CN114605328A - Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine - Google Patents
Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine Download PDFInfo
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- CN114605328A CN114605328A CN202210290907.0A CN202210290907A CN114605328A CN 114605328 A CN114605328 A CN 114605328A CN 202210290907 A CN202210290907 A CN 202210290907A CN 114605328 A CN114605328 A CN 114605328A
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- C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
- C07D231/54—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings condensed with carbocyclic rings or ring systems
- C07D231/56—Benzopyrazoles; Hydrogenated benzopyrazoles
Abstract
The invention discloses a preparation method of 6-chloro-2-methyl-2H-indazole-5-amine, which comprises the following steps in sequence: nitrifying 4-chloro-2-fluorobenzaldehyde to obtain 4-chloro-2-fluoro-5-nitrobenzaldehyde, adding potassium nitrate, sulfuric acid and the like in the reaction process, generating 6-chloro-5-nitro-1H-indazole from the 4-chloro-2-fluoro-5-nitrobenzaldehyde in the presence of hydrazine hydrate, then methylating the indazole with trimethyloxonium tetrafluoroborate to obtain 6-chloro-2-methyl-5-nitro-2H-indazole, and reducing the indazole to obtain 6-chloro-2-methyl-2H-indazole-5-amine; the preparation method reduces toxic reagents and potential explosion risks, and improves the operation convenience.
Description
Technical Field
The invention belongs to the technical field of medicine production, and particularly relates to a preparation method of 6-chloro-2-methyl-2H-indazole-5-amine.
Background
The molecular formula of the 6-chloro-2-methyl-2H-indazol-5-amine is
The synthesis is not easy, and the following routes are reported in related documents at present:
the route starts from compound A, and the target compound is obtained by ring closure with sodium nitrite, methylation and reduction.
The yield of the first step of the reaction of the route is low, and column chromatography is needed; methyl iodide is required in the second step of the reaction in the route, and the toxicity is high; moreover, NaH is mixed with DMF, so that the potential explosiveness is realized, and the reaction risk is high; and the reaction yield is very low, column chromatography is needed, and the price is high.
Disclosure of Invention
The present invention aims to provide a method for preparing 6-chloro-2-methyl-2H-indazol-5-amine, which solves the problems of the background art.
The technical scheme adopted by the invention for solving the technical problems is as follows: a process for the preparation of 6-chloro-2-methyl-2H-indazol-5-amine, comprising the following steps in sequence:
s1, carrying out nitration reaction on the 4-chloro-2-fluorobenzaldehyde and potassium nitrate to obtain 4-chloro-2-fluoro-5-nitrobenzaldehyde, and adding inorganic acid in the reaction process, wherein the reaction solvent is water;
s2, generating 6-chloro-5-nitro-1H-indazole from 4-chloro-2-fluoro-5-nitrobenzaldehyde obtained in the step in the presence of hydrazine hydrate, wherein a reaction solvent is DMF;
s3, carrying out methylation by using a methylation reagent to obtain 6-chloro-2-methyl-5-nitro-2H-indazole, wherein the reaction temperature is room temperature;
s4, reducing the 6-chloro-2-methyl-5-nitro-2H-indazole obtained in the above step by ammonium chloride and iron powder to obtain 6-chloro-2-methyl-2H-indazole-5-amine.
In the preparation method of 6-chloro-2-methyl-2H-indazol-5-amine, the inorganic acid in step S1 is one of sulfuric acid, hydrochloric acid and phosphoric acid.
The preparation method of 6-chloro-2-methyl-2H-indazol-5-amine comprises the following specific steps of S1: adding 500mL of concentrated sulfuric acid into a 1000mL three-mouth reaction bottle, cooling to 0-5 ℃, adding 50g of 4-chloro-2-fluorobenzaldehyde, slowly adding 31.84g of potassium nitrate in batches, keeping the temperature at 0-5 ℃, stirring for 1 hour, controlling the reaction in TLC, adding the reaction solution into cold clear water, stirring for 30 minutes, filtering, and drying a filter cake to obtain 50g of light yellow solid 4-chloro-2-fluoro-5-nitrobenzaldehyde hydrate.
The preparation method of 6-chloro-2-methyl-2H-indazol-5-amine comprises the following specific steps of S2: 20.0g of 4-chloro-2-fluoro-5-nitrobenzaldehyde hydrate, 5.88g of hydrazine hydrate and 200mL of DMF are added into a 500mL three-necked flask, then the mixture is stirred at room temperature for 12 hours, the temperature is naturally reduced to room temperature, the TLC is used for controlling the reaction to be finished, the reaction solution is poured into 1000mL of clear water and stirred for 30 minutes, then the mixture is filtered, and a filter cake is dried to obtain 13.78g of light yellow solid 6-chloro-5-nitro-1H-indazole with the purity of 96.5%.
In the preparation method of 6-chloro-2-methyl-2H-indazol-5-amine, the methylating agent in step S3 is trimethyloxonium tetrafluoroborate or iodomethane. Among them, trimethyloxonium tetrafluoroborate is preferable because the yield is significantly superior to methyl iodide.
The preparation method of 6-chloro-2-methyl-2H-indazol-5-amine comprises the following specific steps of S3: adding 30.00g of 6-chloro-5-nitro-1H-indazole and 300mL of ethyl acetate into a 250mL three-mouth reaction bottle in sequence, then cooling to 0-5 ℃, slowly adding 24.73g of trimethyloxonium tetrafluoroborate into the reaction solution, then stirring for 4 hours at 15-25 ℃, after the TLC control reaction is finished, adding saturated aqueous sodium bicarbonate solution into the reaction solution to adjust the pH to 8-9, separating, washing the organic phase with 50mL of saturated saline solution, drying with anhydrous sodium sulfate, and concentrating to obtain 30g of yellow solid 6-chloro-2-methyl-5-nitro-2H-indazole.
The preparation method of 6-chloro-2-methyl-2H-indazol-5-amine comprises the following specific steps of S4: adding 30g of 6-chloro-2-methyl-5-nitro-2H-indazole into 150mL of EtOH and 150mL of clear water in a 500mL three-mouth reaction bottle, sequentially adding 75.83g of ammonium chloride and 79.16g of iron powder, heating to 75-85 ℃, stirring for 16H, detecting the completion of the reaction by TLC, filtering, washing a filter cake with 500mL of EtOH, concentrating the combined filtrate, adding 200mL of ethyl acetate and 100mL of clear water, separating the liquid, washing the organic phase with 50mL of saturated saline, drying by anhydrous sodium sulfate, concentrating under reduced pressure to remove the solvent, and carrying out flash column chromatography on the residue to obtain 20g of 6-chloro-2-methyl-2H-indazole-5-amine.
The invention has the technical effects and advantages that: because 6-chloro-2-methyl-2H-indazole-5-amine does not have a high-yield synthesis method at present, the market price is high, column chromatography is reduced, post-treatment operation is greatly simplified, and a brand-new reliable high-yield technological synthesis method is provided for synthesizing the compound; the preparation method of the invention reduces toxic reagents and potential explosion risks, and improves the operation convenience.
Detailed Description
The following will clearly and completely describe the technical solutions in the embodiments of the present invention, and it is obvious that the described embodiments are only a part of the embodiments of the present invention, and not all of the embodiments. All other embodiments, which can be derived by a person skilled in the art from the embodiments given herein without making any creative effort, shall fall within the protection scope of the present invention.
Example 1
The invention provides a brand-new and reliable method for synthesizing 6-chloro-2-methyl-2H-indazole-5-amine and optimizing the process for reducing the operation steps and making up for the defect that no mature process route exists at present.
The synthetic route of the 6-chloro-2-methyl-2H-indazole-5-amine disclosed by the invention is as follows:
the method comprises the following specific steps:
s1, structural formula
The 4-chloro-2-fluorobenzaldehyde and the potassium nitrate are subjected to nitration reaction to obtain the compound with the structural formula
Adding nitric acid and sulfuric acid into the 4-chloro-2-fluoro-5-nitrobenzaldehyde during the reaction.
The preparation method comprises the following specific steps: 500mL of concentrated sulfuric acid was added to a 1000mL three-necked reaction flask, the temperature was reduced to 0 to 5 ℃, 4-chloro-2-fluorobenzaldehyde (50g, 0.315mol) was added thereto, and potassium nitrate (31.84g, 0.315mol) was slowly added thereto in portions. Keeping the temperature at 0-5 ℃, stirring for 1 hour, and controlling the reaction to be finished in TLC (thin layer chromatography). The reaction solution was added to cold clear water, stirred for 30 minutes, filtered, and the filter cake was dried to give 4-chloro-2-fluoro-5-nitrobenzaldehyde hydrate (50g, yield 78%) as a pale yellow solid.
S2, the 4-chloro-2-fluoro-5-nitrobenzaldehyde obtained in the step is reacted in the presence of hydrazine hydrate to generate the compound with the structural formula
The reaction solvent is DMF.
The preparation method comprises the following specific steps: 4-chloro-2-fluoro-5-nitrobenzaldehyde hydrate (20.0g, 0.098mol), hydrazine hydrate (5.88g, 0.117mol, 98%) and 200mL of DMF were added into a 500mL three-necked flask, and then stirred at room temperature for 12 hours, after the completion of the TLC control reaction, the reaction solution was poured into 1000mL of clear water, stirred for 30 minutes, filtered, and the filter cake was dried to obtain a pale yellow solid 6-chloro-5-nitro-1H-indazole (13.78 g, 96.5% purity).
S3, followed by methylation with trimethyloxonium tetrafluoroborate to give compounds of formula
The reaction temperature of the 6-chloro-2-methyl-5-nitro-2H-indazole (A) was room temperature.
The preparation method comprises the following specific steps: 6-chloro-5-nitro-1H-indazole (30.00g, 0.152mol) and 300mL of ethyl acetate were sequentially added to a 250mL three-necked reaction flask, the temperature was then reduced to 0 to 5 ℃, trimethyloxonium tetrafluoroborate (24.73g, 0.167mmol) was slowly added to the reaction solution, the reaction solution was stirred at 15 to 25 ℃ for 4 hours, the reaction was controlled to be completed by TLC, a saturated aqueous sodium bicarbonate solution was added to the reaction solution to adjust the pH to 8 to 9, the solution was separated, the organic phase was washed with 50mL of saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain 6-chloro-2-methyl-5-nitro-2H-indazole as a yellow solid (30g, yield 93.3%).
S4, obtaining the productThe 6-chloro-2-methyl-5-nitro-2H-indazole is reduced by ammonium chloride and iron powder to obtain the compound with the structural formula
6-chloro-2-methyl-2H-indazol-5-amine.
The preparation method comprises the following specific steps: 6-chloro-2-methyl-5-nitro-2H-indazole (30g, 0.142mol) is added into 150mL of EtOH and 150mL of clear water in a 500mL three-mouth reaction bottle, then ammonium chloride (75.83g, 1.418mol) and iron powder (79.16g, 1.418mol) are sequentially added, and then the temperature is raised to 75-85 ℃ and stirring is carried out for 16H. TLC detection reaction is completed, filtration is carried out, filter cakes are washed by 500mL of EtOH, combined filtrate is concentrated, 200mL of ethyl acetate and 100mL of clear water are added for liquid separation, organic phase is washed by 50mL of saturated saline solution, dried by anhydrous sodium sulfate, and the solvent is removed by concentration under reduced pressure. The residue was subjected to flash column chromatography to give 6-chloro-2-methyl-2H-indazol-5-amine (20g, yield 77.67%, purity 97.18%).
Example 2
The difference between the preparation method disclosed in this example and example 1 is that methyl iodide is used as the methylating agent in step S3.
Example 3
The difference between the manufacturing method disclosed in this example and example 1 is that the inorganic acid in step S1 is hydrochloric acid or phosphoric acid.
Although the present invention has been described with reference to a preferred embodiment, it should be understood that various changes, substitutions and alterations can be made herein without departing from the spirit and scope of the invention as defined by the appended claims.
Claims (7)
1. A preparation method of 6-chloro-2-methyl-2H-indazol-5-amine is characterized by comprising the following steps: the method comprises the following steps:
s1, carrying out nitration reaction on the 4-chloro-2-fluorobenzaldehyde and potassium nitrate to obtain 4-chloro-2-fluoro-5-nitrobenzaldehyde, and adding inorganic acid in the reaction process, wherein the reaction solvent is water;
s2, generating 6-chloro-5-nitro-1H-indazole from 4-chloro-2-fluoro-5-nitrobenzaldehyde in the presence of hydrazine hydrate, wherein a reaction solvent is DMF;
s3, methylating with a methylating agent to obtain 6-chloro-2-methyl-5-nitro-2H-indazole, wherein the reaction temperature is room temperature;
s4, 6-chloro-2-methyl-5-nitro-2H-indazole is reduced by ammonium chloride and iron powder to obtain 6-chloro-2-methyl-2H-indazole-5-amine.
2. The method of claim 1, wherein the inorganic acid in step S1 is one of sulfuric acid, hydrochloric acid and phosphoric acid.
3. The method for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 2, wherein step S1 specifically comprises: adding concentrated sulfuric acid into a three-mouth reaction bottle, cooling to 0-5 ℃, then adding 4-chloro-2-fluorobenzaldehyde, then slowly adding potassium nitrate in batches, keeping the temperature at 0-5 ℃, stirring for 1 hour, controlling the reaction in TLC, adding the reaction liquid into cold clear water, stirring for 30 minutes, filtering, and drying a filter cake to obtain a light yellow solid 4-chloro-2-fluoro-5-nitrobenzaldehyde hydrate.
4. The method for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 3, wherein the step S2 specifically comprises: adding 4-chloro-2-fluoro-5-nitrobenzaldehyde hydrate, hydrazine hydrate and DMF (dimethyl formamide) into a three-necked flask, stirring at room temperature for 12 hours, pouring into clear water after TLC (thin-layer chromatography) controlled reaction is finished, stirring for 30 minutes, filtering, and drying a filter cake to obtain light yellow solid 6-chloro-5-nitro-1H-indazole.
5. The method of claim 4, wherein the methylating agent in step S3 is trimethyloxonium tetrafluoroborate or iodomethane.
6. The method for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 5, wherein said step S3 specifically comprises: sequentially adding 6-chloro-5-nitro-1H-indazole and ethyl acetate into a three-mouth reaction bottle, cooling to 0-5 ℃, slowly adding trimethyloxonium tetrafluoroborate into a reaction solution, stirring at 15-25 ℃ for 4 hours, controlling the reaction in TLC, adding a saturated sodium bicarbonate aqueous solution into the reaction solution to adjust the pH value to 8-9, separating, washing an organic phase with saturated saline water, drying with anhydrous sodium sulfate, and concentrating to obtain yellow solid 6-chloro-2-methyl-5-nitro-2H-indazole.
7. The method for preparing 6-chloro-2-methyl-2H-indazol-5-amine according to claim 6, wherein said step S4 specifically comprises: adding 6-chloro-2-methyl-5-nitro-2H-indazole into EtOH and clear water in a three-mouth reaction bottle, sequentially adding ammonium chloride and iron powder, heating to 75-85 ℃, stirring for 16H, detecting by TLC (thin layer chromatography), filtering, washing a filter cake by using EtOH, concentrating combined filtrate, adding ethyl acetate and clear water, separating, washing an organic phase by using saturated saline solution, drying by using anhydrous sodium sulfate, concentrating under reduced pressure to remove a solvent, and performing column chromatography on a residue to obtain 6-chloro-2-methyl-2H-indazole-5-amine.
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Cited By (3)
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| CN115108992A (en) * | 2022-06-29 | 2022-09-27 | 浙江手心制药有限公司 | Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine |
| CN115181066A (en) * | 2022-06-14 | 2022-10-14 | 浙江宏元药业股份有限公司 | Synthetic method of 6-chloro-2-methyl-2H-indazole-5-amine |
| CN116023332A (en) * | 2022-12-23 | 2023-04-28 | 上海药坦药物研究开发有限公司 | Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine |
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| US20200331921A1 (en) * | 2018-02-06 | 2020-10-22 | Ontario Institute For Cancer Research (Oicr) | Inhibitors of the bcl6 btb domain protein-protein interaction and uses thereof |
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Cited By (4)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN115181066A (en) * | 2022-06-14 | 2022-10-14 | 浙江宏元药业股份有限公司 | Synthetic method of 6-chloro-2-methyl-2H-indazole-5-amine |
| CN115181066B (en) * | 2022-06-14 | 2023-07-14 | 浙江宏元药业股份有限公司 | Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine |
| CN115108992A (en) * | 2022-06-29 | 2022-09-27 | 浙江手心制药有限公司 | Preparation method of 6-chloro-2-methyl-2H-indazole-5-amine |
| CN116023332A (en) * | 2022-12-23 | 2023-04-28 | 上海药坦药物研究开发有限公司 | Synthesis method of 6-chloro-2-methyl-2H-indazole-5-amine |
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