An isothiazol-3-one and derivatives thereof, synthetic method

Abstract

The application belongs to the technical field of organic synthesis, and specifically discloses isothiazol-3-ketone and a derivative thereof, and a synthesis method thereof. The isothiazol-3-ketone and the derivative thereof provided by the application have a structural formula as shown in formula (I). The application further provides a new method for constructing an isothiazol ring. The method uses methyl propiolate as a raw material, and constructs the isothiazol-3-ketone through one-pot synthesis. The method has the advantages of simple operation and no need for intermediate purification. The raw material methyl propiolate is simple and easy to obtain, and the method for constructing the isothiazol-3-ketone has high yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, specifically to an isothiazol-3-one and its derivatives, and also to a method for their synthesis. Background Technology

[0002] Isothiazol-3-one compounds possess significant biological and pharmaceutical properties, including chemotherapeutic, antioxidant, and radioprotective effects, making them important compounds. Furthermore, isothiazol-3-one derivatives containing the isothiazol ring are also key intermediate structures in pharmaceuticals and functional materials.

[0003] Currently, methods for constructing isothiazole rings generally require raw materials such as sodium sulfide and chlorine. These raw materials have strong odors, affecting the working environment, and are highly toxic, easily causing personnel injury during operation. Furthermore, it is difficult to produce large quantities using these materials. For example, patent application CN110066254A, entitled "An Isothiazole-3-one Compound and its Preparation Method," discloses a method for preparing an isothiazole-3-one compound, with the following reaction formula:

[0004]

[0005] First, the carbon-carbon triple bond in the 2-propynamide derivative (1a) reacts with the S in the metal sulfide. 2- An electrophilic addition reaction occurs to give intermediate A; then the active nitrogen-hydrogen -NH in the amide bond of intermediate A undergoes a [1,3] hydrogen migration to give intermediate B; intermediate B forms an isothiazol-3-one structure under certain conditions to give the target product (2a). The metal sulfide in this product is sodium sulfide or potassium sulfide.

[0006] For the reasons mentioned above, the present invention aims to provide a method for synthesizing isothiazol-3-one and its derivatives, so as to propose a new method for constructing isothiazol rings. Summary of the Invention

[0007] The main technical problem solved by this invention is to provide an isothiazol-3-one and its derivatives, and at the same time, to provide a method for their synthesis. The synthesis method is simple to operate, the raw materials are simple and readily available, and it is easy to carry out industrial production.

[0008] To solve the above-mentioned technical problems, the present invention adopts the following technical solution:

[0009] In a first aspect, the present invention provides an isothiazol-3-one and its derivatives, with the structural formula shown in formula (I) below:

[0010]

[0011] Wherein, R represents hydroxyl, halogen, cyano, carboxyl, amino, or substituted methyl, and the substituent of the substituted methyl is selected from hydroxyl, halogen, or amino.

[0012] In one embodiment of the present invention, the halogen is preferably bromine.

[0013] As one embodiment of the present invention, the isothiazol-3-one and its derivatives provided by the present invention are optionally selected from any of the following compounds:

[0014]

[0015] Secondly, the present invention provides a method for synthesizing isothiazol-3-one and its derivatives, as detailed below.

[0016] When R represents a hydroxyl group, the synthesis method includes: reacting the compound shown in formula A1 with ammonia, then adding ammonium thiosulfate, and then adding iodine to maintain the color of the reaction solution as purple, to produce the compound shown in formula A2.

[0017]

[0018] When R represents bromine, the synthetic method includes: reacting the compound shown in formula A2 with phosphorus tribromooxy in a solvent to produce the compound shown in formula A3;

[0019]

[0020] When R represents a cyano group, the synthetic method includes: reacting the compound shown in formula A3 with CuCN and CuI in a solvent to generate the compound shown in formula A4;

[0021]

[0022] When R represents a carboxyl group, the synthetic method includes: reacting the compound shown in formula A4 with sodium hydroxide in a solvent to produce the compound shown in formula A5;

[0023]

[0024] When R represents an amino group, the synthetic method includes: reacting the compound shown in formula A5 with triethylamine and DPPA in a solvent to generate the compound shown in formula A6; and reacting the compound shown in formula A6 with hydrochloric acid to generate the compound shown in formula A7.

[0025]

[0026] When R represents a hydroxyl-substituted methyl group, the synthetic method includes: reacting the compound shown in formula A5 with BH3 in a solvent to generate the compound shown in formula A8;

[0027]

[0028] When R represents a bromine-substituted methyl group, the synthetic method includes: reacting the compound shown in formula A8 with triphenylphosphine and CBr4 in a solvent to generate the compound shown in formula A9;

[0029]

[0030] When R represents an amino-substituted methyl group, the synthetic method includes: reacting the compound shown in formula A9 with potassium phthalimide in a solvent, and reacting the resulting intermediate with hydrazine hydrate to generate the compound shown in formula A10.

[0031]

[0032] As one embodiment of the present invention, when synthesizing the compound shown in formula A2, the molar ratio of the compound shown in formula A1 to ammonia is 1:(2-4), and / or the molar ratio of the compound shown in formula A1 to ammonium thiosulfate is 1:(1-1.2), and / or the molar ratio of the compound shown in formula A1 to iodine is 1:(0.4-0.6).

[0033] In one embodiment of the present invention, when synthesizing the compound shown in formula A3, the molar ratio of the compound shown in formula A2 to phosphorus tribromooxy is 1:(1-1.2).

[0034] In one embodiment of the present invention, when synthesizing the compound shown in formula A4, the molar ratio of the compound shown in formula A3 to CuCN is 1:(1-3). The amount of CuI used is a catalytic amount, approximately 0.3 to 1.0% of the mass of the compound shown in formula A3.

[0035] In one embodiment of the present invention, when synthesizing the compound shown in formula A5, the molar ratio of the compound shown in formula A4 to sodium hydroxide is 1:(2-3).

[0036] As one embodiment of the present invention, when synthesizing the compound shown in formula A7, the molar ratio of the compound shown in formula A5 to triethylamine is 1:(1-2), and / or the molar ratio of the compound shown in formula A5 to DPPA (diphenyl azidophosphate) is 1:(1-2), and / or the molar ratio of the compound shown in formula A6 to hydrochloric acid is 1:(2-4).

[0037] In one embodiment of the present invention, when synthesizing the compound shown in formula A8, the molar ratio of the compound shown in formula A5 to BH3 is 1:(1-3).

[0038] As one embodiment of the present invention, when synthesizing the compound shown in formula A9, the molar ratio of the compound shown in formula A8 to triphenylphosphine is 1:(1-3), and / or the molar ratio of the compound shown in formula A8 to CBr4 is 1:(1-3).

[0039] As one embodiment of the present invention, when synthesizing the compound shown in formula A10, the molar ratio of the compound shown in formula A9 to potassium phthalimide is 1:(1-2), and / or the molar ratio of the intermediate product to hydrazine hydrate is 1:(1-2).

[0040] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A2, the molar ratio of the compound shown in formula A1 to ammonia is 1:3, the molar ratio of the compound shown in formula A1 to ammonium thiosulfate is 1:1, and the molar ratio of the compound shown in formula A1 to iodine is 1:0.5.

[0041] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A3, the molar ratio of the compound shown in formula A2 to phosphorus tribromooxy is 1:1.1.

[0042] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A4, the molar ratio of the compound shown in formula A3 to CuCN is 1:2.

[0043] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A5, the molar ratio of the compound shown in formula A4 to sodium hydroxide is 1:2.5.

[0044] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A7, the molar ratio of the compound shown in formula A5 to triethylamine is 1:1.5, the molar ratio of the compound shown in formula A5 to DPPA is 1:1.5, and the molar ratio of the compound shown in formula A6 to hydrochloric acid is 1:3.

[0045] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A8, the molar ratio of the compound shown in formula A5 to BH3 is 1:2.

[0046] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A9, the molar ratio of the compound shown in formula A8 to triphenylphosphine is 1:2, and the molar ratio of the compound shown in formula A8 to CBr4 is 1:2.

[0047] As a further preferred embodiment of the present invention, when synthesizing the compound shown in formula A10, the molar ratio of the compound shown in formula A9 to potassium phthalimide is 1:1.5, and the molar ratio of the intermediate product to hydrazine hydrate is 1:1.5.

[0048] In one embodiment of the present invention, when synthesizing the compound shown in formula A3, toluene is used as the solvent, preferably anhydrous toluene.

[0049] As one embodiment of the present invention, the solvent used in synthesizing the compound shown in formula A4 is DMF (N,N-dimethylformamide).

[0050] In one embodiment of the present invention, ethanol is used as the solvent when synthesizing the compound shown in formula A5.

[0051] In one embodiment of the present invention, when synthesizing the compound shown in formula A7, the solvent used to prepare the compound shown in formula A6 is tert-butanol, and the solvent used to react the compound shown in formula A6 with hydrochloric acid is dioxane.

[0052] In one embodiment of the present invention, tetrahydrofuran is used as the solvent when synthesizing the compound shown in formula A8.

[0053] In one embodiment of the present invention, tetrahydrofuran is used as the solvent when synthesizing the compound shown in formula A9.

[0054] In one embodiment of the present invention, when synthesizing the compound shown in formula A10, the solvent used for the reaction of the compound shown in formula A9 with potassium phthalimide is DMF, and the solvent used for the reaction of the intermediate product with hydrazine hydrate is ethanol.

[0055] As a preferred embodiment of the present invention, the synthesis of the compound shown in formula A2 includes the following steps: adding ammonia water to the compound shown in formula A1 at -70 to -80°C, and then maintaining the temperature at -70 to -80°C for 0.5 to 1.5 hours. After that, the temperature is raised to 20 to 30°C and the reaction is continued for another 0.5 to 1.5 hours. Then, the ammonia gas is removed, and the reaction solution is lowered to -5 to 5°C. Ammonium thiosulfate is added, and the reaction is carried out at -5 to 5°C for 2 to 5 hours. Then, iodine is added to make the reaction solution turn purple, thereby generating the compound shown in formula A2.

[0056] As one embodiment of the present invention, the reaction temperature is 105-115°C when synthesizing the compound shown in formula A3.

[0057] As one embodiment of the present invention, when synthesizing the compound shown in formula A4, the reaction temperature is 110-130°C.

[0058] As one embodiment of the present invention, the reaction temperature is 90-100°C when synthesizing the compound shown in formula A5.

[0059] As one embodiment of the present invention, when synthesizing the compound shown in formula A7, the reaction temperature for preparing the compound shown in formula A6 is 85-95°C; the reaction temperature for reacting the compound shown in formula A6 with hydrochloric acid is 20-30°C.

[0060] In one embodiment of the present invention, the reaction temperature is 20–30°C when synthesizing the compound shown in formula A8.

[0061] In one embodiment of the present invention, the reaction temperature is 20–30°C when synthesizing the compound shown in formula A9.

[0062] As one embodiment of the present invention, when synthesizing the compound shown in formula A10, the reaction temperature of the compound shown in formula A9 with potassium phthalimide is 100-120°C; the reaction temperature of the intermediate product with hydrazine hydrate is 50-70°C.

[0063] In a preferred embodiment of the present invention, the reaction temperature is 110°C when synthesizing the compound shown in formula A3.

[0064] In a preferred embodiment of the present invention, the reaction temperature is 120°C when synthesizing the compound shown in formula A4.

[0065] In a preferred embodiment of the present invention, the reaction temperature is 95°C when synthesizing the compound shown in formula A5.

[0066] In a preferred embodiment of the present invention, when synthesizing the compound shown in formula A7, the reaction temperature for preparing the compound shown in formula A6 is 90°C.

[0067] In a preferred embodiment of the present invention, when synthesizing the compound shown in formula A10, the reaction temperature of the compound shown in formula A9 with potassium phthalimide is 110°C; the reaction temperature of the intermediate product with hydrazine hydrate is 60°C.

[0068] This invention provides a novel method for constructing isothiazole rings. Using methyl propargylate as a starting material, isothiazole-3-one is constructed in a one-pot process, achieving transesterification of amino acids, generation of Bunte salt, and closure of the isothiazole ring in a single step. This method has the advantages of simple operation, no need for intermediate purification, and avoids the use of toxic and harmful reagents such as chlorine and sodium sulfide. Methyl propargylate is a readily available and simple starting material. Furthermore, the method for constructing isothiazole-3-one in this invention achieves a high yield, reaching approximately 60%.

[0069] This invention further synthesizes a series of isothiazol-3-one derivatives, such as isothiazol-3-bromo, isothiazol-3-cyano, isothiazol-3-carboxylic acid, isothiazol-3-amine, isothiazol-3-methanol, isothiazol-3-methylbromo, and isothiazol-3-methylamine, using isothiazol-3-one as a raw material. This simplifies the synthesis process of isothiazol-3-one derivatives and has the advantages of a short synthesis route, simple operation, and ease of industrial production. Attached Figure Description

[0070] Figure 1 This is the 1H NMR spectrum of isothiazol-3-one obtained in Example 1 of this invention;

[0071] Figure 2This is the 1H NMR spectrum of the compound of formula A3 obtained in Example 2 of this invention;

[0072] Figure 3 This is the 1H NMR spectrum of the compound of formula A4 obtained in Example 3 of this invention;

[0073] Figure 4 This is the 1H NMR spectrum of the compound of formula A5 obtained in Example 4 of this invention;

[0074] Figure 5 This is the 1H NMR spectrum of the compound of formula A7 obtained in Example 5 of this invention;

[0075] Figure 6 This is the 1H NMR spectrum of the compound of formula A10 obtained in Example 8 of this invention. Detailed Implementation

[0076] The technical solution of the present invention will be described in detail below through embodiments.

[0077] Unless otherwise specified, all raw materials used in the following examples were obtained through purchase.

[0078] Example 1

[0079] This embodiment provides a method for synthesizing isothiazol-3-one (shown in Formula A2):

[0080]

[0081] The synthesis steps are as follows:

[0082] Add methyl propargyl ester (as shown in Formula A1, 84 g, 1 mol) to the reaction flask, cool to -78°C and add ammonia water (280 ml, 3 mol) dropwise. After the addition is complete, keep the temperature at -78°C and stir for 1 h. Slowly raise the temperature to room temperature (about 25°C) and stir for 1 h. Then remove the ammonia gas and lower the reaction solution to 0°C. Add ammonium thiosulfate (148 g, 1 mol) to it and stir at 0°C for 3 h. Add iodine (127 g, 0.5 mol) to keep the color of the reaction solution purple.

[0083] The reaction was monitored by TLC. After the reaction was complete, the resulting reaction solution was extracted five times with 200 mL of diethyl ether (200 mL × 5). The organic phases were combined, dried over anhydrous sodium sulfate, and then concentrated to obtain a solid of 65 g with a purity of 97% and a yield of 62%. The 1H NMR spectrum of isothiazol-3-one is shown below. Figure 1 As shown, MS: [M+23] = 123.9.

[0084] Example 2

[0085] This embodiment provides a method for synthesizing the compound shown in formula A3:

[0086]

[0087] The synthesis steps are as follows:

[0088] Compound A2 (61 g, 0.6 mol) was added to the reaction flask, followed by anhydrous toluene (200 mL), and then phosphorus tribromooxy (188 g, 0.66 mol). The reaction solution was heated to 110 °C and refluxed for 4 h.

[0089] After the reaction was completed, the mixture was cooled to room temperature, quenched in ice water, and alkali adjusted with sodium carbonate. The mixture was filtered, and the filtrate was extracted three times with 200 mL of diethyl ether each time. The organic phase was dried over anhydrous sodium sulfate, concentrated, and then distilled under reduced pressure to obtain an oily substance, totaling 68 g with a purity of 98% and a yield of 68%. The 1H NMR spectrum of the compound shown in Formula A3 is shown below. Figure 2 As shown, MS: [M+1] = 164.9.

[0090] Example 3

[0091] This embodiment provides a method for synthesizing the compound shown in Formula A4:

[0092]

[0093] The synthesis steps are as follows:

[0094] Compound A3 (15.0 g, 91 mmol) was added to the reaction flask, followed by DMF (50 mL), then CuCN (16.2 g, 182 mmol) and CuI (100 mg). The reaction mixture was heated to 120 °C and stirred for 4 h.

[0095] After the reaction was complete, the reaction solution was poured into ice water, ammonia was added, a solid precipitated, and the mixture was filtered. The filtrate was extracted three times with dichloromethane (100 mL * 3). The organic phase was dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain the solid shown in formula A4, totaling 7.8 g with a purity of 98% and a yield of 76%. The 1H NMR spectrum of the compound shown in formula A4 is shown below. Figure 3 As shown, MS: [M] = 109.99.

[0096] Example 4

[0097] This embodiment provides a method for synthesizing the compound shown in Formula A5:

[0098]

[0099] The synthesis steps are as follows:

[0100] Compound A4 (22 g, 0.2 mol) was added to the reaction flask, followed by ethanol (120 mL), and then sodium hydroxide aqueous solution (20 g, 0.5 mol of sodium hydroxide dissolved in 120 mL of water). The reaction solution was then heated to 95 °C and stirred for 12 h.

[0101] After the reaction was complete, the mixture was cooled to room temperature, concentrated to remove ethanol, filtered, and the pH of the filtrate was adjusted to 1 with hydrochloric acid, causing a solid to precipitate. This solid was then filtered, yielding 19.5 g of the compound shown in formula A5, with a purity of 99% and a yield of 75%. The 1H NMR spectrum of the compound shown in formula A5 is shown below. Figure 4 As shown, MS: [M+1] = 130.2.

[0102] Example 5

[0103] This embodiment provides a method for synthesizing the compound shown in Formula A7:

[0104]

[0105] The synthesis steps are as follows:

[0106] Compound A5 (15.5 g, 120 mmol) was added to a reaction flask, followed by the addition of tert-butanol (500 ml) and stirring to dissolve. Then, triethylamine (25 ml, 180 mmol) was added, and the mixture was stirred for 15 min. Next, DPPA (38 ml, 180 mmol) was added, and the mixture was heated to 90 °C and stirred for 12 h. After the reaction was complete, ethyl acetate was added to dissolve the compound, followed by washing with water. The oil phase was collected, and the aqueous phase was extracted with ethyl acetate. The organic phases were combined, dried, concentrated, and purified by column chromatography to give a solid, compound A6, in total, 19 g.

[0107] The obtained compound A6 (18 g, 90 mmol) was dissolved in 200 mL of dichloromethane, followed by the addition of 100 mL of a dioxane solution containing 270 mmol of hydrochloric acid. The mixture was stirred at room temperature for 12 h, then filtered directly to obtain the solid, which was compound A7, in a total quantity of 8.5 g with a purity of 99% and a yield of 70%. The 1H NMR spectrum of compound A7 is shown in [reference needed]. Figure 5 As shown, MS: [M+1] = 101.2.

[0108] Example 6

[0109] This embodiment provides a method for synthesizing the compound shown in Formula A8:

[0110]

[0111] The synthesis steps are as follows:

[0112] Add compound A5 (20 g, 155 mmol) to the reaction flask, add 300 ml of tetrahydrofuran under nitrogen protection, then cool to -10 °C, add 310 ml of borane BH3 tetrahydrofuran solution (1 mol / L) dropwise, keeping the temperature below -5 °C during the dropwise addition, and slowly raise the temperature to room temperature (about 25 °C) after the dropwise addition is complete, and stir for 12 h.

[0113] After the reaction was complete, methanol was slowly added dropwise to quench the reaction until no more bubbles appeared. After quenching, the mixture was directly concentrated to obtain a viscous substance, which is the compound shown in A8, totaling 17.0 g.

[0114] Example 7

[0115] This embodiment provides a method for synthesizing the compound shown in Formula A9:

[0116]

[0117] The synthesis steps are as follows:

[0118] Add 52.5 g (0.2 mol) of triphenylphosphine PPh3 to the reaction flask, then add 200 mL of tetrahydrofuran. Cool the temperature to 0 °C, and add 100 mL of a tetrahydrofuran solution of carbon tetrabromide CBr4 (66.2 g (0.2 mol) dropwise to the reaction solution, keeping the temperature below 5 °C during the dropwise addition. Stir for 30 min after the dropwise addition is complete. Then add 50 mL of a tetrahydrofuran solution of compound A8 (11.5 g (0.1 mol) dropwise. After the dropwise addition is complete, slowly raise the temperature to room temperature (about 25 °C) and continue stirring for 1 h.

[0119] After the reaction was completed, the mixture was filtered, the filter cake was washed with ethyl acetate, the filtrate was concentrated to dryness, and n-hexane was added to precipitate a white solid. The solid was removed by filtration, and the resulting filtrate was concentrated to obtain a liquid, which was the compound shown in A9, totaling 17.4 g.

[0120] Example 8

[0121] This embodiment provides a method for synthesizing the compound shown in formula A10:

[0122]

[0123] The synthesis steps are as follows:

[0124] Compound A9 (10 g, 56 mmol) was added to the reaction flask, followed by 100 mL of DMF. While stirring, potassium phthalimide (15.5 g, 84 mmol) was added. The mixture was heated to 110 °C under nitrogen protection and stirred for 12 h. Then, it was cooled to room temperature, and the reaction was quenched with 400 mL of water. The mixture was extracted twice with ethyl acetate, and the organic phases were combined. The organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, concentrated, and purified by column chromatography to obtain a solid, which was intermediate product A9a, totaling 11 g.

[0125] 200 mL of ethanol was added to the reaction flask, and the intermediate product A9a (11 g, 45 mmol) obtained in the previous step was added while stirring. Hydrazine hydrate (3.4 g, 68 mmol) was added dropwise, and the mixture was heated to 60 °C and stirred for 12 h. After the reaction was complete, the mixture was cooled to room temperature, and a white solid was filtered off. The filtrate was adjusted to pH 2 with concentrated hydrochloric acid, concentrated to dryness, and recrystallized with ethanol and water to obtain a solid, which was compound A10. A total of 3.9 g of the solid was obtained, with a purity of 100% and a yield of 76%. The 1H NMR spectrum of compound A10 is shown in [reference needed]. Figure 6 As shown, MS: [M+1] = 115.2.

[0126] The above description is merely an embodiment of the present invention and does not limit the patent scope of the present invention. Any equivalent transformations made based on the content of the present invention specification, or direct or indirect applications in other related technical fields, are included within the patent protection scope of the present invention.

Claims

1. A method for synthesizing isothiazol-3-one and its derivatives, characterized in that, The isothiazol-3-one and its derivatives may be selected from the following compounds: The synthesis method of compound A2 includes: reacting the compound shown in formula A1 with ammonia water, then adding ammonium thiosulfate, and then reacting with iodine to generate the compound shown in formula A2. When synthesizing the compound shown in formula A2, the molar ratio of the compound shown in formula A1 to ammonia is 1:(2-4), the molar ratio of the compound shown in formula A1 to ammonium thiosulfate is 1:(1-1.2), and the molar ratio of the compound shown in formula A1 to iodine is 1:(0.4-0.6). The synthesis of the compound shown in formula A2 includes the following steps: adding ammonia water to the compound shown in formula A1 at -70 to -80°C, maintaining the temperature at -70 to -80°C for 0.5 to 1.5 hours, then raising the temperature to 20 to 30°C and reacting for another 0.5 to 1.5 hours, then removing the ammonia gas, lowering the reaction solution to -5 to 5°C, adding ammonium thiosulfate, reacting at -5 to 5°C for 2 to 5 hours, and then adding iodine to make the reaction solution turn purple, thus generating the compound shown in formula A2. The synthesis of compounds A3, A4, A5, A7, A8, A9, and A10 all use the compound shown in formula A1 as the starting material and all include a synthesis step of synthesizing the compound shown in formula A2 from the compound shown in formula A1.

2. The synthesis method according to claim 1, characterized in that, The synthetic methods for compound A3 include: (1) The compound A2 was prepared by the synthetic method of compound A2 according to claim 1; (2) React the compound shown in formula A2 with phosphorus tribromooxy in a solvent to produce the compound shown in formula A3; When synthesizing the compound shown in formula A3, the molar ratio of the compound shown in formula A2 to phosphorus tribromooxy is 1:(1-1.2); the solvent used is toluene.

3. The synthesis method according to claim 2, characterized in that, The synthetic methods for compound A4 include: (1) The compound A3 was prepared by the synthetic method of compound A3 according to claim 2; (2) React the compound shown in formula A3 with CuCN and CuI in a solvent to generate the compound shown in formula A4; When synthesizing the compound shown in formula A4, the molar ratio of the compound shown in formula A3 to CuCN is 1:(1-3); the solvent used is DMF.

4. The synthesis method according to claim 3, characterized in that, The synthetic methods for compound A5 include: (1) The compound A4 was prepared by the synthetic method of compound A4 according to claim 3; (2) React the compound shown in formula A4 with sodium hydroxide in a solvent to produce the compound shown in formula A5; When synthesizing the compound shown in formula A5, the molar ratio of the compound shown in formula A4 to sodium hydroxide is 1:(2-3); the solvent used is ethanol.

5. The synthesis method according to claim 4, characterized in that, The synthetic methods for compound A7 include: (1) The compound A5 was prepared by the synthetic method of compound A5 according to claim 4; (2) React the compound shown in formula A5 with triethylamine and DPPA in a solvent to generate the compound shown in formula A6. React the compound shown in formula A6 with hydrochloric acid to generate the compound shown in formula A7. When synthesizing the compound shown in formula A7, the molar ratio of the compound shown in formula A5 to triethylamine is 1:(1-2), the molar ratio of the compound shown in formula A5 to DPPA is 1:(1-2), and the molar ratio of the compound shown in formula A6 to hydrochloric acid is 1:(2-4). The solvent used to prepare the compound shown in formula A6 is tert-butanol, and the solvent used to react the compound shown in formula A6 with hydrochloric acid is dioxane.

6. The synthesis method according to claim 4, characterized in that, The synthetic methods for compound A8 include: (1) The compound A5 was prepared by the synthetic method of compound A5 according to claim 4; (2) React the compound shown in formula A5 with BH3 in a solvent to generate the compound shown in formula A8; When synthesizing the compound shown in formula A8, the molar ratio of the compound shown in formula A5 to BH3 is 1:(1-3); the solvent used is tetrahydrofuran.

7. The synthesis method according to claim 6, characterized in that, The synthetic methods for compound A9 include: (1) The compound A8 was prepared by the synthetic method of compound A8 according to claim 6; (2) React the compound shown in formula A8 with triphenylphosphine and CBr4 in a solvent to generate the compound shown in formula A9; When synthesizing the compound shown in formula A9, the molar ratio of the compound shown in formula A8 to triphenylphosphine is 1:(1-3), and the molar ratio of the compound shown in formula A8 to CBr4 is 1:(1-3); the solvent used is tetrahydrofuran.

8. The synthesis method according to claim 7, characterized in that, The synthetic methods for compound A10 include: (1) The compound A9 was prepared by the synthetic method of compound A9 according to claim 7; (2) React the compound shown in formula A9 with potassium phthalimide in a solvent, and react the intermediate product with hydrazine hydrate to generate the compound shown in formula A10. ； When synthesizing the compound shown in formula A10, the molar ratio of the compound shown in formula A9 to potassium phthalimide is 1:(1-2), and the molar ratio of the intermediate product to hydrazine hydrate is 1:(1-2). The solvent used for the reaction of the compound shown in formula A9 with potassium phthalimide is DMF, and the solvent used for the reaction of the intermediate product with hydrazine hydrate is ethanol.

9. The synthesis method according to claim 1, characterized in that, When synthesizing the compound shown in formula A2, the molar ratio of the compound shown in formula A1 to ammonia is 1:3, the molar ratio of the compound shown in formula A1 to ammonium thiosulfate is 1:1, and the molar ratio of the compound shown in formula A1 to iodine is 1:0.5.

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