CN102351800A - Method for preparing 5-methylbenzimidazole-2-methyl carbamate - Google Patents

Abstract

The invention discloses a preparation method of methyl 5-methylbenzimidazole-2-carbamate. The reaction steps are controlled into three steps of cyanamide, acidification and ring closing, the operation procedure is simplified, and a strong base such as hydrogen is used. Sodium oxide cyanamide, hydrochloric acid acidification, sodium thiosulfate catalyzed ring closing, reduce the generation of waste acid, and reduce the generation of pollutants under the premise of ensuring product quality and yield. The steps of the present invention are as follows: using methyl chloroformate as a raw material, the product is obtained after cyanamide reaction, acidification reaction and ring closure reaction; wherein, the cyanamide reaction is methyl chloroformate and cyanamide under alkaline conditions The reaction generates methyl cyanocarbamate; the acidification reaction is that methyl cyanocarbamate reacts with hydrochloric acid to generate methyl cyanocarbamate; the ring closure reaction is methyl cyanocarbamate and 4-methyl o-phthalate The diamine undergoes condensation reaction under acid-catalyzed conditions to obtain methyl 5-methylbenzimidazole-2-carbamate.

Description

A kind of preparation method of 5-methylbenzimidazole-2-carbamate methyl ester

technical field

The present invention relates to a kind of preparation method of bactericide, more specifically relate to a kind of preparation method of 5-methylbenzimidazole-2-carbamate methyl ester namely 5-methylcarbendazim.

Background technique

5-Methylbenzimidazole-2-carbamate, namely 5-methylcarbendazim, is a highly efficient, broad-spectrum, and low-toxic systemic fungicide with stable chemical properties and low toxicity. The half-lethal dose of acute toxicity is LD50 value: oral administration to rats is greater than 20g/kg (better than the LD50 value of carbendazim, which is 15g/kg). It belongs to the high-efficiency broad-spectrum fungicide, which can be absorbed by plants and transferred to other parts through conduction, interfering with the mitosis of germ cells and inhibiting their growth. It has the control effect on diseases caused by fungi (such as Deuteromycetes, polyascomycetes, etc.) of various crops, and can be used for foliar spraying, seed treatment and soil treatment, etc. It can also be widely used in the fields of anti-mildew and sterilization in wood, papermaking, textile, leather, rubber and other industries. At present, there is no related literature reporting its synthesis method in China.

At present, only Ernest Lacey et al. (Biochemical Pharmacology, Vol.34, No.7, pp.1073-1077, 1985) have reported the use of p-methylaniline as raw material through acetylation, nitration, hydrolysis, reduction, ring formation, rearrangement, etc. The step is to prepare methyl 5-methylbenzimidazole-2-carbamate, wherein the reaction steps are too long, and the reagents used, such as stannous chloride, cyanogen bromide, isothiourea, etc., are highly toxic and difficult for industrial production.

Contents of the invention

The purpose of the present invention is to solve the problems and deficiencies existing in the prior art, and provide a kind of preparation method of 5-methylbenzimidazole-2-carbamate methyl ester, the method of the present invention controls reaction step as cyanamide, acidification 1. Three steps of ring closure, which simplifies the operation procedure. Strong bases such as sodium hydroxide are used for cyanamination, hydrochloric acid acidification, and sodium thiosulfate to catalyze ring closure, which reduces the generation of waste acid. On the premise of ensuring product quality and yield , reducing the generation of pollutants.

Technical scheme of the present invention is as follows:

The preparation method of 5-methylbenzimidazole-2-methyl carbamate of the present invention, the steps are as follows: take methyl chloroformate as raw material, obtain 5-methylbenzene after cyanamide reaction, acidification reaction and ring closure reaction Methyl imidazole-2-carbamate; where,

The cyanamide reaction is that methyl chloroformate reacts with cyanamide under alkaline conditions to generate methyl cyanocarbamate;

The acidification reaction is that methyl cyanocarbamate salt reacts with hydrochloric acid to generate methyl cyanocarbamate;

The ring-closing reaction is a condensation reaction between methyl cyanocarbamate and 4-methyl-o-phenylenediamine under acid-catalyzed conditions to obtain methyl 5-methylbenzimidazole-2-carbamate.

The preparation method of 5-methylbenzimidazole-2-methyl carbamate of the present invention, its further technical scheme is that described cyanamide reaction step is as follows: first prepare cyanamide aqueous solution, and add solvent, then use 5mol /L-10mol/L strong alkali aqueous solution to adjust the pH value to be greater than 9, then add a phase transfer catalyst, heat up and stir, add methyl chloroformate dropwise to undergo cyanamide reaction, after the reaction, pour the product into the ice-water mixture, and precipitate The solid is vacuum filtered, and the filter cake is washed with methanol and water in turn until neutral, and dried to obtain the salt crystal of methyl cyanocarbamate. A further technical solution is that the described cyanamide reaction steps are as follows: under the stirring condition of -10°C-70°C, successively mix 10%-80% mass concentration of cyanamide aqueous solution, solvent, 5mol/L-10mol/L Put the strong alkali aqueous solution and phase transfer catalyst into the reaction kettle, control the pH value of the solution to be greater than 9, and then uniformly drop methyl chloroformate at a rate of 10g/h-100g/h, and react for 1h-8h to obtain methyl cyanocarbamate Pour the salt solution into the ice-water mixture to precipitate crystals, suction filter under 760mmHg vacuum condition, wash the filter cake with methanol and water in turn until neutral, and dry to obtain the salt crystals of methyl cyanocarbamate; among them, methyl chloroformate 1. The molar ratio of cyanamide in the cyanamide solution to the strong base is 1.0: 1.0-2.0: 2.0-5.0.

The preparation method of 5-methylbenzimidazole-2-methyl carbamate of the present invention, its further technical scheme can also be that described strong base is preferably sodium hydroxide or potassium hydroxide; Described solvent is preferably It is one of water, methanol, ethanol, acetone or their mixture, and the consumption of solvent is 1-10 times of the mass consumption of methyl chloroformate; Described phase transfer catalyst is preferably benzyltrimethylammonium chloride, One of benzyltriethylammonium chloride, polyethylene glycol, sodium dodecylbenzene sulfonate or their mixture, the amount of phase transfer catalyst is 0.1%-10% of the mass amount of methyl chloroformate.

The preparation method of 5-methylbenzimidazole-2-methyl carbamate of the present invention, its further technical scheme can also be that described acidification reaction step is as follows: the methyl cyanocarbamate that cyanamide reaction obtains Salt crystals were hydrolyzed and acidified with 4mol/L-5mol/L hydrochloric acid, extracted with ethanol, the organic phase was collected, distilled under reduced pressure, and fractionated to obtain methyl cyanocarbamate. A further technical solution is that the acidification reaction steps are as follows: Under the condition of stirring at 20°C-70°C, fully mix and react methyl cyanocarbamate salt with 4mol/L-5mol/L hydrochloric acid, wherein methyl chloroformate The molar ratio of hydrogen chloride to hydrochloric acid solution is 1.0:1.0-2.0, and the pH value of the solution is controlled between 6-7. After reacting for 1h-3h, extract with ethanol, collect the organic phase, distill under reduced pressure, and obtain cyanide by fractional distillation. Methyl carbamate.

The preparation method of 5-methylbenzimidazole-2-methyl carbamate of the present invention, its further technical scheme can also be that described ring closing reaction step is as follows: take 4-methyl o-phenylenediamine as raw material, Dissolve in an appropriate amount of solvent, add methyl cyanocarbamate and catalyst obtained from the acidification reaction, and evenly add 35% concentrated hydrochloric acid solution dropwise. Stir formaldehyde at 70°C-80°C for 0.5h-1h, filter with suction, and dry to obtain methyl 5-methylbenzimidazole-2-carbamate. A further technical solution is that the steps of the ring-closing reaction are as follows: under the stirring condition of 20°C-100°C, 4-methyl o-phenylenediamine with a purity of 99%, methyl cyanocarbamate, solvent, and catalyst Put it into the reaction kettle, then evenly add 35% concentrated hydrochloric acid dropwise at a rate of 10g/h-100g/h, drop the temperature at 30°C-100°C, control the pH value of the solution at 3-4, and heat it after 2h-3h Filter, then stir with 35% formaldehyde solution at 70°C-80°C for 0.5h-1h, centrifuge, filter with suction, and dry to obtain methyl 5-methylbenzimidazole-2-carbamate; where 4-methyl The molar ratio of o-phenylenediamine to methyl cyanocarbamate is 1.0:1.0-2.0.

The preparation method of 5-methylbenzimidazole-2-methyl carbamate of the present invention, its further technical scheme can also be that described solvent is preferably a kind of in water, chloroform, hexanol, methanol, ethanol Or their mixture, the solvent consumption is 1-10 times of the mass consumption of methyl chloroformate. The catalyst is preferably sodium thiosulfate in an amount of 0.1%-10% of 4-methyl o-phenylenediamine.

The reaction equation that above-mentioned process of the present invention relates to is as follows:

①Cyanamide process: methyl chloroformate reacts with cyanamide and sodium hydroxide to form sodium methyl cyanocarbamate.

②Acidification process: methyl cyanocarbamate sodium salt reacts with hydrochloric acid to generate methyl cyanocarbamate.

③ Ring closing process: methyl cyanocarbamate and 4-methyl o-phenylenediamine undergo condensation reaction under acid-catalyzed conditions to generate methyl 5-methylbenzimidazole-2-carbamate.

Compared with the prior art, the beneficial effects of the present invention are mainly reflected in the following aspects:

1. The process uses cheap and easy-to-obtain methyl chloroformate and 4-methyl-o-phenylenediamine as raw materials, and controls the reaction process into three steps of cyanamide, acidification, and ring closure, which simplifies the operation procedure and reduces the production cost .

2. The process adopts benzyltrimethylammonium chloride as the phase transfer catalyst of cyanamide reaction, the reaction conditions are mild, the catalytic effect is good, and then the amount of sodium hydroxide is reduced to reduce the amount of waste lye.

3. The process uses cheap sodium thiosulfate as the catalyst for the ring-closing reaction. The reaction conditions are mild, the amount of catalyst is low, and it has the characteristics of high conversion rate, green and clean, which can reduce the amount of concentrated hydrochloric acid and make the amount of waste acid Reduce, greatly reduce the discharge of pollutants, friendly to the environment, and have good economic and social benefits.

4. The product 5-methylbenzimidazole-2-carbamate has the same bactericidal effect as carbendazim. It is a high-efficiency, low-toxicity, broad-spectrum, systemic fungicide with long duration and more toxicity. Lower, can be widely used in crops, wood, paper, textiles, leather, rubber and other industries in the field of mildew and sterilization.

Compared with the existing synthetic route, the present invention has the advantages of simple and convenient reaction route, mild reaction conditions, high catalytic activity, cheap and easy-to-obtain raw materials, and simple and clean process.

Description of drawings

Fig. 1 is the MS figure of the 5-methylbenzimidazole-2-methyl carbamate that embodiment 1 makes

Fig. 2 is the ¹ H-NMR chart of methyl 5-methylbenzimidazole-2-carbamate prepared in Example 1.

Detailed ways

The present invention is illustrated below through specific examples, but the present invention is not limited to these examples.

Example 1

In a 250mL four-necked flask with a thermometer and a stirring device, add 16.8g of 50% cyanamide solution (containing 0.2mol of cyanamide), 60ml of methanol solvent, 64g of 25% NaOH solution (containing 0.4mol of NaOH) and 0.5 g benzyltrimethylammonium chloride was used as a phase transfer catalyst, and 18.9 g (0.2 mol) of methyl chloroformate was uniformly added dropwise at a rate of 30 g/h, kept at 45 ° C for about 3 hours, and the reaction solution was cooled, and then poured into a large amount of ice-water mixture, white crystals are precipitated, suction filtration under 760mmHg vacuum condition, the filter cake is washed with methanol and washed to neutrality successively, and dried to obtain 18.7g of methyl cyanocarbamate sodium salt, the yield is 76.8 %.

In a 250mL four-necked flask equipped with a thermometer and a stirring device, mix and react 18.3g (0.15mol) of sodium methyl cyanocarbamate and 30ml of 5mol/L hydrochloric acid (containing 0.15mol of hydrogen chloride) at 40°C for 2.5h Afterwards, extract with ethanol, collect the organic phase, vacuum distillation, and fractional distillation to obtain 13.5 g of methyl cyanocarbamate, and the yield is 90.3%.

In a 250mL four-necked flask with a thermometer and a stirring device, add 12.3g (0.2mol) of 99% 4-methyl o-phenylenediamine, 40ml of methanol solvent, 10g (0.1mol) of methyl cyanocarbamate and 0.8g of sodium thiosulfate catalyst, uniformly drip 35% concentrated hydrochloric acid solution at a rate of 30g/h, the temperature of the addition is 50°C, the end point of the addition is when the pH value is around 3-4, and the reaction is carried out at 90°C for 2 hours. After the heat preservation reaction, cool down to 80°C, add 100ml of complexing agent 35% formaldehyde solution, keep warm for 1 hour, centrifuge again, wash with water until neutral, filter with suction, and dry to obtain methyl 5-methylbenzimidazole-2-carbamate 15.0 g of ester, yield 73.2%, melting point: 330°C-335°C. MS (m/z): 206 [M+1] ⁺ . ¹ H-NMR (300Hz, DMSO-d6), δ: 2.36(s, 3H, 5-CH ₃ ), 3.74(s, 3H, CH ₃ ), 6.89(m, 1H, 6-H), 7.19(d , J=0.63, 1H, 4-H), 7.26 (d, J=8.04, 1H, 7-H), 11.56 (s, 2H, NH, replaceable with _D20 ).

Example 2

In a 250mL four-necked flask with a thermometer and a stirring device, add 33.6g of 50% cyanamide solution (containing 0.4mol of cyanamide), 60ml of methanol solvent, 64g of 25% NaOH solution (containing 0.4mol of NaOH) and 0.5 g benzyltrimethylammonium chloride was used as a phase transfer catalyst, and 18.9 g (0.2 mol) of methyl chloroformate was uniformly added dropwise at a rate of 30 g/h, kept at 45 ° C for about 3 hours, and the reaction solution was cooled, and then poured into a large amount of ice-water mixture, white crystals are precipitated, suction filtration under 760mmHg vacuum condition, the filter cake is washed with methanol and washed to neutrality successively, and dried to obtain 21.0g of methyl cyanocarbamate sodium salt, the yield is 86.0 %.

In a 250mL four-neck flask equipped with a thermometer and a stirring device, mix and react 18.8g (0.15mol) of sodium methyl cyanocarbamate and 60ml of 5mol/L hydrochloric acid (containing 0.3mol of hydrogen chloride) at 40°C for 2.5h Afterwards, extract with ethanol, collect the organic phase, vacuum distillation, fractional distillation to obtain 13.8 g of methyl cyanocarbamate, the yield is 92.3%.

In a 250mL four-necked flask with a thermometer and a stirring device, add 12.3g (0.1mol) of 99% 4-methyl o-phenylenediamine, 40ml of methanol solvent, 15g (0.15mol) of methyl cyanocarbamate and 0.8g of sodium thiosulfate catalyst, uniformly drip 35% concentrated hydrochloric acid solution at a rate of 30g/h, the dropping temperature is 50°C, the end point of the addition is when the pH value is around 3-4, and the temperature is kept at 90°C for 2h. After the heat preservation reaction, cool down to 80°C, add 100ml of complexing agent 35% formaldehyde solution, keep warm for 1 hour, centrifuge again, wash with water until neutral, filter with suction, and dry to obtain methyl 5-methylbenzimidazole-2-carbamate 16.3 g of ester, yield 79.5%, melting point: 330°C-335°C.

Example 3

In a 250mL four-necked flask with a thermometer and a stirring device, add 33.6g of 50% cyanamide solution (containing 0.4mol of cyanamide), 60ml of methanol solvent, 96g of 25% NaOH solution (containing 0.6mol of NaOH) and 0.5 g benzyltrimethylammonium chloride was used as a phase transfer catalyst, and 18.9 g (0.2 mol) of methyl chloroformate was uniformly added dropwise at a rate of 30 g/h, kept at 45 ° C for about 3 hours, and the reaction solution was cooled, and then poured into a large amount of ice-water mixture, white crystals are precipitated, suction filtration under 760mmHg vacuum condition, the filter cake is washed with methanol and washed to neutrality successively, and dried to obtain 20.1g of methyl cyanocarbamate sodium salt, the yield is 82.2 %.

In a 250mL four-necked flask equipped with a thermometer and a stirring device, mix and react 18.3g (0.15mol) of sodium methyl cyanocarbamate and 50ml of 5mol/L hydrochloric acid (containing 0.25mol of hydrogen chloride) at 40°C for 2.5h After that, extract with ethanol, collect the organic phase, distill under reduced pressure, obtain 13.6 g of methyl cyanocarbamate by fractional distillation, and the yield is 90.3%.

In a 250mL four-necked flask with a thermometer and a stirring device, add 12.3g (0.1mol) of 99% 4-methyl o-phenylenediamine, 40ml of methanol solvent, 20g (0.2mol) of methyl cyanocarbamate and 0.8g of sodium thiosulfate catalyst, uniformly drip 35% concentrated hydrochloric acid solution at a rate of 30g/h, the dropping temperature is 50°C, the end point of the addition is when the pH value is around 3-4, and the temperature is kept at 90°C for 2h. After the heat preservation reaction, cool down to 80°C, add 100ml of complexing agent 35% formaldehyde solution, keep warm for 1 hour, centrifuge again, wash with water until neutral, filter with suction, and dry to obtain methyl 5-methylbenzimidazole-2-carbamate 15.8 g of ester, yield 76.8%, melting point: 330°C-335°C.

Claims (10)

1. a preparation method of 5-methylbenzimidazole-2-methyl carbamate, it is characterized in that: take methyl chloroformate as raw material, obtain 5-methanol after cyanamide reaction, acidification reaction and ring closure reaction Methylbenzimidazole-2-carbamate; where, The cyanamide reaction is that methyl chloroformate reacts with cyanamide under alkaline conditions to generate methyl cyanocarbamate; The acidification reaction is that methyl cyanocarbamate salt reacts with hydrochloric acid to generate methyl cyanocarbamate; The ring-closing reaction is a condensation reaction between methyl cyanocarbamate and 4-methyl-o-phenylenediamine under acid-catalyzed conditions to obtain methyl 5-methylbenzimidazole-2-carbamate. 2. the preparation method of 5-methylbenzimidazole-2-methyl carbamate according to claim 1 is characterized in that described cyanamide reaction step is as follows: first prepare cyanamide aqueous solution, and add solvent, Then use 5mol/L-10mol/L strong alkali aqueous solution to adjust the pH value to be greater than 9, then add a phase transfer catalyst, heat up and stir, add methyl chloroformate dropwise to undergo cyanamide reaction, and pour the product into the ice-water mixture , precipitated solid, vacuum filtration, the filter cake was washed with methanol and water to neutral, and dried to obtain the salt crystals of methyl cyanocarbamate. 3. the preparation method of 5-methylbenzimidazole-2-methyl carbamate according to claim 2, is characterized in that described cyanamide reaction step is as follows: under the stirring condition of-10 ℃-70 ℃ , successively put 10%-80% mass concentration of cyanamide aqueous solution, solvent, 5mol/L-10mol/L strong alkali aqueous solution, and phase transfer catalyst into the reactor, control the pH value of the solution to be greater than 9, and then use 10g/h-100g Add methyl chloroformate evenly at a rate of 1h-8h, and after 1h-8h of reaction, obtain methyl cyanocarbamate salt solution, pour it into ice-water mixture, precipitate crystals, suction filter under 760mmHg vacuum condition, and wash the filter cake with methanol successively Wash with water until neutral, and dry to obtain the salt crystal of methyl cyanocarbamate; wherein, the molar ratio of methyl chloroformate, cyanamide in the cyanamide solution, and strong base is 1.0:1.0-2.0:2.0-5.0. 4. according to the preparation method of claim 2 or 3 described 5-methylbenzimidazole-2-methyl carbamates, it is characterized in that described strong base is sodium hydroxide or potassium hydroxide; Described solvent It is one of water, methanol, ethanol, acetone or their mixture, and the consumption of solvent is 1-10 times of the mass consumption of methyl chloroformate; Described phase transfer catalyst is benzyl trimethyl ammonium chloride, benzyl trimethyl ammonium chloride, benzyl Triethylammonium chloride, polyethylene glycol, sodium dodecylbenzene sulfonate or their mixture, the amount of phase transfer catalyst is 0.1%-10% of the mass amount of methyl chloroformate. 5. the preparation method of 5-methylbenzimidazole-2-methyl carbamate according to claim 1 is characterized in that described acidification reaction step is as follows: the methyl cyanocarbamate that cyanamide reaction obtains The salt crystals were hydrolyzed and acidified with 4mol/L-5mol/L hydrochloric acid, extracted with ethanol, the organic phase was collected, distilled under reduced pressure, and fractionated to obtain methyl cyanocarbamate. 6. The preparation method of 5-methylbenzimidazole-2-methyl carbamate according to claim 5, characterized in that the acidification reaction step is as follows: under 20°C-70°C stirring condition, the cyanide Methyl carbamate salt and 4mol/L-5mol/L hydrochloric acid are fully mixed and reacted, wherein the molar ratio of methyl chloroformate salt to hydrogen chloride in the hydrochloric acid solution is 1.0:1.0-2.0, and the pH value of the control solution is between 6-7 After reacting for 1h-3h, extract with ethanol, collect the organic phase, distill under reduced pressure, and obtain methyl cyanocarbamate by fractional distillation. 7. the preparation method of 5-methylbenzimidazole-2-methyl carbamate according to claim 1 is characterized in that described ring-closing reaction step is as follows: getting 4-methyl o-phenylenediamine is raw material , dissolved in an appropriate amount of solvent, add methyl cyanocarbamate and catalyst obtained by acidification reaction, evenly add 35% concentrated hydrochloric acid solution dropwise, the end point of dropping is pH value at 3-4, heat suction filtration after the reaction, and then use 35% % formaldehyde, stirred at 70°C-80°C for 0.5h-1h, filtered with suction, and dried to obtain methyl 5-methylbenzimidazole-2-carbamate. 8. The method for preparing 5-methylbenzimidazole-2-methyl carbamate according to claim 7, characterized in that the steps of the ring closure reaction are as follows: under stirring conditions at 20°C-100°C, successively Put 4-methyl o-phenylenediamine, methyl cyanocarbamate, solvent and catalyst with a purity of 99% into the reaction kettle, then evenly add 35% concentrated hydrochloric acid dropwise at a rate of 10g/h-100g/h, dropwise The temperature is 30°C-100°C, and the pH value of the solution is controlled at 3-4. After reacting for 2h-3h, heat suction filtration, then stir with 35% formaldehyde solution at 70°C-80°C for 0.5h-1h, centrifuge, and suction filtration. After drying, methyl 5-methylbenzimidazole-2-carbamate can be obtained; the molar ratio of 4-methyl-o-phenylenediamine to methyl cyanocarbamate is 1.0:1.0-2.0. 9. the method for preparing 5-methylbenzimidazole-2-methyl carbamate according to claim 8, is characterized in that described solvent is a kind of in water, chloroform, hexanol, methyl alcohol, ethanol or For their mixture, the solvent consumption is 1-10 times of the mass consumption of methyl chloroformate. 10. the method for preparing 5-methylbenzimidazole-2-methyl carbamate according to claim 8, is characterized in that described catalyzer is sodium thiosulfate, and its consumption is 4-methyl phthalate 0.1%-10% of amine.

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