxybenzimidazole to the alcohol is 1:1-10.

9. A method for preparing 2-hydroxybenzimidazole according to claim 8, characterized in that: The alcohol is one of ethanol, methanol and isopropanol or a mixture of several of them.

10. The method for preparing 2-hydroxybenzimidazole according to claim 9, characterized in that: The alcohol is ethanol.

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