CN107118161B - The synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid - Google Patents

Abstract

The invention relates to a method for synthesizing 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. 3,5-Dimethylnitrobenzene is nitrated by nitric acid/concentrated sulfuric acid to generate intermediate product II 3,5-dimethyl-1,2-dinitrobenzene; intermediate product II is in ethanol solution, Pd/C Catalytic hydrogenation reaction to obtain intermediate product III 3,5-dimethyl-1,2-phenylenediamine; intermediate product III reacts with n-butyric acid in polyphosphoric acid solution to obtain intermediate product IV 2-n-propyl- 4,6-dimethylbenzimidazole; the intermediate product IV is oxidized in the air liquid phase of cobalt salt in acetic acid solution to obtain the product V 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid. The invention has simple operation, easy-to-obtain raw materials, all solvents used can be recovered and used mechanically, the product content can reach more than 95%, the yield is as high as 73.2%, the pollution is less, and it is suitable for industrialized production.

Description

The synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid

technical field

The invention belongs to the technical field of chemical pharmacy, and in particular relates to a synthesis method of telmisartan intermediate 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.

Background technique

Telmisartan (telmisartan), as a new type of angiotensin Ⅱ receptor antagonist antihypertensive drug, its unique new bisbenzimidazole structure ensures high receptor affinity and superior pharmacokinetic properties, At the same time, it has many advantages such as advanced mechanism of action, stable blood pressure reduction, no rebound, long-acting and high-efficiency, good tolerance, targeted selection, small side effects, good adaptability, etc. Hypertensive patients have good curative effect.

Over the past 20 years, domestic and foreign scholars have done a lot of research on the production process and technology of telmisartan, and proposed many new processes and technologies, mainly using toluene derivatives and benzimidazole derivatives as raw materials. class of synthetic routes.

2-n-propyl-4-methylbenzimidazole-6-carboxylic acid is an important intermediate in the synthesis of telmisartan. In 1993, RIES et al. (Med.Chem., 1993, 36(25):4040-4051) took 3-methyl-4-aminobenzoic acid methyl ester as the starting material, and carried out acylation with n-butyryl chloride under chlorobenzene reaction, and then carry out nitration reaction with the mixed acid of fuming nitric acid and concentrated sulfuric acid, and the nitration product is hydrogenated under palladium/charcoal catalysis to obtain 3-methyl-4-n-butyramide-5-aminobenzoic acid methyl ester. Then reflux under the action of glacial acetic acid to form the core benzimidazole, which is hydrolyzed by sodium hydroxide to obtain 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.

Cao Wei, Hubei Institute of Chemistry and others (Gansu Petroleum and Chemical Industry, 2010, (2): 18-22) optimized the synthesis process of 2-n-propyl-4-methyl-6-carboxybenzimidazole , it was determined that the target product was obtained through 3-step reaction of reduction, cyclization and hydrolysis with 3-methyl-4-n-butyrylamino-5-nitrobenzoic acid methyl ester as raw material, and the total yield was 76.3%.

CN101983962A, a preparation process of telmisartan bulk drug, wherein the disclosed content includes: 3-methyl-4-nitro-benzoic acid is used as the starting material, and 4-amino-3-benzoic acid is obtained through esterification and reduction Methyl benzoate, after acylation, nitration with fuming nitric acid, reduction, cyclization, hydrolysis to obtain 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.

The patent (WO, 2010149360) applied by HanseImami in 2010 reported the use of cheap o-methylaniline as a starting material, through acylation of n-butyryl chloride, bromination of Br/H ₂ O ₂ system, palladium catalyzed introduction of cyano groups, and mixed acid nitration 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid was synthesized in 6 steps including reduction ring closure with iron powder-glacial acetic acid system and hydrolysis with concentrated hydrochloric acid, with a total yield of 4%. The starting material o-methylaniline of this route is cheap and the route is short. The disadvantage is that the introduction of cyano groups requires the use of potassium ferrocyanide, a highly toxic substance, and the recovery of the solvent DMF is difficult, and the post-treatment is cumbersome; corrosive substances such as sulfuric acid and concentrated hydrochloric acid Chemicals, poor operability and serious pollution. This process is not suitable for industrial production.

The patent (WO, 201081670) applied by Buechime reported that 2-methyl-6-nitroaniline was used as raw material, through HBr/H ₂ O ₂ bromination, Na ₂ S ₂ O ₄ reduction ring closure, introduction of catalysis into carbonyl and 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid was synthesized by sodium hydroxide hydrolysis in four steps. The 4-step reaction yield is as high as 54%. But using hydrosulfite as reducing agent requires a large amount. In addition, because Na ₂ S ₂ O ₄ easily decomposes with water and releases SO ₂ gas to pollute the environment, so its industrial application is limited.

Ma Xuecheng of Fudan University (Master's thesis of Fudan University, 2012) used cheap and easy-to-obtain 2-methyl-6-nitroaniline as raw material, brominated with NBS, acylated with n-butyryl chloride at 100°C, iron powder/ammonium chloride Reduction in ethanol and water, heating and cyclization in acetic acid medium, Pd(dppf)Cl ₂ catalyzed insertion of carbonyl at 100°C, and hydrolysis with sodium hydroxide are a total of 6 steps to obtain 2-n-propyl-4-methylbenzimidazole-6- Carboxylic acid, the total yield reaches 62%. This route has the advantages of high yield, low cost, little pollution, mild process reaction conditions, simple and practical operation, and has good industrial application prospect. However, the catalytic carbonyl insertion reaction requires a high temperature of 100°C, a carbon monoxide pressure of 1.5MPa, and a heavy metal palladium catalyst.

Contents of the invention

The purpose of the present invention is aimed at above-mentioned technical present situation, aims to provide a kind of product yield and purity high, environmental pollution is little, cost is low, has huge economic benefit and social benefit 2-n-propyl-4-methylbenzo Synthetic method of imidazole-6-carboxylic acid.

The realization mode of the object of the present invention is, the synthetic method of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid, and synthetic method is carried out in four steps:

In the first step, 3,5-dimethylnitrobenzene is used as raw material, nitrated by nitric acid/concentrated sulfuric acid, hydrolyzed, and filtered to generate intermediate product II 3,5-dimethyl-1,2-dinitrobenzene;

In the second step, the intermediate product 3,5-dimethyl-1,2-dinitrobenzene obtained in the first step is dissolved in ethanol, and Pd/C catalyzes the hydrogenation reaction to realize the reaction of nitro group into amino group. Filtration and concentration yielded the intermediate product III 3,5-dimethyl-1,2-phenylenediamine;

In the third step, the intermediate product 3,5-dimethyl-1,2-phenylenediamine obtained in the second step is reacted with n-butyric acid in polyphosphoric acid solution, decolorized by activated carbon, filtered, and neutralized by sodium hydroxide To pH8, the intermediate product IV 2-n-propyl-4,6-dimethylbenzimidazole was obtained;

In the fourth step, the intermediate product 2-n-propyl-4,6-dimethylbenzimidazole obtained in the third step is subjected to an air-liquid phase oxidation reaction of cobalt salt in an acetic acid solution to realize the conversion of the methyl group at the 6-position into a carboxyl group The reaction is concentrated, alkali hydrolyzed, filtered, and acidolyzed to obtain product V 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid;

Concrete reaction carries out by following formula:

The present invention uses 3,5-dimethylnitrobenzene as the starting material, nitrates with concentrated nitric acid/concentrated sulfuric acid, catalyzes hydrogenation with palladium/carbon, cyclizes polyphosphoric acid, and oxidizes air under the catalysis of cobalt to obtain 2-normal Propyl-4-methylbenzimidazole-6-carboxylic acid has simple operation, readily available raw materials, all solvents used can be recovered and used mechanically, the yield is as high as 73.2%, and there is less pollution. The invention is suitable for industrial production.

Detailed ways

The synthetic method of the present invention is carried out in four steps:

In the first step, 3,5-dimethylnitrobenzene is used as raw material, nitrated by nitric acid/concentrated sulfuric acid, hydrolyzed, and filtered to generate intermediate product II 3,5-dimethyl-1,2-dinitrobenzene.

Specifically: prepare a mixed acid with 95% fuming nitric acid and 98% concentrated sulfuric acid, and store it at 0°C; add 98% concentrated sulfuric acid and 3,5-dimethylnitrobenzene into the reaction vessel, and cool it under stirring To -10°C, add dropwise the mixed acid prepared by 95% fuming nitric acid and 98% concentrated sulfuric acid, and control the feeding rate so that the reaction temperature is not higher than -5°C. After the dropwise addition, continue to stir in the ice bath for 3 hours, slowly add the reaction mixture to crushed ice for hydrolysis, keep the temperature not exceeding 5°C, and stir vigorously until a large amount of light yellow solid precipitates; filter and filter the cake with ice water, saturated Sodium bicarbonate solution, washed with water, and dried to obtain intermediate product II, 3,5-dimethyl-1,2-dinitrobenzene as light yellow solid.

The volume ratio of the mixed acid prepared by the 95% fuming nitric acid and 98% concentrated sulfuric acid is 1:2, and the dosage ratio of the mixed acid to 3,5-dimethylnitrobenzene is 3ml:1g.

In the second step, the intermediate product 3,5-dimethyl-1,2-dinitrobenzene obtained in the first step is dissolved in ethanol, and Pd/C catalyzes the hydrogenation reaction to realize the reaction of nitro group into amino group. Filtration and concentration yielded the intermediate product III 3,5-dimethyl-1,2-phenylenediamine;

Specifically: add the intermediate product 3,5-dimethyl-1,2-dinitrobenzene obtained in the first step into the autoclave, then add 5% Pd/C catalyst, methanol solvent, The hydrogenation reaction was carried out at a pressure of 0.5Mpa for 6 hours. After the reaction was completed, the temperature and pressure were lowered to open the kettle, the catalyst was recovered by filtration, the solvent was removed, and crystallized to obtain the intermediate product III 3,5-dimethyl-1,2-phenylenediamine;

The catalyst is 5% Pd/C and the amount ratio of intermediate product 3,5-dimethyl-1,2-dinitrobenzene is 1g:10g.

In the third step, the intermediate product 3,5-dimethyl-1,2-phenylenediamine obtained in the second step is reacted with n-butyric acid in polyphosphoric acid solution, decolorized by activated carbon, filtered, and neutralized by sodium hydroxide To pH8, the intermediate product IV 2-n-propyl-4,6-dimethylbenzimidazole was obtained;

Specifically: add 3,5-dimethyl-1,2-phenylenediamine, an intermediate product prepared in the second step, into the reaction vessel, and add butyric acid and polyphosphoric acid into the reaction vessel. Raise the temperature to 120-125°C and react for 16 hours; cool down to 60°C, add water and activated carbon, stir and dissolve until slightly boiling, filter while hot after about 30 minutes. Cool the filtrate, add sodium hydroxide solution to the reaction solution under stirring conditions to neutralize to pH 10; cool and suction filter, filter out the precipitated solid, wash with cold water, and dry to obtain the crude product; the crude product is recrystallized with ethanol, and after the crystals are precipitated Suction filtration and drying at 100°C gave intermediate IV 2-n-propyl-4,6-dimethylbenzimidazole.

The amount ratio of the intermediate product 3,5-dimethyl-1,2-phenylenediamine to butyric acid is 8g:9g, the amount ratio to polyphosphoric acid is 40g:80g, and the amount ratio to activated carbon is 20g:1g , and the amount ratio of ethanol is 4g:50ml.

In the fourth step, the intermediate product 2-n-propyl-4,6-dimethylbenzimidazole obtained in the third step is subjected to an air-liquid phase oxidation reaction of cobalt salt in an acetic acid solution to realize the conversion of the methyl group at the 6-position into a carboxyl group The reaction was concentrated, alkali hydrolyzed, filtered, and acidolyzed to obtain the product V 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid.

Specifically, the intermediate product IV 2-n-propyl-4,6-dimethylbenzimidazole obtained in the third step is added to the reaction vessel, the catalyst 2-ethylhexanoic acid cobalt, and the cocatalyst N-hydroxy-phthalic acid Dicarboximide, glacial acetic acid; at a temperature of 110°C and an oxygen pressure of 1 MPa, react for 2 hours; after the reaction stops, lower the temperature and pressure to open the kettle, depressurize to remove acetic acid, obtain a precipitate, and filter with suction to obtain a crude product, which is used in 10% Sodium hydroxide aqueous solution is neutralized to pH = 8-9, add activated carbon to remove color, filter, the filtrate is acidified with 6N to pH = 3, filter, dry to obtain off-white crystalline solid 2-n-propyl-4-methyl Benzimidazole-6-carboxylic acid (V);

The dosage ratio of the catalyst 2-cobalt ethylhexanoate, cocatalyst N-hydroxyphthalimide and 2-n-propyl-4,6-dimethylbenzimidazole is 0.5g: 20g;

The dosage ratio of glacial acetic acid to 2-n-propyl-4,6-dimethylbenzimidazole is 15ml:20g.

The present invention will be further described below with specific embodiment

The first step, synthesis of 3,5-dimethyl-1,2-dinitrobenzene

Mix 20mL of 95% fuming nitric acid and 40mL of 98% concentrated sulfuric acid to make a mixed acid, and store it under stirring at -10°C. Add 100ml of concentrated sulfuric acid and 20g of 3,5-dimethylnitrobenzene into a 500ml three-necked flask equipped with mechanical stirring. Cool to -10°C with a low-temperature tank under stirring, add fuming nitric acid and 98% concentrated sulfuric acid mixture dropwise in batches, and control the feeding speed so that the reaction temperature is not higher than -5°C. After the addition was complete, stirring was continued in the ice bath for 3 hours. After the color of the reaction mixture became darker, slowly add the reaction solution into crushed ice for hydrolysis, keep the temperature not exceeding 5°C, stir vigorously, and a large amount of light yellow solid can be seen to precipitate. Filtration, the filter cake was washed with ice water, saturated sodium bicarbonate solution, water, and dried to obtain 21g of intermediate product II, light yellow solid 3,5-dimethyl-1,2-dinitrobenzene, yield 92.8 %, melting point 132.7-134.7°C.

Infrared spectrum IR instrument model Perkin-Elmer Spectrum (KBr, cm ^-1 ): 3088 (Ar-H); 2919 (CH ₃ -H); 1547, 1441 (Ar-C); 1547, 1362 (N=O); 1441, 1362 ( _-CH3 ); 1040 (CN); 876-763 (Ar-H).

Nuclear magnetic resonance NMR instrument model Varian Mercury 400, ¹ H-NMR (CDCl ₃ ): 7.79 (S, 1H, Ar-H); 7.43 (S, 1H, Ar-H); 2.50 (S, 3H, Ar-CH ₃ ); 2.40 (S,3H,Ar—CH ₃ ).

Mass spectrometry instrument Xevo TQ. MS: m/z=196.02 (M ⁺ );

The second step, synthesis of 3,5-dimethyl-1,2-phenylenediamine

After confirming that the reactor is airtight, add 15g of 3,5-dimethyl-1,2-dinitrobenzene to the autoclave, then add 1.5g of 5% Pd/C catalyst, and then add 300ml methanol. First pass nitrogen at a certain pressure, empty the air in the reactor, and discharge it three times in a row, then pass in hydrogen at a certain pressure to replace the nitrogen, and replace it three times in a row. Finally, the reaction was carried out at 60° C. under a reaction pressure of 0.5 MPa and 6 hours. Lower the temperature and reduce the pressure to open the kettle, use gas chromatography to detect the content of raw materials, products and by-products in the kettle, filter and recover the catalyst, remove the solvent, and crystallize to obtain 10.5g of intermediate product III 3,5-dimethyl-1,2-benzenedi The amine has a purity of more than 98% detected by GC, a yield of 98.8%, and a melting point of 73.9-74.6°C.

Infrared spectrum IR instrument model Perkin-Elmer Spectrum (KBr, cm ^-1 ): 3392, 3299 (Ar-NH ₂ ); 2916 (Ar-CH ₃ ); 912 (Ar-H).

Nuclear magnetic resonance NMR instrument model Varian Mercury 400, ¹ H-NMR (CDCl ₃ ): 6.23 (S, 1H, Ar-H); 6.12 (S, 1H, Ar-H); 4.11 (br, 4H, Ar-NH ₂ ); 2.03 (S,3H,Ar—CH ₃ ); 1.99 (S,3H,Ar—CH ₃ ).

Mass spectrometry instrument Xevo TQ. MS: m/z = 136.08 (M ⁺ ).

The third step, synthesis of 2-n-propyl-4,6-dimethylbenzimidazole

Take 40g of 3,5-dimethyl-1,2-phenylenediamine, 45g of butyric acid, and 80g of polyphosphoric acid into the reaction flask. Raise the temperature to 120-125°C and react for 16 hours. Cool down to 60°C, add 500g of water and 2g of activated carbon, stir and dissolve until slightly boiling, filter while hot after about 30min. Cool the filtrate, add 10% sodium hydroxide solution to the reaction solution under stirring condition, and neutralize the pH to about 10. Cool and filter with suction, filter out the precipitated solid, wash with cold water, and dry to obtain a crude product.

Put the crude product in a 1000mL beaker, add 500mL ethanol, and heat to dissolve. Cool to room temperature, precipitate crystals, filter with suction, and finally dry at 100°C to obtain 51g of intermediate product IV 2-n-propyl-4,6-dimethylbenzimidazole. The purity detected by HPLC is greater than 98%, the yield is 90%, and the melting point is 167.7-170.2°C.

Infrared spectrum IR instrument model Perkin-Elmer Spectrum (KBr, cm ^-1 ): 3249 (Ar-CH ₃ ); 2962 (-CH ₃ ); 2931 (-CH ₂ -); 1652 (C=N).

Nuclear magnetic resonance NMR instrument model Varian Mercury 400, ¹ H-NMR (CDCl ₃ ): 7.99, 8.31 (S, 3H, Ar-CH ₃ ); 6.74 (S, 1H, Ar-NH-); 2.27 (q, 2H, -CH ₂ -); 2.13, 2.16 (S, 3H, Ar-CH ₃ ); 1.55 (dq, 2H, -CH ₂ -); 0.9 (dt, 3H, Ar-CH ₃ ).

Mass spectrometry instrument Xevo TQ. MS: m/z = 188.19 (M ⁺ ).

The fourth step, synthesis of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid

After confirming that the reactor is airtight, add 20g of 2-n-propyl-4,6-dimethylbenzimidazole to the autoclave, 0.5g of cobalt 2-ethylhexanoate as a catalyst, and 0.5g of cocatalyst N-hydroxy-phthalate Dicarboximide 0.5g, glacial acetic acid 15ml. The temperature is 110°C, the oxygen pressure is 1MPa, and the reaction time is 2h. After the reaction stopped, lower the temperature and reduce the pressure to open the kettle, remove the acetic acid under reduced pressure to obtain a precipitate, filter the obtained precipitate with suction, neutralize the crude product with 10% aqueous sodium hydroxide solution to pH = 8-9, add activated carbon to remove color, filter, The filtrate was acidified with 6N to pH=3, and filtered to obtain V 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid as an off-white crystalline solid.

The single-pass conversion rate of 2-n-propyl-4,6-dimethylbenzimidazole can reach 40%, and the selectivity of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid can reach 100%. The product was recrystallized from ethanol to obtain 20.6g of 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid, the purity of which was detected by HPLC was greater than 98%, the total yield was 88.8%, and the melting point was 257.7-259.3°C.

Infrared spectrum IR instrument model Perkin-Elmer Spectrum (KBr, cm ^-1 ): 3425 (OH); 2965 (Ar-CH ₃ ); 1650 (C=N).

Nuclear magnetic resonance NMR instrument model Varian Mercury 400, ¹ H-NMR (CDCl ₃ ): 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,-CH ₂ -); 2.55(S,3H,Ar-CH ₃ ); 1.81(m,2H,-CH ₂ -); 1.02 (t,3H,Ar—CH ₃ ).

Mass spectrometry instrument Xevo TQ. MS: m/z = 218.25 (M ⁺ ).

Claims (5)

The synthetic method of 1.2-n-propyl group-4-methylbenzimidazole-6-carboxylic acid is characterized in that: synthetic method is carried out in four steps: In the first step, 3,5-dimethylnitrobenzene is used as raw material, nitrated by nitric acid/concentrated sulfuric acid, hydrolyzed, and filtered to generate intermediate product II 3,5-dimethyl-1,2-dinitrobenzene; In the second step, the intermediate product 3,5-dimethyl-1,2-dinitrobenzene obtained in the first step is dissolved in ethanol, and Pd/C catalyzes the hydrogenation reaction to realize the reaction of nitro group into amino group. Filtration and concentration yielded the intermediate product III 3,5-dimethyl-1,2-phenylenediamine; In the third step, the intermediate product 3,5-dimethyl-1,2-phenylenediamine obtained in the second step is reacted with n-butyric acid in polyphosphoric acid solution, decolorized by activated carbon, filtered, and And to pH8, obtain the intermediate product IV 2-n-propyl-4,6-dimethylbenzimidazole; In the fourth step, the intermediate product 2-n-propyl-4,6-dimethylbenzimidazole obtained in the third step is in the acetic acid solution, through the catalyst 2-ethylhexanoic acid cobalt, and the cocatalyst N-hydroxy o-phenyl The air-liquid phase oxidation reaction of dicarboximide realizes the reaction of the 6-position methyl group into a carboxyl group. After concentration, alkali hydrolysis, filtration, and acidolysis, V 2-n-propyl-4-methylbenzimidazole-6 is obtained -carboxylic acid; Concrete reaction carries out by following formula: 2. the synthetic method of 2-n-propyl group-4-methylbenzimidazole-6-carboxylic acid according to claim 1 is characterized in that: the first step reaction is specially with 95% fuming nitric acid and 98% Concentrated sulfuric acid prepared as a mixed acid, stored at 0°C; add 98% concentrated sulfuric acid and 3,5-dimethylnitrobenzene into the reaction vessel, cool to -10°C under stirring, add 95% fuming Mixed acid prepared with nitric acid and 98% concentrated sulfuric acid, control the feeding speed so that the reaction temperature is not higher than -5°C; after the dropwise addition, continue to stir in an ice bath for 3 hours, slowly add the reaction mixture to crushed ice for hydrolysis, and maintain the temperature Stir vigorously at no more than 5°C until a large amount of light yellow solid precipitates; filter, wash the filter cake with ice water, saturated sodium bicarbonate solution, water, and dry to obtain intermediate product II, light yellow solid 3,5-dimethyl Base-1,2-dinitrobenzene; The volume ratio of the mixed acid prepared by the 95% fuming nitric acid and 98% concentrated sulfuric acid is 1:2, and the dosage ratio of the mixed acid to 3,5-dimethylnitrobenzene is 3ml:1g. 3. the synthetic method of 2-n-propyl group-4-methylbenzimidazole-6-carboxylic acid according to claim 1 is characterized in that: the second step reaction is specifically to add the first step in the autoclave The obtained intermediate product 3,5-dimethyl-1,2-dinitrobenzene is then added with 5% Pd/C catalyst and ethanol solvent, and the hydrogenation reaction is carried out at a temperature of 60°C and a pressure of 0.5Mpa for 6h. After the reaction is completed , lower the temperature and reduce the pressure, open the kettle, filter and recover the catalyst, remove the solvent, and crystallize to obtain the intermediate product III, an off-white solid 3,5-dimethyl-1,2-phenylenediamine; The catalyst is 5% Pd/C and the amount ratio of intermediate product II 3,5-dimethyl-1,2-dinitrobenzene is 1g:10g. 4. the synthetic method of 2-n-propyl group-4-methylbenzimidazole-6-carboxylic acid according to claim 1 is characterized in that: the third step reaction is specifically for adding the second step preparation in reaction vessel The intermediate product 3,5-dimethyl-1,2-phenylenediamine, add butyric acid and polyphosphoric acid to the reaction flask; heat up to 120-125°C, react for 16 hours; cool down to 60°C, add water, Activated carbon, stirring and dissolving to a slight boil, and filtering while hot after about 30 minutes; cooling the filtrate, adding sodium hydroxide solution to the reaction solution under stirring conditions to neutralize to pH 10; cooling and suction filtration, filtering out the precipitated solid, and using cold water Washing and drying to obtain the crude product; recrystallization of the crude product with ethanol, suction filtration after precipitation of crystals, drying at 100°C to obtain intermediate IV, white crystal 2-n-propyl-4,6-dimethylbenzimidazole; The amount ratio of intermediate product III 3,5-dimethyl-1,2-phenylenediamine to butyric acid is 8g:9g, the amount ratio to polyphosphoric acid is 40g:80g, and the amount ratio to activated carbon is 20g:1g , and the amount ratio of ethanol is 4g:50ml. 5. the synthetic method of 2-n-propyl group-4-methylbenzimidazole-6-carboxylic acid according to claim 1 is characterized in that: the fourth step reaction is specifically to add the third step gained in reaction vessel The intermediate product 2-n-propyl-4,6-dimethylbenzimidazole, the catalyst 2-ethylhexanoic acid cobalt, the cocatalyst N-hydroxyphthalimide, glacial acetic acid; at a temperature of 110°C , oxygen pressure 1MPa, reaction 2h; After the reaction stops, lower the temperature and reduce the pressure to open the kettle, depressurize to remove acetic acid, obtain a precipitate, filter with suction to obtain a crude product, the crude product is neutralized to pH=8-9 with 10% aqueous sodium hydroxide solution, and added Remove color with activated carbon, filter, and acidify the filtrate to pH=3 with 6N, filter, and dry to obtain product V, an off-white crystalline solid 2-n-propyl-4-methylbenzimidazole-6-carboxylic acid; The dosage ratio of the catalyst 2-cobalt ethylhexanoate, cocatalyst N-hydroxyphthalimide and 2-n-propyl-4,6-dimethylbenzimidazole is 0.5g:0.5g: 20g; The dosage ratio of glacial acetic acid to 2-n-propyl-4,6-dimethylbenzimidazole is 15ml:20g.