A synthesis method of thiodiazaspiro compound, intermediate thereof and synthesis method thereof

Abstract

The present application discloses a method for preparing a thiodiazaspiro compound or a pharmaceutically acceptable salt thereof, comprising the following steps, each step having mild reaction conditions and no other special equipment requirements, and being suitable for industrial production. The present application also provides an intermediate compound, which has a simple preparation process, high yield and high purity, and is conducive to high yield and high purity of subsequent products.

Description

Technical Field

[0001] The invention belongs to the field of drug synthesis, and specifically relates to a method for preparing a thiodiazaspiro compound, an intermediate thereof and a preparation method thereof. Background Art

[0002] Compound 1, whose chemical name is 4-[7-(6-cyano-5-trifluoromethylpyridin-3-yl)-8-oxo-6-thioxo-5,7-diazaspiro[3.4]octan-5-yl]-2-fluoro-N-methylbenzamide (also known as Apalutamide), is a second-generation androgen receptor antagonist developed by Johnson & Johnson. It belongs to the thiodiazaspiro class of compounds and is used for non-metastatic castration-resistant prostate cancer.

[0003]

[0004] Apalutamide is a derivative of diarylthiohydantoin, which is composed of a pyridine ring, a benzene ring, a cyclobutane and a thiohydantoin ring system. Its synthesis mainly revolves around the connection of aromatic amines and the construction of the thiohydantoin ring system, as shown below.

[0005]

[0006] Currently, the synthesis of apalutamide usually has two types: "[3+2] type" and "[4+1] type", as shown in the following table.

[0007]

[0008] Among them, there are two main "[3+2] type" synthetic routes: one is to prepare compound 1 by [3+2] cyclization of α-amino nitrile with thioisocyanate, such as the synthesis methods in CN201180009819.9, CN200780019654.7, CN200780020099.X and China Pharmaceutical Industry Journal, 2018, 49(4), as follows:

[0009]

[0010] This synthetic route uses the highly toxic sodium cyanide and also adopts the microwave method, which increases the difficulty of scale-up production in factories and is not suitable for industrial production.

[0011] The second [3+2] preparation route is to obtain compound 1 by [3+2] cyclization of α-carbamate and thioisocyanate, such as the synthesis methods disclosed in CN201610985993.1, CN201711271655.2, and CN201711474542.2, as follows:

[0012]

[0013] The yield of each step in this synthetic pathway is relatively low, the cost is high, the reaction process and post-treatment process are relatively complicated, the optimization of the purification of the intermediates in each step is not carefully considered, and it is not suitable for industrial production. Therefore, it is necessary to further optimize the design of the reaction process and post-treatment conditions of each step of the above [3+2] pathway to achieve the purpose of improving efficiency and yield and reducing costs to meet the needs of industrial production of this raw material.

[0014] The [4+1] preparation route of apalutamide is to prepare compound 1 by [4+1] cyclization of α-aminoamide and thiocarbonyl compound, for example, the synthesis method in CN201580069602.5, specifically:

[0015]

[0016] This synthetic route requires the use of stoichiometric amounts of copper salts; and the last step of [4+1] cyclization requires the use of relatively expensive thiocarbonyl compounds, which is costly.

[0017] Therefore, providing a method for synthesizing apalutamide with simple process, fewer steps, easy operation and low production cost has become an urgent problem to be solved by those skilled in the art. Summary of the invention

[0018] In view of the above problems in the prior art, the main purpose of the present application is to provide a new synthesis method of apalutamide, which has a simple process, is easy to operate, has mild reaction conditions in each step and does not require other special equipment, and is suitable for industrial production.

[0019] The first aspect of the present application provides a method for preparing a compound 1 represented by the following formula or a pharmaceutically acceptable salt thereof, characterized in that a coupling reaction is carried out between a compound 4 and a compound 2 in the presence of a catalytic amount of a copper salt, an acid-binding agent, a ligand and an aprotic polar solvent to generate a compound 1.

[0020]

[0021] wherein X is selected from chlorine, bromine and iodine.

[0022] In some embodiments, in the preparation method of the above-mentioned compound 1 provided in the present application, the acid binding agent is selected from sodium carbonate, potassium carbonate, cesium carbonate and potassium tert-butoxide.

[0023] In some embodiments, in the method for preparing the above-mentioned compound 1 provided herein, the ligand is selected from 2-acetylcyclohexanone and tetramethylethylenediamine.

[0024] In some embodiments, in the method for preparing the above-mentioned compound 1 provided herein, the aprotic polar solvent is selected from DMF and DMAc.

[0025] In some embodiments, in the preparation method of the above-mentioned compound 1 provided in the present application, the coupling reaction is an Ullmann coupling reaction.

[0026] In some embodiments, in the method for preparing the above-mentioned compound 1 provided herein, the coupling reaction is carried out at a temperature of 105-130°C; more preferably, the coupling reaction is carried out at a temperature of 105-115°C.

[0027] In some embodiments, in the preparation method of the above-mentioned compound 1 provided in the present application, the molar equivalent ratio of the compound 4 to the compound 2 is 1.0:1.1-2.0; preferably 1.0:1.5. In some embodiments, the preparation method of the above-mentioned compound 1 provided in the present application includes the step of purifying the crude product of compound 1, specifically washing the crude product of compound 1, collecting the organic phase and adding anhydrous sodium sulfate, filtering and concentrating, heating to 80±5°C, adding isopropanol dropwise, stirring for 2-3 hours, slowly cooling to 5±5°C, stirring for 12-15 hours, and filtering, and washing the filter cake with 10mL of isopropanol.

[0028] In some embodiments, the compound 4 is prepared by the following steps: Compound 7 and compound 5 are subjected to a cyclization reaction in the presence of a solvent and an acid-binding agent to generate compound 4;

[0029]

[0030] Wherein, R is selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl and six-membered heteroaryl, and the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl and six-membered heteroaryl are optionally substituted by substituents independently selected from halogen, nitro, C2-C4 alkenyl, C2-C4 alkynyl and phenyl; preferably, R is methyl or benzyl.

[0031] In some embodiments, in the preparation method of the above-mentioned compound 4 provided in the present application, the solvent of the cyclization reaction is selected from N'N-dimethylformamide, N'N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and toluene; preferably dimethyl sulfoxide.

[0032] In some embodiments, the acid-binding agent is selected from triethylamine, N'N-diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene and tetramethylethylenediamine; preferably triethylamine.

[0033] In some embodiments, the cyclization reaction is carried out at a temperature of 70°C to 110°C; preferably, the cyclization reaction is carried out at a temperature of 85°C to 95°C.

[0034] In some embodiments, the compound 7 is prepared by the following steps:

[0035]

[0036] wherein R is selected from C1-C6 alkyl, C3-C6 cycloalkyl, phenyl and six-membered heteroaryl, and the C1-C6 alkyl, C3-C6 cycloalkyl, phenyl and six-membered heteroaryl are optionally substituted by a substituent independently selected from halogen, nitro, C2-C4 alkenyl, C2-C4 alkynyl and phenyl; compound 8 is reacted with an acid or a reagent that can be hydrolyzed into an acid in an alcohol medium to convert it into an ester compound 7;

[0037] Alternatively, compound 8 is converted into compound 7 by reacting with benzyl halide with carboxylic acid in the presence of an acid-binding agent.

[0038] In some embodiments, in the preparation method of the above-mentioned compound 7 provided in the present application, the acid or the reagent capable of hydrolyzing into an acid is selected from concentrated sulfuric acid, POCl3 and thionyl chloride; preferably thionyl chloride;

[0039] The alcohol medium is selected from methanol, ethanol, isopropanol and benzyl alcohol; preferably methanol;

[0040] or,

[0041] The benzyl halide is selected from benzyl chloride and benzyl bromide;

[0042] The acid binding agent is selected from sodium carbonate, potassium carbonate and cesium carbonate, preferably potassium carbonate. The carboxylic acid alkylation reaction is carried out in a suitable solvent, and the solvent is selected from acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, preferably N,N-dimethylformamide and acetonitrile.

[0043] In some embodiments, the compound 5 is prepared by the following steps:

[0044]

[0045] Compound 6 is reacted in the presence of thiophosgene to produce compound 5.

[0046] In some embodiments, the compound 2 is prepared by the following steps:

[0047]

[0048] Compound 3 is reacted with an acid or a reagent that can be hydrolyzed into an acid in an alcohol medium to be converted into an ester, and then subjected to a "one-pot" methylamine hydrolysis reaction to generate compound 2.

[0049] In some embodiments, in the preparation method of the above-mentioned compound 2 provided in the present application, the acid or the reagent capable of hydrolyzing into an acid is an organic acid, an inorganic acid or a mixture thereof; preferably, selected from concentrated sulfuric acid, phosphorus oxychloride and thionyl chloride;

[0050] In some embodiments, in the method for preparing the above-mentioned compound 2 provided in the present application, the alcohol medium is selected from methanol, ethanol, isopropanol and benzyl alcohol.

[0051] In a second aspect of the present application, a compound with the structure shown below is provided:

[0052]

[0053] In some embodiments, the compound 4 is prepared by the above preparation method.

[0054] The third aspect of the present application provides the use of the above-mentioned compound 4 in the preparation of compound 1.

[0055] The preparation method of compound 1 provided in this application has the following advantages:

[0056] (1) The preparation method provided in the present application is a convergent synthesis route, which is more conducive to improving the reaction yield and reducing side reactions compared to linear synthesis.

[0057] (2) The synthesis methods of apalutamide disclosed in the prior art all place the construction of the thiohydantoin ring system in the late stage of synthesis, but due to the complex substrate system, the [3+2] cyclization effect is often poor; the present application obtains the intermediate compound 4 by preferential synthesis, creatively places the difficult problem of thiohydantoin ring system construction in the early stage of synthesis, and successfully solves the problems existing in the prior art. The yield of the embodiment of thiohydantoin ring system construction in the present application is 92%, which is significantly improved compared with the prior art; it is conducive to obtaining a high yield of the final product. DETAILED DESCRIPTION

[0058] The following will be combined with the implementation methods to clearly and completely describe the technical solution of the present application. Obviously, the described implementation methods are only part of the implementation methods of the present application, not all of the implementation methods. Based on the implementation methods in the present application, all other implementation methods obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0059] If no specific conditions are specified in the examples of this application, the experiments were carried out according to conventional conditions or conditions recommended by the manufacturer. If no manufacturer is specified for the reagents or instruments used, they are all conventional products that can be purchased commercially.

[0060] definition

[0061] "C1-C6 alkyl" refers to a saturated aliphatic hydrocarbon group, including straight chain and branched groups of 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl and the like.

[0062] "C3-C6 cycloalkyl" refers to a saturated monocyclic, fused, spirocyclic or bridged ring containing a specified number of carbon atoms. For example, a cycloalkyl group is a 3- to 6-membered monocyclic group. It includes, but is not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0063] "Heteroaryl" refers to a 5- or 6-membered aromatic ring containing at least one N, O or S heteroatom, for example pyridyl, pyrimidinyl, pyrazolyl, pyridazinyl, imidazolyl, triazolyl, thienyl or pyrazinyl.

[0064] "Halogen" (or "halo") refers to fluorine, chlorine, bromine, and iodine (alternatively referred to as fluoro, chloro, bromo, and iodo).

[0065] "Optionally substituted" means that the substituent may be (1) unsubstituted or (2) substituted. If a carbon of a substituent is described as optionally substituted with one or more of the listed substituents, then one or more hydrogens on the carbon (to the extent of any hydrogens present) may be replaced, individually and / or together, with independently selected optional substituents. If a nitrogen of a substituent is described as optionally substituted with one or more of the listed substituents, then one or more hydrogens on the nitrogen (to the extent of any hydrogens present) may each be replaced with an independently selected optional substituent.

[0066] instrument

[0067] The structures of the compounds were determined by nuclear magnetic resonance ( 1 H) or mass spectrometry (MS).

[0068] 1 H spectroscopy was performed using a Bruker superconducting nuclear magnetic resonance spectrometer (instrument model: BRUKER AVANCE 400 nuclear magnetic resonance spectrometer); solvent: DMSO-d6; temperature: 22°C;

[0069] LC-MS detection was performed using an Agilent 6120B Ms liquid chromatograph-single quadrupole, positive ion mode, ESI ionization source, scanning range 50 m / z to 3000 m / z

[0070] The abbreviations of the reagents involved in the examples have the following Chinese meanings:

[0071] abbreviation Chinese name abbreviation Chinese name <![CDATA[SOCl2]]> Sulfonyl chloride MeOH Methanol TEA Triethylamine DMSO Dimethyl sulfoxide CuI Cuprous iodide <![CDATA[K2CO3]]> Potassium carbonate TMEDA Tetramethylethylenediamine DMF N,N-Dimethylformamide equiv Molar equivalent ratio DMAc N,N-Dimethylacetamide

[0072] Example 1A: Preparation of Compound 7A (1-aminocyclobutanecarboxylic acid methyl ester) from Compound 8

[0073]

[0074] 1-Aminocyclobutanecarboxylic acid (Compound 8) (86.86 mmol) was dissolved in methanol (50 mL) and protected by nitrogen. The temperature was lowered to 15±5°C. Sulfonyl chloride (130.28 mmol) was slowly added dropwise and the temperature was controlled at 15±5°C. After the addition was completed, the temperature was raised to 25±5°C. After the raw materials reacted completely, 100 mL of purified water was added. Saturated sodium bicarbonate solution was added dropwise to adjust the pH to 8-9. The mixture was extracted twice with 100 mL of ethyl acetate. The organic phase was collected and dried with anhydrous sodium sulfate. The ethyl acetate was concentrated to dryness to obtain a white solid. After air drying, 10.56 g of compound 7A was obtained with a yield of 94%.

[0075] LC-MS: [M+H] + =130

[0076] 1 H NMR (400MHz, CDCl3) δ3.76 (s, 3H), 2.58-2.53 (m, 2H), 2.04-1.91 (m, 4H).

[0077] Example 1B: Preparation of Compound 7B (1-aminocyclobutane-1-carboxylic acid benzyl ester) from Compound 8

[0078]

[0079] 1-Aminocyclobutanecarboxylic acid (Compound 8) (86.86 mmol) was dissolved in acetonitrile (50 mL), and potassium carbonate (173.72 mmol) was added under nitrogen protection, the temperature was raised to 60±5°C, benzyl chloride (95.55 mmol) was slowly added dropwise, and the temperature was controlled at 60±5°C. After the raw materials reacted completely, 150 mL of purified water was added dropwise, and the mixture was filtered to obtain a white solid. After air drying, 15.15 g of Compound 7B was obtained, with a yield of 85%.

[0080] LC-MS: [M+H] + =206.

[0081] 1 H NMR (400MHz, CDCl3): δ7.40-7.20(m,5H), δ5.20(s,2H)2.56-2.46(m,2H), 2.11-2.01(m,2H), 2.00-1.90(m,2H).

[0082] Example 2: Preparation of Compound 5 (5-isothiocyanato-3-trifluoromethyl-2-cyanopyridine) from Compound 6

[0083]

[0084] 5-Amino-3-trifluoromethyl-2-cyanopyridine (Compound 6) (0.53 mol) was dissolved in 0.5 L acetone, thiophosgene (0.64 mol) was added dropwise, and the reaction was carried out at room temperature for 1 to 3 hours. Most of the solvent was removed by distillation under reduced pressure, and 1.0 L n-hexane and 50 g neutral alumina were added to the residue. The mixture was heated to 40±5°C and stirred for 1 hour. After filtration and concentration, 105 g of Compound 5 was obtained as an off-white solid with a yield of 86%.

[0085] 1 H NMR (400MHz, DMSO-d6) δ9.04 (d, J = 2.2 Hz, 1H), 8.57 (d, J = 2.3 Hz, 1H).

[0086] Example 3: Preparation of Compound 2A (N-methyl-4-bromo-2-fluorobenzamide) from Compound 3A

[0087]

[0088] 4-Bromo-2-fluorobenzoic acid (Compound 3A) (45.66mmol) was dissolved in methanol (30mL). Under nitrogen protection, 27.40mmol of thionyl chloride was slowly added dropwise while controlling the temperature at 15±5°C. After the addition was completed, the temperature was raised to 45±5°C. After the reaction of the raw materials was complete, the temperature was slowly lowered to 25±5°C. A methylamine aqueous solution (0.32mol) (25-30%) was slowly added dropwise. After the addition was completed, the temperature was kept at 25±5°C. After the reaction was continued for 2 hours, the temperature was controlled at 25±5°C, and 150mL of purified water was slowly added dropwise. After the addition was completed, stirring was continued for two hours. Filter and collect the filter cake. The filter cake was dried with air at 50±5°C to obtain 10.38g of Compound 2A with a yield of 98%.

[0089] LC-MS: m / z = 231.9 [M+1] + 、233.9[M+3] +

[0090] 1 H NMR (400MHz, DMSO-d6) δ8.25 (s, 1H), 7.64-7.52 (m, 2H), 7.46 (d, J = 8.3Hz, 1H), 2.80 (d, J = 4.8Hz, 3H).

[0091] Example 4A: Preparation of Compound 4 from Compound 7A and Compound 5

[0092]

[0093] Under nitrogen protection, compound 7A (38.71 mmol), DMSO (15 mL) and triethylamine (77.42 mmol) were added to the reaction bottle, the temperature was raised to 90±5°C, compound 5 (77.42 mmol) was added, and the mixture was stirred for 16 hours. The reaction solution was concentrated to dryness, the temperature was raised to 80°C±5, n-heptane (50 mL) was slowly added dropwise, stirred for 2 hours, slowly cooled to room temperature, stirred for 12 hours, filtered, the filter cake was rinsed twice with 10 mL of n-heptane, and the mixture was dried under vacuum at 45±5°C for 16 hours to obtain 11.68 g of compound 4, with a yield of 92%.

[0094] Example 4B: Preparation of Compound 4 from Compound 7B and Compound 5

[0095]

[0096] Under nitrogen protection, compound 7B (38.71 mmol), DMSO (20 mL) and triethylamine (77.42 mmol) were added to the reaction bottle, the temperature was raised to 90±5°C, compound 5 (77.42 mmol) was added, and the mixture was stirred for 16 hours. The reaction solution was concentrated to dryness, the temperature was raised to 80°C±5, n-heptane (50 mL) was slowly added dropwise, stirred for 2 hours, slowly cooled to room temperature, stirred for 12 hours, filtered, the filter cake was rinsed twice with 10 mL of n-heptane, and the mixture was dried under vacuum at 45±5°C for 16 hours to obtain 10.92 g of compound 4, with a yield of 86%.

[0097] [M+H + ]=327.05.

[0098] 1 H-NMR (400Hz, CDCl3): δ11.26(s,1H), δ9.10(s,1H), δ8.65(s,1H), δ2.61–2.54(m,2H), δ2.49–2.41(m,2H), δ1.99–1.81(m,2H).

[0099] Example 5: Preparation of Compound 1 from Compound 4 and Compound 2A

[0100]

[0101] Compound 4 (15.32mmol), compound 2A (22.98mmol), K2CO3 (45.96mmol), CuI (0.77mmol), tetramethylethylenediamine (7.66mmol) were added to 30ml DMF, nitrogen protection, 110±5℃ reaction for 6h, cooled to room temperature, added 7.5mL concentrated ammonia solution and stirred for half an hour, then added 50mL purified water, added 50mL ethyl acetate, extracted three times, and the organic phases were combined. 10mL purified water was added to wash the organic phase twice, the organic phase was collected, anhydrous sodium sulfate was added to the organic phase, filtered, the filtrate was concentrated to dryness, heated to 80±5℃, isopropanol (50mL) was slowly added dropwise, stirred for 2 hours, slowly cooled to 5±5℃, stirred for 12 hours, filtered, the filter cake was rinsed twice with 10mL isopropanol, and the material was vacuum dried at 45±5℃ for 16 hours to obtain 6.42g compound 1, with a yield of 87%.

[0102] LC-MS: m / z=478.1[M+H] +

[0103] 1 H NMR (400MHz, DMSO-d6) δ9.23(d,J=2.0Hz,1H),8.77(d,J=2.0Hz,1H),8.54–8.39(m,1H),7.92(t,J=8.0Hz,1H),7.50(dd,J=10.5,1.8H z,1H),7.43(dd,J=8.1,1.8Hz,1H),2.89(d,J=4.6Hz,3H),2.78–2.66(m,2H),2.64–2.49(m,2H),2.11–1.98(m,1H),1.72–1.55(m,1H).

[0104] The above description is only a preferred embodiment of the present invention, and does not limit the patent scope of the present invention. All equivalent structural changes made by using the present invention specification under the inventive concept of the present invention, or directly / indirectly applied in other related technical fields are included in the patent protection scope of the present invention.

Claims

1. A method for preparing compound 1 or a pharmaceutically acceptable salt thereof, characterized in that: Compound 4 and compound 2 undergo coupling reaction under the action of a catalytic amount of copper salt, an acid-binding agent, a ligand and a non-protonic polar solvent to generate compound 1. wherein X is selected from chlorine, bromine and iodine; The compound 4 is prepared by a method comprising the following steps: subjecting the compound 7 to a cyclization reaction with the compound 5 in the presence of a solvent and an acid-binding agent to generate the compound 4; wherein R is selected from C1-C6 alkyl, and the C1-C6 alkyl is optionally substituted by a substituent independently selected from halogen, nitro and phenyl; The solvent for the cyclization reaction is selected from N'N-dimethylformamide, N'N-dimethylacetamide, dimethyl sulfoxide, N-methylpyrrolidone and toluene; The compound 7 is prepared by a method comprising the following steps, Compound 8 is reacted with an acid or a reagent that can be hydrolyzed into an acid in an alcohol medium to convert it into an ester compound 7; or, Compound 8 is converted into compound 7 by undergoing carboxylic acid alkylation reaction with benzyl halide in the presence of an acid binding agent.

2. According to the preparation method of claim 1, the acid binding agent in the coupling reaction is selected from sodium carbonate, potassium carbonate, cesium carbonate and potassium tert-butoxide; The ligand is selected from 2-acetylcyclohexanone and tetramethylethylenediamine; The aprotic polar solvent is selected from DMF and DMAc; The coupling reaction is carried out at a temperature of 105-130°C; The molar equivalent ratio of the compound 4 to the compound 2 is 1.0:1.1-2.

0.

3. The preparation method according to claim 2, wherein the coupling reaction is carried out at a temperature of 105-115°C.

4. According to the preparation method of claim 2, the molar equivalent ratio of compound 4 to compound 2 is 1.0:1.

5.

5. The preparation method according to claim 1, wherein R is methyl or benzyl.

6. The preparation method according to claim 1, wherein the solvent for the cyclization reaction is dimethyl sulfoxide; The acid-binding agent for the cyclization reaction is selected from triethylamine, N'N-diisopropylethylamine, triethylenediamine, 4-dimethylaminopyridine, pyridine, N-methylmorpholine, 1,8-diazabicycloundec-7-ene and tetramethylethylenediamine; The cyclization reaction is carried out at a temperature of 70°C to 110°C.

7. The preparation method according to claim 6, wherein the acid binding agent in the cyclization reaction is triethylamine.

8. The preparation method according to claim 6, wherein the cyclization reaction is carried out at a temperature of 85-95°C.

9. The preparation method according to claim 1, wherein the acid or the reagent capable of hydrolyzing into an acid is selected from concentrated sulfuric acid, POCl3 and thionyl chloride; The alcohol medium is selected from methanol, ethanol, isopropanol and benzyl alcohol; or, The benzyl halide is selected from benzyl chloride and benzyl bromide; The acid-binding agent for the carboxylic acid alkylation reaction is selected from sodium carbonate, potassium carbonate and cesium carbonate; The carboxylic acid alkylation reaction is carried out in a suitable solvent selected from the group consisting of acetonitrile, toluene, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

10. The preparation method according to claim 9, wherein the acid or the reagent that can be hydrolyzed into an acid is thionyl chloride. The preparation method according to claim 9 , wherein the alcohol medium is methanol.

12. The preparation method according to claim 9, wherein the acid binding agent in the carboxylic acid alkylation reaction is potassium carbonate.

13. The preparation method according to claim 9, wherein the solvent for the carboxylic acid alkylation reaction is N,N-dimethylformamide and acetonitrile.

14. The preparation method according to claim 1, wherein the compound 5 is prepared by a method comprising the following steps: Compound 6 is reacted in the presence of thiophosgene to produce compound 5.

15. The preparation method according to claim 1, wherein the compound 2 is prepared by a method comprising the following steps: Compound 3 is reacted with an acid or a reagent that can be hydrolyzed into an acid in an alcohol medium to be converted into an ester, and then subjected to a "one-pot" methylamine hydrolysis reaction to generate compound 2.

16. The preparation method according to claim 15, wherein the acid or the reagent capable of hydrolyzing into an acid is an organic acid, an inorganic acid or a mixture thereof; The alcohol medium is selected from methanol, ethanol, isopropanol and benzyl alcohol.

17. The preparation method according to claim 15, wherein the acid or the reagent capable of hydrolyzing into an acid is selected from concentrated sulfuric acid, phosphorus oxychloride and thionyl chloride.

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