CN118084798A - Synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid - Google Patents
Synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid Download PDFInfo
- Publication number
- CN118084798A CN118084798A CN202410235341.0A CN202410235341A CN118084798A CN 118084798 A CN118084798 A CN 118084798A CN 202410235341 A CN202410235341 A CN 202410235341A CN 118084798 A CN118084798 A CN 118084798A
- Authority
- CN
- China
- Prior art keywords
- chloro
- methyl
- reaction
- benzimidazole
- nitroaniline
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Pending
Links
- PLUIBRICHWAFJL-UHFFFAOYSA-N 6-chloro-1h-benzimidazole-4-carboxylic acid Chemical compound OC(=O)C1=CC(Cl)=CC2=C1N=CN2 PLUIBRICHWAFJL-UHFFFAOYSA-N 0.000 title claims abstract description 21
- 238000001308 synthesis method Methods 0.000 title claims abstract description 16
- 150000001875 compounds Chemical class 0.000 claims abstract description 17
- FCMRHMPITHLLLA-UHFFFAOYSA-N 2-methyl-6-nitroaniline Chemical compound CC1=CC=CC([N+]([O-])=O)=C1N FCMRHMPITHLLLA-UHFFFAOYSA-N 0.000 claims abstract description 13
- 239000002994 raw material Substances 0.000 claims abstract description 4
- 238000007363 ring formation reaction Methods 0.000 claims abstract description 4
- 238000005660 chlorination reaction Methods 0.000 claims abstract description 3
- 238000007254 oxidation reaction Methods 0.000 claims abstract description 3
- 238000006722 reduction reaction Methods 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 77
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 claims description 36
- XKWUSIGMAXJOMF-UHFFFAOYSA-N 6-chloro-4-methyl-1h-benzimidazole Chemical compound CC1=CC(Cl)=CC2=C1N=CN2 XKWUSIGMAXJOMF-UHFFFAOYSA-N 0.000 claims description 22
- JRNVZBWKYDBUCA-UHFFFAOYSA-N N-chlorosuccinimide Chemical compound ClN1C(=O)CCC1=O JRNVZBWKYDBUCA-UHFFFAOYSA-N 0.000 claims description 20
- QDSCDFKGUAONPC-UHFFFAOYSA-N 4-chloro-2-methyl-6-nitroaniline Chemical compound CC1=CC(Cl)=CC([N+]([O-])=O)=C1N QDSCDFKGUAONPC-UHFFFAOYSA-N 0.000 claims description 17
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 claims description 15
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- JCNVBPMFGXBWOI-UHFFFAOYSA-N 5-chloro-3-methylbenzene-1,2-diamine Chemical compound CC1=CC(Cl)=CC(N)=C1N JCNVBPMFGXBWOI-UHFFFAOYSA-N 0.000 claims description 14
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 claims description 12
- 238000010992 reflux Methods 0.000 claims description 12
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 10
- 239000007868 Raney catalyst Substances 0.000 claims description 10
- NPXOKRUENSOPAO-UHFFFAOYSA-N Raney nickel Chemical compound [Al].[Ni] NPXOKRUENSOPAO-UHFFFAOYSA-N 0.000 claims description 10
- 229910000564 Raney nickel Inorganic materials 0.000 claims description 10
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 10
- 238000010438 heat treatment Methods 0.000 claims description 9
- RTZKZFJDLAIYFH-UHFFFAOYSA-N Diethyl ether Chemical compound CCOCC RTZKZFJDLAIYFH-UHFFFAOYSA-N 0.000 claims description 8
- 238000001914 filtration Methods 0.000 claims description 8
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 claims description 7
- 229910052739 hydrogen Inorganic materials 0.000 claims description 7
- 239000001257 hydrogen Substances 0.000 claims description 7
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 claims description 6
- 235000019253 formic acid Nutrition 0.000 claims description 6
- 239000012286 potassium permanganate Substances 0.000 claims description 6
- 239000003208 petroleum Substances 0.000 claims description 4
- 238000005406 washing Methods 0.000 claims description 4
- 238000001816 cooling Methods 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- 238000004537 pulping Methods 0.000 claims description 2
- 239000012043 crude product Substances 0.000 claims 1
- 238000003786 synthesis reaction Methods 0.000 abstract description 18
- 230000015572 biosynthetic process Effects 0.000 abstract description 16
- 238000000034 method Methods 0.000 abstract description 4
- 230000003647 oxidation Effects 0.000 abstract description 2
- 238000004809 thin layer chromatography Methods 0.000 description 24
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 18
- 229940125782 compound 2 Drugs 0.000 description 14
- 229940126214 compound 3 Drugs 0.000 description 11
- 229940125904 compound 1 Drugs 0.000 description 8
- 229940125898 compound 5 Drugs 0.000 description 7
- KWYUFKZDYYNOTN-UHFFFAOYSA-M Potassium hydroxide Chemical compound [OH-].[K+] KWYUFKZDYYNOTN-UHFFFAOYSA-M 0.000 description 3
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 3
- 230000002378 acidificating effect Effects 0.000 description 3
- 229940058303 antinematodal benzimidazole derivative Drugs 0.000 description 3
- 239000008346 aqueous phase Substances 0.000 description 3
- 238000010009 beating Methods 0.000 description 3
- 150000001556 benzimidazoles Chemical class 0.000 description 3
- 239000011541 reaction mixture Substances 0.000 description 3
- 239000000741 silica gel Substances 0.000 description 3
- 229910002027 silica gel Inorganic materials 0.000 description 3
- 238000003756 stirring Methods 0.000 description 3
- 238000005303 weighing Methods 0.000 description 3
- 238000012986 modification Methods 0.000 description 2
- 230000004048 modification Effects 0.000 description 2
- 238000006467 substitution reaction Methods 0.000 description 2
- 230000002194 synthesizing effect Effects 0.000 description 2
- 229930003779 Vitamin B12 Natural products 0.000 description 1
- 230000004075 alteration Effects 0.000 description 1
- FDJOLVPMNUYSCM-WZHZPDAFSA-L cobalt(3+);[(2r,3s,4r,5s)-5-(5,6-dimethylbenzimidazol-1-yl)-4-hydroxy-2-(hydroxymethyl)oxolan-3-yl] [(2r)-1-[3-[(1r,2r,3r,4z,7s,9z,12s,13s,14z,17s,18s,19r)-2,13,18-tris(2-amino-2-oxoethyl)-7,12,17-tris(3-amino-3-oxopropyl)-3,5,8,8,13,15,18,19-octamethyl-2 Chemical compound [Co+3].N#[C-].N([C@@H]([C@]1(C)[N-]\C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C(\C)/C1=N/C([C@H]([C@@]1(CC(N)=O)C)CCC(N)=O)=C\C1=N\C([C@H](C1(C)C)CCC(N)=O)=C/1C)[C@@H]2CC(N)=O)=C\1[C@]2(C)CCC(=O)NC[C@@H](C)OP([O-])(=O)O[C@H]1[C@@H](O)[C@@H](N2C3=CC(C)=C(C)C=C3N=C2)O[C@@H]1CO FDJOLVPMNUYSCM-WZHZPDAFSA-L 0.000 description 1
- 239000012153 distilled water Substances 0.000 description 1
- 239000003814 drug Substances 0.000 description 1
- 125000002883 imidazolyl group Chemical group 0.000 description 1
- 239000003112 inhibitor Substances 0.000 description 1
- 239000000203 mixture Substances 0.000 description 1
- 230000000144 pharmacologic effect Effects 0.000 description 1
- 239000012071 phase Substances 0.000 description 1
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 1
- 230000001766 physiological effect Effects 0.000 description 1
- 238000006479 redox reaction Methods 0.000 description 1
- 238000010189 synthetic method Methods 0.000 description 1
- 239000011715 vitamin B12 Substances 0.000 description 1
- 235000019163 vitamin B12 Nutrition 0.000 description 1
Landscapes
- Nitrogen Condensed Heterocyclic Rings (AREA)
Abstract
The invention belongs to the technical field of organic synthesis, and discloses a synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid. The synthesis method comprises the following steps: the method takes 2-methyl-6-nitroaniline as a raw material, and prepares the 5-chloro-1H-benzimidazole-7-carboxylic acid through four steps of chlorination, reduction, cyclization and oxidation, thereby providing a method with less steps, low cost and high yield for the synthesis of the compound.
Description
Technical Field
The invention belongs to the technical field of organic synthesis, and relates to a synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid.
Background
Benzimidazole derivatives are an important class of aza-ring compounds, the molecular structure of which comprises benzene rings and imidazole rings. Benzimidazole derivatives are widely present in nature and have very important physiological and pharmacological activities. Benzimidazole derivatives can be obtained by a variety of synthetic methods, including redox reactions, cyclization reactions, substitution reactions, and the like (RSC adv.,2023,13,32734-32771). For example, the 5-chloro-1H-benzimidazole-7-carboxylic acid synthesized by the method can be widely used as an intermediate for synthesizing other medicaments such as vitamin B12, inhibitors and the like. However, there are fewer domestic patents for the synthesis of 5-chloro-1H-benzimidazole-7-carboxylic acid. Therefore, in order to enrich the synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid and improve the synthesis efficiency, the design of a novel synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid has important significance.
Disclosure of Invention
The invention aims to provide a synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid, which can be used as a compound of a medical intermediate, and is simple, high in yield and low in cost.
In order to achieve the above purpose, the technical scheme of the invention is as follows:
The invention provides a method for synthesizing 5-chloro-1H-benzimidazole-7-carboxylic acid, which takes 2-methyl-6-nitroaniline (compound 1) as a raw material, and synthesizes the compound through four steps of reactions, wherein the synthetic route is shown as the following formula:
The synthesis method comprises the following steps:
S1, adding 2-methyl-6-nitroaniline (compound 1) and methanol into a reaction bottle, heating, adding N-chlorosuccinimide (NCS), controlling the reaction temperature, reacting for 12 hours, concentrating, and pulping the obtained product to obtain 4-chloro-2-methyl-6-nitroaniline (compound 2);
S2, adding 4-chloro-2-methyl-6-nitroaniline (compound 2) into a reaction bottle, dissolving in ethanol, adding Raney nickel (RE-NI), placing in a hydrogen kettle, heating for reaction for 8 hours, filtering and concentrating to obtain 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3);
s3, adding 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) into a reaction bottle, adding distilled water and formic acid, slowly heating to reflux, reacting overnight, cooling, washing to alkalescence, filtering, and drying to obtain 5-chloro-7-methyl-1H-benzimidazole (compound 4);
S4, adding 5-chloro-7-methyl-1H-benzimidazole (compound 4) into a reaction bottle, adding sodium hydroxide solution, slowly heating to reflux, adding potassium permanganate (KMnO 4), continuously heating and refluxing for 2 hours, filtering, and washing the water phase with dichloromethane to obtain 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5).
Further, the reaction temperature in the step S1 is 55-65 ℃.
Further, in the step S2, the reaction temperature in the hydrogen kettle is 30-40 ℃.
Further, the reaction temperature in the step S3 is 105 to 115 ℃.
Further, the reaction temperature in the step S4 is 95-105 ℃.
Compared with the prior art, the invention provides a synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid, which takes 2-methyl-6-nitroaniline as a raw material, synthesizes a compound through four steps of chlorination, reduction, cyclization and oxidation, and has the advantages of few synthesis steps, low cost and high yield.
Detailed description of the preferred embodiments
The following detailed description of specific embodiments of the invention is provided. These embodiments are provided only for illustrating and not limiting the scope or practice of the invention, which is defined by the appended claims and includes obvious variations or modifications made thereon.
Example 1
Synthesis of S1, 4-chloro-2-methyl-6-nitroaniline (compound 2):
450g (2.96 mol) of 2-methyl-6-nitroaniline (compound 1) are weighed, added into a 10L reaction bottle, 4.5L of methanol (CH 3 OH) is added into the reaction bottle, the 2-methyl-6-nitroaniline (compound 1) is completely dissolved, the temperature is slowly increased to 60 ℃, 428g (3.23 mol) of N-chlorosuccinimide (NCS) is added in portions, the reaction is controlled and stabilized, and the reaction is carried out for 12 hours. The progress of the reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction mixture was concentrated by a rotary evaporator, ethyl acetate was added, washed three times with 5% sodium hydroxide solution, and the ethyl acetate was concentrated, and the product was purified by beating with petroleum ether to give 484g (2.59 mol) of 4-chloro-2-methyl-6-nitroaniline (compound 2) in 88% yield.
Synthesis of S2, 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3):
484g (2.59 mol) of 4-chloro-2-methyl-6-nitroaniline (compound 2) were weighed, added to a 10L reaction flask, 3.4L of ethanol (C 2H5 OH) was added to the reaction flask, 4-chloro-2-methyl-6-nitroaniline (compound 2) was completely dissolved, 50g of Raney nickel (RE-NI) was added, the reaction solution was added to a hydrogen still, and the temperature was raised to 30℃for reaction for 12 hours. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was filtered through basic silica gel and concentrated using a rotary evaporator to obtain 393g (2.51 mol) of 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) in a yield of 96.7%.
Synthesis of S3, 5-chloro-7-methyl-1H-benzimidazole (compound 4):
393g (2.51 mol) of 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) were weighed into a 5L reaction flask, 347.7mL of formic acid was weighed, 2.4L of water was added into the reaction flask, and the temperature was slowly raised to 110℃and stirred under reflux overnight. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was cooled to room temperature, washed to be weakly basic with potassium hydroxide solution, filtered using buchner funnel, and the product was dried to obtain 403g (2.42 mol) of 5-chloro-7-methyl-1H-benzimidazole (compound 4) in 96.4% yield.
Synthesis of S4, 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5):
Weighing 18L of water, weighing 360g of sodium hydroxide, pouring into a reaction bottle, preparing 0.5mol/L of sodium hydroxide solution, weighing 300g (1.80 mol) of 5-chloro-7-methyl-1H-benzimidazole (compound 4) into the reaction bottle, slowly raising the temperature to 100 ℃ for stirring, adding 1422mL of potassium permanganate solution (KMnO 4) in batches, and continuously refluxing and stirring for 2 hours. The reaction was followed using Thin Layer Chromatography (TLC) until completion. The reaction mixture was filtered while hot, the aqueous phase was collected, washed with dichloromethane and made acidic, and filtered to give 170g (0.86 mol) of 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5) in 48% yield.
Example 2
Synthesis of S1, 4-chloro-2-methyl-6-nitroaniline (compound 2):
450g (2.96 mol) of 2-methyl-6-nitroaniline (compound 1) are weighed, added into a 10L reaction bottle, 4.5L of methanol (CH 3 OH) is added into the reaction bottle, the 2-methyl-6-nitroaniline (compound 1) is completely dissolved, the temperature is slowly increased to 60 ℃, 428g (3.23 mol) of N-chlorosuccinimide (NCS) is added in portions, the reaction is controlled and stabilized, and the reaction is carried out for 12 hours. The reaction was followed by Thin Layer Chromatography (TLC) until completion, and the reaction solution was concentrated using a rotary evaporator, ethyl acetate was added, washed three times with 5% sodium hydroxide solution, and the ethyl acetate was concentrated, and the product was purified by beating with petroleum ether to give 491.3g (2.63 mol) of 4-chloro-2-methyl-6-nitroaniline (compound 2) in 89% yield.
Synthesis of S2, 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3):
491.3g (2.63 mol) of 4-chloro-2-methyl-6-nitroaniline (compound 2) was weighed, added into a 10L reaction flask, 3.4L of ethanol (C 2H5 OH) was added into the reaction flask, 4-chloro-2-methyl-6-nitroaniline (compound 2) was completely dissolved, 50g of Raney nickel (RE-NI) was added, the reaction solution was added into a hydrogen still, and the temperature was raised to 30℃for reaction for 12 hours. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was filtered through basic silica gel and concentrated using a rotary evaporator to give 395g (2.52 mol) of 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) in a yield of 95.8%.
Synthesis of S3, 5-chloro-7-methyl-1H-benzimidazole (compound 4):
395g (2.52 mol) of 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) was weighed into a 5L reaction flask, 347.7mL of formic acid and 2.4L of water were added into the reaction flask, and the temperature was slowly raised to 110℃and the mixture was stirred under reflux overnight. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was cooled to room temperature, washed with potassium hydroxide solution to be weakly alkaline, filtered using buchner funnel, and the product was dried to give 402.2g (2.41 mol) of 5-chloro-7-methyl-1H-benzimidazole (compound 4) in a yield of 95.7%.
Synthesis of S4, 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5):
18L of water was weighed, 360g of sodium hydroxide was weighed and poured into a reaction flask to prepare a 0.5mol/L sodium hydroxide solution. 300g (1.80 mol) of 5-chloro-7-methyl-1H-benzimidazole (compound 4) are weighed into a reaction flask, slowly heated to 100 ℃, stirred and reacted, 1422mL of potassium permanganate solution (KMnO 4) is added in portions, and reflux stirring is continued for 2H. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was filtered while hot, the aqueous phase was collected, washed with dichloromethane and made acidic, and 173g (0.88 mol) of 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5) was obtained by filtration in a yield of 48.8%.
Example 3
Synthesis of S1, 4-chloro-2-methyl-6-nitroaniline (compound 2):
450g (2.96 mol) of 2-methyl-6-nitroaniline (compound 1) are weighed, added into a 10L reaction bottle, 4.5L of methanol (CH 3 OH) is poured into the reaction bottle, the 2-methyl-6-nitroaniline (compound 1) is completely dissolved, the temperature is slowly raised to 60 ℃, 428g (3.23 mol) of N-chlorosuccinimide (NCS) is added in portions, the reaction is controlled and stabilized, and the reaction is carried out for 12 hours. The reaction was followed by Thin Layer Chromatography (TLC) until completion, and the reaction solution was concentrated using a rotary evaporator, ethyl acetate was added, washed three times with 5% sodium hydroxide solution, and the ethyl acetate was concentrated, and the product was purified by beating with petroleum ether to yield 496g (2.66 mol) of 4-chloro-2-methyl-6-nitroaniline (compound 2) in 89.9% yield.
Synthesis of S2, 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3):
496g (2.66 mol) of 4-chloro-2-methyl-6-nitroaniline (compound 2) were weighed, added to a 10L reaction flask, 3.4L of ethanol (C 2H5 OH) was poured into the reaction flask, 4-chloro-2-methyl-6-nitroaniline (compound 2) was completely dissolved, 50g of Raney nickel (RE-NI) was added, the reaction solution was added to a hydrogen still, and the temperature was raised to 30℃for reaction for 12 hours. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was filtered through basic silica gel and concentrated using a rotary evaporator to obtain 397.6g (2.54 mol) of 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) in a yield of 95.5%.
Synthesis of S3, 5-chloro-7-methyl-1H-benzimidazole (compound 4):
397.6g (2.54 mol) of 5-chloro-3-methyl-1, 2-phenylenediamine (compound 3) are weighed into a 5L reaction flask, 347.7mL of formic acid and 2.4L of water are weighed into the reaction flask, slowly heated to 110℃and stirred under reflux overnight. The reaction was followed by Thin Layer Chromatography (TLC) until completion, the reaction solution was cooled to room temperature, washed to be weakly basic with potassium hydroxide solution, filtered using buchner funnel, and the product was dried to give 404.5g (2.43 mol) of 5-chloro-7-methyl-1H-benzimidazole (compound 4) in a yield of 95.6%.
Synthesis of S4, 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5):
18L of water was weighed, 360g of sodium hydroxide was weighed and poured into a reaction flask to prepare a 0.5mol/L sodium hydroxide solution. 300g (1.80 mol) of 5-chloro-7-methyl-1H-benzimidazole (compound 4) are weighed into a reaction flask, stirred for reaction, slowly heated to 100 ℃, added with 1422mL of potassium permanganate solution (KMnO 4) in portions, and stirred under reflux for 2 hours. The reaction was followed using Thin Layer Chromatography (TLC) until completion. The reaction mixture was filtered while hot, the aqueous phase was collected, washed with dichloromethane and made acidic, and filtered to give 175g (0.89 mol) of 5-chloro-1H-benzimidazole-7-carboxylic acid (compound 5) in 49.4% yield.
While the fundamental and principal features of the invention and advantages of the invention have been shown and described, it will be apparent to those skilled in the art that the invention is not limited to the details of the foregoing exemplary embodiments, but may be embodied in other specific forms without departing from the spirit or essential characteristics thereof. The present embodiments are, therefore, to be considered in all respects as illustrative and not restrictive, the scope of the invention being indicated by the appended claims rather than by the foregoing description, and all changes which come within the meaning and range of equivalency of the claims are therefore intended to be embraced therein. Although embodiments of the present invention have been shown and described, it will be understood by those skilled in the art that various changes, modifications, substitutions and alterations can be made therein without departing from the principles and spirit of the invention, the scope of which is defined in the appended claims and their equivalents.
Claims (5)
1. A synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid is characterized in that 2-methyl-6-nitroaniline is used as a raw material, and a compound is synthesized through chlorination, reduction, cyclization and oxidation reactions, wherein the synthetic route is shown as the following formula:
The synthesis method comprises the following steps:
S1, dissolving 2-methyl-6-nitroaniline in methanol at the temperature of 5-30 ℃, slowly heating to reflux, adding N-chlorosuccinimide, concentrating after the reaction is finished, washing, concentrating again, and pulping a crude product with petroleum ether to obtain 4-chloro-2-methyl-6-nitroaniline;
S2, dissolving the 4-chloro-2-methyl-6-nitroaniline obtained in the step S1 in ethanol, adding Raney nickel, placing in a hydrogen kettle, heating to 30 ℃, filtering after the reaction is completed, and concentrating to obtain 5-chloro-3-methyl-1, 2-phenylenediamine;
s3, adding water and formic acid into the 5-chloro-3-methyl-1, 2-phenylenediamine obtained in the step S2, slowly heating to 110 ℃, refluxing overnight, cooling, weakly alkaline, filtering and drying to obtain 5-chloro-7-methyl-1H-benzimidazole after the reaction is completed;
s4, adding the 5-chloro-7-methyl-1H-benzimidazole obtained in the step S3 into a sodium hydroxide solution, slowly heating to 100 ℃, adding potassium permanganate, refluxing for 2 hours, filtering after the reaction is finished, washing a water phase with dichloromethane, and filtering after acidity adjustment to obtain the 5-chloro-1H-benzimidazole-7-carboxylic acid.
2. The synthesis method according to claim 2, wherein in the step S1, the molar ratio of the 2-methyl-6-nitroaniline to the N-chlorosuccinimide is 1:1.1, and the reaction temperature is 60 ℃.
3. The synthesis method according to claim 2, wherein in step S2, the molar ratio of 4-chloro-2-methyl-6-nitroaniline to raney nickel is 1:0.1 and the reaction temperature in the hydrogen still is 30 ℃.
4. The synthesis method according to claim 2, wherein in step S3, the molar ratio of 5-chloro-3-methyl-1, 2-phenylenediamine to formic acid is 1:3 and the reaction temperature is 110 ℃.
5. The synthesis method according to claim 2, wherein in step S4, the molar ratio of 5-chloro-7-methyl-1H-benzimidazole, sodium hydroxide and potassium permanganate is 1:5:5, and the reaction temperature is 100 ℃.
Priority Applications (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410235341.0A CN118084798A (en) | 2024-03-01 | 2024-03-01 | Synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid |
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| CN202410235341.0A CN118084798A (en) | 2024-03-01 | 2024-03-01 | Synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid |
Publications (1)
| Publication Number | Publication Date |
|---|---|
| CN118084798A true CN118084798A (en) | 2024-05-28 |
Family
ID=91150148
Family Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| CN202410235341.0A Pending CN118084798A (en) | 2024-03-01 | 2024-03-01 | Synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid |
Country Status (1)
| Country | Link |
|---|---|
| CN (1) | CN118084798A (en) |
-
2024
- 2024-03-01 CN CN202410235341.0A patent/CN118084798A/en active Pending
Similar Documents
| Publication | Publication Date | Title |
|---|---|---|
| CN108069831B (en) | Method for synthesizing 2, 3-dimethyl-4-fluorophenol | |
| JP2012255005A (en) | Method for producing 5-(4-[4-(5-cyano-3-indolyl)butyl]-1-piperazinyl)benzofuran-2-carboxamide | |
| CN112079848A (en) | Synthesis method of baroxavir key intermediate | |
| CN118084798A (en) | Synthesis method of 5-chloro-1H-benzimidazole-7-carboxylic acid | |
| CN110551123A (en) | Preparation method of 5- (tert-butyloxycarbonyl) -2-methyl-4, 5,6, 7-tetrahydro-2H-pyrazolo [4,3-C ] pyridine-7-carboxylic acid | |
| CN115894540A (en) | Preparation method of lithium tri-sec-butyl borohydride | |
| JPS6024781B2 (en) | Method for producing cis-2-hydroxy-2-phenyl-r-1-cyclohexanecarboxylic acid | |
| CN111100042B (en) | Preparation method of 2-methoxy-5-sulfonamide benzoic acid | |
| CN112679363A (en) | Method for preparing pentazocine intermediate | |
| CN113045475A (en) | Preparation method of 5-bromo-7-methylindole | |
| CN112574106B (en) | Synthesis method of 7-amino-5-bromoquinoline | |
| CN115677559B (en) | One-step synthesis method of ondansetron intermediate tetrahydrocarbazolone | |
| CN114736217B (en) | Preparation method of toraseplug Mi Huange impurity | |
| CN116574108A (en) | Synthesis method of psoralen | |
| CN116655481B (en) | Industrial synthesis method of levocarnitine | |
| CN113512003B (en) | Preparation method of 4- (imidazole-1-yl) phenol | |
| CN116589440B (en) | Synthesis method of methyl esculetin sodium acetate | |
| CN113354623B (en) | Preparation method of ilaprazole key intermediate 5- (1H-pyrrole-1-yl) -2-mercaptobenzimidazole | |
| CN112225736B (en) | Preparation method of 6-bromoimidazo [1.2-a ] pyridine-3-formaldehyde | |
| CN111978320B (en) | Synthesis method of 1H-pyrrolo [3, 2-c ] pyridine-6-alcohol | |
| CN116283798B (en) | Novel preparation method of urapidil | |
| CN111423437B (en) | Preparation method of palbociclib intermediate | |
| CN110845511B (en) | Preparation method of 3-benzimidazole-4-arylpyranocoumarin derivative | |
| CN116715675A (en) | Synthetic method of isopsoralen | |
| CN106883166A (en) | 4-（3- piperidyls）The preparation method of aniline and its tartrate |
Legal Events
| Date | Code | Title | Description |
|---|---|---|---|
| PB01 | Publication | ||
| PB01 | Publication | ||
| SE01 | Entry into force of request for substantive examination |