Synthesis method of 3-amino-4-methyl-6-chloropyridazine

Abstract

The invention discloses a synthesis method of 3-amino-4-methyl-6-chloropyridazine, which comprises the following steps: S1001, adding a compound 1, namely 3, 6-dichloro-4-methylpyridazine, 1, 8-diazabicyclo [5.4. 0] undec-7-alkene and 4-methoxybenzylamine, into an organic solvent I, heating to 40-80 DEG C under the protection of inert gas, reacting for 1-3 hours, cooling to room temperature, filtering, washing, and drying to obtain 3-amino-4-methyl-6-chloropyridazine, namely 3, 6-dichloro-4-methylpyridazine, 1, 8-diazabicyclo [5.4. 0] undec-7-alkene and 4-methoxybenzylamine. And stirring and reacting for 10-40 hours. After the reaction is completed, the reaction liquid is subjected to first post-treatment to obtain a crude product of the compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazine-3-amine), and the crude product does not need to be further purified; and S1002, adding the compound 2 into an organic solvent II, slowly adding trifluoroacetic acid, carrying out stirring reaction at room temperature for 10-40 hours, and after the reaction is completed, carrying out secondary post-treatment on the reaction liquid to obtain a target compound 3, namely 3-amino-4-methyl-6-chloropyridazine.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for synthesizing 3-amino-4-methyl-6-chloropyridazine. Background Art

[0002] The compound 3-amino-4-methyl-6-chloropyridazine is an important pyridazine compound and an important molecular building block. It serves as a key intermediate. In patent WO2020 / 261114, the compound 3-amino-4-methyl-6-chloropyridazine is used to synthesize a 2,3-dihydroquinazoline compound as a NAV1.8 inhibitor, which can be used to treat pain or pain-related diseases; in patent US2009 / 186879, the compound 3-amino-4-methyl-6-chloropyridazine is used to synthesize a novel tricyclic compound with adrenocorticotropin-releasing factor antagonist activity.

[0003] In the prior art, there are two conventional synthetic routes for 3-amino-4-methyl-6-chloropyridazine. The first involves reacting 3-amino-4-bromo-6-chloropyridazine with a zinc halide in the presence of a palladium catalyst and a grignard to obtain the product. This method has the following disadvantages: high reaction risk, high palladium catalyst cost, complicated post-processing, and low yield. The second method involves a nucleophilic substitution reaction between 3,6-dichloro-4-methylpyridazine and aqueous ammonia under high pressure and high temperature conditions to obtain the product. This method has the disadvantages of producing numerous reaction byproducts, most of which are isomers, making purification difficult or even impossible. Therefore, the development of new synthetic methods for 3-amino-4-methyl-6-chloropyridazine is of great significance. Summary of the Invention

[0004] To solve the above technical problems, the present application provides a method for synthesizing 3-amino-4-methyl-6-chloropyridazine, which comprises: S1001, adding compound 1, i.e., 3,6-dichloro-4-methylpyridazine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 4-methoxybenzylamine to an organic solvent I, and heating to 40-80° C. under an inert gas atmosphere, stirring and reacting for 10-40 hours. After completion of the reaction, the reaction solution is subjected to a first post-treatment to obtain a crude product of compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), which does not require further purification. S1002, compound 2 is added to organic solvent II, trifluoroacetic acid is slowly added, and the reaction is stirred at room temperature for 10 to 40 hours. After the reaction is completed, the reaction solution is subjected to a second post-treatment to obtain the target compound 3, namely 3-amino-4-methyl-6-chloropyridazine.

[0005] Preferably, in step S1001, at least one of the following conditions is met: The molar ratio of 3,6-dichloro-4-methylpyridazine to 1,8-diazabicyclo[5.4.0]undec-7-ene is 1:1 to 3; The molar ratio of the compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to 4-methoxybenzylamine is 1:1-3; The mass volume ratio of the compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to the organic solvent I is 1:5-40 g / mL.

[0006] Preferably, in step S1001, the organic solvent I is selected from any one, any two or more of dichloromethane, chloroform, chloroform, dichloroethane, dichloropropane and trichloroethane.

[0007] Preferably, in step S1001, the inert gas is selected from any one, any two or more of nitrogen or argon.

[0008] Preferably, in step S1001, the first post-treatment process includes: after the reaction is completed, cooling the reaction solution to room temperature, adding it to water, stirring for 8 to 40 minutes, filtering, collecting the solid on the filter cake, and drying to obtain a crude product of compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), which does not require further purification.

[0009] Preferably, in step S1002, at least one of the following conditions is met: The molar ratio of the compound 2, i.e., 6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine, to trifluoroacetic acid is 1:1-5; The mass volume ratio of the compound 2, i.e., 6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine, to the organic solvent II is 1:5-40 g / mL.

[0010] Preferably, in step S1002, the organic solvent II is selected from any one, any two or more of dichloromethane, chloroform, chloroform, dichloroethane, dichloropropane and trichloroethane.

[0011] Preferably, in step S1002, the second post-processing process includes: S10021, after the reaction is completed, the reaction solution is added to ice water, the pH is adjusted to 8-9 with an alkaline aqueous solution, and the solid on the filter cake is collected by filtration and dried to obtain a crude product of compound 3 (3-amino-4-methyl-6-chloropyridazine); S10022, add the crude product of compound 3 (3-amino-4-methyl-6-chloropyridazine) to organic solvent III, slowly add p-toluenesulfonic acid, stir for 8 to 40 minutes, filter, add the filtrate to water, extract with organic solvent IV, combine the organic phases, wash the organic phases, and dry to obtain highly pure target compound 3, i.e., 3-amino-4-methyl-6-chloropyridazine.

[0012] Preferably, in step S10021, the alkaline aqueous solution is selected from any one, any two or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution.

[0013] Preferably, in step S10022, at least one of the following conditions is satisfied: The organic solvent III is selected from any one, any two or more of tetrahydrofuran, 1,4-dioxane, and toluene; The organic solvent IV is selected from any one, any two or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

[0014] Compared with the prior art, the beneficial technical effects of the present invention are: The present invention provides a method for preparing 3-amino-4-methyl-6-chloropyridazine. The method comprises the following steps: using the compound 3,6-dichloro-4-methylpyridazine as a raw material, reacting with 1,8-diazabicyclo[5.4.0]undec-7-ene and 4-methoxybenzylamine to obtain an intermediate 6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine, and then converting the intermediate into the target compound 3-amino-4-methyl-6-chloropyridazine.

[0015] The synthesis method of the present invention has mild reaction conditions, simple post-treatment and purification, and can achieve process scale-up. Ultimately, a high-purity compound 3-amino-4-methyl-6-chloropyridazine is prepared through short steps, simple operation, low cost, and relatively mild reaction conditions, that is, the purity can reach ≥98%. BRIEF DESCRIPTION OF THE DRAWINGS

[0016] Figure 1 A schematic diagram showing the synthesis method of 3-amino-4-methyl-6-chloropyridazine is shown.

[0017] Figure 2 The H NMR spectrum of the obtained compound 3-amino-4-methyl-6-chloropyridazine is shown. DETAILED DESCRIPTION

[0018] The preferred embodiments described below are for illustrative purposes only, and those skilled in the art may readily conceive of other obvious variations. The basic principles of the present invention defined in the following description may be applied to other embodiments, variations, improvements, equivalents, and other technical solutions that do not depart from the spirit and scope of the present invention.

[0019] The synthesis method of 3-amino-4-methyl-6-chloropyridazine according to a preferred embodiment of the present invention will be described in detail below. As an example, using compound 1 (3,6-dichloro-4-methylpyridazine) as a raw material, under the action of 1,8-diazabicyclo[5.4.0]undec-7-ene and 4-methoxybenzylamine, the intermediate compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine) is obtained, and then converted into the target compound 3 (3-amino-4-methyl-6-chloropyridazine). The synthesis route is as follows. Figure 1 shown.

[0020] Specifically, the synthesis method of 3-amino-4-methyl-6-chloropyridazine described in the present application includes: S1001, Compound 1 (3,6-dichloro-4-methylpyridazine), 1,8-diazabicyclo[5.4.0]undec-7-ene, and 4-methoxybenzylamine) are added to organic solvent I. Under inert gas, the mixture is heated to 40-80°C and stirred for 10-40 hours. After completion of the reaction, the reaction solution undergoes a first post-treatment to obtain a crude product of Compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), which does not require further purification. S1002, compound 2 is added to organic solvent II, trifluoroacetic acid is slowly added, and the reaction is stirred at room temperature for 10 to 40 hours. After the reaction is completed, the reaction solution is subjected to a second post-treatment to obtain the target compound 3, namely 3-amino-4-methyl-6-chloropyridazine.

[0021] In a preferred embodiment, in step S1001, the molar ratio of compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to 1,8-diazabicyclo[5.4.0]undec-7-ene, is 1:1-3.

[0022] In a preferred embodiment, in step S1001, the molar ratio of compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to 4-methoxybenzylamine is 1:1-3.

[0023] In a preferred embodiment, in step S1001, the mass volume ratio of the compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to the organic solvent I is 1:5-40 g / mL.

[0024] In a preferred embodiment, in step S1001, the organic solvent I is selected from any one, any two or more of dichloromethane, chloroform, chloroform, dichloroethane, dichloropropane, and trichloroethane.

[0025] In a preferred embodiment, in step S1001, the inert gas is selected from any one, any two or more of nitrogen or argon.

[0026] In a preferred embodiment, in step S1001, the first post-treatment process includes: after the reaction is completed, cooling the reaction solution to room temperature, adding it to water, stirring for 8 to 40 minutes, filtering, collecting the solid on the filter cake, and drying to obtain a crude product of compound 2 ((6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine)), which does not require further purification.

[0027] In a preferred embodiment, in step S1002, the molar ratio of the compound 2, i.e., (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), to trifluoroacetic acid is 1:1-5.

[0028] Furthermore, in step S1002, the organic solvent II is selected from any one, any two or more of dichloromethane, chloroform, chloroform, dichloroethane, dichloropropane and trichloroethane.

[0029] In a preferred embodiment, in step S1002, the mass volume ratio of the compound 2, i.e. (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), to the organic solvent II is 1:5-40 g / mL.

[0030] In a preferred embodiment, in step S1002, the second post-processing process includes: S10021, after the reaction is completed, the reaction solution is added to ice water, the pH is adjusted to 8-9 with an alkaline aqueous solution, and the solid on the filter cake is collected by filtration and dried to obtain a crude product of compound 3 (3-amino-4-methyl-6-chloropyridazine); S10022, add the crude product of compound 3 (3-amino-4-methyl-6-chloropyridazine) to organic solvent III, slowly add p-toluenesulfonic acid, stir for 8 to 40 minutes, filter, add the filtrate to water, extract with organic solvent IV, combine the organic phases, wash the organic phases, and dry to obtain highly pure target compound 3, i.e., 3-amino-4-methyl-6-chloropyridazine.

[0031] In a preferred embodiment, in step S10022, the organic solvent III is selected from any one, any two or more of tetrahydrofuran, 1,4-dioxane, and toluene.

[0032] In a preferred embodiment, in step S10022, the organic solvent IV is selected from any one, any two or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane, and dichloroethane.

[0033] In a preferred embodiment, in step S10021, the alkaline aqueous solution is selected from any one, any two or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution.

[0034] It is worth mentioning that the present invention proposes a method for preparing 3-amino-4-methyl-6-chloropyridazine, using the compound 3,6-dichloro-4-methylpyridazine as a raw material, under the action of 1,8-diazabicyclo[5.4.0]undec-7-ene and 4-methoxybenzylamine, to obtain the intermediate 6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine, which is then converted into the target compound 3-amino-4-methyl-6-chloropyridazine.

[0035] The synthetic method of the present invention has mild reaction conditions, simple post-treatment and purification, and can achieve process scale-up; ultimately, the compound 3-amino-4-methyl-6-chloropyridazine is prepared with short steps, simple operation, low cost and relatively mild reaction conditions.

[0036] The technical solution of the present invention is further explained below through examples.

[0037] Example 1

[0038] Step 1: Compound 1, i.e., 3,6-dichloro-4-methylpyridazine (200.00 g, 1.23 mol, 1.00 eq), 1,8-diazabicyclo[5.4.0]undec-7-ene (205.48 g, 1.35 mol, 1.10 eq), and 4-methoxybenzylamine (185.15 g, 1.35 mol, 1.10 eq) were added to dichloromethane (2.0 L). Under nitrogen protection, the mixture was heated to 60° C. and stirred for 12 h.

[0039] After the reaction was completed, the reaction solution was cooled to room temperature and added to water (1.5 L), stirred for 10 minutes, filtered, and the filter cake was washed twice with water (0.5 L × 2). The solid on the filter cake was collected and dried to obtain a crude product of compound 2 (weight 319.60 g, purity 97%, yield 96%). The crude product did not require further purification.

[0040] Step 2: Compound 2 (300.00 g, 1.14 mol, 1.00 eq) was added to dichloromethane (3.0 L). Trifluoroacetic acid (389.12 g, 3.41 mol, 3.00 eq) was slowly added dropwise at room temperature. The mixture was stirred at room temperature for 12 h. After completion of the reaction, the reaction mixture was added to ice water (2.0 L), the pH was adjusted to 8 with an alkaline aqueous solution, and the mixture was filtered. The filter cake was washed twice with water (0.5 L x 2). The solid on the filter cake was collected and dried to obtain the crude product of compound 3.

[0041] Step 3: The crude product of compound 3 was added to tetrahydrofuran (2.0 L), and p-toluenesulfonic acid (58.77 g, 341.26 mmol, 0.30 eq) was slowly added. The mixture was stirred for 10 minutes and filtered. The mixture was stirred for 10 minutes and filtered. The filtrate was added to water (2.0 L) and extracted twice with ethyl acetate (1.5 L × 2). The organic phases were combined, washed with saturated brine, and dried to obtain the target compound 3, namely 3-amino-4-methyl-6-chloropyridazine (weight 158.10 g, purity 98%, yield 95%).

[0042] The H NMR spectrum of the obtained compound 3 (3-amino-4-methyl-6-chloropyridazine) is as follows: Figure 2 The characterization data are as follows: 1 H NMR (400 MHz, DMSO) δ 7.30 (s, 1H), 6.45 (s, 2H), 2.08 (s, 3H).

[0043] Those skilled in the art will appreciate that the embodiments of the present invention described above are intended to be illustrative only and are not intended to limit the present invention. The objectives of the present invention have been fully and effectively achieved. The functional and structural principles of the present invention have been demonstrated and illustrated in the embodiments. Any variations or modifications may be made to the embodiments of the present invention without departing from the principles described.

Claims

1. A method for synthesizing 3-amino-4-methyl-6-chloropyridazine, characterized in that: The synthetic method of described 3-amino-4-methyl-6-chloropyridazine comprises: S1001, adding compound 1, i.e., 3,6-dichloro-4-methylpyridazine, 1,8-diazabicyclo[5.4.0]undec-7-ene, and 4-methoxybenzylamine to an organic solvent I, and heating to 40-80° C. under an inert gas atmosphere, stirring and reacting for 10-40 hours. After completion of the reaction, the reaction solution is subjected to a first post-treatment to obtain a crude product of compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), which does not require further purification. S1002, compound 2 is added to organic solvent II, trifluoroacetic acid is slowly added, and the reaction is stirred at room temperature for 10 to 40 hours. After the reaction is completed, the reaction solution is subjected to a second post-treatment to obtain the target compound 3, namely 3-amino-4-methyl-6-chloropyridazine.

2. The synthetic method of 3-amino-4-methyl-6-chloropyridazine according to claim 1, characterized in that In step S1001, at least one of the following conditions is met: The molar ratio of 3,6-dichloro-4-methylpyridazine to 1,8-diazabicyclo[5.4.0]undec-7-ene is 1:1 to 3; The molar ratio of the compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to 4-methoxybenzylamine is 1:1-3; The mass volume ratio of the compound 1, i.e., 3,6-dichloro-4-methylpyridazine, to the organic solvent I is 1:5-40 g / mL.

3. The synthetic method of 3-amino-4-methyl-6-chloropyridazine according to claim 1, characterized in that In step S1001, the organic solvent I is selected from any one, any two or more of dichloromethane, chloroform, chloroform, dichloroethane, dichloropropane and trichloroethane.

4. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 1, wherein In step S1001, the inert gas is selected from any one, any two or more of nitrogen or argon.

5. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 1, wherein In step S1001, the first post-treatment process includes: after the reaction is completed, cooling the reaction solution to room temperature, adding it to water, stirring it for 8 to 40 minutes, filtering it, collecting the solid on the filter cake, and drying it to obtain a crude product of compound 2 (6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine), which does not require further purification.

6. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 1, wherein In step S1002, at least one of the following conditions is met: The molar ratio of the compound 2, i.e., 6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine, to trifluoroacetic acid is 1:1-5; The mass volume ratio of the compound 2, i.e., 6-chloro-N-(4-methoxybenzyl)-4-methylpyridazin-3-amine, to the organic solvent II is 1:5-40 g / mL.

7. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 1, wherein In step S1002, the organic solvent II is selected from any one, any two or more of dichloromethane, chloroform, chloroform, dichloroethane, dichloropropane and trichloroethane.

8. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 1, wherein In step S1002, the second post-processing process includes: S10021, after the reaction is completed, the reaction solution is added to ice water, the pH is adjusted to 8-9 with an alkaline aqueous solution, and the solid on the filter cake is collected by filtration and dried to obtain a crude product of compound 3 (3-amino-4-methyl-6-chloropyridazine); S10022, add the crude product of compound 3 (3-amino-4-methyl-6-chloropyridazine) to organic solvent III, slowly add p-toluenesulfonic acid, stir for 8 to 40 minutes, filter, add the filtrate to water, extract with organic solvent IV, combine the organic phases, wash the organic phases, and dry to obtain highly pure target compound 3, i.e., 3-amino-4-methyl-6-chloropyridazine.

9. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 8, wherein In step S10021, the alkaline aqueous solution is selected from any one, any two or more of sodium bicarbonate solution, sodium carbonate solution, potassium carbonate solution, sodium hydroxide solution or potassium hydroxide solution.

10. The method for synthesizing 3-amino-4-methyl-6-chloropyridazine according to claim 8, characterized in that: In step S10022, at least one of the following conditions is met: The organic solvent III is selected from any one, any two or more of tetrahydrofuran, 1,4-dioxane, and toluene; The organic solvent IV is selected from any one, any two or more of ethyl acetate, butyl acetate, chloroform, toluene, dichloromethane and dichloroethane.

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