CN112358450A - Synthesis method of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid - Google Patents
Synthesis method of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid Download PDFInfo
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Abstract
The invention discloses a synthesis method of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid, belonging to the field of synthesis of fine chemical intermediates, and comprising the following six steps: step 1: 2-amino-3-nitrophenol is taken as a raw material and reacts with benzyl chloride under the action of inorganic base to obtain an intermediate (I); step 2: the intermediate (I) reacts with N-chlorosuccinimide to obtain 2-benzyloxy-4-chloro-6-nitroaniline (II); and step 3: carrying out acylation reaction on the intermediate (II) and acetic anhydride to obtain N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III); and 4, step 4: dissolving the intermediate (III) with dimethylformamide to obtain 4-acetamido-3-benzyloxy-5-nitrobenzamide (IV) under the catalysis of CuI; and 5: carrying out cyclization reaction on the Intermediate (IV) to obtain 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V); step 6: and (3) carrying out hydrolysis reaction on the intermediate (V) and potassium hydroxide solution to obtain 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI). The method has the advantages of easily-purchased raw materials, low price, simple preparation method, mild reaction conditions and low equipment requirement, and is suitable for industrial production.
Description
Technical Field
The invention relates to the field of synthesis of fine chemical intermediates, in particular to a synthesis method of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid.
Background
4- (Benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (formula (VI)), the English name is 4- (Benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid; the molecular weight is 282.10; CAS: 942195-83-7; the structural formula is shown as formula VI:
the method for selectively synthesizing the benzimidazole intermediate under the catalysis of CuI can be used for constructing an important benzimidazole scaffold in GSK-3 beta and GSK-484 (shown in a structure below). In addition, it can be used to facilitate the study of SAR to find more effective PAD4 in inhibitors. PAD4 is a promising epigenetic drug target for various cancers and immune diseases, so the synthetic method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid is of great significance.
Disclosure of Invention
The invention provides a synthesis method of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid, which has the advantages of reasonable process design, high yield, mild reaction conditions and low raw material price.
The technical scheme of the invention is as follows:
2-amino-3-nitrophenol with low price is taken as a raw material and reacts with benzyl chloride under the action of inorganic base to obtain 2-benzyloxy-6-nitroaniline;
dissolving the mixture in solvents such as acetonitrile, reacting the mixture with N-chlorosuccinimide at the temperature of 70 ℃, and treating the mixture after the reaction is finished to obtain 2-benzyloxy-4-chloro-6-nitroaniline;
carrying out acylation reaction on 2-benzyloxy-4-chloro-6-nitroaniline and acetic anhydride to obtain N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide;
dissolving N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide in a solvent such as dimethylformamide and the like, and obtaining 4-acetamido-3-benzyloxy-5-nitrobenzamide under the action of a catalyst;
4-acetamido-3-benzyloxy-5-nitrobenzamide is subjected to cyclization reaction under the action of Fe and the like to obtain 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide;
dissolving 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide in inorganic alkali solution such as potassium hydroxide, and performing hydrolysis reaction to obtain 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid.
The route has the advantages of low cost of the adopted raw material 2-amino-3-nitrophenol, good regioselectivity of the cyclization reaction and high purity of the final product.
The specific route is as follows:
step 1: preparation of 2-benzyloxy-6-nitroaniline (I)
Taking 2-amino-3-nitrophenol as a raw material, and reacting the raw material with benzyl chloride under the action of inorganic base to obtain 2-benzyloxy-6-nitroaniline shown in a formula (I);
the route is described as follows:
wherein the inorganic base can be sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, and potassium carbonate is most preferable;
the method comprises the following specific steps:
dissolving 2-amino-3-nitrophenol in ethanol, and adding a proper amount of inorganic base; adding 1 equivalent of benzyl chloride at normal temperature; after the reaction is finished, standing and layering to obtain an organic layer of the product; and distilling the organic layer under reduced pressure to recover the solvent to obtain a crude product of the 2-benzyloxy-6-nitroaniline, wherein the crude product is directly used for the next reaction.
Step 2: preparation of 2-benzyloxy-4-chloro-6-nitroaniline (II)
Dissolving the 2-benzyloxy-6-nitroaniline crude product obtained in the step 1 as shown in the formula (I) in a solvent, and reacting the solvent with N-chlorosuccinimide to obtain 2-benzyloxy-4-chloro-6-nitroaniline as shown in the formula (II);
the route is described as follows:
wherein the solvent is aprotic solvent, and can be selected from acetonitrile, dimethylformamide, N, N-dimethyl-2-thio-1, 2-dihydro-3-pyridinecarboxamide (DMI), dimethyl sulfoxide, etc., and the most preferable solvent is acetonitrile;
the reaction temperature may range from 20 to 100 deg.C, more preferably from 60 to 80 deg.C.
The method comprises the following specific steps:
dissolving 2-benzyloxy-6-nitroaniline (I) in an aprotic solvent such as acetonitrile and the like, dropwise adding an acetonitrile solution of N-chlorosuccinimide, reacting at 70 ℃ until the reaction is finished, cooling to room temperature, adding water, stirring, standing for layering to obtain an organic layer of a product, and decompressing the organic layer to remove the solvent to obtain a crude product; the crude product is purified to obtain the 2-benzyloxy-4-chloro-6-nitroaniline shown in the formula (II).
And step 3: preparation of N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III)
Dissolving the 2-benzyloxy-4-chloro-6-nitroaniline shown in the formula (II) obtained in the step 2 and acetic anhydride in a solvent, and adding an acid solution to carry out an acylation reaction to obtain N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide shown in the formula (III);
the route is described as follows:
wherein the solvent is a protic solvent, which can be selected from acetic acid, ethanol, water, formic acid, etc., and the most preferable solvent is acetic acid;
the reaction temperature is 20-100 ℃, and the preferable reaction temperature is 60-80 ℃.
The method comprises the following specific steps:
dissolving 2-benzyloxy-4-chloro-6-nitroaniline (II) in acetic acid, adding acetic acid solution of acetic anhydride, heating to 70 ℃, and dropwise adding concentrated sulfuric acid. And (3) stirring the mixture at 70 ℃ to react until the reaction is finished, cooling to room temperature, adding water, stirring, filtering, and washing a filter cake with a solvent to obtain a crude product of the N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III).
And 4, step 4: preparation of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (IV)
Dissolving the N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide crude product shown in the formula (III) obtained in the step (3) in a solvent, and obtaining 4-acetamido-3-benzyloxy-5-nitrobenzamide shown in the formula (IV) under the action of a catalyst;
the route is described as follows:
wherein the solvent is an aprotic solvent, and can be selected from dimethylformamide, formamide, acetamide, sulfolane, dimethylacetamide, DMSO and the like, and the preferred solvent is DMF;
the reaction temperature is 100-200 ℃, and the preferable reaction temperature is 140-170 ℃.
Wherein the catalyst is CuI/CuCN, Pd (PPh)3)4/Zn(CN)2，Pd(OAc)2，Pd2(dba)3Most preferred is CuI/CuCN.
The method comprises the following specific steps:
n- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III), ketone iodide and cuprous cyanide were dissolved in DMF solvent, and the mixture was reacted at 170 ℃ for 6 hours. After the reaction was completed, the reaction mixture was cooled to room temperature, and the suspension was filtered, washed with ethyl acetate, and the organic layers were combined. Removing the solvent from the organic layer under reduced pressure to obtain a crude product; the crude product is purified to obtain the 4-acetamido-3-benzyloxy-5-nitrobenzamide shown in the formula (IV).
And 5: preparation of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V)
Dissolving the 4-acetamido-3-benzyloxy-5-nitrobenzamide shown in the formula (IV) obtained in the step (4) in a solvent, and carrying out cyclization reaction under the action of Fe and the like to obtain the 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide shown in the formula (V).
The route is described as follows:
wherein the solvent is a protic solvent, which can be selected from acetic acid, ethanol, water, formic acid, etc., and the preferable solvent is acetic acid;
the reaction temperature is 20-100 ℃, and the preferable reaction temperature is 60-80 ℃.
The method comprises the following specific steps:
4-acetamido-3-benzyloxy-5-nitrobenzamide (IV) and iron powder were dissolved in acetic acid and the mixture was reacted at 70 ℃ for 2 hours. After the reaction is finished, cooling to normal temperature, filtering suspended matters, and removing the solvent from the filtrate. The residue was poured into water, extracted with ethyl acetate and methanol, and the organic layers were combined. And (3) decompressing the organic layer to remove the solvent to obtain the 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide shown in the formula (V).
Step 6: preparation of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI)
And (3) dissolving the 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide shown in the formula (V) obtained in the step (5) in a solvent, and performing hydrolysis reaction with inorganic base to obtain the 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI).
The route is described as follows:
wherein the solvent is a protic solvent, which can be selected from ethylene glycol, ethanol, water, formic acid, acetic acid, etc., and the preferable solvent is ethylene glycol;
wherein the inorganic base can be potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate and the like, and is preferably potassium hydroxide;
the reaction temperature may be 100-200 deg.C, and more preferably 140-180 deg.C.
The method comprises the following specific steps:
7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) and potassium hydroxide are dissolved in ethylene glycol solvent, and the mixture is reacted at 170 ℃ for 12 hours. After the reaction is finished, cooling to normal temperature, acidifying the reaction system by using hydrochloric acid solution, and filtering to obtain 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid shown as a formula (VI).
Has the advantages that:
the invention has the advantages of simple and easily obtained raw materials and low synthesis cost.
The invention has simple and convenient synthesis operation, high yield and few by-products, and greatly improves the quality of the product.
Drawings
FIG. 1 Process route of the present Synthesis method
FIG. 2 HPLC chart of step 6 of example 1
FIG. 3 HNMR map of step 6 of example 1
Detailed Description
The technical solutions in the embodiments of the present invention will be clearly and completely described below, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all embodiments.
Example 1
Step 1: synthesis of 2-benzyloxy-6-nitroaniline (I)
Into a 2L reaction flask were charged 75g of 2-amino-3-nitrophenol, 202g of potassium carbonate, 14.4g of sodium iodide and 400mL of ethanol solution, and 61.5g of benzyl chloride was added under nitrogen protection, followed by stirring and warming to 80 ℃ for 6 hours. Cooling to room temperature after the reaction is finished, filtering to remove precipitates, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was desolventized to give 90g of 2-benzyloxy-6-nitroaniline (I) in a yield of 76%.
Step 2: synthesis of 2-benzyloxy-4-chloro-6-nitroaniline (II)
Into a 2L reaction flask, 90g of 2-benzyloxy-6-nitroaniline (I) and 100mL of acetonitrile as a solvent were charged, and 49g N-chlorosuccinimide (dissolved in 50mL of acetonitrile) was added dropwise under nitrogen protection. After the dropwise addition, the reaction mixture was stirred and heated to 70 ℃ to react for 1 hour. After the reaction is finished, cooling to room temperature, adding ethyl acetate and water, standing for layering to obtain an organic layer of the product, and removing the solvent from the organic layer under reduced pressure to obtain 98g of 2-benzyloxy-4-chloro-6-nitroaniline (II), wherein the yield is 95%.
And step 3: synthesis of N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III)
In a 2L reaction bottle, 98g of 2-benzyloxy-4-chloro-6-nitroaniline (II), 54g of acetic anhydride and 300mL of acetic acid as a solvent are put into the reaction bottle, the temperature is raised to 70 ℃ under the protection of nitrogen gas and stirring, and 6 drops of concentrated sulfuric acid are added dropwise. The mixture was stirred at 70 ℃ until the reaction was complete, cooled to room temperature, water was added and stirred, the mixture was filtered, and the filter cake was washed with diisopropyl ether to give 91g of n- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III) with a yield of 81%.
And 4, step 4: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (IV)
In a 1L autoclave, 30g N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III), 3.6g of ketone iodide and 16.6g of cuprous cyanide were dissolved in 500mL of DMF solvent, and the mixture was stirred under nitrogen and heated to 170 ℃ for 6 hours. Cooling to normal temperature after the reaction is finished, filtering the suspended matters, washing with ethyl acetate, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was freed of solvent and purified to give 18g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) in 59% yield.
And 5: synthesis of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V)
In a 1L reaction flask, 20g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) and 10.8g of iron powder were put into a 400mL of acetic acid, and the mixture was stirred under nitrogen and warmed to 70 ℃ for 2 hours. After the reaction is finished, cooling to normal temperature, filtering suspended matters, and removing the solvent from the filtrate. The residue was poured into water, extracted with ethyl acetate and methanol, and the organic layers were combined. The organic layer was desolvated under reduced pressure to give 13g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) in a yield of 76%.
Step 6: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI)
In a 500mL autoclave, 10g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) and 1.6g of potassium hydroxide were dissolved in 100mL of ethylene glycol solvent, and the mixture was stirred and heated to 170 ℃ under nitrogen protection to react for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, and the reaction system was acidified with a hydrochloric acid solution and filtered to obtain 9.2g of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI) in a yield of 92%.
1H NMR(DMSO-d6,400MHz)δ:12.68(brs,2H),7.73-7.34(m,7H),5.33(s,2H),2.50(s, 3H)ppm.
HPLC purity and HNMR of the product are shown in FIG. 2 and FIG. 3.
The product of the invention adopts the following HPLC detection conditions:
example 2
Step 1: synthesis of 2-benzyloxy-6-nitroaniline (I)
In a 2L reaction flask, 70g of 2-amino-3-nitrophenol, 54.5g of sodium hydroxide and 400mL of ethanol solution were charged, 57.3g of benzyl chloride was added under nitrogen protection, and the mixture was stirred and heated to 80 ℃ for reaction for 6 hours. Cooling to room temperature after the reaction is finished, filtering to remove precipitates, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was desolventized to give 76g of 2-benzyloxy-6-nitroaniline (I) in a yield of 68%.
Step 2: synthesis of 2-benzyloxy-4-chloro-6-nitroaniline (II)
A2L reaction flask was charged with 75g of 2-benzyloxy-6-nitroaniline (I) and 100mL of solvent DMF, and 38.7g of N-chlorosuccinimide (dissolved in 50mL of DMF) was added dropwise under nitrogen. After the dropwise addition, the reaction mixture was stirred and heated to 70 ℃ to react for 1 hour. After the reaction is finished, cooling to room temperature, adding ethyl acetate and water, standing for layering to obtain an organic layer of the product, and removing the solvent from the organic layer under reduced pressure to obtain 80g of 2-benzyloxy-4-chloro-6-nitroaniline (II), wherein the yield is 94.1%.
And step 3: synthesis of N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III)
70g of 2-benzyloxy-4-chloro-6-nitroaniline (II), 38.4g of acetic anhydride and 300mL of ethanol as a solvent are put into a 2L reaction bottle, the temperature is raised to 70 ℃ under the protection of nitrogen and stirring, and 6 drops of concentrated sulfuric acid are added dropwise. The mixture was stirred at 70 ℃ until the reaction was complete, cooled to room temperature, water was added and stirred, the mixture was filtered, and the filter cake was washed with diisopropyl ether to give 62g of n- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III) in 77% yield.
And 4, step 4: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (IV)
In a 1L reaction flask, 33g N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III), 3.96g of ketone iodide and 18.26g of cuprous cyanide were dissolved in 500mL of DMF solvent, and the mixture was stirred under nitrogen and heated to 170 ℃ for 6 hours. Cooling to normal temperature after the reaction is finished, filtering the suspended matters, washing with ethyl acetate, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was freed of the solvent and purified to give 14.6g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) in 43% yield.
And 5: synthesis of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V)
In a 1L reaction flask, 15g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) and 5.1g of iron powder were put into a 400mL of acetic acid, and the mixture was stirred under nitrogen and warmed to 70 ℃ for 2 hours. After the reaction is finished, cooling to normal temperature, filtering suspended matters, and removing the solvent from the filtrate. The residue was poured into water, extracted with ethyl acetate and methanol, and the organic layers were combined. The organic layer was desolvated under reduced pressure to give 8.2g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) in 64% yield.
Step 6: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI)
In a 500mL autoclave, 9g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) and 1.44g of potassium hydroxide were dissolved in 100mL of formic acid solvent, and the mixture was stirred and heated to 170 ℃ under nitrogen protection to react for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, and the reaction system was acidified with a hydrochloric acid solution and filtered to obtain 7.86g of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI) in a yield of 87%.
Example 3
Step 1: synthesis of 2-benzyloxy-6-nitroaniline (I)
68g of 2-amino-3-nitrophenol, 202g of potassium carbonate and 400mL of ethanol solution are put into a 2L reaction flask, 55.6g of benzyl chloride is added under the protection of nitrogen, and the mixture is stirred and heated to 80 ℃ for reaction for 6 hours. Cooling to room temperature after the reaction is finished, filtering to remove precipitates, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was desolventized to give 74g of 2-benzyloxy-6-nitroaniline (I) with a yield of 74%.
Step 2: synthesis of 2-benzyloxy-4-chloro-6-nitroaniline (II)
A2L reaction flask was charged with 82g of 2-benzyloxy-6-nitroaniline (I) and 100mL of acetonitrile as a solvent, and 55g N-chlorosuccinimide (dissolved in 50mL of acetonitrile) was added dropwise under nitrogen. After the dropwise addition, the reaction mixture was stirred and heated to 70 ℃ to react for 1 hour. After the reaction is finished, cooling to room temperature, adding ethyl acetate and water, standing for layering to obtain an organic layer of the product, and removing the solvent from the organic layer under reduced pressure to obtain 82.2g of 2-benzyloxy-4-chloro-6-nitroaniline (II), wherein the yield is 88%.
And step 3: synthesis of N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III)
78g of 2-benzyloxy-4-chloro-6-nitroaniline (II), 42.9g of acetic anhydride and 300mL of acetic acid as a solvent are put into a 2L reaction bottle, the temperature is raised to 100 ℃ under the protection of nitrogen and stirring, and 6 drops of concentrated sulfuric acid are added dropwise. The mixture was stirred at 100 ℃ until the reaction was complete, cooled to room temperature, water was added and stirred, the mixture was filtered, and the filter cake was washed with diisopropyl ether to give 71.8g N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III) with 80% yield.
And 4, step 4: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (IV)
In a 1L autoclave, 25g N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III), 2.9g of ketone iodide and 13.9g of cuprous cyanide were dissolved in 500mL of DMF solvent, and the mixture was stirred under nitrogen and heated to 100 ℃ for 6 hours. Cooling to normal temperature after the reaction is finished, filtering the suspended matters, washing with ethyl acetate, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was freed of solvent and purified to give 9.8g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) in 38% yield.
And 5: synthesis of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V)
In a 1L reaction flask, 10g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) and 5.4g of iron powder were put into a 400mL of methanol, and the mixture was stirred under nitrogen and warmed to 70 ℃ for 2 hours. After the reaction is finished, cooling to normal temperature, filtering suspended matters, and removing the solvent from the filtrate. The residue was poured into water, extracted with ethyl acetate and methanol, and the organic layers were combined. The organic layer was desolvated under reduced pressure to give 5.4g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) in a yield of 63%.
Step 6: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI)
In a 500mL reaction flask, 6g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) and 0.96g of potassium hydroxide were dissolved in 100mL of ethylene glycol solvent, and the mixture was stirred and heated to 170 ℃ under nitrogen protection to react for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, and the reaction system was acidified with a hydrochloric acid solution and filtered to obtain 4.76g of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI) in a yield of 79%.
Example 4
Step 1: synthesis of 2-benzyloxy-6-nitroaniline (I)
Into a 2L reaction flask were charged 75g of 2-amino-3-nitrophenol, 168g of potassium carbonate, 7.2g of sodium iodide and 400mL of ethanol solution, and 61.5g of benzyl chloride was added under nitrogen protection, followed by stirring and warming to 80 ℃ for 6 hours. Cooling to room temperature after the reaction is finished, filtering to remove precipitates, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was desolventized to give 84.6g of 2-benzyloxy-6-nitroaniline (I) with a yield of 71%.
Step 2: synthesis of 2-benzyloxy-4-chloro-6-nitroaniline (II)
Into a 2L reaction flask, 80g of 2-benzyloxy-6-nitroaniline (I) and 100mL of acetonitrile as a solvent were charged, and 41.3g N-chlorosuccinimide (dissolved in 50mL of acetonitrile) was added dropwise under nitrogen atmosphere. After the dropwise addition, the reaction mixture was stirred and heated to 100 ℃ to react for 1 hour. After the reaction is finished, cooling to room temperature, adding ethyl acetate and water, standing for layering to obtain an organic layer of the product, and removing the solvent from the organic layer under reduced pressure to obtain 78.4g of 2-benzyloxy-4-chloro-6-nitroaniline (II), wherein the yield is 86%.
And step 3: synthesis of N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III)
75g of 2-benzyloxy-4-chloro-6-nitroaniline (II), 27.5g of acetic anhydride and 300mL of acetic acid as a solvent are put into a 2L reaction bottle, the temperature is raised to 70 ℃ under the protection of nitrogen and stirring, and 6 drops of concentrated sulfuric acid are added dropwise. The mixture was stirred at 70 ℃ until the reaction was complete, cooled to room temperature, water was added and stirred, the mixture was filtered, and the filter cake was washed with diisopropyl ether to give 64.7g of n- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III) with a yield of 75%.
And 4, step 4: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (IV)
28g N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide (III), 20.2g of tetratriphenylphosphine palladium and 20.3g of zinc cyanide were dissolved in 500mL of DMF solvent in a 1L autoclave, and the mixture was stirred under nitrogen and warmed to 170 ℃ for 6 hours. Cooling to normal temperature after the reaction is finished, filtering the suspended matters, washing with ethyl acetate, decompressing the filtrate to remove the solvent, adding ethyl acetate and water into the obtained residue, and stirring to separate an organic layer; the organic layer was desolventized and purified to give 14.1g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) in 49% yield.
And 5: synthesis of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V)
In a 1L reaction flask, 12g of 4-acetylamino-3-benzyloxy-5-nitrobenzamide (IV) and 6.5g of iron powder were put into a 400mL of acetic acid, and the mixture was stirred under nitrogen and warmed to 100 ℃ for 2 hours. After the reaction is finished, cooling to normal temperature, filtering suspended matters, and removing the solvent from the filtrate. The residue was poured into water, extracted with ethyl acetate and methanol, and the organic layers were combined. The organic layer was desolvated under reduced pressure to give 7.6g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) in 74% yield.
Step 6: synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI)
In a 500mL autoclave, 8g of 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide (V) and 3.3g of sodium carbonate were dissolved in 100mL of ethylene glycol solvent, and the mixture was stirred and heated to 170 ℃ under nitrogen protection to react for 12 hours. After the reaction, the reaction mixture was cooled to room temperature, and the reaction system was acidified with a hydrochloric acid solution and filtered to obtain 6.9g of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid (VI) in a yield of 86%.
The above description is only for the preferred embodiment of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art should be considered to be within the technical scope of the present invention, and the technical solutions and the inventive concepts thereof according to the present invention should be equivalent or changed within the scope of the present invention.
Claims (10)
1. A method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid is characterized by comprising the following steps:
step 1: taking 2-amino-3-nitrophenol as a raw material, taking ethanol as a solvent, and reacting with benzyl chloride under the action of inorganic base to obtain 2-benzyloxy-6-nitroaniline shown in a formula (I);
step 2: dissolving the 2-benzyloxy-6-nitroaniline shown in the formula (I) obtained in the step 1 and N-chlorosuccinimide by using a solvent, and reacting to obtain 2-benzyloxy-4-chloro-6-nitroaniline shown in the formula (II);
and step 3: dissolving the 2-benzyloxy-4-chloro-6-nitroaniline shown in the formula (II) obtained in the step 2 and acetic anhydride by using a solvent, and carrying out acylation reaction to obtain N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide shown in the formula (III);
and 4, step 4: dissolving the N- (2-benzyloxy-4-chloro-6-nitro-phenyl) acetamide shown in the formula (III) obtained in the step (3) and dimethylformamide by using a solvent, and obtaining 4-acetamido-3-benzyloxy-5-nitrobenzamide shown in the formula (IV) under the action of a catalyst;
and 5: dissolving the 4-acetamido-3-benzyloxy-5-nitrobenzamide shown in the formula (IV) obtained in the step (4) by using a solvent, and carrying out cyclization reaction to obtain 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide shown in the formula (V);
step 6: and (3) dissolving the 7-benzyloxy-2-methyl-3H-benzimidazole-5-carboxylic acid amide shown in the formula (V) obtained in the step (5) by using a solvent, and performing hydrolysis reaction on the obtained product and an inorganic alkali solution to obtain the 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid shown in the formula (VI).
2. The method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid according to claim 1, which comprises the following steps: in the step 1, the inorganic base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
3. The method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid according to claim 1, which comprises the following steps: in the step 2, the solvent used for the reaction of the 2-benzyloxy-6-nitroaniline and the N-chlorosuccinimide is any one of acetonitrile, dimethylformamide, N-dimethyl-2-thio-1, 2-dihydro-3-pyridinecarboxamide (DMI) and dimethyl sulfoxide, and the reaction temperature is 20-100 ℃.
4. The method of claim 2 for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid, wherein: in the step 2, the solvent used in the reaction is acetonitrile, and the reaction temperature is 60-80 ℃.
5. The method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid according to claim 1, which comprises the following steps: in the step 3, the used solvent is any one of acetic acid, ethanol, water and formic acid, and the reaction temperature is 20-100 ℃.
6. The method of claim 5 for the synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid, wherein: in the step 3, the solvent used in the reaction is acetic acid, and the reaction temperature is 60-80 ℃.
7. A4- (benzyloxy) -2-methyl-1H-benzo [ d ] according to claim 1]The method for synthesizing imidazole-6-carboxylic acid is characterized by comprising the following steps: in the step 4, the solvent used is any one of dimethylformamide, formamide, acetamide, sulfolane, dimethylacetamide and DMSO, the reaction temperature is 100-200 ℃, and the catalyst is selected from CuI/CuCN and Pd (PPh)3)4/Zn(CN)2，Pd(OAc)2，Pd2(dba)3Any one of them.
8. The method of claim 7, wherein the synthesis of 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid comprises: in the step 4, the solvent is DMF, the reaction temperature is 140-170 ℃, and the catalyst is CuI/CuCN.
9. The method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid according to claim 1, which comprises the following steps: in the step 5, the solvent used is any one of acetic acid, ethanol, water and formic acid, and the reaction temperature is 20-100 ℃.
10. The method for synthesizing 4- (benzyloxy) -2-methyl-1H-benzo [ d ] imidazole-6-carboxylic acid according to claim 1, which comprises the following steps: in the step 6, the solvent is selected from any one of ethylene glycol, ethanol, water, formic acid and acetic acid, and the reaction temperature is 100-200 ℃; the inorganic base is any one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium bicarbonate and potassium bicarbonate.
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