A synthetic method for preparing 4-bromo-7-methyl-1h-indazole by boronic acid promoted ring closure

Abstract

The application relates to a novel ideal method for synthesizing 4-bromo-7-methyl-1H-indazole. In the method, 2-fluoro-4-bromotoluene which is cheap and easy to obtain is used as raw material, and is subjected to reaction with N,N-dimethylformamide in the presence of a lithium reagent to prepare 6-bromo-2-fluoro-3-methylbenzaldehyde; and then 6-bromo-2-fluoro-3-methylbenzaldehyde is subjected to ring closure under the action of hydrazine hydrate and boric acid to obtain the target compound 4-bromo-7-methyl-1H-indazole. The synthetic method route is simple, the operation is simple and convenient, the safety hidden danger is low, the selectivity of each step is high, the yield is high, the post-treatment is simple, and the method is suitable for industrialized production.

Description

Technical Field

[0001] This application belongs to the field of organic synthesis, specifically relating to a synthetic method for preparing 4-bromo-7-methyl-1H-indazole by promoting cyclization with boric acid. Background Technology

[0002] 4-Bromo-7-methyl-1H-indazole is an important pharmaceutical intermediate, attracting widespread attention as a crucial building block in various drugs. In existing technologies, the synthesis of 4-bromo-7-methyl-1H-indazole primarily employs a cyclization strategy, such as cyclization reactions via diazotization, as detailed below:

[0003]

[0004] In the above reaction, 2,4-dimethylbromobenzene is used as a starting material for nitration, followed by reduction of the nitro group to obtain compound C. Finally, the amino group of compound C is converted to a diazonium salt, and then cyclized under alkaline conditions to obtain 4-bromo-7-methyl-1H-indazole. This method requires a nitration reaction in the first step, which poses significant safety risks and demands sophisticated equipment. Furthermore, in practice, the selectivity of the first and third steps is poor, resulting in unsatisfactory yields. More importantly, during the synthesis of the target product D, the product and its isomers are very similar in properties, making purification difficult. Therefore, the existing technology lacks a simple, easy-to-operate, low-safety-risk, highly selective and high-yield synthetic route for 4-bromo-7-methyl-1H-indazole, which also features simple post-processing and is suitable for industrial production. Summary of the Invention

[0005] In view of the problems of low yield, difficult post-processing purification, high safety risks, high equipment requirements and difficulty in scaling up industrial production in the existing synthesis method of 4-bromo-7-methyl-1H-indazole, the inventors provide an ideal new method for synthesizing 4-bromo-7-methyl-1H-indazole.

[0006] This application provides a method M1 for preparing 4-bromo-7-methyl-1H-indazole, comprising the following steps:

[0007]

[0008] 6-Bromo-2-fluoro-3-methylbenzaldehyde (hereinafter referred to as compound 2) was dissolved in an organic solvent, hydrazine hydrate was added, and the reaction was carried out at a raised temperature. Boric acid was added and the reaction was continued at a raised temperature. After post-treatment, the target compound 4-bromo-7-methyl-1H-indazole (hereinafter referred to as compound 3) was obtained.

[0009] In one embodiment of the present invention, the organic solvent is selected from one or more of dimethyl sulfoxide, dioxane, chloroform, toluene and diethyl ether, preferably dimethyl sulfoxide.

[0010] In one embodiment of the present invention, the volume-to-mass ratio of the organic solvent to compound 2 is 2-10 mL / g, preferably 3-5 mL / g.

[0011] In one embodiment of the present invention, the molar ratio of compound 2 to hydrazine hydrate and boric acid is 1:1.0-6.0:1.0-3.0, preferably 1:5.5:1.5.

[0012] In one embodiment of the present invention, the reaction temperature is 70-120°C, preferably 90-110°C, and more preferably 100°C.

[0013] In one embodiment of the present invention, the reaction time under elevated temperature is 0.5-2 hours.

[0014] In one embodiment of the present invention, the reaction time after adding boric acid and continuing the reaction at a constant temperature is 1-10 hours, preferably 2-8 hours, and more preferably 3-5 hours.

[0015] In one embodiment of the invention, water and some solvent are removed before adding boric acid, preferably by using a water separator.

[0016] In one embodiment of the present invention, the post-processing step includes: quenching the reaction solution in water, extracting with an organic solvent, and then purifying by vacuum distillation to obtain compound 3. In one embodiment of the present invention, the organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane, and toluene, preferably ethyl acetate.

[0017] In one embodiment of the invention, the purification step is selected from one or more of recrystallization and column chromatography. In another embodiment of the invention, the purification step is carried out by recrystallization, preferably using a mixture of ethyl acetate and petroleum ether. More specifically, the volume ratio of ethyl acetate to petroleum ether is 1:1.2-2.

[0018] This application also provides a method M2 for preparing 4-bromo-7-methyl-1H-indazole, comprising the following steps:

[0019]

[0020] Step 1: Dissolve 2-fluoro-4-bromotoluene (hereinafter referred to as compound 1) in organic solvent 1, and react it with N,N-dimethylformamide in the presence of lithium reagent. After post-treatment, compound 2 is obtained.

[0021] Step 2: Dissolve compound 2 in organic solvent 2, add hydrazine hydrate, and react under elevated temperature. After adding boric acid, continue the reaction at elevated temperature. After post-treatment, obtain target compound 3.

[0022] In one embodiment of the present invention, step 1 is performed under an inert gas atmosphere. In one embodiment of the present invention, the inert gas is argon or nitrogen.

[0023] In one embodiment of the present invention, the organic solvent 1 is selected from one or more of acetonitrile, dimethyl sulfoxide, dioxane, tetrahydrofuran, and diethyl ether, preferably tetrahydrofuran or diethyl ether.

[0024] In one embodiment of the present invention, the lithium reagent is selected from one or more of diisopropylaminolithium and n-butyllithium, preferably diisopropylaminolithium.

[0025] In one embodiment of the present invention, the volume-to-mass ratio of organic solvent 1 to compound 1 is 5-15 mL / g.

[0026] In one embodiment of the present invention, the molar ratio of compound 1 to lithium reagent is 1:1-1.5.

[0027] In one embodiment of the present invention, the mass-to-volume ratio of compound 1 to N,N-dimethylformamide is 1 g / 0.5-1 mL.

[0028] In one embodiment of the present invention, the reaction temperature in step 1 is room temperature.

[0029] In one embodiment of the present invention, the reaction time of step 1 is 0.5-3 hours.

[0030] In one embodiment of the present invention, the post-processing step of step 1 includes: quenching the reaction, extracting with an organic solvent, followed by vacuum distillation and purification to obtain compound 2.

[0031] In one embodiment of the present invention, the organic solvent 2 is selected from one or more of dimethyl sulfoxide, dioxane, chloroform, toluene and diethyl ether, preferably dimethyl sulfoxide.

[0032] In one embodiment of the present invention, the volume-to-mass ratio of organic solvent 2 to compound 2 is 2-10 mL / g, preferably 3-5 mL / g.

[0033] In one embodiment of the present invention, the molar ratio of compound 2 to hydrazine hydrate and boric acid is 1:1.0-6.0:1.0-3.0, preferably 1:5.5:1.5.

[0034] In one embodiment of the present invention, the reaction temperature in step 2 is 70-120°C, preferably 90-110°C, and more preferably 100°C.

[0035] In one embodiment of the present invention, the reaction time for the reaction carried out at elevated temperature in step 2 is 0.5-2 hours.

[0036] In one embodiment of the present invention, the reaction time after adding boric acid in step 2 and continuing the reaction at a constant temperature is 1-10 hours, preferably 2-8 hours, and more preferably 3-5 hours.

[0037] In one embodiment of the present invention, in step 2, before adding boric acid, it is necessary to remove water and part of the solvent, preferably by using a water separator.

[0038] In one embodiment of the present invention, the post-processing step of step 2 includes: adding the reaction solution to water for quenching, extracting with an organic solvent, and then purifying by vacuum distillation to obtain compound 3.

[0039] In one embodiment of the present invention, in steps 1 and 2, the organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane, and toluene, preferably ethyl acetate;

[0040] In one embodiment of the present invention, in steps 1 and 2, the purification process can be one or more of column chromatography purification and recrystallization purification.

[0041] In one embodiment of the present invention, step 1 is as follows: under inert gas protection, compound 1 is added to organic solvent 1, the temperature is controlled to -78°C, lithium reagent is added dropwise, the mixture is kept warm and stirred for 1-3 hours, N,N-dimethylformamide is added, the temperature is raised to room temperature, and the reaction is carried out. After the reaction is completed, the reaction is quenched, the resulting solution is extracted with organic solvent, the organic phases are combined, the solvent is removed by vacuum distillation, and the residue is purified to obtain compound 2.

[0042] In one embodiment of the present invention, step 2 is as follows: Compound 2 is added to organic solvent 2, and hydrazine hydrate is added under stirring. After the addition is complete, the temperature is raised for 0.5-2 hours, water and part of the solvent are separated and removed, boric acid is added, and the reaction is continued at the temperature for 1-5 hours. After the reaction is complete, the reaction solution is poured into water, and the organic solvent is extracted. The obtained organic phase is distilled under reduced pressure to remove the solvent, and the residue is purified to obtain the target compound 3.

[0043] This application has the following beneficial effects:

[0044] 1. This invention provides a simple and effective synthetic route. By creatively adding boric acid as an auxiliary reagent in the ring-closing step, the ring-closing reaction is promoted to proceed in the forward direction, ensuring that the oxime intermediate can be completely converted into the product, which greatly improves the yield, avoids the formation of isomers in the prior art, thereby improving the reaction yield, reducing the difficulty of product purification, and providing a reliable route for the industrial production of the compound.

[0045] 2. The synthesis process does not employ nitration, thus avoiding the high safety risks and stringent requirements on reaction equipment caused by nitration in existing technologies;

[0046] 3. The raw materials and reagents used in this invention are all commercially available and easy to obtain. The post-processing and purification operations are simple and suitable for large-scale production, providing a reliable reference for the preparation of similar compounds. Detailed Implementation

[0047] To enable those skilled in the art to better understand the present application, the technical solutions in the embodiments will be clearly and completely described below. Obviously, the described embodiments are merely some, not all, of the embodiments in this application. Based on the embodiments in this application, all other embodiments obtained by those skilled in the art without creative effort should fall within the scope of protection of this application. In the following embodiments, unless otherwise stated, the specific conditions of the test methods are generally implemented according to conventional conditions or conditions recommended by the manufacturer; raw materials and reagents are obtained commercially or prepared using publicly available information.

[0048] Example 1

[0049] Step 1: Synthesis of Compound 2

[0050]

[0051] Compound 1 (10 g, 5.18 mmol, 1 eq) was added to 100 mL of tetrahydrofuran. Under argon protection, the temperature was controlled to -78 °C, and diisopropylaminolithium (LDA) (31.2 mL, 62.21 mmol, 1.2 eq, 2 M in THF) was added dropwise. The mixture was kept at this temperature for 2 h, and then 8 mL of DMF was added. The mixture was allowed to react at room temperature for 0.5 h. The mixture was then flushed with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was soluble in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 5:10 (25 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 9.4 g of compound 2 with a purity of 98.3% and a yield of 83.52%.

[0052] Step 2: Synthesis of Compound 3

[0053]

[0054] Compound 2 (9.0 g, 40.76 mmol, 1 eq) was dissolved in dimethyl sulfoxide (30 mL), and a 50% aqueous solution of hydrazine hydrate (22.45 g, 224.19 mmol, 5.5 eq) was added with stirring. The reaction was heated to 100 °C for 0.5 h, and water and part of the solvent were removed using a water separator. Boric acid (3.8 g, 61.14 mmol, 1.5 eq) was then added to the reaction mixture, and the reaction was continued at 100 °C for 5 h. After the reaction was complete, the reaction solution was poured into 150 mL of water, extracted with ethyl acetate (50 mL × 3), the organic phases were combined, and the solvent was removed by vacuum distillation. The resulting crude product was dissolved in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 8:10 (30 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 7.17 g of target compound 3 with a purity of 97.6% and a yield of 83.38%.

[0055] 1 H NMR (400MHz, DMSO) δ8.02 (s, 1H), 7.22 (d, J = 7.4Hz, 1H), 7.06 (dd, J = 7.4, 0.8Hz, 1H), 2.49 (s, 3H).

[0056] [M+H] + =210.8

[0057] Example 2:

[0058] Step 1: Synthesis of Compound 2

[0059]

[0060] Compound 1 (10 g, 5.18 mmol, 1 eq) was added to 100 mL of tetrahydrofuran. Under argon protection, the temperature was controlled to -78 °C, and diisopropylaminolithium (LDA) (26 mL, 51.84 mmol, 1 eq, 2 M in THF) was added dropwise. The mixture was kept at this temperature for 2 h, and then 8 mL of DMF was added. The mixture was then allowed to react at room temperature for 0.5 h. The mixture was flushed with saturated ammonium chloride solution (100 mL), and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was soluble in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 5:10 (25 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 8.3 g of compound 2 with a purity of 97.85% and a yield of 72.18%.

[0061] Step 2: Synthesis of Compound 3

[0062]

[0063] Compound 2 (8.0 g, 36.07 mmol, 1 eq) was dissolved in dimethyl sulfoxide (27 mL), and a 50% aqueous solution of hydrazine hydrate (19.86 g, 198.37 mmol, 5.5 eq) was added with stirring. The reaction was heated to 100 °C for 0.5 h, and water and part of the solvent were removed. Boric acid (2.24 g, 36.07 mmol, 1 eq) was then added to the reaction mixture, and the reaction was continued at 100 °C for 5 h. After the reaction was complete, the reaction solution was poured into 130 mL of water, extracted with ethyl acetate (45 mL * 3), the organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was dissolved in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 8:10 (25 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 5.15 g of target compound 3 with a purity of 96.8% and a yield of 67.65%.

[0064] 1 H NMR (400MHz, DMSO) δ8.02 (s, 1H), 7.22 (d, J = 7.4Hz, 1H), 7.06 (dd, J = 7.4, 0.8Hz, 1H), 2.49 (s, 3H).

[0065] [M+H] + =210.8

[0066] Example 3:

[0067] Step 1: Synthesis of Compound 2

[0068]

[0069] Compound 1 (10 g, 5.18 mmol, 1 eq) was added to 100 mL of tetrahydrofuran. Under argon protection, the temperature was controlled to -78 °C, and n-butyllithium (38.88 mL, 77.77 mmol, 1.5 eq, 2 M in THF) was added dropwise. The mixture was kept at this temperature for 2 h, and then 8 mL of DMF was added. The mixture was allowed to react at room temperature for 0.5 h. The mixture was then flushed with saturated ammonium chloride solution (100 mL) and extracted with ethyl acetate (80 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was soluble in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 5:10 (30 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 5.93 g of compound 2 with a purity of 96.37% and a yield of 50.79%.

[0070] Step 2: Synthesis of Compound 3

[0071]

[0072] Compound 2 (5.0 g, 22.65 mmol, 1 eq) was dissolved in dimethyl sulfoxide (17 mL), and a 50% aqueous solution of hydrazine hydrate (12.47 g, 124.55 mmol, 5.5 eq) was added with stirring. The reaction was heated to 100 °C for 0.5 h, and water and part of the solvent were removed. Boric acid (3.56 g, 57.29 mmol, 2.53 eq) was then added to the reaction mixture, and the reaction was continued at 100 °C for 5 h. After the reaction was complete, the reaction solution was poured into 80 mL of water, extracted with ethyl acetate (25 mL * 3), the organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was dissolved in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 8:10 (15 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 3.3 g of target compound 3 with a purity of 97.34% and a yield of 67.21%.

[0073] 1 H NMR (400MHz, DMSO) δ8.02 (s, 1H), 7.22 (d, J = 7.4Hz, 1H), 7.06 (dd, J = 7.4, 0.8Hz, 1H), 2.49 (s, 3H).

[0074] [M+H] + =210.8

[0075] Comparative Examples

[0076] Step 2: Synthesis of Compound 3

[0077]

[0078] Compound 2 (10.0 g, 40.76 mmol, 1 eq) was dissolved in dimethyl sulfoxide (35 mL), and a 50% aqueous solution of hydrazine hydrate (24.86 g, 248.34 mmol, 6.1 eq) was added with stirring. The mixture was heated to 100 °C and reacted for 0.5 h. Water and some solvent were removed, and the reaction was continued at 100 °C for 5 h. After the reaction was complete, the reaction solution was poured into 160 mL of water and extracted with ethyl acetate (55 mL × 3). The organic phases were combined, and the solvent was removed by vacuum distillation. The crude product was dissolved in ethyl acetate and petroleum ether (V... EA :V PE In a mixture of 8:10 (40 mL), the mixture was heated and stirred until the solid was completely dissolved. The mixture was then slowly cooled to room temperature, filtered, and dried to obtain 3.53 g of target compound 3 with a purity of 90.32% and a yield of 33.45%.

[0079] In the comparative examples above, without the use of boric acid to promote the cyclization of the intermediate oxime, the yield of the target product was only 33.45%, and the purity was only 90.32%. Therefore, the reaction results are sufficient to demonstrate that boric acid plays a positive promoting role in the preparation of the target compound in step two.

[0080] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of this application, and are not intended to limit them. Although this application has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some or all of the technical features therein. Such modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the scope of the technical solutions of the embodiments of this application.

Claims

1. A method for preparing 4-bromo-7-methyl-1H-indazole, characterized in that, Includes the following steps: Compound 2 was dissolved in an organic solvent, hydrazine hydrate was added, and the reaction was carried out at a raised temperature. Boric acid was added, and the reaction was continued at a raised temperature. After post-treatment, the target compound 4-bromo-7-methyl-1H-indazole was obtained. The molar ratio of compound 2 to hydrazine hydrate and boric acid was 1:1.0-6.0:1.0-3.

0.

2. The preparation method according to claim 1, characterized in that, The organic solvent is selected from one or more of dimethyl sulfoxide, dioxane, chloroform, toluene, and diethyl ether; and / or The volume-to-mass ratio of the organic solvent to compound 2 is 2-10 mL / g.

3. The preparation method according to claim 1 or 2, characterized in that, The reaction temperature is 70-120℃; and / or The reaction time under elevated temperature is 0.5-2 hours; and / or After adding boric acid, the reaction is continued at a constant temperature for 1-10 hours.

4. The preparation method according to claim 1, characterized in that, It also includes removing water and some solvents before adding boric acid.

5. The preparation method according to claim 1, wherein the post-processing step includes: The reaction solution was quenched in water, extracted with an organic solvent, and then purified by vacuum distillation.

6. The preparation method according to claim 5, characterized in that, The organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane, and toluene; and / or The purification step is selected from recrystallization or column chromatography.

7. A method for preparing 4-bromo-7-methyl-1H-indazole, characterized in that, Includes the following steps: Step 1: Dissolve compound 1 in organic solvent 1, react it with N,N-dimethylformamide in the presence of lithium reagent, and obtain compound 2 after post-treatment; Step 2: Dissolve compound 2 in organic solvent 2, add hydrazine hydrate, and react under elevated temperature. After adding boric acid, continue the reaction at elevated temperature. After post-treatment, the target compound 4-bromo-7-methyl-1H-indazole is obtained. The molar ratio of compound 2 to hydrazine hydrate and boric acid is 1:1.0-6.0:1.0-3.

0.

8. The preparation method according to claim 7, characterized in that, Step 1 is performed under an inert gas atmosphere; and / or The organic solvent 1 is selected from one or more of acetonitrile, dimethyl sulfoxide, dioxane, tetrahydrofuran, and diethyl ether; and / or The lithium reagent is selected from lithium diisopropylaminolithium or n-butyllithium; and / or The volume-to-mass ratio of organic solvent 1 to compound 1 is 5-15 mL / g; and / or The molar ratio of compound 1 to the lithium reagent is 1:1-1.5; and / or The mass-to-volume ratio of compound 1 to N,N-dimethylformamide is 1 g / 0.5-1 mL; and / or; The reaction temperature in step 1 is room temperature; and / or The reaction time for step 1 is 0.5-3 hours; and / or The post-processing steps of step 1 include: quenching the reaction, extraction with organic solvent, followed by vacuum distillation and purification.

9. The preparation method according to claim 7 or 8, characterized in that, Organic solvent 2 is selected from one or more of dimethyl sulfoxide, dioxane, chloroform, toluene, and diethyl ether; and / or The volume-to-mass ratio of organic solvent 2 to compound 2 is 2-10 mL / g; and / or The reaction temperature in step 2 is 70-120℃; and / or The reaction time under elevated temperature in step 2 is 0.5-2 hours; and / or In step 2, after adding boric acid, the reaction is continued at a constant temperature for 1-10 hours; and / or Step 2 also includes removing water and some solvent before adding boric acid; and / or The post-processing steps in step 2 include: quenching the reaction solution in water, extracting it with an organic solvent, and then purifying it by vacuum distillation.

10. The preparation method according to claim 9, characterized in that, In steps 1 and 2, the organic solvent used for extraction is selected from one or more of ethyl acetate, dichloromethane, dichloroethane, and toluene; and / or In steps 1 and 2, the purification step is selected from column chromatography purification or recrystallization purification.

Images