CN116903615A - Preparation method of tocartinib and intermediate thereof - Google Patents

Abstract

The application discloses a preparation method of tofacitinib and an intermediate thereof, which comprises the steps of enabling 7-hydroxy- [1,2,4] triazolo [1,5-a ] pyridine and 1-fluoro-2-methyl-4-nitrobenzene to undergo substitution reaction in an aqueous phase micelle medium in the presence of alkaline substances, adding reduced metal powder and ammonium halide into a mixed solution after the reaction, and generating 4- ([ 1,2,4] triazolo [1,5-a ] pyridine-7-yloxy) -3-methylaniline through nitroreduction reaction after the reaction is finished; the method not only ensures that an organic solvent, particularly the existing common polar aprotic solvent is not required in the reaction process, improves the environmental protection, but also can greatly reduce the reaction temperature, ensures that the reaction process is milder, the production safety is higher, and the yield is more ideal; in addition, the whole route is simple in post-treatment, green and environment-friendly, and suitable for mass production of tocartinib.

Description

A kind of preparation method of tucatinib and its intermediates

Technical field

The invention relates to the field of drug synthesis, and in particular to a preparation method of tucatinib and its intermediates.

Background technique

Tucatinib is an oral TKI (tyrosine kinase) inhibitor that is highly specific for HER2. On April 17, 2020, the U.S. FDA approved tucatinib in combination with trastuzumab and capecitabine for the treatment of adult patients with surgically unresectable or metastatic advanced HER2-positive breast cancer. The structural formula of Ni is:

4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline It is an important intermediate for the synthesis of tucatinib. The current methods for synthesizing this compound mainly include the following:

(1) Use 4-chloro-2-aminopyridine as raw material to synthesize the target product through etherification, cyclization and nitro reduction reaction (Synthesis, 2019, 51, 2660);

Among them, the first step of the etherification reaction requires reaction in the polar aprotic solvent NMP at 150°C for 72 hours, and the yield is only 64%;

(2) Use 4-chloro-2-aminopyridine as raw material to synthesize the target product through cyclization and etherification reactions (Organic Preparations and Procedures International, 2021, 53, 554);

Among them, the last step of the etherification reaction requires reaction in the polar aprotic solvent DMF at 140°C for 16 hours, and the yield is only 73%;

(3) Use 4-hydroxy-2-aminopyridine as raw material to synthesize the target product (WO 2021/179274 A1) through etherification and cyclization reactions;

Among them, the first step of the etherification reaction is carried out in the polar aprotic solvent DMF, and the yield is only 22%, which has the problem of poor selectivity;

(4) After the reaction of 4-chloropyrido-2-amine (compound L in the formula) and N,N-dimethylformamide dimethyl acetal (DMF-DMA), hydroxylamine hydrochloride is added for reaction. Product I (compound N in the formula), the yield of this step is up to 89%; then product I is reacted with trifluoroacetic anhydride (TFAA) to prepare product II (compound O in the above formula), the yield of this step is up to 70% ; The final product II and 4-amino-2-methylphenol (compound P in the formula) are heated in a DMF/potassium carbonate system to prepare tucatinib intermediate 4-([1,2,4]triazolo[ 1,5-a]pyridin-7-yloxy)-3-methylaniline (compound A in the formula), the yield of this step is up to 73% (patent document CN112898298A), and the total yield is about 45%;

Among them, the third step of the etherification reaction is carried out in the polar aprotic solvent DMF, and the reaction temperature needs to be 130-140°C;

That is to say, the etherification reactions of the above-mentioned synthetic routes all require polar aprotic solvents that are highly toxic, difficult to volatilize, and easily soluble in water as the reaction medium, and there is a problem of low reaction selectivity. Therefore, the above-mentioned processes have complicated post-processing. , many three wastes, difficult to handle, low yield and other problems; at the same time, the reaction temperature of etherification in some routes is as high as 130-150°C, which results in poor operational safety and high energy consumption.

Contents of the invention

The object of the present invention is to overcome one or more deficiencies in the prior art and provide an improved and environmentally friendly method for preparing 4-([1,2,4]triazolo[1,5-a]pyridin-7-yl Oxy)-3-methylaniline (intermediate for preparing tucatinib), and has a relatively ideal yield and relatively mild reaction conditions.

The present invention also provides a tocacarbamate comprising the preparation process of the above-mentioned 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline. Preparation method of tinib.

In order to achieve the above object, a technical solution adopted by the present invention is:

A preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (compound represented by formula (I)) and 1-fluoro-2-methyl-4-nitrobenzene (formula (I)) The compound shown in Ⅱ) undergoes a substitution reaction in an aqueous micelle medium in the presence of an alkaline substance to generate 7-(2-methyl-4-nitrophenoxy)-[1,2,4]tri Azolo[1,5-a]pyridine (compound represented by formula (III)) is obtained containing 7-(2-methyl-4-nitrophenoxy)-[1,2,4]triazolo[ The reaction mixture of 1,5-a]pyridine;

Add reduced metal powder and ammonium halide to the reaction mixture to generate 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3 through nitro reduction reaction -Methylaniline (compound represented by formula (IV));

Wherein, the aqueous micelle medium is obtained by combining one or more selected from the group consisting of laureth polyoxyethylene ether, polyethylene glycol octylphenyl ether, and cetyltrimethylammonium bromide. Micelles formed by dispersing in water, the alkaline substance is a salt of anion selected from carbonate and/or phosphate.

According to the present invention, the reaction route of the present invention is basically as follows:

In some embodiments of the present invention, 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (compound represented by formula (I)) is commercially available or prepared by the following method :

The compound represented by formula (V) is used to prepare the compound represented by formula (I):

For example, 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine can be prepared by referring to the method in the literature: CN114671867. 2-amino-4-hydroxypyridine is used as the raw material, and the condensation and Preparation by cyclization reaction.

According to the present invention, the method of the present invention can be used to carry out the reaction at a lower temperature, making the reaction conditions milder, safer and easier to operate. In some preferred embodiments of the invention, the substitution reaction is carried out at 25-60°C. Further, the substitution reaction is carried out at 40-60°C.

According to some specific aspects of the invention, the substitution reaction is performed at 40-55°C.

In some preferred embodiments of the present invention, the nitro reduction reaction is performed at 15-25°C. According to a specific aspect of the invention, the nitro reduction reaction is carried out at room temperature.

In some preferred and specific embodiments of the present invention, the reaction times of the substitution reaction and the nitro reduction reaction are controlled to be 12-24 h respectively.

In the present invention, in the aqueous micelle medium, the molecular structure of the surfactant is composed of two parts. One end of the molecule is a lipophilic non-polar group, also called a hydrophobic group; the other end of the molecule is a hydrophilic polar group. Sexual group or ionic group, also known as hydrophilic group. As the concentration of the surfactant aqueous solution increases, the hydrophobic groups of the surfactant molecules gather to form nuclei, and the hydrophilic groups expand outward to form micelles. The minimum concentration of surfactant that produces micelles is called the critical micelle concentration (CMC). Depending on the type of surfactant and the solution conditions, the micelle shapes formed are also different, which may be round, ellipsoidal or rod-shaped micelles.

The preferred surfactant in the present invention is selected from laureth polyoxyethylene ether (also known as Brij-30), polyethylene glycol octylphenyl ether (also known as Triton X-100), cetyl trimethyl bromide Practice shows that using one or more combinations of ammonium (also called CTAB) as a solvent can achieve better reaction yields in the reaction of the present invention.

Further, according to some preferred and specific aspects of the present invention, the concentration of the aqueous micelle medium is 0.5wt.%-4.0wt.%.

In some embodiments of the present invention, the concentration of the aqueous micelle medium can be 0.5wt.%, 0.6wt.%, 0.8wt.%, 1.0wt.%, 1.2wt.%, 1.3wt.%, 1.5wt.%, 1.8wt.%, 2.0wt.%, 2.1wt.%, 2.2wt.%, 2.3wt.%, 2.4wt.%, 2.5wt.%, 3.0wt.%, 3.2wt.%, 3.5wt.%, 4.0wt.%, etc.

According to some preferred and specific aspects of the invention, the alkaline substance is an alkali metal carbonate and/or an alkali metal phosphate.

In some preferred and specific embodiments of the present invention, the alkaline substance is one or a combination of more selected from potassium phosphate, sodium phosphate, cesium phosphate, potassium carbonate, sodium carbonate, and cesium carbonate.

Further, according to some preferred aspects of the present invention, the aqueous micelle medium is polyethylene glycol octylphenyl ether aqueous micelles, and the polyethylene glycol octylphenyl ether aqueous micelles are formed by Polyethylene glycol octylphenyl ether is formed by dispersing in water;

The alkaline substance is an alkali metal phosphate.

Further, the concentration of the polyethylene glycol octylphenyl ether aqueous phase micelles is 1.0wt.%-3.0wt.%.

According to some preferred aspects of the present invention, the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine, the 1-fluoro-2-methyl-4-nitrobenzene and The feeding molar ratio of the alkaline substance is 1:1-1.5:1-1.5.

According to some preferred aspects of the present invention, the concentration of the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine in the aqueous micelle medium is 0.1 to 1.5 mol/L .

In some embodiments of the present invention, the concentration of the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine in the aqueous micelle medium is 0.1 mol/L, 0.2mol/L, 0.3mol/L, 0.5mol/L, 0.6mol/L, 0.8mol/L, 0.9mol/L, 1.0mol/L, 1.1mol/L, 1.2mol/L, 1.5mol/L, etc. .

According to some preferred aspects of the present invention, the molar ratio of the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine, the reduced metal powder and the ammonium halide is 1: 3～5:2～4.

According to some preferred aspects of the present invention, the reduced metal powder is iron powder and/or zinc powder.

According to some preferred aspects of the present invention, the ammonium halide is ammonium chloride and/or ammonium bromide.

Further, according to a preferred aspect of the present invention, the reduced metal powder is zinc powder, and the ammonium halide is ammonium chloride.

In some preferred embodiments of the present invention, the preparation method is a one-pot method, which specifically includes: combining 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine, 1 -Fluoro-2-methyl-4-nitrobenzene and alkaline substances are added to the aqueous micelle medium, stirred at room temperature, and heated up for reaction. After the reaction is completed, return to room temperature, and directly add reduced metal powder and Ammonium halide, react at room temperature. After the reaction is completed, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline is obtained after purification.

Further, the purification includes: filtering to remove reduced metal powder, extraction, drying, concentration, and column chromatography.

Another technical solution provided by the invention: a preparation method of tucatinib, which preparation method includes preparing 4-([1,2,4]triazolo[1,5-a] using the method described above. Procedure for pyridin-7-yloxy)-3-methylaniline.

Due to the application of the above technical solutions, the present invention has the following advantages compared with the prior art:

The invention innovatively involves the preparation of tucatinib intermediate 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline. , introducing a specific aqueous micelle medium and alkaline substances. It has been found in practice that this method not only eliminates the need for organic solvents, especially commonly used polar aprotic solvents, in the reaction process, improves environmental protection, but can also greatly reduce The reaction temperature makes the reaction process gentler, the production safety is higher, and the yield is relatively ideal; in addition, the entire route of this application is simple to process, green and environmentally friendly, and suitable for large-scale application.

Description of the drawings

Figure 1 is the hydrogen nuclear magnetic spectrum of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline prepared in Example 1 of the present invention. .

Detailed ways

The above solution will be further described below with reference to specific examples; it should be understood that these examples are used to illustrate the basic principles, main features and advantages of the present invention, and the present invention is not limited by the scope of the following examples; The implementation conditions can be further adjusted according to specific requirements. Unspecified implementation conditions are usually the conditions in routine experiments.

There are no special instructions in the following examples. All raw materials are commercially available or prepared by conventional methods in this field.

In the following, "wt.%" refers to the weight percentage concentration.

Polyethylene glycol octylphenyl ether (also known as Triton X-100), purchased from Aladdin, CAS number: 9002-93-1; Lauryl polyoxyethylene ether (also known as Brij-30), purchased from Aladdin , CAS number: 9002-92-0; cetyltrimethylammonium bromide (also known as CTAB), purchased from Aladdin, CAS number: 57-09-0; sodium dodecyl sulfate (also known as SDS ), purchased from Aladdin, CAS number: 151-21-3; zinc powder (Aladdin), the particle size is 600 mesh, iron powder (Aladdin), the particle size is 600 mesh.

In the following examples, the 2wt.% Triton Micellar solution (2wt.%, refers to the weight percentage concentration of Triton X-100 in the aqueous micellar medium (Triton X-100 and water)). The preparation methods for other aqueous micellar solutions are the same.

Example 1

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 2wt.% Triton After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction is completed, the metal powder is removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain the target product 4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylaniline (its hydrogen nuclear magnetic spectrum is shown in Figure 1) 2.06g, purity 98%, yield 86%.

Example 2

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium carbonate (1.66g) was added to 10 mL of 2wt.% Triton After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the metal powder was removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain 1.78 g of the target product, with a purity of 95% and a yield of 74%.

Example 3

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 2wt.% Triton After the reaction was completed, it was lowered to room temperature, 40 mmol iron powder (2.24 g) and 30 mmol ammonium chloride (1.60 g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 h. After the reaction was completed, the metal powder was removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain 1.87 g of the target product, with a purity of 96% and a yield of 78%.

Example 4

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 2wt.% Brij-30 aqueous micellar medium, stirred at room temperature for 5 min, then raised to 50°C and continued to react for 16 h. After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the metal powder was removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain 1.99 g of the target product, with a purity of 98% and a yield of 83%.

Example 5

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 2wt.% CTAB aqueous micellar medium, stirred at room temperature for 5 min, then raised to 50°C and continued to react for 16 h. After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the metal powder was removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain 1.94 g of the target product, with a purity of 96% and a yield of 81%.

Example 6

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 2wt.% Triton After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction is completed, the metal powder is removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain the target product 4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylaniline 1.56g, purity 93%, yield 65%.

Example 7

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 2wt.% Triton After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction is completed, the metal powder is removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain the target product 4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylaniline 2.09g, purity 98%, yield 87%.

Example 8

This example provides a preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, which preparation method includes:

10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) and 12mmol Potassium phosphate (2.55g) was added to 10 mL of 3wt.% Triton X-100 aqueous micellar medium (the preparation method is the same as in Example 1, except that the proportion of Triton Continue the reaction for 16h. After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction is completed, the metal powder is removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain the target product 4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylaniline 2.04g, purity 98%, yield 85%.

Comparative example 1

Basically the same as Example 1, the only difference is that water is directly used as the solvent to replace the 2wt.% Triton X-100 aqueous micelle medium;

The specific steps are as follows: 10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) ) and 12 mmol potassium phosphate (2.55 g) were added to 10 mL of water, stirred at room temperature for 5 min, then raised to 50°C and continued to react for 16 h. After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction is completed, the metal powder is removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain the target product 4-([1,2,4]triazolo[1,5-a ]pyridin-7-yloxy)-3-methylaniline 0.84g, purity 89%, yield 35%.

Comparative example 2

Basically the same as Example 1, the only difference is that potassium phosphate is replaced by sodium hydroxide in an equivalent molar amount;

The specific steps are as follows: 10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) ) and 12 mmol sodium hydroxide (0.48g) were added to 10 mL of 2wt.% Triton After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the metal powder was removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain 1.46 g of the target product, with a purity of 96% and a yield of 61%.

Comparative example 3

Basically the same as Example 1, the only difference is that "2wt.% Triton X-100 aqueous micelle medium" is replaced with 2wt.% SDS aqueous micelle medium;

The specific steps are as follows: 10mmol 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine (1.35g), 12mmol 1-fluoro-2-methyl-4-nitrobenzene (1.86g) ) and 12 mmol potassium phosphate (2.55g) were added to 10 mL of 2wt.% SDS aqueous micellar medium, stirred at room temperature for 5 min, and then raised the temperature to 50°C to continue the reaction for 16 h. After the reaction was completed, it was lowered to room temperature, 40 mmol zinc powder (2.62g) and 30 mmol ammonium chloride (1.60g) were added directly without post-treatment, and the reaction was continued at room temperature for 16 hours. After the reaction was completed, the metal powder was removed by filtration, extracted (ethyl acetate 15 mL × 3), dried, concentrated, and subjected to silica gel column chromatography to obtain 1.39 g of the target product, with a purity of 96% and a yield of 58%.

The above embodiments are only for illustrating the technical concepts and characteristics of the present invention. Their purpose is to enable those familiar with this technology to understand the content of the present invention and implement it accordingly. They cannot limit the scope of protection of the present invention. All equivalent changes or modifications made based on the spirit and essence of the present invention should be included in the protection scope of the present invention.

The endpoints of ranges and any values disclosed herein are not limited to the precise range or value, but these ranges or values are to be understood to include values approaching such ranges or values. For numerical ranges, the endpoint values of each range, the endpoint values of each range and individual point values, and the individual point values can be combined with each other to obtain one or more new numerical ranges. These values The scope shall be deemed to be specifically disclosed herein.

Claims (10)

1. A preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline, characterized in that the preparation method include: Make 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine and 1-fluoro-2-methyl-4-nitrobenzene in an aqueous micelle medium and in an alkaline substance In the presence of The reaction mixture of methyl-4-nitrophenoxy)-[1,2,4]triazolo[1,5-a]pyridine; Add reduced metal powder and ammonium halide to the reaction mixture to generate 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3 through nitro reduction reaction -Methylaniline; Wherein, the aqueous micelle medium is obtained by combining one or more selected from the group consisting of laureth polyoxyethylene ether, polyethylene glycol octylphenyl ether, and cetyltrimethylammonium bromide. Micelles formed by dispersing in water, the alkaline substance is a salt of anion selected from carbonate and/or phosphate. 2. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the substitution reaction is carried out at 25-60°C; and/or the nitro reduction reaction is carried out at 15-25°C. 3. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the concentration of the aqueous micelle medium is 0.5wt.%-4.0wt.%. 4. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the alkaline substance is an alkali metal carbonate and/or an alkali metal phosphate. 5. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 4, characterized in that , the alkaline substance is one or a combination of more selected from potassium phosphate, sodium phosphate, cesium phosphate, potassium carbonate, sodium carbonate, and cesium carbonate. 6. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the aqueous micelle medium is polyethylene glycol octylphenyl ether aqueous micelle, and the polyethylene glycol octylphenyl ether aqueous micelle is made by dispersing polyethylene glycol octylphenyl ether formed in water; The alkaline substance is an alkali metal phosphate. 7. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the feeding of the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine, the 1-fluoro-2-methyl-4-nitrobenzene and the alkaline substance The molar ratio is 1:1 to 1.5:1 to 1.5; wherein, the concentration of the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine in the aqueous micelle medium 0.1～1.5mol/L; and / or, The feeding molar ratio of the 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine, the reduced metal powder and the ammonium halide is 1:3~5:2~4. 8. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the reduced metal powder is iron powder and/or zinc powder; and/or, the ammonium halide is ammonium chloride and/or ammonium bromide. 9. The preparation method of 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline according to claim 1, characterized in that , the implementation of the preparation method is a one-pot method, specifically including: combining 7-hydroxy-[1,2,4]triazolo[1,5-a]pyridine, 1-fluoro-2-methyl-4 - Nitrobenzene and alkaline substances are added to the aqueous micelle medium, stirred at room temperature, and the temperature is raised for reaction. After the reaction is completed, the temperature is lowered to room temperature. Reduced metal powder and ammonium halide are directly added without post-treatment, and the reaction is carried out at room temperature. After the reaction is completed , after purification, 4-([1,2,4]triazolo[1,5-a]pyridin-7-yloxy)-3-methylaniline was obtained. 10. A method for preparing tucatinib, characterized in that the preparation method includes preparing 4-([1,2,4]triazolo using the method described in any one of claims 1-9. Procedure for [1,5-a]pyridin-7-yloxy)-3-methylaniline.