2, 3-dimethyl-2H-indazole-6-amine and preparation method thereof

Abstract

The invention provides 2, 3-dimethyl-2H-indazole-6-amine and a preparation method thereof, and relates to the technical field of medicine synthesis. According to the preparation method of the 2, 3-dimethyl-2H-indazole-6-amine, 2, 4-dichloroacetophenone is used as a raw material, condensation, cyclization, methylation reaction and ammonolysis reaction are sequentially performed to obtain the 2, 3-dimethyl-2H-indazole-6-amine, and the preparation method is low in raw material cost, small in reaction pollution and high in product yield.

Description

Technical Field

[0001] The present invention relates to the technical field of pharmaceutical synthesis, and in particular to 2,3-dimethyl-2H-indazole-6-amine and a preparation method thereof. Background Art

[0002] Pazopanib hydrochloride, whose chemical name is 5-[[4-[(2,3-dimethyl-2H-indazol-6-yl)methylamino]pyrimidin-2-yl]amino]-2-methylbenzenesulfonamide hydrochloride, is a second-generation multi-target tyrosine kinase inhibitor developed by the British company GlaxoSmithKline. It was approved for marketing by the US FDA in 2009 and is clinically used to treat advanced renal cancer.

[0003] At present, 2,3-dimethyl-2H-indazole-6-amine generally uses o-ethylaniline as a raw material, and is prepared through four steps of nitration, diazotization cyclization, methylation and nitro reduction (such as W02003106416, US20060252943). Nitro reduction uses a noble metal catalyst and requires nitration and diazotization reactions, which results in high costs for raw materials and routes and high pollution. Patent CN103450085 B optimizes this method, selects o-nitroethylbenzene as a raw material, and is prepared through halogenation, nitro reduction, diazotization cyclization, methylation and aminolysis. Although the use of noble metal catalysts is avoided, the raw material cost is still high, and highly polluting reactions such as nitro reduction and diazotization cannot be avoided, and the diazotization reaction is relatively dangerous. Summary of the invention

[0004] 1. Technical issues to be resolved

[0005] In view of the deficiencies in the prior art, the present invention provides a 2,3-dimethyl-2H-indazole-6-amine and a preparation method thereof, which solves the technical problems of high raw material cost and large reaction pollution in the prior preparation method.

[0006] (II) Technical solution

[0007] To achieve the above objectives, the present invention is implemented through the following technical solutions:

[0008] In a first aspect, the present invention provides a method for preparing 2,3-dimethyl-2H-indazole-6-amine, which uses 2,4-dichloroacetophenone as a raw material and sequentially undergoes condensation, cyclization, methylation reaction and aminolysis reaction to obtain 2,3-dimethyl-2H-indazole-6-amine.

[0009] Its synthetic route is:

[0010]

[0011] A method for preparing 2,3-dimethyl-2H-indazole-6-amine comprises the following steps:

[0012] S1, dissolving the compound of formula 1 in a solvent, adding hydrazine hydrate, stirring and reacting at temperature T1, concentrating and drying after the reaction, adding a crystallization solvent for crystallization, centrifuging and drying to obtain a compound of formula 2;

[0013] S2, dissolving the compound of formula 2 in a solvent, adding a base and a copper salt, heating to T2 for reaction, and after the reaction is completed, pouring water to quench, extracting with an extractant, and concentrating to obtain a compound of formula 3;

[0014] S3, dissolving the compound of formula 3 in a solvent, adding alkali and a methylating agent, stirring and reacting at temperature T3, after the reaction is complete, washing with alkaline water, separating the liquids, drying, concentrating, and crystallizing with a crystallization solvent to obtain a compound of formula 4.

[0015] S4. Dissolve the compound of formula 4 in a solvent, add an amination reagent, a base, and a metal salt catalyst, and react by stirring at a temperature of T4. After the reaction is complete, add an extraction solvent, wash with water, separate the liquids, dry, concentrate, and crystallize with a crystallization solvent to obtain a compound of formula 5, i.e., 2,3-dimethyl-2H-indazole-6-amine.

[0016] Preferably, in S1, the mass volume ratio of the compound of formula 1 to the solvent is 1:(2-10), preferably 1:(5-8), and the solvent is ethanol.

[0017] Preferably, in S1, the molar ratio of the compound of formula 1 to hydrazine hydrate is 1:(1-5), preferably 1:(2-3).

[0018] Preferably, in said S1, the temperature T1 is 60-110°C, preferably 85-105°C.

[0019] Preferably, in said S2, the solvent is dimethyl sulfoxide.

[0020] Preferably, in S2, the mass volume ratio of the compound of formula 2 to the solvent is 1:(2-10), preferably 1:(6-8).

[0021] Preferably, in S2, the base is selected from one or more of sodium carbonate, potassium carbonate, DBU, sodium methoxide or potassium tert-butoxide, preferably potassium tert-butoxide; the copper salt is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cupric acetate, cupric chloride, cupric bromide and cupric iodide, preferably cuprous iodide.

[0022] Preferably, in said S2, the temperature of T2 is 0-100°C, preferably 10-60°C.

[0023] Preferably, in S2, the molar ratio of compound 2 to base and copper salt is 1:(1-4):(0.01-0.1), preferably 1:(1.5-2):(0.01-0.05).

[0024] Preferably, in S3, the mass volume ratio of the compound of formula 3 and the solvent is 1:(2-10), preferably 1:(6-8), and the solvent is a mixed solvent of dichloromethane and dimethyl sulfoxide, and the mixed volume ratio is 5:(1-2).

[0025] Preferably, in S3, the base is selected from sodium methoxide, sodium bicarbonate, sodium carbonate, potassium carbonate, preferably potassium carbonate; the methylating agent is selected from dimethyl sulfate, dimethyl carbonate or methyl iodide, preferably dimethyl sulfate; the molar ratio of the compound of formula (3), the base and the methylating agent is 1:(0-3):(1-4), preferably 1:(0-2):(1-3); the temperature of T3 is 20-80°C, preferably 40-50°C; in S3, the crystallization solvent is selected from one or more of methanol, ethanol and isopropanol, preferably isopropanol.

[0026] Preferably, in S4, the mass volume ratio of the compound of formula 4 and the solvent is 1:(3-10), preferably 1:(6-10), and the solvent is selected from one or more of ethanol, ethylene glycol, dimethyl ether, 1,4-dioxane, NMP, and DMF, preferably 1,4-dioxane.

[0027] Preferably, in S4, the amination agent is selected from ammonia water, ammonia gas or ammonium salts such as ammonium sulfate and ammonium chloride, preferably ammonia water; the base is selected from one or more of potassium phosphate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, preferably potassium carbonate; the catalyst is selected from one or more of cuprous bromide, cuprous iodide, cupric oxide, cuprous oxide or bis(1,5-cyclooctadiene)nickel, nickel powder, preferably cuprous iodide; the molar ratio of the compound of formula (4), the amination agent, the base and the catalyst is 1:(2-8):(1-3):(0.01-0.05), preferably 1:(4-6):(2-3):(0.03-0.05); the temperature of T4 is 40-110°C, preferably 80-100°C; in S4, the crystallization solvent is selected from one or more of ethanol, isopropanol, ethyl acetate and petroleum ether.

[0028] In a second aspect, the present invention provides 2,3-dimethyl-2H-indazole-6-amine obtained by the preparation method described in the first aspect, and the structural formula of the 2,3-dimethyl-2H-indazole-6-amine is as follows:

[0029]

[0030] (III) Beneficial effects

[0031] The present invention provides a 2,3-dimethyl-2H-indazole-6-amine and a preparation method thereof. Compared with the prior art, the present invention has the following beneficial effects:

[0032] The advantages of the present invention are that the price of the raw material 2,4-dichloroacetophenone used is much lower than the raw material used in the above-mentioned route, and at the same time, the nitro reduction with large pollution or high cost and the diazotization reaction with large pollution and high risk are avoided. Compared with the prior art, the synthesis route of the present invention is novel, the raw materials and reagents used in the reaction are cheap and easy to obtain, and there is no need to use expensive palladium catalysts and dangerous reagents. It is green and environmentally friendly, the reaction conditions are mild and controllable, the operation is simple, the product purity is high, the yield is high, and it is suitable for industrial production. The present invention has broad prospects and industrial application value. DETAILED DESCRIPTION

[0033] In order to make the purpose, technical solutions and advantages of the embodiments of the present invention clearer, the technical solutions in the embodiments of the present invention are clearly and completely described. Obviously, the described embodiments are part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.

[0034] In order to better understand the above technical solution, the above technical solution will be described in detail below in conjunction with specific implementation methods.

[0035] Example 1

[0036] This embodiment provides a method for preparing 2,3-dimethyl-2H-indazole-6-amine, which specifically comprises the following steps:

[0037] S1, Synthesis of compounds of formula 2:

[0038] At room temperature, 2,4-dichloroacetophenone (18.9 g of compound 1, 0.10 mol) was dissolved in 100 mL of ethanol, and 85% hydrazine hydrate (11.8 g, 0.20 mol) was added, and the temperature was raised to 95°C for 6 h. HPLC detected that the raw material reaction was complete, and most of the solvent was concentrated. DCM 40 mL and water 20 mL were added, and the mixture was separated after stirring. The organic layer was taken, dried, and most of the solvent was concentrated. The mixture was cooled to room temperature, and 40 mL of n-hexane was added dropwise to stir and crystallize. The mixture was filtered to obtain a white solid, i.e., 19.4 g of compound 2, with a purity of 99.6% and a yield of 95.7%.

[0039] The reaction equation is as follows:

[0040]

[0041] S2. Synthesis of compounds of formula 3

[0042] At room temperature, the compound of formula 2 (4.1 g, 0.02 mol) was dissolved in 32 mL DMSO, and cuprous iodide (0.08 g, 0.0004 mol) and potassium tert-butoxide (3.4 g, 0.03 mol) were added under stirring, and the reaction was carried out at 20° C. for 20 h. After the reaction, 60 ml of water was added to quench, and then 60 ml of dichloromethane was added for extraction. After separation, the organic layer was washed once with 60 mL of saturated brine, and finally dried and concentrated to obtain a brown oily liquid. 40 mL of petroleum ether was added for stirring and crystallization, and the mixture was filtered and dried to obtain a light brown-gray solid, i.e. 2.76 g of the compound of formula 3, with a purity of 98.8% and a yield of 82.8%.

[0043] The reaction equation is as follows:

[0044]

[0045] S3. Synthesis of compounds of formula 4

[0046] At room temperature, the compound of formula 3 (25 g, 0.15 mol) was dissolved in 125 mL of dichloromethane, and then 25 mL of DMSO and dimethyl sulfate (37.8 g, 0.3 mol) were added. After the addition, the temperature was raised to 45°C and stirred for reaction for 24 hours. After HPLC detection of the reaction was complete, 100 ml of saturated NaHCO3 solution was added and washed once, and then washed once with water, and then dried to concentrate most of the solvent, and isopropanol was added for crystallization, filtered, and dried to obtain an off-white solid, namely 22.2 g of the compound of formula 4, with a yield of 82%.

[0047] The reaction equation is as follows:

[0048]

[0049] S4. Synthesis of compounds of formula 5

[0050] At room temperature, the compound of formula 4 (9.0 g, 0.05 mol) was dissolved in 54 mL of 1,4-dioxane, and cuprous iodide (0.285 g, 0.0015 mol) and potassium carbonate (13.8 g, 0.1 mol) were added under stirring, and then 25% ammonia water (17 g, 0.25 mol) was added dropwise, and the reaction was carried out at 110° C. for 24 h. After the reaction, 60 ml of water was added, and then 80 ml of dichloromethane was added and stirred for extraction. After separation, the organic layer was washed once with 60 mL of water, and finally dried and concentrated. The oily liquid was added with 15 mL of isopropanol and stirred to dissolve. The temperature was maintained at 0-10° C., and ethanolic hydrogen chloride was added dropwise to adjust the pH to 2-3 to form a salt. The solid was crystallized, filtered, and dried to obtain 6.84 g of 2,3-dimethyl-2H-indazole-6-amine with a purity of 99.1% and a yield of 84.9%.

[0051] The reaction equation is as follows:

[0052]

[0053] Example 2

[0054] This embodiment provides a method for preparing 2,3-dimethyl-2H-indazole-6-amine, which specifically comprises the following steps:

[0055] S1, Synthesis of compounds of formula 2:

[0056] At room temperature, 2,4-dichloroacetophenone (200 g, 1.06 mol of the compound of formula 1) was dissolved in 1200 mL of ethanol, and then 85% hydrazine hydrate (187 g, 3.18 mol) was added, and the temperature was raised to 85°C for reaction for 6 hours; HPLC detected that the raw material reaction was complete, most of the solvent was concentrated, 400 mL of DCM and 200 mL of water were added, and the mixture was separated after stirring. The organic layer was taken, dried, most of the solvent was concentrated, cooled to room temperature, 400 mL of n-hexane was added, stirred and crystallized, and filtered to obtain a white solid, i.e. 203.6 g of the compound of formula 2, with a purity of 99.5% and a yield of 94.6%.

[0057] S2. Synthesis of compounds of formula 3

[0058] At room temperature, the compound of formula 2 (18.3 g, 0.09 mol) was dissolved in 110 mL DMSO, and cuprous iodide (0.34 g, 0.0018 mol) and sodium tert-butoxide (17.3 g, 0.18 mol) were added under stirring conditions. The reaction was carried out at 10° C. for 24 h. After the reaction, 200 mL of water was added, and then 220 mL of dichloromethane was added for extraction. After separation, the organic layer was washed once with 200 mL of saturated brine, and finally dried and concentrated to obtain a brown oily liquid. 130 mL of petroleum ether was added for stirring and crystallization. The mixture was filtered and dried to obtain 11.7 g of a light brown-gray solid with a purity of 98.2% and a yield of 78%.

[0059] S3. Synthesis of compounds of formula 4

[0060] At room temperature, the compound of formula 3 (12.5 g, 0.075 mol) was dissolved in 62.5 mL of dichloromethane, and then 25 mL of DMSO and iodomethane (10.6 g, 0.075 mol) were added. After the addition, the temperature was raised to 50°C and stirred for reaction for 24 hours. After HPLC detection of the reaction was complete, 50 ml of saturated NaHCO3 solution was added and washed once, and then washed once with water, and then dried to concentrate most of the solvent, and isopropanol was added for crystallization, filtered, and dried to obtain 10.9 g of an off-white solid with a yield of 80.7%.

[0061] S4. Synthesis of compounds of formula 5

[0062] At room temperature, the compound of formula 4 (9.0 g, 0.05 mol) was dissolved in 54 mL of 1,4-dioxane, and nickel (0.09 g, 0.0015 mol) and potassium carbonate (20.7 g, 0.15 mol) were added under stirring, and then 25% ammonia water (21 g, 0.3 mol) was added dropwise, and the reaction was carried out at 110°C for 24 h. After the reaction, 60 ml of water was added, and then 80 ml of dichloromethane was added for stirring and extraction. After separation, the organic layer was washed once with 60 mL of water, and finally dried and concentrated. 15 mL of isopropanol was added to the oily liquid and stirred to dissolve it. The temperature was maintained at 0-10°C, and ethanolic hydrogen chloride was added dropwise to adjust the pH to 2-3 to form a salt. The solid was crystallized, filtered, and dried to obtain 6.55 g of solid with a purity of 99.2% and a yield of 81.3%.

[0063] It should be noted that, in this article, relational terms such as first and second, etc. are only used to distinguish one entity or operation from another entity or operation, and do not necessarily require or imply any such actual relationship or order between these entities or operations. Moreover, the terms "include", "comprise" or any other variants thereof are intended to cover non-exclusive inclusion, so that a process, method, article or device including a series of elements includes not only those elements, but also other elements not explicitly listed, or also includes elements inherent to such process, method, article or device. In the absence of further restrictions, the elements defined by the sentence "comprise a ..." do not exclude the existence of other identical elements in the process, method, article or device including the elements.

[0064] The above embodiments are only used to illustrate the technical solutions of the present invention, rather than to limit the same. Although the present invention has been described in detail with reference to the aforementioned embodiments, those skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some of the technical features may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the spirit and scope of the technical solutions of the embodiments of the present invention.

[0065] The present invention illustrates the detailed process flow of the present invention through the above-mentioned embodiments, but the present invention is not limited to the above-mentioned detailed process flow, that is, it does not mean that the present invention must rely on the above-mentioned detailed process flow to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of various raw materials of the product of the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A method for preparing 2,3-dimethyl-2H-indazol-6-amine, characterized in that: Using 2,4-dichloroacetophenone as the raw material, 2,3-dimethyl-2H-indazole-6-amine is obtained through condensation, cyclization, methylation and aminolysis reactions in sequence; Its synthetic route is:

2. The preparation method according to claim 1, characterized in that The following steps are involved: S1, dissolving the compound of formula 1 in a solvent, adding hydrazine hydrate, stirring and reacting at a temperature of T1, concentrating and drying after the reaction, adding a crystallization solvent for crystallization, centrifuging and drying to obtain a compound of formula 2; S2, dissolving the compound of formula 2 in a solvent, adding a base and a copper salt, heating to T2 for reaction, and after the reaction is completed, pouring water to quench, extracting with an extractant, and concentrating to obtain a compound of formula 3; S3, dissolving the compound of formula 3 in a solvent, adding a base and a methylating agent, stirring and reacting at a temperature of T3, after the reaction is complete, washing with alkaline water, separating the liquids, drying, concentrating, and crystallizing with a crystallization solvent to obtain a compound of formula 4; S4. Dissolve the compound of formula 4 in a solvent, add an amination reagent, a base, and a catalyst, and react by stirring at a temperature of T4. After the reaction is complete, add an extraction solvent, wash with water, separate the liquids, dry, concentrate, and crystallize with a crystallization solvent to obtain a compound of formula 5, i.e., 2,3-dimethyl-2H-indazole-6-amine.

3. The preparation method according to claim 2, characterized in that: S1 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 1 to the solvent is 1:(2-10), preferably 1:(5-8); The molar ratio of the compound of formula 1 to hydrazine hydrate is 1:(1-5), preferably 1:(2-3); The T1 temperature is 60-110°C, preferably 85-105°C.

4. The preparation method according to claim 2 or 3, characterized in that: In the S1, the solvent is ethanol.

5. The preparation method according to claim 2, characterized in that: S2 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 2 to the solvent is 1:(2-10), preferably 1:(6-8); The molar ratio of the compound 2 to the base and the copper salt is 1:(1-4):(0.01-0.1), preferably 1:(1.5-2):(0.01-0.05); The temperature T2 is 0-100°C, preferably 10-60°C.

6. The preparation method according to claim 2 or 5, characterized in that: S2 satisfies at least one of the following conditions: The solvent was dimethyl sulfoxide; The base is selected from one or more of sodium carbonate, potassium carbonate, DBU, sodium methoxide or potassium tert-butoxide, preferably potassium tert-butoxide; The copper salt is selected from one or more of cuprous iodide, cuprous bromide, cuprous chloride, cuprous oxide, cupric acetate, cupric chloride, cupric bromide and cupric iodide, preferably cuprous iodide.

7. The preparation method according to claim 2, characterized in that: S3 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 3 to the solvent is 1:(2-10), preferably 1:(6-8); The molar ratio of the compound of formula 3, the base and the methylating agent is 1:(0-3):(1-4), preferably 1:(0-2):(1-3); The temperature of T3 is 20-80°C, preferably 40-50°C.

8. The preparation method according to claim 2, characterized in that: S3 satisfies at least one of the following conditions: The solvent is a mixed solvent of dichloromethane and dimethyl sulfoxide, and the mixed volume ratio is 5:(1-2); The base is selected from any one of sodium methoxide, sodium bicarbonate, sodium carbonate and potassium carbonate, preferably potassium carbonate; The methylating agent is selected from dimethyl sulfate, dimethyl carbonate or methyl iodide, preferably dimethyl sulfate; The crystallization solvent is selected from one or more of methanol, ethanol and isopropanol, preferably isopropanol.

9. The preparation method according to claim 2, characterized in that: S4 satisfies at least one of the following conditions: The mass volume ratio of the compound of formula 4 to the solvent is 1:(3-10), preferably 1:(6-10); The solvent is selected from one or more of ethanol, ethylene glycol, dimethyl ether, 1,4-dioxane, NMP, and DMF, preferably 1,4-dioxane; The amination reagent is selected from any one of aqueous ammonia, ammonia gas, ammonium sulfate, and ammonium chloride, preferably aqueous ammonia; The base is selected from one or more of potassium phosphate, sodium carbonate, potassium carbonate, sodium tert-butoxide, potassium tert-butoxide, preferably potassium carbonate; The catalyst is selected from one or more of cuprous bromide, cuprous iodide, cupric oxide, cuprous oxide, bis(1,5-cyclooctadiene)nickel, and nickel powder, preferably cuprous iodide; The molar ratio of the compound of formula 4, the amination reagent, the base and the catalyst is 1:(2-8):(1-3):(0.01-0.05), preferably 1:(4-6):(2-3):(0.03-0.05); T4 temperature is 40-110°C, preferably 80-100°C; The crystallization solvent is selected from one or more of ethanol, isopropanol, ethyl acetate and petroleum ether.

10. 2,3-dimethyl-2H-indazol-6-amine obtained by the preparation method according to any one of claims 1 to 9, characterized in that: The structural formula of the 2,3-dimethyl-2H-indazole-6-amine is shown below:

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