Preparation method of Erdatinib and intermediate compound used in method

Abstract

The invention belongs to the technical field of organic synthesis route design and preparation of raw material medicines and intermediates, and particularly relates to a preparation method of Erdatinib and an intermediate compound used for the method. The present invention relates to a process for preparing Erdatinib using an intermediate compound II (2-{N-(3, 5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl) quinoxaline-6-yl] amino}-N-isopropylacetamide), and provides a process for preparing Erdatinib using a compound III (N-(3, 5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl) quinoxaline-6-yl] amino)-N-isopropylacetamide The invention relates to a method for preparing a compound II by carrying out nucleophilic substitution reaction on 2-(3, 5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl) quinoxaline-6-amine) and N-isopropyl-2-chloroacetamide or N-isopropyl-2-bromoacetamide, and a method for preparing a compound III by using the compound VI (2-(3, 5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl) quinoxaline-6-amine). The invention relates to a method for preparing a compound II by carrying out a coupling reaction on a compound I (2, 5-dimethoxyphenyl amino)-N-isopropylacetamide) and a compound VII (7-bromo-2-(1-methyl-1H-pyrazol-4-yl) quinoxaline). According to the present invention, the new synthesis technology is adopted, such that the side reaction is avoided through the amino group positioning and the timely conversion of the amide structure, the Erdatinib is conveniently and rapidly prepared, and the new way with the practical application value is provided for the industrial production of the Erdatinib bulk drug.

Description

Technical Field

[0001] The present application belongs to the technical field of organic synthesis route design and preparation of raw materials and intermediates, and particularly relates to a preparation method of Erdafitinib, and also relates to an intermediate used in the method and a preparation method thereof. Background Art

[0002] Erdafitinib (trade name Balversa) is a fibroblast growth factor receptor (FGFR) kinase inhibitor developed by Janssen, a subsidiary of Johnson & Johnson. It was approved by the US FDA in April 2019 for use in patients with advanced in situ or potential FGFR2 or FGFR3 mutations who have developed metastatic urothelial carcinoma during or after at least one platinum-containing chemotherapy. Clinical research results in recent years have shown that Erdafitinib has a certain effect on 14 cancer patients with different types of FGFR driver mutations, and is known as an FGFR inhibitor for all cancer types.

[0003] There are five reported methods for preparing Erdafitinib: including two methods disclosed in the international patent WO 2011135376, which respectively synthesize N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine from different intermediates through coupling reaction, and then react with N-(2-chloroethyl)isopropylamine to prepare Erdafitinib through N-alkylation reaction. These two methods have fewer synthetic steps, but N-(2-chloroethyl)isopropylamine is prone to intramolecular and intermolecular side reactions, resulting in complex products. International patent WO 2020208592 discloses a third preparation method, which uses isopropylamine as the starting material, undergoes a two-step nucleophilic substitution reaction with chloroacetyl chloride and 3,5-dimethoxyaniline, and then undergoes lithium aluminum hydride reduction to synthesize the intermediate N-(3,5-dimethoxyphenyl)-N'-isopropyl-1,2-ethylenediamine, and finally undergoes a coupling reaction with 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline to prepare Erdafitinib. This preparation method changes the splicing order, but N and N' in N-(3,5-dimethoxyphenyl)-N'-isopropyl-1,2-ethylenediamine are both reaction sites, the reaction selectivity is poor, and there are cyclization byproducts, resulting in a decrease in yield and purity. Chinese patent CN 112125889A discloses a fourth method, using 4-bromo-2-nitroaniline as the starting material, and obtaining the intermediate 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline through five steps of reaction, coupling the intermediate with N-{2-{[(1,1-dimethylethyl)dimethylsilyl]oxy}ethyl}-3,5-dimethoxyaniline, reacting with methanesulfonyl chloride to generate mesylate, and finally reacting with isopropylamine to obtain erdafitinib. This synthesis method has lengthy steps, cumbersome operation, and the use of protective groups is uneconomical and environmentally unfriendly. The fifth method (Sun XH, et al. Synthesis of quinoxaline derivatives as intermediates to obtain Erdafitinib. Pharm Chem J, 2021, 55 (9): 951-953) uses 1-methylpyrazole as the starting material, and obtains the intermediate 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline through three steps, and then catalytically couples with 3,5-dimethoxyaniline to obtain N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine, and finally prepares Erdafitinib in one pot with 1,2-dibromoethane and isopropylamine. The last step of this synthesis method has many by-products, which need to be purified by column chromatography.

[0004] Among the above five preparation methods, four preparation methods have two reaction sites that lead to side reactions, making purification difficult or cumbersome to operate. Only the fourth preparation method takes reaction selectivity into consideration, but it is not economical or environmentally friendly. Summary of the invention

[0005] In view of the deficiencies in the prior art, the present application adopts a new synthesis technology to avoid side reactions by positioning the amino group and timely converting the amide structure, and conveniently and quickly prepares Erdafitinib. The specific scheme is as follows:

[0006] 1. A method for synthesizing compound I using compound II, wherein compound I is as follows:

[0007]

[0008] Compound II is shown below:

[0009]

[0010] 2. The method according to item 1, characterized in that it comprises the step of reducing compound II to compound I through a reduction reaction:

[0011]

[0012] 3. The method according to item 2 is characterized in that the reduction reaction is carried out in a solvent selected from the following: methanol, ethanol, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, xylene, benzene, toluene or acetone.

[0013] 4. The method according to item 2 is characterized in that the reduction reaction is carried out using a reducing agent selected from the following: lithium aluminum hydride, sodium borohydride, and borane.

[0014] 5. The method according to item 2 is characterized in that the reduction reaction uses Lewis acid as a catalyst, and the Lewis acid includes aluminum trichloride and boron trifluoride.

[0015] 6. The method according to item 2, characterized in that, in the reduction reaction, the molar ratio between the compound II, the reducing agent and the catalyst is:

[0016] Compound II: reducing agent: catalyst = 1: (1-10): (1-10).

[0017] 7. The method according to item 2 is characterized in that the reduction reaction time is 3 to 20 hours.

[0018] 8. The method according to item 2 is characterized in that the reduction reaction temperature is 0 to 120°C.

[0019] 9. The method according to item 1, characterized in that it also includes the step of preparing compound II by nucleophilic substitution reaction of compound III and compound IV:

[0020]

[0021] Wherein, the R1 is selected from Cl or Br.

[0022] 10. The method according to item 9 is characterized in that the nucleophilic substitution reaction is carried out in a solvent selected from the following: methanol, ethanol, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, dioxane, xylene, benzene, toluene, acetonitrile or acetone.

[0023] 11. The method according to item 9 is characterized in that the nucleophilic substitution reaction is carried out in a base selected from the following: potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, sodium ethoxide.

[0024] 12. The method according to item 9, characterized in that the molar ratio between the compound III, the base and the compound IV is:

[0025] Compound III: base: compound IV = 1: (2-3): (1-2).

[0026] 13. The method according to item 9 is characterized in that the nucleophilic substitution reaction time is 1 to 24 hours.

[0027] 14. The method according to item 9 is characterized in that the nucleophilic substitution reaction temperature is 40 to 110°C.

[0028] 15. The method according to item 1, characterized in that it also includes the step of preparing compound II by coupling reaction of compound VI and compound VII:

[0029]

[0030] 16. The method according to item 15 is characterized in that the coupling reaction is carried out in a solvent selected from the following: diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane and dimethoxyethane, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, glycerol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, toluene, DMF, DMSO or DMAc.

[0031] 17. The method according to item 15 is characterized in that the coupling reaction is carried out using a catalyst selected from the following: tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium chloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium or tetrakis(triphenylphosphine)palladium.

[0032] 18. The method according to item 15, characterized in that the coupling reaction is carried out using a ligand selected from the following: Xantphos, PPh3, dppf, dppb or BINAP.

[0033] 19. The method according to item 15 is characterized in that the coupling reaction is carried out in a base selected from the following: sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, potassium tert-butoxide, diisopropylethylaminepyridine, 2,6-lutidine or N,N-dimethylaminopyridine.

[0034] 20. The method according to item 15, characterized in that the molar ratio between the compound II, the reducing agent and the catalyst is:

[0035] Compound VI: Compound VII: Catalyst = 1: (1-2): (0.0001-0.005).

[0036] 21. The method according to item 15, characterized in that the coupling reaction time is 5 to 20 hours.

[0037] 22. The method according to item 15, characterized in that the coupling reaction temperature is 40 to 170°C.

[0038] 23. A method for preparing compound I using compound III and compound IV, comprising the following steps:

[0039] Compound I is shown below:

[0040]

[0041]

[0042] , wherein said R1 is selected from Cl or Br.

[0043] 24. A method for preparing compound I using compound VI and compound VII, comprising the following steps:

[0044] Compound I is shown below:

[0045]

[0046]

[0047] , wherein said R1 is selected from Cl or Br.

[0048] 25. An intermediate compound for preparing Erdafitinib, characterized in that it is as follows:

[0049]

[0050] 26. Use of the intermediate compound shown below for preparing Erdafitinib:

[0051]

[0052] Beneficial effects:

[0053] The present application provides a novel method for preparing Erdafitinib, which avoids side reactions through the positioning of the amino group and the timely conversion of the amide structure, and conveniently and quickly completes the preparation of Erdafitinib. The preparation method provides a new approach with practical application value for the industrial production of Erdafitinib raw materials. DETAILED DESCRIPTION

[0054] The following specific implementations more specifically illustrate exemplary embodiments of the present application. In the following description, it should be understood that the following specific implementations are not restrictive, and other implementations can be expected without departing from the scope and spirit of the present application.

[0055] Unless otherwise indicated, in all cases, the numbers used in this specification and claims to describe dimensions, quantities and physical properties should be understood to be modified by the term "about". Therefore, unless otherwise indicated, the numbers described in this specification and the claims are approximate values, and these approximate values ​​may vary according to the method proposed by the technicians in this field to achieve the desired characteristics using the method proposed by the present invention. Numerical ranges expressed using end values ​​include all numbers within the range and any range within the range.

[0056] In the present application, "Compound I" refers to "Erdafitinib", whose trade name is Balversa, which is a fibroblast growth factor receptor (FGFR) kinase inhibitor.

[0057] In the present application, "H" represents a hydrogen atom; "C" represents a carbon atom; "O" represents an oxygen atom; "F" represents a fluorine atom; "N" represents a nitrogen atom; "Cl" represents a chlorine atom; "Br" represents a bromine atom; and "R1" represents a variable chemical group.

[0058] In the present specification, "C1-C6 alcohol" refers to an alcohol containing 1 carbon atom, 2 carbon atoms, 3 carbon atoms, 4 carbon atoms, 5 carbon atoms or 6 carbon atoms in the compound.

[0059] In this application specification, "yield" is the percentage of the actual output of a product to the theoretical output.

[0060] The present application provides a method for synthesizing compound I using compound II, wherein compound 1 is as follows:

[0061]

[0062] Compound II is shown below:

[0063]

[0064] In a specific embodiment of the present application, the compound I is prepared by a reduction reaction of compound II with a reducing agent under the catalytic action of a catalyst; and the compound II is prepared by a nucleophilic substitution reaction of compound III with compound IV.

[0065] In a specific embodiment of the present application, the compound II is used to prepare the compound I through a reduction reaction, and the reaction is carried out under normal pressure.

[0066] In a specific embodiment of the present application, the compound II is prepared into compound I by reduction reaction, and the reaction temperature of the reaction is 0-120°C, for example, it can be 10°C, 20°C, 30°C, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, and the preferred reaction temperature is 40-60°C, for example, it can be 40°C, 45°C, 50°C, 55°C, 60°C.

[0067] In a specific embodiment of the present application, the compound II is prepared into compound I by reduction reaction, and the reaction time of the reaction is 3 to 20 hours, for example, it can be 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, and the preferred reaction time is 4 to 18 hours, for example, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours.

[0068] In a specific embodiment of the present application, the compound II is prepared into the compound I by a reduction reaction, and the solvent in the reaction is selected from one or more of methanol, ethanol, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, xylene, benzene, toluene, and acetone, preferably tetrahydrofuran.

[0069] In a specific embodiment of the present application, the compound II is prepared into the compound I by a reduction reaction, and the reducing agent in the reaction is selected from one or more of lithium aluminum hydride, sodium borohydride, and borane, preferably sodium borohydride.

[0070] In a specific embodiment of the present application, the compound II is used to prepare the compound I through a reduction reaction, and the catalyst in the reaction is a Lewis acid, such as aluminum trichloride or boron trifluoride.

[0071] In a specific embodiment of the present application, the compound II is prepared into compound I by a reduction reaction, in which compound II: reducing agent: catalyst = 1: (1 to 10): (1 to 10), for example, the ratio can be 1: 1: 1, 1: 2: 2, 1: 3: 3, 1: 4: 4, 1: 5: 5, 1: 6: 6, 1: 7: 7, 1: 8: 8, 1: 9: 9, 1: 10: 10, 1: 5: 10, 1: 10: 5, preferably the ratio is 1: 5: 5.

[0072] In the present application, it should be noted that compound I can also be prepared by reducing compound II in the form of an inorganic salt or an organic salt. Specifically, compound I can be prepared by reducing compound II freed from an inorganic salt or an organic salt of compound II. It can be an inorganic salt of compound II, such as a hydrochloride or a sulfate; it can be an organic salt of compound II, such as a methanesulfonate, a benzenesulfonate, or a p-toluenesulfonate; it can be an alkaline inorganic salt of compound II, such as an anhydrous phosphate; it can be a salt of compound II with triethylamine or diisopropylethylamine; the above salt-forming method of compound II is not limited and can be prepared by methods known in the art.

[0073] The present application provides a method for synthesizing compound II, which is prepared by reacting compound III with compound IV through a nucleophilic substitution reaction, and the steps are as follows:

[0074]

[0075] Wherein, the R1 is selected from Cl or Br.

[0076] In a specific embodiment of the present application, the compound III and the compound IV are subjected to a nucleophilic substitution reaction to prepare the compound II, and the solvent in the reaction is selected from methanol, ethanol, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, dioxane, xylene, benzene, toluene, acetonitrile, acetone, preferably acetone and tetrahydrofuran. The base is one or more of potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, and sodium ethoxide, preferably acetone and tetrahydrofuran.

[0077] In a specific embodiment of the present application, the compound III and compound IV are reacted via a nucleophilic substitution reaction to prepare compound II, and the base in the reaction is selected from one or more of potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, and sodium ethoxide, preferably sodium hydride and potassium carbonate.

[0078] In a specific embodiment of the present application, the compound III and compound IV are reacted by nucleophilic substitution to prepare compound II. In the reaction, compound III: base: compound IV = 1: (2-3): (1-2), for example, it can be 1:2:1, 1:2:1.5, 1:2:2, 1:2.5:1, 1:2.5:1.5, 1:2.5:2, 1:3:1, 1:3:1.5, 1:3:2, and the preferred ratio is 1:2.5:1.6.

[0079] In a specific embodiment of the present application, the compound III and compound IV are reacted via nucleophilic substitution to prepare compound II. In the reaction, the reaction temperature is 40-110°C, for example, it can be 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, and the preferred reaction temperature is 50°C, 55°C, 60°C, 65°C, 70°C, 75°C, 80°C.

[0080] In a specific embodiment of the present application, the compound III and compound IV are reacted by nucleophilic substitution to prepare compound II. In the reaction, the reaction time is 1 to 24 hours, for example, it can be 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, 21 hours, 22 hours, 23 hours, 24 hours. The preferred reaction time is 1 to 4 hours, for example, it can be 1 hour, 1.5 hours, 2 hours, 2.5 hours, 3 hours, 3.5 hours, or 4 hours.

[0081] The present application provides a method for synthesizing compound II, which is prepared by coupling reaction of compound VI and compound VII, and the steps are as follows:

[0082]

[0083] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II, and the solvent in the reaction can be an ether, for example, one or more of diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane and dimethoxyethane; the solvent in the reaction can be an alcohol, for example, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, glycerol and C1 to C6 alcohol; the solvent in the reaction can be a halogenated hydrocarbon, for example, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene; the solvent in the reaction can be an aromatic hydrocarbon, for example, toluene; the solvent in the reaction can be an aliphatic hydrocarbon, a nitrile, an ester and a polar aprotic solvent, for example, DMF, DMSO, DMAc, and the preferred solvent is dioxane.

[0084] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II, and the catalyst in the reaction is selected from one or more of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium chloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium, and tetrakis(triphenylphosphine)palladium, and the preferred catalyst is palladium acetate.

[0085] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II, and the ligand in the reaction is selected from one or more of Xantphos, PPh3, dppf, dppb, and BINAP, preferably BINAP.

[0086] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II, and the base in the reaction is an inorganic base, for example, it can be one or more of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, and sodium hydride.

[0087] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II, and the base in the reaction is an organic base, for example, it can be one or more of triethylamine, potassium tert-butoxide, diisopropylethylamine pyridine, 2,6-lutidine, and N,N-dimethylaminopyridine, and the base is preferably potassium tert-butoxide.

[0088] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II, in which the reaction temperature is 40-170°C, for example, 40°C, 50°C, 60°C, 70°C, 80°C, 90°C, 100°C, 110°C, 120°C, 130°C, 140°C, 150°C, 160°C, or 170°C.

[0089] In a specific embodiment of the present application, the compound VI and the compound VII are coupled to prepare the compound II. In the reaction, the reaction time is 5 to 20 hours, for example, it can be 5 hours, 6 hours, 7 hours, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours, 19 hours, 20 hours, preferably 8 to 18 hours, for example, 8 hours, 9 hours, 10 hours, 11 hours, 12 hours, 13 hours, 14 hours, 15 hours, 16 hours, 17 hours, 18 hours.

[0090] In the art, international patent WO 2011135376 discloses two methods for preparing Erdafitinib, and the steps are as follows:

[0091] The first route uses 7-bromoquinoxaline-2-one (2) as the starting material, which undergoes a chlorination reaction with phosphorus oxychloride to synthesize intermediate 3. Then, using triphenylphosphine as a ligand, intermediate 3 undergoes a Suzuki coupling reaction with compound 4 under the catalysis of palladium acetate to synthesize intermediate 5. Subsequently, intermediate 3 undergoes a Buchwald-Hartwig coupling reaction with compound 6 under the catalysis of palladium acetate to synthesize intermediate 7. Finally, intermediate 7 undergoes an N-alkylation reaction to synthesize the target compound erdafitinib (1).

[0092] The second route uses 7-bromoquinoxaline-2-one (2) and 3,5-dimethoxyaniline (6) as starting materials. Raw material 6 undergoes nucleophilic substitution reaction and hydrolysis under alkaline conditions to synthesize intermediate 10, and then tert-butyldimethylsilyl chloride is used to protect the hydroxyl group under the catalysis of imidazole to synthesize intermediate 11. Intermediate 11 and intermediate 5 are synthesized into intermediate 12 under the catalysis of palladium acetate. The coupling product is deprotected with tetrabutylammonium fluoride to obtain intermediate 13, which is then subjected to esterification reaction to synthesize intermediate 14, and finally an aminolysis reaction is carried out to synthesize the target compound erdafitinib (1).

[0093] Patent WO 2011135376 reports the above two methods for preparing Erdafitinib. The raw material 7-bromoquinoxaline-2-one (2) is relatively expensive, and has undergone Suzuki coupling. The reaction conditions of this reaction are harsh, the amount of palladium acetate used is relatively large, the cost is high but the yield is low, and it is not suitable for mass production. In the process of preparing intermediate 7 from intermediate 5 and compound 6 through nucleophilic substitution reaction, since compound 6 is a primary amine and has high activity, a byproduct 36 will be generated.

[0094]

[0095] In the art, Chinese patent CN 112125889A discloses a method for preparing Erdafitinib, which specifically requires 6 steps of reaction to prepare Erdafitinib, and at least 64 hours of reaction is required to complete the preparation of Erdafitinib, and the steps are lengthy;

[0096] In the art, a method for preparing Erdafitinib in the prior art (Sun XH, et al. Synthesis of quinoxaline derivatives as intermediates to obtain Erdafitinib. Pharm Chem J, 2021, 55(9): 951-953) comprises the following steps:

[0097] This route uses 1-methylpyrazole (23) as the starting material, undergoes FC acylation with acetic anhydride to obtain intermediate 24, then undergoes bromination with pyridinium tribromide to obtain intermediate 25, and then undergoes nucleophilic substitution and condensation reaction with compound 26 to obtain intermediate 5, and then intermediate 5 is coupled with compound 6 under the catalysis of palladium acetate to obtain intermediate 7, and finally intermediate 7 undergoes N-alkylation reaction with compound 8 to obtain the target compound erdafitinib (1). Among them, the reaction product of bromide 25 and 4-bromo-o-phenylenediamine (26) contains not only 5 but also isomer 37 of 5, and the yields of 5 and 37 are comparable and difficult to separate.

[0098]

[0099] The preparation method of Erdafitinib disclosed in the present application is convenient and quick, and avoids side reactions, which will be described in the form of specific embodiments below.

[0100] Example

[0101] 1 H-NMR and 13 C-NMR was measured using a Bruker-Avance-600 nuclear magnetic resonance analyzer; liquid chromatography was measured using Shimadzu LC-15C, Shimadzu LC-2010A and Agilent 1260 Infinity II high performance liquid chromatographs.

[0102] All reagents were commercially available products of chemical or analytical grade.

[0103] The present application is further described in detail with reference to the embodiments, but the scope of the present application is not limited thereto.

[0104] Example 1

[0105] Synthesis of Compound I

[0106] In a 100 mL eggplant-shaped bottle, 2.90 g (21.71 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran were added, and 0.82 g (21.71 mmol) of sodium borohydride was slowly added at 0°C. After stirring for 0.5 h, 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide was added to the reaction solution, and the temperature was raised to 50°C for 4 h. Add 8 mL of sodium hydroxide solution (1 mol / L) and reflux for 2 h. Evaporate tetrahydrofuran under reduced pressure. Add dichloromethane (10 mL×3) to the eggplant-shaped flask for extraction. Wash twice with saturated brine. Combine the organic phases, concentrate, and recrystallize from isopropanol to obtain 1.36 g of a yellow solid with a yield of 70.3% and a purity of 99.79% (HPLC area normalization method).

[0107] mp138-139℃,ESI-MS(m / z):447.2[M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.95(s,1H),8.55(s,1H),8.21(s,1H),7.77(d,J=9.2Hz,1H),7.28(dd,J=9.2,2.7Hz,1H),7.15(d,J=2.7Hz,1H),6.47(d,J= 2.3Hz,2H),6.41(t,J=2.2Hz,1H),3.93(s,3H),3.88(t,J=7.1Hz,2H),3.7 5(s,6H),2.80(t,J=7.1Hz,2H),2.73-2.67(m,1H),0.96(d,J=6.2Hz,6H).

[0108] Example 2

[0109] Synthesis of Compound I

[0110] In a 100 mL eggplant-shaped bottle, add 2.90 g (21.71 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran, slowly add 0.82 g (21.60 mmol) of lithium aluminum hydride at 0°C, stir for 0.5 h, add 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide to the reaction solution, heat to 50°C and react for 4 h. Add 8 mL of sodium hydroxide solution (1 mol / L) and reflux for 2 h, evaporate tetrahydrofuran under reduced pressure, add dichloromethane (10 mL×3) to the eggplant-shaped bottle for extraction, wash twice with saturated brine, combine the organic phases, concentrate, and recrystallize from isopropanol to obtain 1.34 g of yellow solid, with a yield of 69.5%.

[0111] Example 3

[0112] Synthesis of Compound I

[0113] Add 20 mL of anhydrous tetrahydrofuran to a 100 mL eggplant-shaped bottle, add 0.82 g (21.71 mmol) of sodium borohydride at 0°C, stir for 0.5 h, add 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide to the reaction solution, heat to 50°C and react for 4 h. Distill off the tetrahydrofuran under reduced pressure, add dichloromethane (10 mL×3) to the eggplant-shaped bottle for extraction, wash twice with saturated brine, combine the organic phases, concentrate, and separate the product to obtain 0.38 g of a yellow solid with a yield of 19.9%.

[0114] Example 4

[0115] Synthesis of Compound I

[0116] In a 100 mL eggplant-shaped bottle, add 0.58 g (4.34 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran, add 0.16 g (4.34 mmol) of sodium borohydride at 0°C, stir for 0.5 h, add 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide to the reaction solution, heat to 50°C and react for 4 h. Add 8 mL of sodium hydroxide solution (1 mol / L) and reflux for 2 h, evaporate tetrahydrofuran under reduced pressure, add dichloromethane (10 mL×3) to the eggplant-shaped bottle for extraction, wash twice with saturated brine, combine the organic phases, concentrate, and separate the product to obtain 0.62 g of yellow solid with a yield of 31.9%.

[0117] Example 5

[0118] Synthesis of Compound I

[0119] In a 100 mL eggplant-shaped bottle, 1.74 g (13.02 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran were added, and 0.49 g (13.02 mmol) of sodium borohydride was added at 0°C. After stirring for 0.5 h, 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide was added to the reaction solution, and the temperature was raised to 50°C for 4 h. 8 mL of sodium hydroxide solution (1 mol / L) was added and refluxed for 2 h. The tetrahydrofuran was evaporated under reduced pressure, and dichloromethane (10 mL×3) was added to the eggplant-shaped bottle for extraction. The mixture was washed twice with saturated brine, and the organic phases were combined and concentrated to separate the product to obtain 1.04 g of a yellow solid with a yield of 53.7%.

[0120] Example 6

[0121] Synthesis of Compound I

[0122] In a 100 mL eggplant-shaped bottle, 4.05 g (30.38 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran were added, and 1.15 g (30.38 mmol) of sodium borohydride was added at 0°C. After stirring for 0.5 h, 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide was added to the reaction solution, and the temperature was raised to 50°C for 4 h. 8 mL of sodium hydroxide solution (1 mol / L) was added and refluxed for 2 h. The tetrahydrofuran was evaporated under reduced pressure, and dichloromethane (10 mL×3) was added to the eggplant-shaped bottle for extraction. The mixture was washed twice with saturated brine, and the organic phases were combined, concentrated, and recrystallized from isopropanol to obtain 1.36 g of a yellow solid with a yield of 70.3%.

[0123] Example 7

[0124] Synthesis of Compound I

[0125] In a 100 mL eggplant-shaped bottle, add 2.90 g (21.71 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran, add 0.82 g (21.71 mmol) of sodium borohydride at 0°C, stir for 0.5 h, add 2.00 g (4.34 mmol) of compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide to the reaction solution, heat to 50°C and react for 1 h. Add 8 mL of sodium hydroxide solution (1 mol / L) and reflux for 2 h, evaporate tetrahydrofuran under reduced pressure, add dichloromethane (10 mL×3) to the eggplant-shaped bottle for extraction, wash twice with saturated brine, combine the organic phases, concentrate, and recrystallize from isopropanol to obtain 0.64 g of a yellow solid with a yield of 33.1%.

[0126] Example 8

[0127] Synthesis of Compound I

[0128] In a 100 mL eggplant-shaped bottle, add 2.90 g (21.71 mmol) of anhydrous aluminum chloride and 20 mL of anhydrous tetrahydrofuran, add 0.82 g (21.71 mmol) of sodium borohydride at 0°C, stir for 0.5 h, add compound II 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide 2.00 g (4.34 mmol) to the reaction solution, heat to 50°C and react for 2 h. After TLC monitoring, add 8 mL of sodium hydroxide solution (1 mol / L) and reflux for 2 h, evaporate tetrahydrofuran under reduced pressure, add dichloromethane (10 mL×3) to the eggplant-shaped bottle for extraction, wash twice with saturated brine, combine the organic phases, concentrate, and recrystallize from isopropanol to obtain 1.28 g of yellow solid, with a yield of 66.5%.

[0129] Table 1 Synthesis of Compound I using Compound II

[0130]

[0131]

[0132] Note: The symbol “\” in the table means that there is no such substance in the reaction.

[0133] It can be seen from Examples 1 and 2 that, in terms of the selection of reducing agents, sodium borohydride is slightly better than lithium aluminum hydride, so that the yield of Example 1 reaches 70.3%. It can be seen from the results of Example 3 that the presence or absence of a catalyst seriously affects the reaction effect. In the absence of a catalyst, the yield of Compound I is only 19.9%. It can be seen from Examples 4-6 that with the increase in raw material input, the overall yield of the reaction gradually increases. It can be seen from Examples 7 and 8 that the reaction time represents the reaction process, and Example 7 does not react completely, which seriously affects the yield.

[0134] Example 9

[0135] Compound III and compound IV were used to synthesize compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide. In a 100 mL eggplant-shaped bottle, 3.00 g (8.30 mmol) of compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine and 25 mL of anhydrous tetrahydrofuran were added. Under nitrogen protection, 0.83 g (20.75 mmol) of sodium hydride (60%) was slowly added in batches with stirring at 0°C. After 2 h, 2.40 g (13.28 mmol) of compound IV N-isopropyl-2-bromoacetamide was added to the reaction solution, and the temperature was raised to 66°C for reaction for 2 h. Tetrahydrofuran was evaporated under reduced pressure, 30 mL of water was added to the eggplant-shaped flask, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate) to obtain 3.26 g of a yellow oil with a yield of 85.3%.

[0136] ESI-MS (m / z): 461.0 [M+H] + . 1 H-NMR (600MHz, DMSO-d6) δ8.98(s,1H),8.54(s,1H),8.20(s,1H),7.78(d,J=9.1Hz,1H),7.28(dd,J=9.2,2.7Hz,1H),7.11(d,J=2.7Hz,1H ), 6.49 (d, J = 2.2Hz, 2H), 6.39 (t, J = 2.2Hz, 1H), 4.41 (s, 2H), 3.90 (s, 3H), 3.73 (s, 6H), 2.78 (m, J = 14.2, 7.8Hz, 1H), 0.93 (d, J = 2.2Hz, 6H).

[0137] Example 10

[0138] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0139] In a 100 mL eggplant-shaped bottle, add compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine 3.00 g (8.30 mmol) and anhydrous tetrahydrofuran 25 mL. Under nitrogen protection, potassium carbonate 2.87 g (20.75 mmol) and potassium iodide 0.11 g (0.66 mmol) are slowly added in batches with stirring at 0°C. KI is used as a catalyst. After 2 h, compound IV N-isopropyl-2-bromoacetamide 2.40 g (13.28 mmol) is added to the reaction solution, and the temperature is raised to 66°C for reaction for 2 h. The solvent was evaporated under reduced pressure, 30 mL of water was added to the eggplant-shaped flask, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate) to obtain 1.44 g of a yellow oil with a yield of 37.7%.

[0140] Embodiment 11

[0141] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0142] Compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine 3.00g (8.30mmol) and anhydrous tetrahydrofuran 25mL were added to a 100mL eggplant-shaped bottle. Under nitrogen protection, potassium hydroxide 0.87g (15.56mmol) was slowly added in batches under stirring at 0°C. After 2h, compound IV N-isopropyl-2-bromoacetamide 2.40g (13.28mmol) was added to the reaction solution, and the temperature was raised to 66°C for reaction for 2h. The solvent was evaporated under reduced pressure, 30mL of water was added to the eggplant-shaped bottle, and extracted with dichloromethane (15mL×3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, concentrated, and the crude product was separated and purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate) to obtain 2.88g of yellow oil with a yield of 75.4%.

[0143] Example 12

[0144] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0145] In a 100 mL eggplant-shaped bottle, add 3.00 g (8.30 mmol) of compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine and 25 mL of anhydrous tetrahydrofuran, and slowly add 1.16 g (20.75 mmol) of potassium hydroxide in batches under nitrogen protection and stirring at 0°C. After 2 hours, add 2.40 g (13.28 mmol) of compound IV N-isopropyl-2-bromoacetamide to the reaction solution, and heat to 66°C for 2 hours. Evaporate the solvent under reduced pressure, add 30 mL of water to the eggplant-shaped bottle, extract with dichloromethane (15 mL×3), combine the organic phases, wash twice with saturated brine, dry with anhydrous sodium sulfate, filter, concentrate, and separate and purify the crude product by column chromatography on silica gel (eluent is petroleum ether-ethyl acetate) to obtain 3.06 g of yellow oil with a yield of 80.1%.

[0146] Embodiment 13

[0147] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0148] Compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine 3.00g (8.30mmol) and anhydrous tetrahydrofuran 25mL were added to a 100mL eggplant-shaped bottle, and sodium hydride (60%) 0.83g (20.75mmol) was slowly added in batches under nitrogen protection and stirring at 0°C. After 2h, compound IV N-isopropyl-2-chloroacetamide 1.35g (9.96mmol) was added to the reaction solution, and the temperature was raised to 66°C for reaction for 2h. Tetrahydrofuran was evaporated, 30mL of water was added to the eggplant-shaped bottle, and extracted with dichloromethane (15mL×3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography on silica gel (eluent was petroleum ether-ethyl acetate) to obtain 3.07g of yellow oil with a yield of 80.3%.

[0149] Embodiment 14

[0150] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0151] In a 100 mL eggplant-shaped bottle, 3.00 g (8.30 mmol) of compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine and 25 mL of anhydrous tetrahydrofuran were added. Under nitrogen protection, 0.83 g (20.75 mmol) of sodium hydride (60%) was slowly added in batches with stirring at 0°C. After 2 h, 1.58 g (11.62 mmol) of compound IV N-isopropyl-2-chloroacetamide was added to the reaction solution, and the temperature was raised to 66°C for reaction for 2 h. Tetrahydrofuran was evaporated under reduced pressure, 30 mL of water was added to the eggplant-shaped flask, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily crude product. The crude product was separated and purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate) to obtain 3.20 g of a yellow oily substance with a yield of 83.8%.

[0152] Embodiment 15

[0153] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0154] Compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine 3.00g (8.30mmol) and anhydrous tetrahydrofuran 25mL were added to a 100mL eggplant-shaped bottle, and sodium hydride (60%) 0.83g (20.75mmol) was slowly added in batches under nitrogen protection and stirring at 0°C. After 2h, compound IV N-isopropyl-2-chloroacetamide 1.80g (13.28mmol) was added to the reaction solution, and the temperature was raised to 66°C for 1h. Tetrahydrofuran was evaporated under reduced pressure, 30mL of water was added to the eggplant-shaped bottle, and extracted with dichloromethane (15mL×3), the organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered, and concentrated. The crude product was separated and purified by column chromatography on silica gel (eluent was petroleum ether-ethyl acetate) to obtain 2.28g of yellow oil with a yield of 59.7%.

[0155] Example 16

[0156] Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-yl]amino}-N'-isopropylacetamide is synthesized by using compound III and compound IV

[0157] In a 100 mL eggplant-shaped bottle, 3.00 g (8.30 mmol) of compound III N-(3,5-dimethoxyphenyl)-3-(1-methyl-1H-pyrazol-4-yl)quinoxaline-6-amine and 25 mL of anhydrous tetrahydrofuran were added. Under nitrogen protection, 0.66 g (16.60 mmol) of sodium hydride (60%) was slowly added in batches with stirring at 0°C. After 2 h, 1.80 g (13.28 mmol) of compound IV N-isopropyl-2-chloroacetamide was added to the reaction solution, and the temperature was raised to 66°C for reaction for 2 h. Tetrahydrofuran was evaporated under reduced pressure, 30 mL of water was added to the eggplant-shaped flask, and the mixture was extracted with dichloromethane (15 mL×3). The organic phases were combined, washed twice with saturated brine, dried over anhydrous sodium sulfate, filtered and concentrated to obtain a yellow oily crude product. The crude product was separated and purified by column chromatography on silica gel (eluent: petroleum ether-ethyl acetate) to obtain 3.20 g of a yellow oily substance with a yield of 83.9%.

[0158] Table 2 Synthesis of Compound II using Compound III and Compound IV

[0159]

[0160]

[0161] It can be seen from Examples 9 and 10 that when compound IV is N-isopropyl-2-bromoacetamide, anhydrous tetrahydrofuran is used as the solvent, and sodium hydride (60%) is used as the base, the yield is higher than when a mixture of potassium carbonate and potassium iodide is used as the base.

[0162] It can be seen from Examples 11 and 12 that Example 11 did not react completely, and further addition of potassium hydroxide can further increase the yield.

[0163] It can be seen from Examples 13 and 14 that compound IV uses N-isopropyl-2-chloroacetamide, and further adding compound IV can further increase the yield.

[0164] It can be seen from Examples 15 and 16 that reaction time is one of the main factors affecting yield. Example 16 uses less sodium hydride, but because the reaction time is longer, the yield is higher.

[0165] Embodiment 17

[0166] Compound VI and Compound VII are used to synthesize Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide

[0167] In a 100 mL three-necked flask, add 3.00 g (11.89 mmol) of compound VI 2-[(3,5-dimethoxyphenyl)amino]-N-isopropylacetamide, 3.44 g (11.89 mmol) of compound VII 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline, 2.67 g (23.78 mmol) of potassium tert-butoxide, 0.03 g (0.12 mmol) of palladium acetate, 0.07 g (0.12 mmol) of BINAP, and 25 mL of 1,4-dioxane, and react at 101° C. for 12 h under N2. Filter with suction, and concentrate the filtrate. To the concentrated reaction solution, 30 mL of water and 30 mL of dichloromethane were added and stirred, and the organic phase and the aqueous phase were separated. The aqueous phase was extracted with dichloromethane (30 mL×2), and the organic phase was washed with saturated sodium chloride solution, dried, and concentrated. The crude product was recrystallized from methyl tert-butyl ether to obtain 3.89 g of a yellow solid with a yield of 71.1%.

[0168] ESI-MS (m / z): 461.2 [M+H] + . 1H NMR (600MHz, DMSO-d6) δ8.98(s,1H),8.55(s,1H),8.20(s,1H),8.12(d,J=7.8Hz,1H),7.78(d,J=9.2Hz,1H),7.29(dd,J=9.2,2.7Hz,1H),7.11( d,J=2.7Hz,1H),6.50(d,J=2.2Hz,2H),6.39(t,J=2.3Hz,1H),4.43(s,2 H), 3.93 (s, 3H), 3.91-3.88 (m, 1H), 3.73 (s, 6H), 1.08 (d, J = 6.6Hz, 6H).

[0169] Embodiment 18

[0170] Compound VI and Compound VII are used to synthesize Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide

[0171] In a 100 mL three-necked flask, add 3.00 g (11.89 mmol) of compound VI 2-[(3,5-dimethoxyphenyl)amino]-N-isopropylacetamide, 3.44 g (11.89 mmol) of compound VII 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline, 3.29 g (23.78 mmol) of potassium carbonate, 0.03 g (0.12 mmol) of palladium acetate, 0.07 g (0.12 mmol) of BINAP, and 25 mL of 1,4-dioxane. Under N2, react at 101°C for 12 h, filter, and concentrate the filtrate. Add 30 mL of water and 30 mL of dichloromethane to the concentrated reaction solution, stir, separate the organic phase and the aqueous phase, extract the aqueous phase with dichloromethane (30 mL×2), wash the organic phase with a saturated sodium chloride solution, dry, and concentrate. The product is separated to obtain 1.67 g of a yellow solid with a yield of 30.5%.

[0172] Embodiment 19

[0173] Compound VI and Compound VII are used to synthesize Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide

[0174] In a 100mL three-necked flask, add 3.00g (11.89mmol) of compound VI 2-[(3,5-dimethoxyphenyl)amino]-N-isopropylacetamide, 3.44g (11.89mmol) of compound VII 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline, 0.95g (23.78mmol) of sodium hydroxide, 0.03g (0.12mmol) of palladium acetate, 0.07g (0.12mmol) of BINAP, and 25mL of 1,4-dioxane, and react at 101°C for 12h under N2. Filter and concentrate the filtrate. Add 30mL of water and 30mL of dichloromethane to the concentrated reaction solution and stir, separate the organic phase and the aqueous phase, extract the aqueous phase with dichloromethane (30mL×2), wash the organic phase with a saturated sodium chloride solution, dry, and concentrate, separate the product, and obtain 2.23g of a yellow solid with a yield of 40.7%.

[0175] Embodiment 20

[0176] Compound VI and Compound VII are used to synthesize Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide

[0177] In a 100 mL three-necked flask, added compound VI 2-[(3,5-dimethoxyphenyl)amino]-N-isopropylacetamide 3.00 g (11.89 mmol), compound VII 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline 3.44 g (11.89 mmol), potassium tert-butoxide 2.00 g (17.84 mmol), palladium acetate 0.03 g (0.12 mmol), BINAP 0.07 g (0.12 mmol), 1,4-dioxane 25 mL, and reacted at 101 ° C for 12 h under N2. The mixture was filtered and the filtrate was concentrated. 30 mL of water and 30 mL of dichloromethane were added to the concentrated reaction solution and stirred. The organic phase and the aqueous phase were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phase was washed with saturated sodium chloride solution, dried and concentrated. The crude product was recrystallized from methyl tert-butyl ether to obtain 3.77 g of a yellow solid product with a yield of 68.9%.

[0178] Embodiment 21

[0179] Compound VI and Compound VII are used to synthesize Compound II: 2-{N-(3,5-dimethoxyphenyl)-N-[3-(1-methyl-1H-pyrazol-4-yl)quinoxalin-6-yl]amino}-N'-isopropylacetamide

[0180] In a 100 mL three-necked flask, added compound VI 2-[(3,5-dimethoxyphenyl)amino]-N-isopropylacetamide 3.00 g (11.89 mmol), compound VII 7-bromo-2-(1-methyl-1H-pyrazol-4-yl)quinoxaline 3.44 g (11.89 mmol), potassium tert-butoxide 3.34 g (29.73 mmol), palladium acetate 0.03 g (0.12 mmol), BINAP 0.07 g (0.12 mmol), 1,4-dioxane 25 mL, and reacted at 101 ° C for 12 h under N2. The mixture was filtered and the filtrate was concentrated. 30 mL of water and 30 mL of dichloromethane were added to the concentrated reaction solution and stirred. The organic phase and the aqueous phase were separated. The aqueous phase was extracted with dichloromethane (30 mL × 2). The organic phase was washed with saturated sodium chloride solution, dried and concentrated. The crude product was recrystallized from methyl tert-butyl ether to obtain 3.85 g of a yellow solid product with a yield of 70.3%.

[0181] Table 3 Synthesis of Compound II using Compound VI and Compound VII

[0182]

[0183]

[0184] It can be seen from Examples 17-19 that when the molar mass of the base is the same, the yield of potassium tert-butoxide is the highest, which is 71.1%; the yield when sodium hydroxide is used is second, which is 40.7%; and the yield when potassium carbonate is used is the lowest, which is 30.5%.

[0185] It can be seen from Examples 17, 20 and 21 that the yield is best when the potassium tert-butoxide input amount is 2.67 g (i.e., Example 17). When the potassium tert-butoxide input amount is too high (i.e., Example 21) or too low (i.e., Example 20), the yield will decrease compared to Example 17.

[0186] The above is only the preferred embodiment of the present application, and does not limit the present application in other forms. Any technician familiar with the profession may use the above disclosed technical content to change or modify it into an equivalent embodiment with equivalent changes. However, any simple modification, equivalent change and modification made to the above embodiment based on the technical essence of the present application without departing from the technical solution of the present application still falls within the protection scope of the technical solution of the present application.

Claims

1. A method for synthesizing compound I using compound II, wherein: Compound I is shown below: Compound II is shown below:

2. The method according to claim 1, characterized in that The method comprises the steps of reducing compound II to compound I through a reduction reaction:

3. The method according to claim 2, characterized in that The reduction reaction is carried out in a solvent selected from the group consisting of methanol, ethanol, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, xylene, benzene, toluene or acetone.

4. The method according to claim 2, characterized in that: The reduction reaction is carried out using a reducing agent selected from the group consisting of lithium aluminum hydride, sodium borohydride, and borane.

5. The method according to claim 2, characterized in that: The reduction reaction uses Lewis acid as a catalyst, and the Lewis acid includes aluminum trichloride and boron trifluoride.

6. The method according to claim 2, characterized in that In the reduction reaction, the molar ratio of the compound II, the reducing agent and the catalyst is: Compound II: reducing agent: catalyst = 1: (1-10): (1-10).

7. The method according to claim 2, characterized in that The reduction reaction time is 3 to 20 hours.

8. The method according to claim 2, characterized in that: The reduction reaction temperature is 0-120°C.

9. The method according to claim 1, characterized in that: The invention also includes the step of preparing compound II by a nucleophilic substitution reaction between compound III and compound IV: Wherein, the R1 is selected from Cl or Br.

10. The method according to claim 9, characterized in that The nucleophilic substitution reaction is carried out in a solvent selected from the group consisting of methanol, ethanol, dichloromethane, tetrahydrofuran, methyltetrahydrofuran, dioxane, xylene, benzene, toluene, acetonitrile or acetone.

11. The method according to claim 9, characterized in that The nucleophilic substitution reaction is carried out in a base selected from the group consisting of potassium carbonate, sodium hydride, sodium hydroxide, potassium hydroxide, triethylamine, sodium ethoxide.

12. The method according to claim 9, characterized in that The molar ratio between the compound III, the base and the compound IV is: Compound III: base: compound IV = 1: (2-3): (1-2).

13. The method according to claim 9, characterized in that The nucleophilic substitution reaction time is 1 to 24 hours.

14. The method according to claim 9, characterized in that The nucleophilic substitution reaction temperature is 40-110°C.

15. The method according to claim 1, characterized in that The invention also includes the step of preparing compound II by coupling reaction of compound VI and compound VII:

16. The method according to claim 15, characterized in that The coupling reaction is carried out in a solvent selected from the group consisting of diethyl ether, diisopropyl ether, tetrahydrofuran, MTBE, dioxane and dimethoxyethane, methanol, ethanol, ethylene glycol, 1-propanol, 2-propanol, 2-methoxyethanol, 1-butanol, 2-butanol, isobutanol, tert-butanol, glycerol, dichloromethane, chloroform, carbon tetrachloride, chlorobenzene, toluene, DMF, DMSO or DMAc.

17. The method according to claim 15, characterized in that The coupling reaction is carried out using a catalyst selected from the group consisting of tris(dibenzylideneacetone)dipalladium, bis(dibenzylideneacetone)palladium, palladium chloride, palladium acetate, [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium or tetrakis(triphenylphosphine)palladium.

18. The method according to claim 15, characterized in that The coupling reaction is carried out using a ligand selected from the group consisting of Xantphos, PPh3, dppf, dppb or BINAP.

19. The method according to claim 15, characterized in that The coupling reaction is carried out in a base selected from the group consisting of sodium carbonate, potassium carbonate, cesium carbonate, sodium bicarbonate, sodium hydroxide, potassium hydroxide, sodium hydride, triethylamine, potassium tert-butoxide, diisopropylethylamine pyridine, 2,6-lutidine or N,N-dimethylaminopyridine.

20. The method according to claim 15, characterized in that The molar ratio of the compound II, the reducing agent and the catalyst is: Compound VI: Compound VII: Catalyst = 1: (1-2): (0.0001-0.005).

21. The method according to claim 15, characterized in that The coupling reaction time is 5 to 20 hours.

22. The method according to claim 15, characterized in that The coupling reaction temperature is 40-170°C.

23. A method for preparing compound I using compound III and compound IV, comprising the following steps: Compound I is shown below: ， in, The R1 is selected from Cl or Br.

24. A method for preparing compound I using compound VI and compound VII, comprising the following steps: Compound I is shown below: ， in, The R1 is selected from Cl or Br.

25. An intermediate compound for preparing Erdafitinib, characterized in that: The intermediate compound is shown below:

26. Use of the intermediate compound shown below for preparing Erdafitinib:

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