CN107118161B - Synthesis method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid - Google Patents
Synthesis method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid Download PDFInfo
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Abstract
The invention relates to a synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. 3, 5-dimethyl nitrobenzene is subjected to nitration reaction by nitric acid/concentrated sulfuric acid to generate an intermediate product II, 3, 5-dimethyl-1, 2-dinitrobenzene; carrying out Pd/C catalytic hydrogenation reaction on the intermediate product II in an ethanol solution to obtain an intermediate product III 3, 5-dimethyl-1, 2-phenylenediamine; reacting the intermediate product III with n-butyric acid in a polyphosphoric acid solution to obtain an intermediate product IV 2-n-propyl-4, 6-dimethylbenzimidazole; and (3) carrying out cobalt salt air liquid phase oxidation reaction on the intermediate product IV in an acetic acid solution to obtain a product V2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. The method has the advantages of simple operation, easily obtained raw materials, recovery and reuse of the used solvent, high product content of over 95 percent, high yield of 73.2 percent, less pollution and suitability for industrial production.
Description
Technical Field
The invention belongs to the technical field of chemical pharmacy, and particularly relates to a synthesis method of a telmisartan intermediate 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.
Background
Telmisartan (telmisartan) as a novel angiotensin II receptor antagonist antihypertensive drug has a unique novel bisbenzimidazole structure, ensures high receptor affinity and superior pharmacokinetic properties, has an advanced action mechanism, stably reduces blood pressure, does not rebound, has long-acting and high-efficiency properties, good tolerance, targeting selection, small side effect, good adaptability and other advantages, is clinically used for treating primary hypertension, and has a good curative effect on patients with hypertension.
Over twenty years, scholars at home and abroad make a great deal of research on the production process and technology of telmisartan, and provide a plurality of new processes and new technologies, mainly two synthetic routes which take toluene derivatives and benzimidazole derivatives as raw materials.
2-n-propyl-4-methylbenzimidazole-6-carboxylic acid is an important intermediate for synthesizing telmisartan. In 1993, RIES et al (Med. chem., 1993, 36(25): 4040-. Refluxing and cyclizing under the action of glacial acetic acid to form core benzimidazole, and hydrolyzing by sodium hydroxide to obtain 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.
Optimized research is carried out on the synthesis process of 2-n-propyl-4-methyl-6-carboxyl benzimidazole by Cao Wei et al (Gansu petroleum and chemical industry, 2010, (2): 18-22) in chemical research institute of Hubei province, and the target product is prepared by using 3-methyl-4-n-butylamido-5-nitrobenzoate as a raw material through reduction, cyclization and hydrolysis in 3 steps, wherein the total yield is 76.3%.
CN101983962A, a preparation process of telmisartan bulk drug, wherein the disclosure content is as follows: 3-methyl-4-nitro-benzoic acid is used as an initial raw material, 4-amino-3-methyl benzoate is obtained through esterification and reduction, and 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid is obtained through acylation, fuming nitric acid nitration, reduction, cyclization and hydrolysis.
The 2010 patent of HanseImami (WO,2010149360) reported that cheap o-toluidine was used as the starting material and N-butyryl chloride acylation, Br/H2O2Brominating a system, introducing cyano group by palladium catalysis, nitrifying mixed acid, reducing and closing a ring by an iron powder-glacial acetic acid system, and hydrolyzing concentrated hydrochloric acid to synthesize the 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid by 6 steps, wherein the total yield is 4%. The o-toluidine as the starting raw material of the route is cheap and short, and has the defects that the introduction of cyano needs to be carried out on potassium ferrocyanide highly toxic products, the recovery of a DMF solvent is difficult, and the post-treatment is complicated; corrosive chemicals such as sulfuric acid and concentrated hydrochloric acid, poor operability and serious pollution. The process is not suitable for industrial production.
The patent of Buechim (WO,201081670) reports the use of 2-methyl-6-nitroaniline as starting material by HBr/H2O2Brominating, Na2S2O4Reducing and closing a ring, introducing carbonyl into catalysis, and hydrolyzing with sodium hydroxide for 4 steps to synthesize the 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. The reaction yield of 4 steps is up to 54 percent. However, the amount of sodium hydrosulfite used as a reducing agent is large. In addition, due to Na2S2O4SO is easily decomposed when meeting water2The gas pollutes the environment and thus its industrial application is limited.
The horse academic completion of the university of Compound Dan (Master thesis of Compound Dan, 2012) uses cheap and easily available 2-methyl-6-nitroaniline as raw material, and adopts the processes of NBS bromination, acylation of n-butyryl chloride at 100 deg.C, reduction of iron powder/ammonium chloride in ethyl alcohol and water, heating and cyclization in acetic acid medium, Pd (dppf) Cl2The 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid is obtained by 6 steps of carbonyl insertion and sodium hydroxide hydrolysis at 100 ℃, and the total yield reaches 62%. The method has the advantages of high yield, low cost, little pollution, mild reaction conditions of the process, simple and practical operation and good industrial application prospect. But do notThe catalytic carbonyl insertion reaction needs high pressure with the temperature of 100 ℃ and the carbon monoxide pressure of 1.5MPa and the catalysis of heavy metal palladium.
Disclosure of Invention
The invention aims to provide a method for synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid, which has the advantages of high product yield and purity, small environmental pollution, low cost and great economic and social benefits, aiming at the technical current situation.
The purpose of the invention is realized by a synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid, which comprises the following four steps:
firstly, 3, 5-dimethyl nitrobenzene is used as a raw material and is subjected to nitration reaction of nitric acid/concentrated sulfuric acid, hydrolysis and filtration to generate an intermediate product II, 3, 5-dimethyl-1, 2-dinitrobenzene;
secondly, dissolving the intermediate product 3, 5-dimethyl-1, 2-dinitrobenzene obtained in the first step in ethanol, carrying out Pd/C catalytic hydrogenation reaction to realize the reaction of changing nitro groups into amino groups, and filtering and concentrating to obtain an intermediate product III, 5-dimethyl-1, 2-phenylenediamine;
thirdly, reacting the intermediate product 3, 5-dimethyl-1, 2-phenylenediamine obtained in the second step with n-butyric acid in a polyphosphoric acid solution, decoloring by activated carbon, filtering, and neutralizing by sodium hydroxide to a pH value of 8 to obtain an intermediate product IV 2-n-propyl-4, 6-dimethylbenzimidazole;
fourthly, the intermediate product 2-n-propyl-4, 6-dimethyl benzimidazole obtained in the third step is subjected to cobalt salt air liquid phase oxidation reaction in an acetic acid solution to realize the reaction that 6-methyl is changed into carboxyl, and the product V2-n-propyl-4-methyl benzimidazole-6-carboxylic acid is obtained through concentration, alkaline hydrolysis, filtration and acidolysis;
the specific reaction proceeds by the following formula:
the method takes 3, 5-dimethyl nitrobenzene as an initial raw material, and obtains the 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid by nitration with concentrated nitric acid/concentrated sulfuric acid, catalytic hydrogenation with palladium/carbon, cyclization with polyphosphoric acid and air oxidation under the catalysis of cobalt, the method is simple to operate, the raw materials are easy to obtain, all solvents can be recycled, the yield is up to 73.2%, the pollution is less, and the method is suitable for industrial production.
Detailed Description
The synthesis method of the invention is carried out by four steps:
firstly, 3, 5-dimethyl nitrobenzene is used as a raw material, and is subjected to nitration reaction of nitric acid/concentrated sulfuric acid, hydrolysis and filtration to generate an intermediate product II, 3, 5-dimethyl-1, 2-dinitrobenzene.
The method specifically comprises the following steps: preparing mixed acid from 95% fuming nitric acid and 98% concentrated sulfuric acid, and storing at 0 ℃; adding 98% concentrated sulfuric acid and 3, 5-dimethyl nitrobenzene into a reaction vessel, cooling to-10 ℃ while stirring, dropwise adding mixed acid prepared from 95% fuming nitric acid and 98% concentrated sulfuric acid, and controlling the feeding speed to ensure that the reaction temperature is not higher than-5 ℃. After the dropwise addition, continuing to stir in ice bath for 3 hours, slowly adding the reaction mixture into crushed ice for hydrolysis, maintaining the temperature not to exceed 5 ℃, and violently stirring until a large amount of light yellow solid is separated out; filtering, washing the filter cake with ice water, saturated sodium bicarbonate solution and clear water, and drying to obtain an intermediate product II, namely a light yellow solid 3, 5-dimethyl-1, 2-dinitrobenzene.
The volume ratio of the mixed acid prepared from 95% fuming nitric acid and 98% concentrated sulfuric acid is 1:2, and the dosage ratio of the mixed acid to 3, 5-dimethyl nitrobenzene is 3ml:1 g.
Secondly, dissolving the intermediate product 3, 5-dimethyl-1, 2-dinitrobenzene obtained in the first step in ethanol, carrying out Pd/C catalytic hydrogenation reaction to realize the reaction of changing nitro groups into amino groups, and filtering and concentrating to obtain an intermediate product III, 5-dimethyl-1, 2-phenylenediamine;
the method specifically comprises the following steps: adding the intermediate product 3, 5-dimethyl-1, 2-dinitrobenzene obtained in the first step into a high-pressure reaction kettle, then adding 5% of Pd/C catalyst and methanol solvent, carrying out hydrogenation reaction at 60 ℃ and 0.5Mpa for 6 hours, after the reaction is finished, reducing the temperature and the pressure, opening the kettle, filtering and recovering the catalyst, removing the solvent, and crystallizing to obtain an intermediate product III 3, 5-dimethyl-1, 2-phenylenediamine;
the catalyst is prepared by mixing 5 percent Pd/C and an intermediate product 3, 5-dimethyl-1, 2-dinitrobenzene in a dosage ratio of 1 g: 10 g.
Thirdly, reacting the intermediate product 3, 5-dimethyl-1, 2-phenylenediamine obtained in the second step with n-butyric acid in a polyphosphoric acid solution, decoloring by activated carbon, filtering, and neutralizing by sodium hydroxide to a pH value of 8 to obtain an intermediate product IV 2-n-propyl-4, 6-dimethylbenzimidazole;
the method specifically comprises the following steps: adding the intermediate product 3, 5-dimethyl-1, 2-phenylenediamine in the second step into a reaction vessel, and adding butyric acid and polyphosphoric acid into a reaction bottle. Heating to 120 ℃ and 125 ℃, and reacting for 16 hours; cooling to 60 deg.C, adding water and active carbon, stirring to slightly boil, and filtering after about 30 min. Cooling the filtrate, adding sodium hydroxide solution into the reaction solution under the stirring condition to neutralize the reaction solution to pH 10; cooling and suction filtering, filtering out precipitated solid, washing with cold water, and drying to obtain a crude product; recrystallizing the crude product with ethanol, separating out crystals, filtering, and drying at 100 ℃ to obtain the intermediate IV 2-n-propyl-4, 6-dimethyl benzimidazole.
The dosage ratio of the intermediate product 3, 5-dimethyl-1, 2-phenylenediamine to butyric acid is 8g:9g, the dosage ratio to polyphosphoric acid is 40g:80g, the dosage ratio to active carbon is 20g:1g, and the dosage ratio to ethanol is 4g:50 ml.
And fourthly, carrying out air liquid phase oxidation reaction on the intermediate product 2-n-propyl-4, 6-dimethylbenzimidazole obtained in the third step in an acetic acid solution by using cobalt salt to realize the reaction of changing 6-methyl into carboxyl, and carrying out concentration, alkaline hydrolysis, filtration and acidolysis to obtain the product V2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.
Adding the intermediate product IV 2-N-propyl-4, 6-dimethyl benzimidazole obtained in the third step into a reaction container, adding a catalyst 2-cobalt ethylhexanoate, a cocatalyst N-hydroxyphthalimide and glacial acetic acid; reacting for 2 hours at the temperature of 110 ℃ and the oxygen pressure of 1 MPa; after the reaction is stopped, cooling, reducing the pressure, opening the kettle, removing acetic acid under reduced pressure to obtain a precipitate, performing suction filtration to obtain a crude product, neutralizing the crude product with a 10% sodium hydroxide aqueous solution until the pH value is 8-9, adding activated carbon to remove color, filtering, acidifying the filtrate by 6N until the pH value is 3, filtering, and drying to obtain a white crystalline solid 2-N-propyl-4-methylbenzimidazole-6-carboxylic acid (V);
the dosage ratio of the catalyst 2-cobalt ethylhexanoate, the cocatalyst N-hydroxyphthalimide and the 2-N-propyl-4, 6-dimethylbenzimidazole is 0.5 g: 20g of the total weight of the mixture;
the dosage ratio of the glacial acetic acid to the 2-n-propyl-4, 6-dimethylbenzimidazole is 15 ml: 20 g.
The invention will now be further described by way of the following specific examples
First step, synthesizing 3, 5-dimethyl-1, 2-dinitrobenzene
20mL of 95% fuming nitric acid and 40mL of 98% concentrated sulfuric acid are prepared into mixed acid, and the mixed acid is cooled to-10 ℃ under stirring and stored. To a 500ml three-necked flask equipped with mechanical stirring, 100ml of concentrated sulfuric acid, 20g of 3, 5-dimethylnitrobenzene were added. Cooling to-10 deg.C with low temperature tank under stirring, adding dropwise mixed acid of fuming nitric acid and 98% concentrated sulfuric acid, and controlling the feeding speed to make the reaction temperature not higher than-5 deg.C. After the addition was complete, stirring was continued for 3 hours in ice bath. After the color of the reaction mixture is darkened, slowly adding the reaction liquid into crushed ice for hydrolysis, keeping the temperature not to exceed 5 ℃, and violently stirring to separate out a large amount of light yellow solids. Filtering, washing the filter cake with ice water, saturated sodium bicarbonate solution and clear water, and drying to obtain 21g of intermediate product II, light yellow solid 3, 5-dimethyl-1, 2-dinitrobenzene with yield of 92.8% and melting point of 132.7-134.7 ℃.
Infrared Spectroscopy IR Instrument model Perkin-Elmer Spectrum (KBr, cm)-1):3088(Ar-H)；2919(CH3-H)；1547,1441(Ar-C)；1547,1362(N＝O)；1441,1362(-CH3)；1040(C-N)；876-763(Ar-H)。
Nuclear magnetic resonance NMR apparatus model Varian Mercury 400,1H-NMR(CDCl3):7.79(S,1H,Ar-H)；7.43(S,1H,Ar-H)；2.50(S,3H,Ar-CH3)；2.40(S,3H,Ar-CH3)。
mass spectrometer instrument Xevo TQ. MS M/z 196.02 (M)+)；
The second step, synthesizing 3, 5-dimethyl-1, 2-phenylenediamine
After confirming that the reaction kettle has no air leakage, 15g of 3, 5-dimethyl-1, 2-dinitrobenzene is added into the high-pressure reaction kettle, 1.5g of 5 percent Pd/C catalyst is added, and 300ml of methanol is added into the high-pressure container. Firstly introducing nitrogen with certain pressure, evacuating air in the reaction kettle, continuously discharging for three times, then introducing hydrogen with certain pressure to replace nitrogen, and continuously replacing for three times. Finally, the reaction is carried out at 60 ℃ and under the reaction pressure of 0.5Mpa for 6 h. Cooling, reducing the pressure, opening the kettle, detecting the content of the raw materials, the products and the byproducts in the kettle by using gas chromatography, filtering and recovering the catalyst, removing the solvent, and crystallizing to obtain 10.5g of intermediate product III, namely 3, 5-dimethyl-1, 2-phenylenediamine, wherein the purity is higher than 98 percent, the yield is 98.8 percent and the melting point is 73.9-74.6 ℃ by GC detection.
Infrared Spectroscopy IR Instrument model Perkin-Elmer Spectrum (KBr, cm)-1):3392,3299(Ar-NH2)；2916(Ar-CH3)；912(Ar-H)。
Nuclear magnetic resonance NMR apparatus model Varian Mercury 400,1H-NMR(CDCl3):6.23(S,1H,Ar-H)；6.12(S,1H,Ar-H)；4.11(br,4H,Ar-NH2)；2.03(S,3H,Ar-CH3)；1.99(S,3H,Ar-CH3)。
mass spectrometer instrument Xevo TQ. MS M/z 136.08 (M)+)。
Step three, synthesizing 2-n-propyl-4, 6-dimethyl benzimidazole
40g of 3, 5-dimethyl-1, 2-phenylenediamine, 45g of butyric acid and 80g of polyphosphoric acid were added to a reaction flask. The temperature is raised to 120 ℃ and 125 ℃, and the reaction is carried out for 16 hours. Cooling to 60 deg.C, adding water 500g and active carbon 2g, stirring to slightly boil, and filtering after about 30 min. The filtrate was cooled, and 10% sodium hydroxide solution was added to the reaction solution under stirring to neutralize the pH to about 10. Cooling and filtering, filtering out the precipitated solid, washing with cold water, and drying to obtain a crude product.
The crude product was placed in a 1000mL beaker, 500mL of ethanol was added and dissolved by heating. Cooling to room temperature, precipitating crystals, filtering, and drying at 100 ℃ to obtain 51g of intermediate product IV 2-n-propyl-4, 6-dimethyl benzimidazole. Purity is more than 98%, yield is 90% and melting point is 167.7-170.2 ℃ by HPLC detection.
Infrared Spectroscopy IR Instrument model Perkin-Elmer Spectrum (KBr, cm)-1):3249(Ar-CH3)；2962(-CH3)；2931(-CH2-)；1652(C＝N)。
Nuclear magnetic resonance NMR apparatus model Varian Mercury 400,1H-NMR(CDCl3):7.99,8.31(S,3H,Ar-CH3)；6.74(S,1H,Ar-NH-)；2.27(q,2H,-CH2-)；2.13,2.16(S,3H,Ar-CH3)；1.55(dq,2H,-CH2-)；0.9(dt,3H,Ar-CH3)。
mass spectrometer instrument Xevo TQ. MS M/z 188.19 (M)+)。
Step four, synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid
After the gas leakage of the reaction kettle is confirmed, 20g of 2-N-propyl-4, 6-dimethylbenzimidazole, 0.5g of catalyst 2-cobalt ethylhexanoate, 0.5g of cocatalyst N-hydroxyphthalimide and 15ml of glacial acetic acid are added into the high-pressure reaction kettle. The temperature is 110 ℃, the oxygen pressure is 1MPa, and the reaction time is 2 h. After the reaction is stopped, cooling, reducing the pressure, opening the kettle, removing acetic acid under reduced pressure to obtain a precipitate, performing suction filtration on the obtained precipitate, neutralizing a crude product by using a 10% sodium hydroxide aqueous solution to the pH value of 8-9, adding activated carbon to remove color, filtering, acidifying the filtrate by 6N to the pH value of 3, and filtering to obtain a white crystalline solid V2-N-propyl-4-methylbenzimidazole-6-carboxylic acid.
The single pass conversion rate of the 2-n-propyl-4, 6-dimethyl benzimidazole can reach 40 percent, and the selectivity of the 2-n-propyl-4-methyl benzimidazole-6-carboxylic acid can reach 100 percent. The product is recrystallized by ethanol to obtain 20.6g of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid, the purity is higher than 98 percent by HPLC detection, the total yield is 88.8 percent, and the melting point is 257.7-259.3 ℃.
Infrared Spectroscopy IR Instrument model Perkin-Elmer Spectrum (KBr, cm)-1):3425(O-H)；2965(Ar-CH3)；1650(C＝N)。
Nuclear magnetic resonance NMR apparatus model Varian Mercury 400,1H-NMR(CDCl3):12.59(b,1H,Ar-COOH)；7.93(S,1H,Ar-H)；7.61(S,1H,Ar-H)；3.55(b,1H,Ar-NH-)；2.88(t,2H,-CH2-)；2.55(S,3H,Ar-CH3)；1.81(m,2H,-CH2-)；1.02(t,3H,Ar-CH3)。
mass spectrometer instrument Xevo TQ. MS M/z 218.25 (M)+)。
Claims (5)
- A method for synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid is characterized by comprising the following steps: the synthesis method comprises four steps:firstly, 3, 5-dimethyl nitrobenzene is used as a raw material and is subjected to nitration reaction of nitric acid/concentrated sulfuric acid, hydrolysis and filtration to generate an intermediate product II, 3, 5-dimethyl-1, 2-dinitrobenzene;secondly, dissolving the intermediate product 3, 5-dimethyl-1, 2-dinitrobenzene obtained in the first step in ethanol, carrying out Pd/C catalytic hydrogenation reaction to realize the reaction of changing nitro groups into amino groups, and filtering and concentrating to obtain an intermediate product III, 5-dimethyl-1, 2-phenylenediamine;thirdly, reacting the intermediate product 3, 5-dimethyl-1, 2-phenylenediamine obtained in the second step with n-butyric acid in polyphosphoric acid solution, decoloring by activated carbon, filtering, and neutralizing by sodium hydroxide to pH8 to obtain an intermediate product IV 2-n-propyl-4, 6-dimethylbenzimidazole;fourthly, the intermediate product 2-N-propyl-4, 6-dimethyl benzimidazole obtained in the third step is subjected to air liquid phase oxidation reaction of catalyst 2-cobalt ethylhexanoate and cocatalyst N-hydroxyphthalimide in acetic acid solution to realize the reaction of changing 6-methyl into carboxyl, and the V2-N-propyl-4-methyl benzimidazole-6-carboxylic acid is obtained through concentration, alkaline hydrolysis, filtration and acidolysis;the specific reaction proceeds by the following formula:
- 2. the method of synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid according to claim 1, wherein: the first step of reaction is to prepare mixed acid from 95 percent fuming nitric acid and 98 percent concentrated sulfuric acid and store the mixed acid at 0 ℃; adding 98% concentrated sulfuric acid and 3, 5-dimethyl nitrobenzene into a reaction vessel, cooling to-10 ℃ while stirring, dropwise adding mixed acid prepared from 95% fuming nitric acid and 98% concentrated sulfuric acid, and controlling the feeding speed to ensure that the reaction temperature is not higher than-5 ℃; after the dropwise addition, continuing to stir in ice bath for 3 hours, slowly adding the reaction mixture into crushed ice for hydrolysis, maintaining the temperature not to exceed 5 ℃, and violently stirring until a large amount of light yellow solid is separated out; filtering, washing filter cakes with ice water, saturated sodium bicarbonate solution and clear water respectively, and airing to obtain an intermediate product II, namely a light yellow solid 3, 5-dimethyl-1, 2-dinitrobenzene;the volume ratio of the mixed acid prepared from 95% fuming nitric acid and 98% concentrated sulfuric acid is 1:2, and the dosage ratio of the mixed acid to 3, 5-dimethyl nitrobenzene is 3ml:1 g.
- 3. The method of synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid according to claim 1, wherein: the second step of reaction is specifically that the intermediate product 3, 5-dimethyl-1, 2-dinitrobenzene obtained in the first step is added into a high-pressure reaction kettle, then 5 percent Pd/C catalyst and ethanol solvent are added, hydrogenation reaction is carried out for 6 hours at the temperature of 60 ℃ and the pressure of 0.5Mpa, after the reaction is finished, the kettle is opened by reducing the temperature and the pressure, the catalyst is recovered by filtration, the solvent is removed, and crystallization is carried out, so as to obtain an intermediate product III, namely a white-like solid 3, 5-dimethyl-1, 2-phenylenediamine;the catalyst is prepared by mixing 5 percent Pd/C and an intermediate product II, 3, 5-dimethyl-1, 2-dinitrobenzene in a dosage ratio of 1 g: 10 g.
- 4. The method of synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid according to claim 1, wherein: the third step of reaction is to add the intermediate product 3, 5-dimethyl-1, 2-phenylenediamine prepared in the second step into a reaction vessel, add butyric acid and polyphosphoric acid into a reaction bottle; heating to 120 ℃ and 125 ℃, and reacting for 16 hours; cooling to 60 deg.C, adding water and active carbon, stirring to slightly boil, and filtering after about 30 min; cooling the filtrate, adding sodium hydroxide solution into the reaction solution under the stirring condition to neutralize the reaction solution to pH 10; cooling and suction filtering, filtering out precipitated solid, washing with cold water, and drying to obtain a crude product; recrystallizing the crude product with ethanol, separating out crystals, filtering, and drying at 100 deg.C to obtain intermediate IV and white crystal 2-n-propyl-4, 6-dimethyl benzimidazole;the dosage ratio of the intermediate product III 3, 5-dimethyl-1, 2-phenylenediamine to butyric acid is 8g:9g, the dosage ratio to polyphosphoric acid is 40g:80g, the dosage ratio to active carbon is 20g:1g, and the dosage ratio to ethanol is 4g:50 ml.
- 5. The method of synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid according to claim 1, wherein: the fourth step of reaction is specifically that the intermediate product 2-N-propyl-4, 6-dimethyl benzimidazole obtained in the third step, the catalyst 2-cobalt ethylhexanoate, the cocatalyst N-hydroxyphthalimide and glacial acetic acid are added into a reaction container; reacting for 2 hours at the temperature of 110 ℃ and the oxygen pressure of 1 MPa; after the reaction is stopped, cooling, reducing the pressure, opening the kettle, removing acetic acid under reduced pressure to obtain a precipitate, performing suction filtration to obtain a crude product, neutralizing the crude product by using a 10% sodium hydroxide aqueous solution until the pH value is 8-9, adding activated carbon to remove the color, filtering, acidifying the filtrate by 6N until the pH value is 3, filtering, and drying to obtain a product V, namely a white crystalline solid 2-N-propyl-4-methylbenzimidazole-6-carboxylic acid;the dosage ratio of the catalyst 2-cobalt ethylhexanoate, the cocatalyst N-hydroxyphthalimide and the 2-N-propyl-4, 6-dimethylbenzimidazole is 0.5 g: 0.5 g: 20g of the total weight of the mixture;the dosage ratio of the glacial acetic acid to the 2-n-propyl-4, 6-dimethylbenzimidazole is 15 ml: 20 g.
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