A process for the preparation of a pazopanib intermediate, 2,3-dimethyl-6-amino-2H-indazole and analogs thereof

Abstract

This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole and its analogues. The method includes the following steps: nitrifying the compound shown in Formula II under acidic conditions to obtain Compound III; oxidizing Compound III to obtain Compound IV; condensing Compound IV with an amine to obtain Compound V, and then performing a reduction cyclization reaction to obtain Compound I. This invention uses Formulas II and III as raw materials and prepares Compound I with a purity >98% through simple steps such as nitration, oxidation, and reduction cyclization. This invention is a low-cost and simple-to-operate synthetic technique suitable for large-scale commercial production.

Description

Technical Field

[0001] This invention relates to the field of pharmaceutical synthesis technology, and in particular to a method for preparing pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole and its analogues. Background Technology

[0002] Pazopanib is a novel oral angiogenesis inhibitor developed by GlaxoSmithKline (GSK) that interferes with angiogenesis, a process essential for the survival and growth of refractory tumors. It was approved by the U.S. Food and Drug Administration (FDA) in 2009. Pazopanib effectively inhibits VEGFR1, VEGFR2, VEGFR3, PDGFRα, PDGFRβ, Kit, FGFR1, and FGFR3, making it a small-molecule, orally administered, multi-target inhibitor primarily focused on anti-angiogenesis. Formulation and strength: Tablets: 200mg. Indications: This product is indicated for first-line treatment of advanced renal cell carcinoma (RCC) and for the treatment of advanced RCC patients who have previously received cytokine therapy. In February 2017, pazopanib was approved for marketing in China for the first-line treatment of advanced renal cell carcinoma and for the treatment of advanced RCC patients who have previously received cytokine therapy. The original drug was first approved for marketing in China in 2017, and the domestic market for this product has continued to expand in recent years. According to data from Menet, in 2020, the sales of pazopanib tablets in China's three major terminals and six major markets exceeded 300 million yuan, a year-on-year increase of 111.16%; in 2021, its sales exceeded 400 million yuan, a year-on-year increase of 20.16%.

[0003] 2,3-Dimethyl-6-nitro-2H-indazole compound (I) is an important structural fragment for the synthesis of pazopanib. All reported processes for the preparation of pazopanib use formula I as a reaction intermediate.

[0004]

[0005] Currently, there are relatively few reported methods for synthesizing compound I in the literature. The commercially available route uses 2-ethylaniline as a starting material, first undergoing a nitration reaction, then preparing a pyrazole ring via sodium nitrite under acidic conditions, and finally preparing compound I through methylation and nitro reduction. This route has significant drawbacks: ① The cyclization step produces many byproducts and has a low yield; ② The nitrogen methylation step uses reagents such as dimethyl sulfate and iodomethane, which are highly toxic and corrosive, posing a strong carcinogenic risk and significant safety risks during production and use. Furthermore, the production process generates large amounts of industrial wastewater, causing severe environmental pollution; ③ The methylation step has a low yield. Due to the high reactivity of both nitrogen atoms in the indole heterocycle, the selectivity is poor, and positional isomers are inevitably formed during the reaction, increasing the difficulty of product purification.

[0006]

[0007] Since 2,3-dimethyl-6-amino-2H-indazole and its analogues (I) are key intermediates in the preparation of pazopanib, developing a simple, low-cost technology suitable for commercial production would have great market application value. Summary of the Invention

[0008] The purpose of this invention is to overcome the shortcomings of the prior art and provide a new method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole and its analogues.

[0009] To achieve the above objectives, the technical solution adopted in this invention is as follows:

[0010] A method for preparing pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole and its derivatives, the method comprising the following steps:

[0011] Compound S1, represented by formula II, is nitrated under acidic conditions to produce compound IV.

[0012]

[0013] R1 is selected from hydrogen, fluorine, chlorine, bromine, methyl, ethyl, and nitro; R2 is selected from hydrogen or C1 to C6 alkanes.

[0014] Compound S2 III was oxidized to prepare compound IV;

[0015]

[0016] Compound S3 IV was synthesized into compound V via a condensation reaction.

[0017]

[0018] Compound S4V was subjected to a reductive cyclization reaction to obtain the compound shown in Formula I.

[0019]

[0020] In a preferred embodiment, the NH2-R3 is selected from one of amines, methylamine, ethylamine, glycine, sarcosine, aniline, and p-methoxyaniline.

[0021] In a preferred embodiment, concentrated sulfuric acid is used as the acid in step S1, and the amount added is 2 to 6 times the mass ratio of Formula II, and the reaction temperature is 0 to 80°C.

[0022] In a preferred embodiment, the nitrifying agent in step S1 is nitric acid, with Formula II as a reference, and the amount added is 1 to 3 molar equivalents.

[0023] In a preferred embodiment, step S2 specifically involves oxidizing compound III to compound IV in the presence of an oxidant, a catalyst, and a solvent.

[0024] The oxidizing agent is Oxone, with Formula III as a reference, and the molar ratio used is 1 to 2 equivalents.

[0025] The catalyst is one of sodium bromide, potassium bromide, or hydrogen bromide.

[0026] The solvent may be one or a mixture of several of the following: dichloromethane, ethanol, methanol, tetrahydrofuran, water, and toluene.

[0027] In a preferred embodiment, the solvent used in S3 is selected from one or a mixture of several of tetrahydrofuran, toluene, methanol, ethanol, isopropanol, and ethyl acetate;

[0028] The catalyst used in the reaction is one of acetic acid, formic acid, hydrochloric acid, or trifluoroacetic acid, with Formula VI as a reference, and the amount of acid used is 0.1 to 1 equivalent.

[0029] In a preferred embodiment, the NH2-R3 is selected from amines, methylamine, ethylamine, glycine, methylglycine, aniline, and p-methoxyaniline.

[0030] In a preferred embodiment, the reducing agent used in step S4 is palladium on carbon, with a palladium content of 3-10%, and the mass ratio of the reducing agent used with reference to Formula V is 5%-20%.

[0031] The solvent used is one or a mixture of several of the following: methanol, ethanol, isopropanol, tetrahydrofuran, water, toluene, and glacial acetic acid.

[0032] The technical solution of this invention has the following beneficial effects:

[0033] This invention uses Formula II and Formula III as raw materials and prepares Formula I through steps such as nitration, oxidation, condensation, and reductive condensation. The purity is >98.5%, and the reaction process does not require the use of alkylating agents for methylation.

[0034] This invention is a low-cost and easy-to-operate synthesis technique suitable for large-scale commercial production. Detailed Implementation

[0035] The present invention is further illustrated below by way of embodiments, but the invention is not limited to the scope of the embodiments described herein. Experimental methods in the following embodiments that do not specify specific conditions were performed according to conventional methods and conditions, or as selected according to the product instructions.

[0036] Example 1

[0037] (1) Preparation of compound 2,4-dinitroethylbenzene

[0038] Add 4.45 kg of concentrated sulfuric acid to the reaction vessel, maintain the temperature at 0–10 °C, and add 1.06 kg (10 mol) of ethylbenzene dropwise. After stirring until homogeneous, slowly add 1.26 kg of nitric acid dropwise to the reaction vessel, maintain the temperature at 0–20 °C, and continue the reaction at 60–70 °C for 3–5 hours until complete. Slowly pour the system into 10.1 kg of ice water to dilute, maintain the temperature below 10 °C, and continue stirring for 0.5 hours. Adjust the pH to 6–8 by adding sodium hydroxide aqueous solution dropwise, centrifuge, rinse the filter cake with water, and dry to obtain 1.63 kg of compound 2,4-dinitroethylbenzene, yield 83%, purity 95.6%, mass spectrometry: m / s 197.06 [M]. + .

[0039] (2) Preparation of compound 2,4-dinitroacetophenone

[0040] 2,4-Dinitroethylbenzene (980 g, 5 mol), dichloromethane (9.8 kg), potassium bromide (714 g, 6 mol), and water (980 g) were added to a reaction flask and stirred until homogeneous at room temperature. Oxone (2.08 kg, 6 mol) was added in batches and reacted at room temperature for 10–15 h. The reaction was monitored until completion. After completion, water was added for extraction and separation. The organic layer was concentrated and then slurried with methanol / water to obtain the target product, 967 g, yield 92%, purity 97.6%. Mass spectrometry: m / s 211.08 [M] + .

[0041] (3) Preparation of compound 1-(2,4-dinitrophenyl)-N-methylethyl-1-imine

[0042] Add 42.6 g (0.2 mol) of 2,4-dinitroacetophenone, 300 ml of ethanol, 32 ml of methylammonium aqueous solution (25% concentration), and 2 ml of glacial acetic acid to a reaction flask, stir overnight at room temperature; add water to precipitate the solid, filter and dry to obtain the target product, 37.4 g, 85%.

[0043] (4) Preparation of compound 2,3-dimethyl-6-amino-2H-indazole

[0044] Compound 1-(2,4-dinitrophenyl)-N-methylethyl-1-imine (22.3 g, 0.1 mol), isopropanol (150 mL), and palladium on carbon (3%, 2.2 g) were added to a hydrogenation reactor. The hydrogen pressure was controlled at 0.05–1 MPa, and the mixture was stirred at room temperature for 3 h. Then, the temperature was raised to 60–70 °C and the reaction was continued for 3–5 h. After the reaction was completed, the palladium on carbon was filtered off, and an ethanol solution of HCl was added to the filtrate, precipitating a solid. The solid was filtered, and the filter cake was dissolved in 100 mL of water. The pH was adjusted to neutral with sodium bicarbonate, resulting in the precipitation of a large amount of solid. After filtration and drying, 10.5 g of the target product was obtained, with a yield of 65%.

[0045] Example 2

[0046] Preparation of compound 2,3-dimethyl-6-amino-2H-indazole

[0047] Add 42.6 g (0.2 mol) of 2,4-dinitroacetophenone, 300 ml of isopropanol, and 20 g (0.22 mol) of sarcosine to a reaction flask. Reflux the reaction mixture for 4–6 hours, removing water using a water separator. Cool to room temperature, add 3% palladium on carbon (6.3 g), maintain the hydrogen pressure at 0.05–1 MPa, and stir overnight at 50–60 °C. After the reaction is complete, filter off the palladium on carbon. Add an ethanol solution of HCl to the reaction mixture, precipitating a solid. Filter, dissolve the filter cake in 150 ml of water, adjust the pH to neutral with sodium bicarbonate, filter, and dry to obtain the target product, 10.5 g, yield 65%.

[0048] Example 3

[0049] Preparation of compound 1-(2,4-dinitrophenyl)-N-(4-methoxyphenyl)ethane-1-imine

[0050] Add 42.6 g (0.2 mol) of 2,4-dinitroacetophenone, 300 ml of ethanol, 27 g (0.22 mol) of 4-methoxyaniline, and 2 ml of glacial acetic acid to a reaction flask, and stir overnight at room temperature; add water, filter and dry to obtain the target product, 60.5 g, 96%.

[0051] Preparation of compound 2-(4-methoxyphenyl)-3-methyl-6-amino-2H-indazole

[0052] Compound 1-(2,4-dinitrophenyl)-N-(4-methoxyphenyl)ethane-1-imine (15.7 g, 0.05 mol), isopropanol (120 mL), and palladium on carbon (3%, 1.6 g) were added to a hydrogenation reactor. The hydrogen pressure was controlled at 0.05–1 MPa, and the mixture was stirred at room temperature for 2 hours. Then, the temperature was raised to 60–70 °C and the reaction was continued for 5–8 hours. After the reaction was completed, the palladium on carbon was filtered off, and an ethanol solution of HCl was added to the reaction solution, precipitating a solid. The solid was filtered, and the filter cake was dissolved in 100 mL of water. The pH was adjusted to neutral with sodium bicarbonate, filtered, and dried to obtain the target product, 9.8 g, with a yield of 78%.

[0053] Example 4

[0054] (1) Preparation of compound 2,4-dinitrotoluene

[0055] 450g of concentrated sulfuric acid was added to the reaction vessel. After the addition was complete, the temperature was controlled at 0-10℃, and toluene (92.1g, 1mol) was added dropwise. After stirring evenly, 130g of nitric acid was slowly added dropwise to the reaction vessel while maintaining the temperature at 0-20℃. The temperature was raised to 60-70℃ and the reaction was continued for 3-5 hours until complete. The system was slowly poured into 1500g of ice water for dilution, and the temperature was kept below 10℃ while stirring was continued for 0.5 hours. A pre-prepared sodium hydroxide aqueous solution was added dropwise to adjust the pH to 6-8. After centrifugation, the filter cake was washed with water and dried to obtain 142g of compound 2,4-dinitrotoluene, with a yield of 78% and a purity of 97.7%. Mass spectrometry: m / s 183.16 [M] + .

[0056] (2) Preparation of compound 2,4-dinitrobenzaldehyde

[0057] 2,4-Dinitrotoluene (91 g, 0.5 mol), dichloromethane (910 ml), potassium bromide (71.4 g, 0.6 mol), and water (90 g) were added to a reaction flask and stirred until homogeneous at room temperature. Oxone (208 g, 0.6 mol) was added in batches and reacted at room temperature for 10–15 h. The reaction was monitored until completion. After completion, water was added for extraction and separation. The organic layer was concentrated and then slurried with methanol / water to obtain the target product, 81.3 g, yield 83%, purity 95.9%. Mass spectrometry: m / s 197.1 [M] + .

[0058] (3) Preparation of compound 2-methyl-6-amino-2H-indazole

[0059] Compound 2,4-dinitrobenzaldehyde (19.6 g, 0.1 mol), sarcosine (10 g, 0.11 mol), glacial acetic acid (2 ml), isopropanol (150 mL), and palladium on carbon (3%, 2.2 g) were added to a hydrogenation reactor. The hydrogen pressure was controlled at 0.05–1 MPa. After stirring at room temperature for 2 h, the temperature was raised to 60–70 °C and the reaction was continued for 5–8 h. After the reaction was completed, the palladium on carbon was filtered off, and an ethanol solution of HCl was added to the reaction solution, precipitating a solid. The solid was filtered, and the filter cake was dissolved in 100 ml of water. The pH was adjusted to neutral with sodium bicarbonate, filtered, and dried to obtain the target product, 8.67 g, yield 59%. Mass spectrometry: m / s 148.18 [M]+.

[0060] Example 5

[0061] (1) Preparation of compound 2-nitro-4-fluoroethylbenzene

[0062] 120g of concentrated sulfuric acid was added to the reaction vessel. After the addition was complete, the temperature was controlled at 0-10℃, and 24.8g (0.2mol) of 4-fluoroethylbenzene was added dropwise. After stirring evenly, 16g of nitric acid was slowly added dropwise to the reaction vessel while controlling the temperature at 0-20℃. The temperature was raised to 40-50℃ and the reaction was continued for 3-5 hours until complete. The system was slowly poured into 300g of ice water for dilution, and the temperature was kept below 10℃. Stirring was continued for 0.5 hours. A pre-prepared sodium hydroxide aqueous solution was added dropwise to adjust the pH to 6-8. The mixture was centrifuged, the filter cake was washed with water, and dried to obtain 29.4g of the target compound, with a yield of 87% and a purity of 98.4%. Mass spectrometry: m / s 170.16 [M] + .

[0063] (2) Preparation of compound 2-nitro-4-fluoroacetophenone

[0064] 2-Nitro-4-fluoroethylbenzene (16.9 g, 0.13 mol), dichloromethane (170 ml), potassium bromide (16.7 g, 0.14 mol), and water (17 g) were added to a reaction flask and stirred until homogeneous at room temperature. Oxone (48 g, 0.14 mol) was added in batches and reacted at room temperature for 10–15 h. The reaction was monitored until completion. After completion, water was added for extraction and separation. The organic layer was concentrated and then slurried with methanol / water to obtain the target product, 20.2 g, yield 85%, purity 97.2%. Mass spectrometry: m / s 184.1 [M] + .

[0065] Example 6

[0066] (1) Preparation of compound 1,4-diethyl-2-nitrobenzene

[0067] 120g of concentrated sulfuric acid was added to the reaction vessel. After the addition was complete, the temperature was controlled at 0-10℃, and 26.8g (0.2mol) of 1,4-diethylbenzene was added dropwise. After stirring evenly, 16g of nitric acid was slowly added dropwise to the reaction vessel while controlling the temperature at 0-20℃. The temperature was raised to 40-50℃ and the reaction was continued for 3-5 hours until complete. The system was slowly poured into 300g of ice water for dilution, and the temperature was kept below 10℃. Stirring was continued for 0.5 hours. A pre-prepared sodium hydroxide aqueous solution was added dropwise to adjust the pH to 6-8. The mixture was centrifuged, the filter cake was washed with water, and dried to obtain 29.4g of the target compound, with a yield of 87% and a purity of 98.4%. Mass spectrometry: m / s 170.16 [M] + .

[0068] (2) Preparation of compound 2-nitro-4-ethylacetophenone

[0069] 1,4-Diethyl-2-nitrobenzene (23.27 g, 0.13 mol), dichloromethane (230 ml), potassium bromide (16.7 g, 0.14 mol), and water (23 g) were added to a reaction flask and stirred until homogeneous at room temperature. Oxone (48 g, 0.14 mol) was added in batches and reacted at room temperature for 10–15 h. The reaction was monitored until completion. After completion, water was added for extraction and separation. The organic layer was concentrated and then slurried with methanol / water to obtain the target product, 23.2 g, yield 92%, purity 95.9%. Mass spectrometry: m / s 194.1 [M] + .

[0070] The embodiments described above are merely illustrative of several implementations of the present invention, and while the descriptions are specific and detailed, they should not be construed as limiting the scope of the invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these all fall within the scope of protection of the present invention. Therefore, the scope of protection of the present invention should be determined by the appended claims.

Claims

1. A method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole, characterized in that: The method includes the following steps: Compound S1, represented by formula II, is nitrated under acidic conditions to produce compound III. ； Where R1 is selected from nitro; R2 is selected from methyl; Concentrated sulfuric acid should be used as the acid. The nitrating agent is nitric acid; Compound S2 III is oxidized to compound S2 IV in the presence of an oxidant, a catalyst and a solvent. ； The oxidizing agent is Oxone; Potassium bromide was selected as the catalyst. Compound S3 IV was synthesized into compound V via a condensation reaction. ； Acetic acid was selected as the catalyst in the reaction. NH2-R3 is selected from methylamine; Compound S4V was subjected to a reductive cyclization reaction in the presence of palladium on carbon and hydrogen to obtain the compound shown in Formula I. 。 2. The method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole according to claim 1, characterized in that: In step S1, the amount of acid added is 2 to 6 times the mass ratio of Formula II, and the reaction temperature is 0 to 80°C.

3. The method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole according to claim 1, characterized in that: The nitrifying agent in step S1 is based on Formula II and is added in an amount of 1 to 3 molar equivalents.

4. The method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole according to claim 1, characterized in that: In step S2, The oxidizing agent is based on Formula III, and the molar ratio used is 1 to 2 equivalents. The catalyst is based on Formula III, and the amount of catalyst used is 0.1 to 1 equivalent. The solvent may be one or a mixture of several of the following: dichloromethane, ethanol, methanol, tetrahydrofuran, water, and toluene.

5. The method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole according to claim 1, characterized in that: The solvent used in S3 is selected from one or a mixture of several of tetrahydrofuran, toluene, methanol, ethanol, isopropanol, and ethyl acetate; The catalyst used in the reaction is based on Formula IV, and the amount of acid used is 0.1 to 1 equivalent.

6. The method for preparing the pazopanib intermediate 2,3-dimethyl-6-amino-2H-indazole according to claim 1, characterized in that: The palladium content of palladium on carbon used in step S4 is 3-10%, and the mass ratio of palladium on carbon used with reference to formula V is 5%-20%. The solvent used in step S4 is one or a mixture of several of methanol, ethanol, isopropanol, tetrahydrofuran, water, toluene, and glacial acetic acid.

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