Preparation process of 4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-oxy)-3-methylaniline as intermediate of Fikatinib

Abstract

The invention relates to the technical field of medicines, in particular to a preparation process of a Fikatinib intermediate 4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-oxy)-3-methylaniline, which comprises the following steps: step 1, in a nitrogen atmosphere, carrying out substitution reaction on a compound B and a compound C in a formula in an alkali and organic solvent system to obtain a compound D in a formula; step 2, adding the compound D into a reduction catalysis solution system protected by nitrogen, reacting at 70-120 DEG C for 8-30 hours, tracking by TLC until the reaction is complete, adding water which is 2-8 times of the volume of the compound D, and performing post-treatment and purification to obtain a compound A; wherein the reduction catalysis solution system comprises a reducing agent, a catalyst and inorganic acid, the reducing agent comprises reducing phosphoric acid, and the catalyst comprises iodine or metal salt of iodine. According to the preparation process of the 4-([1, 2, 4] triazolo [1, 5-a] pyridine-7-oxy)-3-methylaniline intermediate, the reaction condition is mild, the prepared product is high in yield and purity, the preparation process is environmentally friendly, and the preparation process can be used for industrial production.

Description

Technical Field

[0001] The present application relates to the field of pharmaceutical technology, and in particular to a process for preparing a tucatinib intermediate, 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline. Background Art

[0002] Breast cancer is one of the most common malignant tumors among women worldwide, of which human epidermal growth factor receptor 2 (HER2)-positive breast cancer accounts for about 20-25% of all breast cancers. It is characterized by high malignancy, rapid disease progression, and easy lymph node metastasis. For HER2-positive advanced breast cancer, the most basic treatment principle is systemic treatment combined with anti-HER2 treatment. The current 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 U.S. FDA for combination with trastuzumab and capecitabine for the treatment of adult patients with advanced unresectable or metastatic HER2-positive breast cancer. The structural formula is as follows: 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline is its key intermediate, and its structural formula is as follows: The methods disclosed in patents WO2019214651, CN111825604, CN109942576, etc. all use palladium carbon hydrogenation to reduce nitro groups. The synthesis route is long, and some reaction steps require high temperature and high pressure conditions. Special hydrogenation equipment is also required. The reaction process is highly exothermic, and there are safety hazards such as heat storage spraying and explosion. The method disclosed in patent CN116903615 uses traditional iron powder or zinc powder to reduce nitro groups, which will generate difficult-to-handle metal waste. On the other hand, due to the large specific gravity of iron powder and zinc powder, the stirring capacity of the equipment is required to be high. During the amplification, insufficient stirring often leads to incomplete reaction and the generation of impurities. It requires cumbersome post-processing processes and a large amount of metal waste pollution, low production efficiency, and is not suitable for process treatment. It seriously increases production costs and does not conform to the production concept of green chemistry. Summary of the invention

[0003] In order to effectively improve the above problems, the present application provides a preparation process of tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline. The method does not involve precious metal catalysis, metal reducing agents, etc., which may cause post-processing difficulties and large amounts of waste pollution. The reaction conditions are mild, the process is simple and stable, and it is suitable for large-scale production.

[0004] The preparation process of the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline provided in the present application adopts the following technical scheme: The preparation process of tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline comprises the following steps: Step 1: Under nitrogen atmosphere, compound B and compound C in the formula are subjected to substitution reaction in a base and organic solvent system to obtain compound D in the formula; Step 2: Add compound D to a nitrogen-protected reduction catalytic solution system, react at 70-120° C. for 8-30 hours, track the reaction by TLC until the reaction is complete, add 2-8 times the volume of compound D in water, and post-treat and purify to obtain compound A; wherein 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.

[0005] By adopting the above technical scheme, the present application firstly conducts a nucleophilic substitution reaction between the simply available 7-hydroxy-[1,2,4]triazolo[1,5-A]pyridine and 2-fluoro-5-nitrotoluene, and then adds a base and an organic solvent system to move the substitution reaction as far as possible in the direction of the product, thereby accelerating the reaction rate and increasing the yield of the generated compound D. The obtained compound D is used as a reactant in the catalytic reduction process in the next step, thereby improving the conversion rate of compound A.

[0006] Compound D is put into a reduction catalytic solution system. Through highly selective reducing phosphoric acid, in the conversion process of heterocyclic nitrobenzene compounds, it has high activity and good selectivity. The ([1,2,4]triazolo[1,5-a]pyridine-7-oxy) substituent connected to the 4th position of the nitrobenzene ring is protected and does not participate in the nitro reduction reaction. The reducing phosphoric acid can be activated by the electrophilicity of the inorganic Lewis acid to produce a phosphoryl cation PO + or PO 2+ The intermediate nucleophilic active substance is then combined with the electrophilic NO2 in the reaction raw material, and the NO bond is broken after rearrangement to form a nitrosobenzene intermediate. The above process is repeated, and hydroiodic acid is generated in a Lewis acid environment through iodine or iodine metal salt. Hydroiodic acid has high reactivity and further catalyzes the kinetic rate-determining step of the nitrobenzene reduction reaction to finally obtain the target amino product. The reduction catalytic solution system with the above three components is applied to the reduction system of step 2, which makes the reaction speed fast, the side reactions are few, and the product purity is high.

[0007] In a specific embodiment, the reducing phosphoric acid includes one or both of phosphorous acid and hypophosphorous acid; preferably, the reducing phosphoric acid is phosphorous acid.

[0008] By adopting the above technical scheme, by selecting phosphorous acid and hypophosphorous acid with higher reducing properties, a more thorough reduction reaction can be carried out with the nitro group of the reactant to ensure that the nitro group is converted into an amine group. Further preferred is phosphorous acid which is not only reducing but also selective. Under the action of a catalyst and a Lewis acid, the reaction is relatively mild, usually only the nitro group is reduced, no more impurities of the reduced product are generated, and other functional groups in the molecule are not affected, so as to ensure high yield and selectivity, and the crystal form of the reduced product is stable and reproducible.

[0009] In a specific embodiment, the metal salt of iodine includes lithium iodide, sodium iodide, potassium iodide, and preferably, the metal salt of iodine is sodium iodide.

[0010] By adopting the above technical scheme, by selecting the metal salt of iodine, alkali metal salts such as lithium iodide, sodium iodide, potassium iodide, etc. are selected, which have high reaction activity under standard conditions; the catalytic efficiency is greatly improved, and during the reaction process, solid impurities are not easily generated, and no unnecessary impurity removal steps are generated.

[0011] In a specific embodiment, the inorganic acid includes one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid, and acetic acid; preferably, the inorganic acid is hydrobromic acid.

[0012] By selecting a Lewis acid with higher activity, on the one hand, the reducing agent is activated to reduce the reaction potential energy, and on the other hand, it reacts with iodine or an alkali metal salt of iodine to generate hydroiodic acid with higher catalytic efficiency, further enhancing the selectivity of the product and improving the yield. In addition, the Lewis acid also acts as an important H source and participates in the amination reaction.

[0013] In a specific embodiment, the molar equivalent ratio of the reducing agent, the catalyst and the inorganic acid is (3.0-5):(1-2):5.

[0014] Preferably, the molar equivalent ratio of the reducing agent, the catalyst and the inorganic acid is (3.5-4):(1.4-1.7):5.

[0015] The inventors found that, based on the synergistic effect of the components of the above-mentioned reduction system, the component ratio within the above-mentioned range unexpectedly obtained a better technical effect. This may be because, within a specific range, on the one hand, the reducibility, catalyticity and reaction activity can be made higher, the possibility of by-products is small, and the conversion yield is improved. On the other hand, the degree of protonation of the reducing agent is appropriate to avoid oxidation of other reaction-sensitive functional groups, the generation of impurities and the like to reduce the yield. The ratio limit within the above-mentioned range maintains high reducibility and high selectivity at the same time, which is conducive to the joint action of the three components, greatly improving the yield and purity. In addition, under this ratio, the catalyst dosage can be moderate while maintaining high yield and high activity. If the catalyst dosage is too high, more crystal nucleation will occur, the product crystal form is not good, and the excess catalyst will easily be adsorbed on the product, making post-processing purification difficult. Even if the post-processing is adjusted to be filtered while hot, because the catalyst cannot be recovered in the reaction liquid after participating in the reaction process, it will also cause catalyst waste, increasing the difficulty and cost of the purification process.

[0016] Preferably, the mass ratio of the compound D to the reduction catalytic solution system is 1:(2.8-4.2).

[0017] By adding compound D and the reducing catalytic solution system into the reaction within a certain ratio range, the nitro group in compound D can be completely reduced, thereby increasing the conversion rate. It is also avoided that the reducing catalytic solution system is excessive, which causes over-reaction and produces unnecessary by-products, thereby affecting the yield.

[0018] In a specific embodiment, the post-treatment purification includes cooling, adding alkali to neutralize the acid to precipitate the solid, filtering or recrystallizing it; wherein the alkali includes one or more of alkali metal hydroxides, carbonates, phosphates, and ammonia water.

[0019] By adopting the above technical scheme, alkali is added to neutralize the reaction at a relatively low temperature, and the excess acidic substances in the reaction are removed efficiently and quickly, and the reaction moves to the product, and then the product is precipitated. It can be efficiently purified by filtration and recrystallization, thereby increasing the product yield.

[0020] In a specific embodiment, the recrystallization operation is as follows: adding a crystallization solvent, cooling to -10--8°C, stirring, filtering, washing the filter cake with the crystallization solvent, collecting the filtrate, concentrating the filtrate at 30-38°C, adding a crystallization solvent again, cooling to -10--8°C, stirring, filtering, and collecting the filter cake.

[0021] By adopting the above technical solution, adding the crystallization solvent at a lower temperature is beneficial to reducing the solubility of the product system, which is beneficial to better crystallize the product and improve the product yield. The crystallization solvent meets the requirements of multiple crystallizations to obtain a high-purity product.

[0022] Preferably, the reaction temperature in step 2 is 90-100° C. and the reaction time is 24 h.

[0023] 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, the particle size and shape of the crystal can be effectively controlled, and high-quality, high-purity products are obtained by crystallization with good reproducibility, which is suitable for expanding production and preventing the temperature from being too high, which easily produces unnecessary by-products and affects the purity and yield of the reaction.

[0024] In a specific embodiment, the post-processing purification is to add alkali solution to adjust the pH, stir, filter, heat to extract, cool to crystallize, filter and dry.

[0025] By adopting the above technical scheme, the pH is adjusted by adding alkaline solution to neutralize the acid in the reaction system, and then filtration and extraction are performed to increase the extraction speed, facilitate collection and separation, cool the product to precipitate, and obtain a dry high-purity product.

[0026] In summary, the present application includes at least one of the following beneficial technical effects: 1. A nucleophilic substitution reaction is carried out between 7-hydroxy-[1,2,4]triazolo[1,5-A]pyridine and 2-fluoro-5-nitrotoluene, and a base and an organic solvent system are added to move the substitution reaction as far as possible toward the direction of the product, thereby accelerating the reaction rate and increasing the yield of the generated compound D. The obtained compound D is used as a reactant in the next step of the catalytic reduction process, thereby increasing the conversion rate of the compound A.

[0027] Compound D is put into a reduction catalytic solution system. Through highly selective reducing phosphoric acid, in the conversion process of heterocyclic nitrobenzene compounds, it has high activity and good selectivity. Different substituents modified on the benzene ring, such as ([1,2,4]triazolo[1,5-a]pyridine-7-oxyl) at the 4th position of the nitrobenzene ring and the methyl at the 3rd position, are protected and do not participate in the nitro reduction reaction. The reducing phosphoric acid can be activated by the electrophilicity of inorganic Lewis acid to produce phosphoryl cation PO + or PO 2+ The intermediate nucleophilic active substance is then combined with the electrophilic NO2 in the reaction raw material, and the NO bond is broken after rearrangement to form a nitrosobenzene intermediate. The above process is repeated, and hydroiodic acid is generated in a Lewis acid environment through iodine or iodine metal salt. Hydroiodic acid has high reactivity and further catalyzes the kinetic rate-determining step of the nitrobenzene reduction reaction to finally obtain the target amino product. The reduction catalytic solution system with the above three components is applied to the reduction system of step 2, which makes the reaction speed fast, the side reactions are few, and the product purity is high.

[0028] 2. By selecting different catalysts and reducing agents and adjusting the component ratio of the reduction catalytic solution system, a better technical effect is unexpectedly obtained. This may be because, within a specific range, on the one hand, the reducibility, catalyticity and reaction activity can be made higher, the possibility of by-products is small, and the conversion yield is improved. On the other hand, the degree of protonation of the reducing agent is appropriate to avoid oxidation of other reaction-sensitive functional groups, the generation of impurities and the like to reduce the yield. The ratio limit within the above range maintains high reducibility and high selectivity at the same time, which is conducive to the joint action of the three components, greatly improving the yield and purity. Under this ratio, the catalyst dosage can be moderate while maintaining high yield and high activity. If the catalyst dosage is too high, more crystal nucleation will occur, the product crystal form is not good, and the excess catalyst will easily be adsorbed on the product, making post-processing purification difficult. Even if the post-processing is adjusted to be filtered while hot, because the catalyst cannot be recovered in the reaction liquid after participating in the reaction process, it will also cause catalyst waste, increasing the difficulty and cost of the purification process.

[0029] 3. Adding the crystallization solvent at a lower temperature is beneficial to reducing the solubility of the product system, which is beneficial to better crystallize the product and improve the product yield. The crystallization solvent meets the needs of multiple crystallizations to obtain a high-purity product. DETAILED DESCRIPTION

[0030] In step 1 of the present application, the base and organic solvent system is a potassium carbonate and N,N-dimethylformamide reaction system; the raw materials of the present application can be obtained commercially.

[0031] Example 1 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 90°C for reaction for 24h, track by TLC until the reaction is complete, cool 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, heat to 80°C to dissolve, and then stand to separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 90% and a purity of 99.4%.

[0032] Example 2 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 100°C for reaction for 18h, track by TLC until the reaction is complete, cool to room temperature, add 195ml of water, then drop 28% ammonia water 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, heat to 80°C to dissolve, stand and separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 89.8% and a purity of 99.2%.

[0033] Example 3 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and hypophosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 90°C for reaction for 24h, track by TLC until the reaction is complete, cool to room temperature, add 195ml of water, then drop 28% ammonia water 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, heat to 80°C to dissolve, stand and separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 89.4% and a purity of 98.7%.

[0034] Example 4 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, iodine and phosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 90°C for reaction for 24h, track the reaction by TLC until the reaction is complete, cool 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, heat to 80°C to dissolve, stand and separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A with a yield of 89.6% and a purity of 98.8%.

[0035] Example 5 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is acetic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 90°C for reaction for 24h, track the reaction by TLC until the reaction is complete, cool 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, heat to 80°C to dissolve, and then stand to separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 89.3% and a purity of 98.5%.

[0036] Example 6 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:2.5; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 90°C for reaction for 24h, track by TLC until the reaction is complete, cool to room temperature, add 195ml of water, then drop 28% ammonia water 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, heat to 80°C to dissolve, stand and separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A with a yield of 87.5% and a purity of 89.7%.

[0037] Example 7 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:4.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.6:3.6; heat to 90°C for reaction for 24h, track by TLC until the reaction is complete, cool to room temperature, add 195ml of water, then drop 28% ammonia water 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, heat to 80°C to dissolve, stand and separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 88.1% and a purity of 85.4%.

[0038] Example 8 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1:3; heat to 90°C for reaction for 24h, track the reaction by TLC until the reaction is complete, cool 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, heat to 80°C to dissolve, stand and separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 89.7% and a purity of 99.0%.

[0039] Example 9 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.5:2.5; heat to 90°C for reaction for 24h, track by TLC until the reaction is complete, cool to room temperature and add 195ml of water, then drop 28% ammonia water 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, heat to 80°C to dissolve and then stand to separate the water layer, cool the organic layer to 10°C for crystallization, filter and dry at 60°C to obtain compound A, with a yield of 87.1% and a purity of 86.9%.

[0040] Example 10 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.5:3; heat to 90°C for 24h, track by TLC until the reaction is complete, cool to room temperature, add 195ml of water, then cool to 10°C, add 168ml of sodium carbonate to neutralize the acid to precipitate the solid, filter, and dry at 60°C to obtain compound A, with a yield of 90% and a purity of 99.5%.

[0041] Embodiment 11 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is hydrobromic acid, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:1.5:3; heat to 90°C for 24h, track the reaction by TLC until the reaction is complete, add 195ml of water after cooling to room temperature, then cool to 10°C, add 168ml of sodium carbonate to neutralize the acid and precipitate the solid, add the crystallization solvent toluene, cool to -10--8°C, stir, filter, rinse the filter cake with toluene, collect the filtrate, concentrate the filtrate at 30-38°C, add toluene, cool to -10--8°C, stir, filter, collect the filter cake, and dry at 60°C to obtain compound A, with a yield of 90.1% and a purity of 99.6%.

[0042] Comparative Example 1 A preparation process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxyl)-3-methylaniline, comprising 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 bottle, the temperature is raised to 80°C and stirred for 10h, and 1% of the raw material remains after TLC detection, the temperature is lowered to 10°C, 320ml of water is added dropwise, stirred for 2h, and then filtered, and the filter cake is rinsed with 240ml of water, and then the filter cake is rinsed with 160ml of a mixed solvent of methanol and water (the volume ratio of methanol to water is 1:4), and then dried under reduced pressure at 50°C for 8h to obtain compound D; Step 2: Add 65g of compound D to the reaction bottle, and add 382g of a mixture of a reduction catalytic solution system and water under nitrogen protection, wherein the mass ratio of compound D to the reduction catalytic solution system is 1:3.8; the reduction catalytic solution system is water, sodium iodide and phosphorous acid in a molar equivalent ratio of 5:0.6:3.6; heat to 90°C for reaction for 24h, track by TLC until the reaction is complete, cool 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, heat to 80°C to dissolve, and then stand to separate the water layer, cool the organic layer to 10°C for crystallization, filter, and dry at 60°C to obtain compound A, with a yield of 74.1% and a purity of 76.9%.

[0043] The preparation process of the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline of the embodiments and comparative examples of the present application has mild reaction conditions, simple process, high yield of the prepared target product, high purity, small content of by-product isomers, low cost of reagents used, and is suitable for industrial scale-up production. In order to avoid the need for hydrogenation at high temperatures, harsh reaction conditions and safety issues during precious metal catalytic hydrogenation, as well as incompatibility of structures sensitive to reduction hydrogenation such as heterocycles, side reactions occur, yields are reduced, and substrate selectivity is also limited. Among them, compared to Example 1 and Comparative Example 1, in this reaction system, the reduction catalytic solution system is different, so that the reducing agent is not activated enough, and the hydrogen source is not easily available, resulting in side reactions of the reactants, so that both yield and purity are reduced. Compared with Examples 6-7, the feed ratio of the reaction raw material compound D and the reduction catalytic solution system in Example 1 is too small, so that some reactants are not reduced or side reactions occur. The feed ratio of the reaction raw material compound D and the reduction catalytic solution system is too large, which causes excessive reduction catalytic reaction, and then more adverse reactions occur, affecting the purification effect. Compared with Examples 8-9, the molar equivalent of the reducing agent in the reduction catalytic solution system in Example 1 exceeds the scope of this application, so that the content of the reducing agent affinity active substance is low, the reaction activity is low, and the probability of adverse reactions increases, affecting the yield and purity; Compared with Example 10, the target product obtained in Example 11 undergoes two recrystallization separation processes. Part of the product is not effectively separated in the filtration operation, and the recrystallization is effectively separated, and the product purity and yield are improved.

[0044] The above are all preferred embodiments of the present application, and the protection scope of the present application is not limited thereto. Therefore, any equivalent changes made according to the structure, shape, and principle of the present application should be included in the protection scope of the present application.

Claims

1. A process for preparing tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline, characterized in that: The steps include: Step 1: Under nitrogen atmosphere, compound B and compound C in the formula are subjected to substitution reaction in a base and organic solvent system to obtain compound D in the formula; Step 2: Add compound D to a nitrogen-protected reduction catalytic solution system, react at 70-120° C. for 8-30 hours, track the reaction by TLC until the reaction is complete, add 2-8 times the volume of compound D in water, and post-treat and purify to obtain compound A; wherein 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.

2. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 1, characterized in that: The reducing phosphoric acid includes one or both of phosphorous acid and hypophosphorous acid.

3. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 1, characterized in that: The metal salt of iodine includes lithium iodide, sodium iodide and potassium iodide.

4. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 1, characterized in that: The inorganic acid includes one or more of hydrochloric acid, hydrobromic acid, hydroiodic acid and acetic acid.

5. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 4, characterized in that: The molar equivalent ratio of the reducing agent, the catalyst and the inorganic acid is (3.0-5):(1-2):

5.

6. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 1, characterized in that: The post-treatment purification includes cooling, adding alkali to neutralize the acid to precipitate solids, filtering or recrystallizing; wherein the alkali includes one or more of alkali metal hydroxides, carbonates, phosphates, and ammonia water.

7. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 6, characterized in that: The specific operation of the recrystallization is: adding a crystallization solvent, cooling to -10--8°C, stirring, filtering, washing the filter cake with the crystallization solvent, collecting the filtrate, concentrating the filtrate at 30-38°C, adding the crystallization solvent again, cooling to -10--8°C, stirring, filtering, and collecting the filter cake.

8. The process for preparing the tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridine-7-oxy)-3-methylaniline according to claim 1, characterized in that: The post-treatment purification comprises adding alkali solution to adjust pH, stirring, suction filtration, heating extraction, cooling crystallization, suction filtration and drying.

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