Process for the preparation of the intermediate of Tucatinib 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline

Abstract

The application relates to the technical field of medicines, in particular to a preparation process of a Tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which comprises the following steps: step 1: under a nitrogen atmosphere, a substitution reaction is carried out on a compound B and a compound C in a base and an organic solvent system to obtain a compound D; step 2: the compound D is added into a reduction catalytic solution system protected by nitrogen, after 8-30h of reaction at 70-120 DEG C, TLC tracking is carried out until the reaction is completed, 2-8 times the volume of the compound D is added into water, post-treatment and purification are carried out, and the compound A is obtained; wherein the reduction catalytic solution system comprises a reducing agent, a catalyst and an inorganic acid, the reducing agent comprises a reducing phosphoric acid, and the catalyst comprises iodine or a metal salt of iodine. The preparation process of the Tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline in the application has mild reaction conditions, high product yield and high purity, the preparation process is environment-friendly, and can be used for industrial production.

Description

Technical Field

[0001] This application relates to the field of pharmaceutical technology, specifically to the preparation process of 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline, an intermediate of tucatinib. Background Technology

[0002] Breast cancer is one of the most common malignant tumors among women worldwide. Human epidermal growth factor receptor 2 (HER2) positive breast cancer accounts for approximately 20-25% of all breast cancers, characterized by high malignancy, rapid disease progression, and a high likelihood of lymph node metastasis. For HER2-positive advanced breast cancer, the most basic treatment principle is systemic therapy combined with anti-HER2 therapy. Currently, the first-line standard of treatment is trastuzumab combined with pertuzumab combined with taxanes. Tucatinib is a highly selective oral HER2 inhibitor. In April 2020, it was approved by the US FDA for use in combination with trastuzumab and capecitabine for the treatment of adult patients with advanced, unresectable, or metastatic HER2-positive breast cancer. Its structural formula is as follows:

[0003]

[0004] 4-([1,2,4]triazolo[1,5-a]pyridin-7-oxy)-3-methylaniline is its key intermediate, with the following structural formula:

[0005]

[0006] The methods disclosed in patents WO2019214651, CN111825604, CN109942576, etc., all employ palladium-carbon hydrogenation to reduce nitro groups. This synthetic route is lengthy, some reaction steps require high temperature and pressure conditions, and specialized hydrogenation equipment is also necessary. The reaction process is violently exothermic, posing safety hazards such as heat regeneration during spraying and potential explosions. The method disclosed in patent CN116903615, which uses traditional iron or zinc powder to reduce nitro groups, generates difficult-to-treat metal waste. Furthermore, due to the high density of iron and zinc powders, the equipment requires high stirring capacity. During scale-up, insufficient stirring often leads to incomplete reactions and impurity generation, requiring cumbersome post-processing and generating significant metal waste pollution. This results in low production efficiency, unsuitability for process control, and significantly increased production costs, contradicting the principles of green chemistry. Summary of the Invention

[0007] To effectively address the aforementioned issues, this application provides a process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline from Tucatinib. This method does not involve precious metal catalysis, nor does it involve the difficulties in post-processing and the large amount of waste pollution caused by metal reducing agents. The reaction conditions are mild, the process is simple and stable, and it is suitable for scale-up production.

[0008] The preparation process of the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline provided in this application adopts the following technical solution:

[0009] The preparation process of the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline from Tucatinib includes the following steps:

[0010] Step 1: Under a nitrogen atmosphere, compounds B and C in the formula undergo a substitution reaction in a system of alkali and organic solvent to obtain compound D in the formula;

[0011] Step 2: Add compound D to a nitrogen-protected reduction catalytic solution system and react at 70-120℃ for 8-30 hours. After the reaction is completed by TLC, add 2-8 times the volume of water of compound D and then purify to obtain compound A. The reduction catalytic solution system includes a reducing agent, a catalyst and an inorganic acid. The reducing agent includes reducing phosphoric acid and the catalyst includes iodine or a metal salt of iodine.

[0012] By adopting the above technical solution, this application first uses readily available 7-hydroxy-[1,2,4]triazolo[1,5-A]pyridine and 2-fluoro-5-nitrotoluene to undergo a nucleophilic substitution reaction. By adding a base and an organic solvent system, the substitution reaction is shifted as much as possible towards the product, thereby accelerating the reaction rate and increasing the yield of compound D. The obtained compound D is used as a reactant in the next step of catalytic reduction, which can further improve the conversion rate of compound A.

[0013] Compound D is added to a reduction catalytic solution system. Through highly selective reducing phosphoric acid, it exhibits high activity and selectivity in the conversion of heterocyclic nitrobenzene compounds. It protects the ([1,2,4]triazolo[1,5-a]pyridin-7-oxy) substituent at position 4 of the nitrobenzene ring, preventing it from participating in the nitro reduction reaction. The reducing phosphoric acid is activated by the electrophilicity of the inorganic Lewis acid, resulting in the formation of a phosphoric acid cation (PO). + or PO 2+The intermediate nucleophilic active substance combines with the electrophilic NO2 in the reactants, and after rearrangement, the NO bond breaks to form a nitrosylbenzene intermediate. The above process is repeated, and then iodine or iodine metal salt is used to generate hydroiodic acid in a Lewis acid environment. Hydroiodic acid has high reactivity and further catalyzes the kinetic rate-determining step of the nitrosylbenzene reduction reaction, finally yielding the target amine product. The above three components synergistically reduce catalyze the reduction system in step 2, resulting in a fast reaction rate, fewer side reactions, and high product purity.

[0014] In one specific implementation, the reducing phosphoric acid includes one or both of phosphorous acid and hypophosphorous acid; preferably, the reducing phosphoric acid is phosphorous acid.

[0015] By adopting the above technical solution and selecting phosphorous acid and hypophosphorous acid with high reducing power, a more thorough reduction reaction can be carried out with the nitro group of the reactant, ensuring that the nitro group is converted into an amino group. Further optimization is made by selecting phosphorous acid, which not only has reducing power but also selectivity. Under the action of catalyst and Lewis acid, the reaction is relatively mild, usually only reducing the nitro group, without producing more reduction product impurities, and without affecting other functional groups in the molecule, thus ensuring high yield and selectivity. In addition, the crystal form of the reduced product is stable and has good reproducibility.

[0016] In one specific implementation, the metal salt of iodine includes lithium iodide, sodium iodide, and potassium iodide, preferably sodium iodide.

[0017] By adopting the above technical solution, and by selecting alkali metal salts such as lithium iodide, sodium iodide, and potassium iodide as the metal salt of iodine, high reactivity is achieved under standard conditions. This greatly improves the catalytic efficiency and reduces the generation of solid impurities during the reaction process, eliminating the need for unnecessary impurity removal steps.

[0018] In one specific implementation scheme, the inorganic acid includes one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, and acetic acid; preferably, the inorganic acid is hydrobromic acid.

[0019] By selecting Lewis acids with higher activity, the reducing agent is activated, thereby reducing the reaction potential. On the other hand, it reacts with iodine or alkali metal salts of iodine to generate hydroiodic acid with higher catalytic efficiency, further enhancing the selectivity of the product and increasing the yield. In addition, Lewis acids also serve as an important source of hydrogen and participate in the amination reaction.

[0020] In one specific feasible implementation, the molar equivalent ratio of the reducing agent, catalyst and inorganic acid is (3.0-5):(1-2):5.

[0021] Preferably, the molar equivalent ratio of the reducing agent, catalyst and inorganic acid is (3.5-4):(1.4-1.7):5.

[0022] The inventors discovered that, based on the synergistic effect of the components in the aforementioned reduction system, the component ratio within the aforementioned range unexpectedly yielded superior technical results. This may be because, within a specific range, on the one hand, the reducing power, catalytic activity, and reactivity are higher, the possibility of byproducts is lower, thereby increasing the conversion yield. On the other hand, the appropriate degree of protonation of the reducing agent avoids the oxidation of other reaction-sensitive functional groups, preventing the generation of impurities and reducing the yield. The ratio within the aforementioned range maintains both high reducing power and high selectivity, thus facilitating the synergistic effect of the three components, greatly improving the yield and purity. Furthermore, this ratio maintains high yield and high activity while ensuring a moderate amount of catalyst. If the amount of catalyst is too high, more crystal nucleation occurs, resulting in poor crystal form of the product. Excessive catalyst is also prone to adsorbing onto the product, making post-processing purification difficult. Even if post-processing is adjusted to hot filtration, the catalyst is not recoverable in the reaction solution after participating in the reaction process, leading to catalyst waste and increasing the difficulty and cost of the purification process.

[0023] Preferably, the mass ratio of compound D to the reduction catalytic solution system is 1:(2.8-4.2).

[0024] By adding compound D and the reduction catalytic solution system in a certain proportion, the nitro group in compound D is completely reduced, increasing the conversion rate. This also avoids excessive reduction catalytic solution system, which could lead to over-reaction, unnecessary byproducts, and reduced yield.

[0025] In one specific implementation scheme, the post-processing purification includes cooling, adding alkali to neutralize the acid to precipitate the solid, and filtering or recrystallizing to obtain the product; wherein the alkali includes one or more of alkali metal hydroxides, carbonates, phosphates, and ammonia.

[0026] By adopting the above technical solution, an alkali neutralization reaction is added at a lower temperature, which efficiently and quickly removes excess acidic substances in the reaction. The reaction shifts towards the product, and the product is then precipitated. The product can be efficiently purified by filtration and recrystallization, thereby increasing the product yield.

[0027] In one specific implementation, the recrystallization operation is as follows: add crystallization solvent, cool to -10 to -8°C, stir, filter, wash the filter cake with crystallization solvent, collect the filtrate, concentrate the filtrate at 30 to 38°C, add crystallization solvent again, cool to -10 to -8°C, stir, filter, and collect the filter cake.

[0028] By adopting the above technical solution, adding the crystallization solvent at a lower temperature helps to reduce the solubility of the product system, facilitates better crystallization of the product, improves the product yield, and the crystallization solvent meets the requirements of multiple crystallizations, resulting in a high-purity product.

[0029] Preferably, the reaction temperature in step 2 is 90-100℃ and the reaction time is 24h.

[0030] By optimizing the reduction reaction at a suitable temperature and further controlling the efficiency of the reduction catalytic system, the product crystal form is complete, and the particle size and shape of the crystals can be effectively controlled. High-quality, high-purity products are obtained through crystallization, with good reproducibility, suitable for large-scale production. This prevents excessively high temperatures from generating excess byproducts that could affect the purity and yield of the reaction.

[0031] In one specific implementation scheme, the post-processing purification involves adjusting the pH with alkali solution, stirring, filtration, heating extraction, cooling crystallization, filtration and drying.

[0032] By adopting the above technical solution, the pH is adjusted by adding alkali solution to neutralize the acid in the reaction system, and then filtration and extraction are performed to improve the extraction speed, facilitate collection and separation, cool down to precipitate the product, and dry the high-purity product.

[0033] In summary, this application includes at least one of the following beneficial technical effects:

[0034] 1. A nucleophilic substitution reaction is carried out between 7-hydroxy-[1,2,4]triazolo[1,5-A]pyridine and 2-fluoro-5-nitrotoluene. By adding a base and an organic solvent system, the substitution reaction is shifted as much as possible towards the product, thereby accelerating the reaction rate and increasing the yield of compound D. The obtained compound D is used as a reactant in the next step of catalytic reduction, which can further improve the conversion rate of compound A.

[0035] Compound D is added to a reduction catalytic solution system. Through highly selective reducing phosphoric acid, it exhibits high activity and selectivity in the conversion of heterocyclic nitrobenzene compounds. It protects different substituents modified on the benzene ring, such as the [1,2,4]triazolo[1,5-a]pyridin-7-oxy] group at position 4 and the methyl group at position 3, preventing them from participating in the nitro reduction reaction. The reducing phosphoric acid is activated by the electrophilicity of the inorganic Lewis acid, generating a phosphoric acid cation containing the PO4 ion. + or PO 2+ The intermediate nucleophilic active substance combines with the electrophilic NO2 in the reactants, and after rearrangement, the NO bond breaks to form a nitrosylbenzene intermediate. The above process is repeated, and then iodine or iodine metal salt is used to generate hydroiodic acid in a Lewis acid environment. Hydroiodic acid has high reactivity and further catalyzes the kinetic rate-determining step of the nitrosylbenzene reduction reaction, finally yielding the target amine product. The above three components synergistically reduce catalyze the reduction system in step 2, resulting in a fast reaction rate, fewer side reactions, and high product purity.

[0036] 2. By selecting different catalysts and reducing agents and adjusting the component ratios of the reduction catalytic solution system, superior technical results were unexpectedly achieved. This may be because, within a specific range, on the one hand, the reducing power, catalytic activity, and reactivity are higher, the possibility of by-products is lower, and thus the conversion yield is improved. On the other hand, the appropriate degree of protonation of the reducing agent avoids the oxidation of other reaction-sensitive functional groups, preventing impurities and other factors that reduce the yield. The above-mentioned ratio limits maintain both high reducing power and high selectivity, which is beneficial for the synergistic effect of the three components, greatly improving the yield and purity. Moreover, at this ratio, the catalyst dosage is moderate while maintaining high yield and high activity. If the catalyst dosage is too high, more crystal nucleation occurs, resulting in poor crystal form of the product. Excessive catalyst is also prone to adsorbing onto the product, making post-processing purification difficult. Even if post-processing is adjusted to hot filtration, the catalyst cannot be recovered from the reaction solution after participating in the reaction process, resulting in catalyst waste and increasing the difficulty and cost of the purification process.

[0037] 3. Adding a crystallization solvent at a lower temperature helps reduce the solubility of the product system, which facilitates better crystallization, increases product yield, and allows the crystallization solvent to meet the requirements of multiple crystallizations, resulting in a high-purity product. Detailed Implementation

[0038] In step 1 of this application, the alkali and organic solvent system is a reaction system of potassium carbonate and N,N-dimethylformamide; all raw materials used in this application are commercially available.

[0039] Example 1

[0040] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0041] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of hydrobromic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until it is complete. After cooling to room temperature, add 195ml of water, then add 28% ammonia dropwise to adjust the pH to 8. Stir for 2h and filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene and heat to 80℃ to dissolve. Allow to stand and separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 90%, purity: 99.4%.

[0042] Example 2

[0043] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0044] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of hydrobromic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 100℃ and reacting for 18h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia water dropwise to adjust the pH to 8. Stir for 2h and filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene and heat to 80℃ to dissolve. After standing, separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 89.8%, purity: 99.2%.

[0045] Example 3

[0046] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0047] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of hydrobromic acid, sodium iodide, and hypophosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene, heat to 80℃ to dissolve, and allow to stand to separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 89.4%, purity: 98.7%.

[0048] Example 4

[0049] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0050] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of hydrobromic acid, iodine, and phosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia water dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene, heat to 80℃ to dissolve, and allow to stand to separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 89.6%, purity: 98.8%.

[0051] Example 5

[0052] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0053] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of acetic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene, heat to 80℃ to dissolve, and allow to stand to separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 89.3%, purity: 98.5%.

[0054] Example 6

[0055] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0056] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:2.5. The reduction catalytic solution consists of hydrobromic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene and heat to 80℃ to dissolve. After standing, separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 87.5%, purity: 89.7%.

[0057] Example 7

[0058] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0059] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:4.8. The reduction catalytic solution consists of hydrobromic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene and heat to 80℃ to dissolve. After standing, separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 88.1%, purity: 85.4%.

[0060] Example 8

[0061] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0062] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution system and water, wherein the mass ratio of compound D to reduction catalytic solution system is 1:3.8. The reduction catalytic solution system consists of hydrobromic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1:3. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until it is complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia water dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene, heat to 80℃ to dissolve, and let stand to separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 89.7%, purity: 99.0%.

[0063] Example 9

[0064] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0065] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of hydrobromic acid, sodium iodide, and phosphorous acid in a molar ratio of 5:1.5:2.5. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water. Then, add 28% ammonia water dropwise to adjust the pH to 8. After stirring for 2h, filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene, heat to 80℃ to dissolve, and allow to stand to separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 87.1%, purity: 86.9%.

[0066] Example 10

[0067] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0068] Step 2: Add 65g of compound D to the reaction flask, and under nitrogen protection, add a mixture of 382g of reduction catalytic solution system and water, wherein the mass ratio of compound D to reduction catalytic solution system is 1:3.8; the reduction catalytic solution system consists of hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.5:3; after heating to 90℃ and reacting for 24h, the reaction is monitored by TLC until complete, and after cooling to room temperature, add 195ml of water, then cool to 10℃, add 168ml of sodium carbonate to neutralize the acid and precipitate the solid, filter, and dry at 60℃ to obtain compound A, yield: 90%, purity: 99.5%.

[0069] Example 11

[0070] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0071] Step 2: Add 65g of compound D to the reaction flask, and under nitrogen protection, add a mixture of 382g of reduction catalytic solution system and water, wherein the mass ratio of compound D to reduction catalytic solution system is 1:3.8; the reduction catalytic solution system consists of hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.5:3; heat to 90℃ and react for 24h, then monitor the reaction by TLC until complete, cool to room temperature and add 195ml of water, then cool to 10℃, add 168ml of sodium carbonate to neutralize the acid and precipitate the solid, add toluene as the crystallization solvent, cool to -10 to -8℃, stir and filter, wash the filter cake with toluene, collect the filtrate, concentrate the filtrate at 30-38℃, add toluene again, cool to -10 to -8℃, stir and filter, collect the filter cake, dry at 60℃ to obtain compound A, yield: 90.1%, purity: 99.6%.

[0072] Comparative Example 1

[0073] A process for preparing the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of tucatinib includes the following steps: Step 1: Under nitrogen protection, 40g of compound B, 45g of compound C, 61.4g of potassium carbonate and 160ml of N,N-dimethylformamide are added to a reaction flask. The mixture is heated to 80℃ and stirred for 10h. TLC analysis shows that 1% of the raw material remains. After cooling to 10℃, 320ml of water is added dropwise and stirred for 2h. The mixture is then filtered, and the filter cake is washed with 240ml of water. The filter cake is then washed with a mixed solvent of 160ml of methanol and water (methanol to water volume ratio of 1:4). The mixture is then dried under reduced pressure at 50℃ for 8h to obtain compound D.

[0074] Step 2: Add 65g of compound D to the reaction flask. Under nitrogen protection, add a mixture of 382g of reduction catalytic solution and water, wherein the mass ratio of compound D to reduction catalytic solution is 1:3.8. The reduction catalytic solution consists of water, sodium iodide, and phosphorous acid in a molar ratio of 5:0.6:3.6. After heating to 90℃ and reacting for 24h, monitor the reaction by TLC until complete. After cooling to room temperature, add 195ml of water, then add 28% ammonia dropwise to adjust the pH to 8. Stir for 2h, then filter. Wash the filter cake with 50ml of water. Add the wet filter cake to 455ml of toluene, heat to 80℃ to dissolve, and allow to stand to separate the aqueous layer. Cool the organic layer to 10℃ to crystallize. After filtration, dry at 60℃ to obtain compound A. Yield: 74.1%, purity: 76.9%.

[0075] The preparation process of the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline in the embodiments and comparative examples of this application features mild reaction conditions, simple process, high yield and purity of the target product, low content of by-product isomers, and low reagent cost, making it suitable for industrial-scale production. This avoids the high-temperature hydrogenation, stringent reaction conditions and safety issues inherent in noble metal catalytic hydrogenation, as well as the incompatibility of heterocyclic structures sensitive to reductive hydrogenation, which can lead to side reactions, reduced yields, and limited substrate selectivity. Specifically, compared to Example 1 and Comparative Example 1, the different reduction catalytic solution system in this reaction system results in insufficient activation of the reducing agent and difficulty in obtaining hydrogen, leading to side reactions and reduced yields and purity. Compared to Examples 6-7, Example 1 had a lower feed ratio of reactant compound D to the reduction catalytic solution system, resulting in some reactants not being reduced or undergoing side reactions. Conversely, a higher feed ratio of reactant compound D to the reduction catalytic solution system led to excessive reduction catalysis, resulting in more adverse reactions and affecting purification efficiency. Compared to Examples 8-9, Example 1 had a lower molar equivalent of the reducing agent in the reduction catalytic solution system than the range specified in this application, resulting in a lower content of the reducing agent's affinity and active substances, lower reactivity, and a higher probability of adverse reactions, affecting yield and purity. Compared to Example 10, Example 11 showed that the target product obtained in Example 11, after two recrystallization separation processes, showed that some products that were not effectively separated during filtration were effectively separated by recrystallization, thus improving product purity and yield.

[0076] The above are all preferred embodiments of this application, and are not intended to limit the scope of protection of this application. Therefore, all equivalent changes made in accordance with the structure, shape and principle of this application should be covered within the scope of protection of this application.

Claims

1. Process for the preparation of the intermediate of Tucatinib, 4-([1,2,4]triazolo[1,5- a]pyridine-7-yloxy)-3-methylaniline, characterized by: comprising the steps of: Step 1: under nitrogen atmosphere, compound B and compound C are subjected to substitution reaction in a base and organic solvent system to obtain compound D; Step 2: compound D is added into a nitrogen-protected reduction catalytic solution system, after reaction at 90℃ for 24h, TLC tracking is performed until the reaction is completed, 2-8 times volume of water of compound D is added, and after-treatment and purification are performed to obtain compound A; wherein, the reduction catalytic solution system is composed of a reducing agent, a catalyst and an inorganic acid, the reducing agent is a reducing phosphoric acid, and the catalyst is selected from iodine or a metal salt of iodine; the reducing phosphoric acid is phosphorous acid; the metal salt of iodine is selected from lithium iodide, sodium iodide and potassium iodide; the inorganic acid is selected from one or more of hydrochloric acid, hydrobromic acid and hydroiodic acid; the molar equivalent ratio of the reducing agent, the catalyst and the inorganic acid is (3.5-4):(1.4-1.7):5; the mass ratio of compound D and the reduction catalytic solution system is 1:(2.8-4.2).

2. A process for the preparation of the formulation of the intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylaniline of formula (I) according to claim 1, characterized by: The after-treatment and purification comprises acid precipitation of solid by cooling and alkali neutralization, filtration or recrystallization; wherein, the alkali comprises one or more of alkali metal hydroxide and ammonia.

3. A process for the preparation of the formulation of the intermediate 4-([1,2,4]triazolo[1,5- a]pyridine-7-yloxy)-3-methylaniline of formula (I) according to claim 2, characterized by: The recrystallization is specifically performed as follows: a crystallization solvent is added, the temperature is lowered to -10--8℃, stirring and filtration are performed, the filter cake is washed with the crystallization solvent, the filtrate is collected, the filtrate is concentrated at 30-38℃, the crystallization solvent is added again, the temperature is lowered to -10--8℃, stirring and filtration are performed, and the filter cake is collected.

4. A process for the preparation of the formulation of the intermediate of futuxanib, 4-([1,2,4]triazolo[1,5-a]pyridine-7-yloxy)-3-methylaniline according to claim 1, characterized in that, The after-treatment and purification is adjusting pH by adding alkali solution, stirring, suction filtration, heating extraction, cooling crystallization, suction filtration and drying.

Images