Synthetic method of AEEA-AEA

Abstract

The invention belongs to the technical field of compound synthesis, and particularly relates to a synthesis method of AEA-AEA. Triethylene glycol is adopted as a starting material, in the first step, p-toluenesulfonate with high leaving property is formed through TsCl, then nucleophilic substitution is performed, and a product 2 is obtained; the preparation method comprises the following steps: preparing a product 3, oxidizing by adopting TEMPO capable of being industrially produced, removing Pht through quantitative hydrazine hydrate to obtain a product 4, esterifying and extracting to obtain a product 5, acylating through the product 3 to obtain amide, washing, extracting and pulping to obtain an esterified product 6; and finally, quantitatively removing Pht, hydrolyzing and pulping to obtain a pure product. According to the method, complex operation steps of using metal hydride and alkylating column passing are avoided, process production can be realized, and the product yield and purity are relatively high.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis, and particularly relates to a method for synthesizing AEEA-AEEA. Background Art

[0002] 17-amino-10-oxo-3,6,12,15-tetraoxa-9-azaheptadecanoic acid (AEEA-AEEA for short) has the following chemical structure:

[0003]

[0004] AEEA-AEEA is a key raw material for the synthesis of the side chains of multiple glucose-lowering and weight-loss drugs such as semaglutide and telpotide. Semaglutide and telpotide are a new class of long-acting glucagon-like peptide-1 (GLP-1) analogs, used to control blood sugar in adult patients with type 2 diabetes who do not meet blood sugar targets on metformin and / or sulfonylurea drugs on the basis of diet control and exercise, and to reduce the risk of major adverse cardiovascular events (cardiovascular death, non-fatal myocardial infarction or non-fatal stroke) in adult patients with type 2 diabetes and cardiovascular disease.

[0005] At present, the synthesis of AEEA-AEEA generally uses the same material diglycolamine, which is synthesized by protecting the amino group and extending the carbon chain. The reaction route is as follows:

[0006]

[0007] The above-mentioned route involves 7-8 steps of reaction as a whole, in which the reaction reagents include some metal hydrides (NaH) and other unconventional reagents, and also involves column chromatography purification issues, which increases the difficulty of scaled-up production of AEEA-AEEA. Summary of the invention

[0008] In view of the shortcomings of the prior art, the present invention provides an AEEA-AEEA synthesis method. Using triethylene glycol as a starting material, the present invention avoids the complicated operation steps of using metal hydride and column passing of alkylation products, and can be mass-produced.

[0009] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:

[0010] A method for synthesizing AEEA-AEEA comprises the following steps:

[0011] (1) After mixing triethylene glycol, triethylamine and solvent 1, p-toluenesulfonyl chloride solution is added to react to obtain product 1;

[0012] (2) mixing product 1, potassium phthalimide and solvent 2, and reacting them to obtain product 2;

[0013] (3) mixing the product 2, 2,2,6,6-tetramethylpiperidinyl oxide and the solvent 3, adding a sodium bromide solution, adjusting the pH, and then adding a sodium hypochlorite solution, stirring, and reacting to obtain a product 3;

[0014] (4) mixing the product 3, hydrazine hydrate and solvent 4, and reacting them to obtain the product 4;

[0015] (5) Mix product 4 and methanol, add concentrated sulfuric acid, and heat under reflux to obtain product 5;

[0016] (6) mixing product 5, N,N-diisopropylethylamine and solvent 5, adding the refluxing solution of product 3, and reacting to obtain product 6;

[0017] (7) After mixing the product 6, sodium hydroxide and solvent 6, hydrazine hydrate is added and reacted to obtain AEEA-AEEA.

[0018] The reaction route is as follows:

[0019]

[0020] Preferably, in step (1), the molar ratio of triethylene glycol, triethylamine and p-toluenesulfonyl chloride is 3.5-4.5:3.5-4.5:1, the solvent 1 is dichloromethane, the mass volume ratio of triethylene glycol and solvent 1 is 1g:1.5-2mL, the solvent of the p-toluenesulfonyl chloride solution is dichloromethane, the concentration of the p-toluenesulfonyl chloride solution is 0.8-1.2mol / L, the reaction temperature is -5 to 5°C, the reaction time is 0.8-1.2h, and after the reaction, the steps of washing, drying, filtering and concentrating are also included.

[0021] Preferably, in step (2), the molar ratio of the product 1 to potassium phthalimide is 1:0.8-1.2, the solvent 2 is N,N-dimethylformamide, the mass volume ratio of the product 1 to the solvent 2 is 1g:0.9-1.1mL, the reaction temperature is 95-105°C, the reaction time is 12-14h, and the reaction further includes the steps of extraction, drying, filtering and concentration.

[0022] Preferably, in step (3), the molar ratio of the product 2 to sodium hypochlorite is 1:1.8-2.2, the amount of the 2,2,6,6-tetramethylpiperidinyl oxide is 0.5mol%-1.0mol%, the amount of sodium bromide is 0.8mol%-1.2mol%, the solvent 3 is dichloromethane, and the mass volume ratio of the product 2 to the solvent 3 is 1g:1.5-2.5mL.

[0023] Preferably, the solution for adjusting the pH in step (3) is a sodium bicarbonate solution, the pH is adjusted to 8-9, the chlorine content in the sodium hypochlorite solution is 7%-8%, the molar ratio of sodium hypochlorite to product 2 is 1.8-2:1, the reaction temperature is 0-5°C, and the reaction further includes the steps of extraction, drying, filtering and concentration.

[0024] Preferably, in step (4), the molar ratio of the product 3 to hydrazine hydrate is 1:1.8-2.2, the solvent 4 is water, the mass volume ratio of the product 3 to the solvent 4 is 1g:4-6mL, the reaction temperature is room temperature, the reaction time is 12-14h, and the reaction further includes purification, filtration and concentration steps.

[0025] Preferably, in step (5), the mass volume ratio of the product 4 to methanol is 1 g: 8-10 mL, the mass concentration of the concentrated sulfuric acid is 95%-99%, the molar ratio of concentrated sulfuric acid to the product 4 is 0.8-1.2: 1, the heating reflux temperature is 60-70° C., the heating reflux time is 12-14 h, and a concentration step is further included after heating reflux.

[0026] Preferably, in step (6), the molar ratio of the product 5 to N,N-diisopropylethylamine is 1:3.5-4.5, the solvent 5 is dichloromethane, the mass volume ratio of the product 5 to dichloromethane is 1g:14-15mL, and the reflux solution of the product 3 is a mixture of the product 3 and thionyl chloride, heated to 80-90°C, refluxed for 0.8-1.2h, concentrated, and then added with dichloromethane to obtain a diluent.

[0027] Preferably, the reaction temperature in step (6) is room temperature, the reaction time is 0.8-1.2 h, and the reaction further includes extraction, drying, filtration and concentration steps.

[0028] Preferably, in step (7), the molar ratio of the product 6, sodium hydroxide and hydrazine hydrate is 1:1.5-2.5:1.5-2.5, the solvent 6 is methanol, the mass volume ratio of the product 6 to the solvent 6 is 1g:4-5mL, the reaction temperature is room temperature, the reaction time is 10-12h, and the reaction further includes purification, filtration and concentration steps.

[0029] Compared with the prior art, the present invention has the following beneficial effects:

[0030] (1) The present invention uses a cheaper starting material, triethylene glycol, and converts the hydroxyl group into an amine through a nucleophilic reaction. In addition, this route does not use any hazardous reagents and has a relatively simple purification process, which is more advantageous for production.

[0031] (2) The present invention avoids the use of metal hydrides and the complicated operation steps of alkylation column, and can be mass-produced; the route reaction time is short and can be carried out continuously.

[0032] (3) The condensation reaction of the present invention avoids the use of a condensation agent and adopts a more efficient acyl chloride as the reaction system. BRIEF DESCRIPTION OF THE DRAWINGS

[0033] Figure 1 is the mass spectrum of product 1 in Example 1 of the present invention;

[0034] Figure 2 is the NMR spectrum of product 1 in Example 1 of the present invention;

[0035] Figure 3 is the mass spectrum of product 2 in Example 1 of the present invention;

[0036] Figure 4 is the NMR spectrum of product 2 in Example 1 of the present invention;

[0037] Figure 5 is the mass spectrum of product 3 in Example 1 of the present invention;

[0038] Figure 6 is the NMR spectrum of product 3 in Example 1 of the present invention;

[0039] Figure 7 is the mass spectrum of product 4 in Example 1 of the present invention;

[0040] Figure 8 is the NMR spectrum of product 4 in Example 1 of the present invention;

[0041] Fig. 9 is the mass spectrum of product 5 in Example 1 of the present invention;

[0042] Fig.10 is the NMR spectrum of product 5 in Example 1 of the present invention;

[0043] Fig.11 is the mass spectrum of product 6 in Example 1 of the present invention;

[0044] Fig.12 is the NMR spectrum of product 6 in Example 1 of the present invention;

[0045] Fig.13 is the mass spectrum of the product AEEA-AEEA in Example 1 of the present invention;

[0046] Fig.14 is the NMR spectrum of the product AEEA-AEEA in Example 1 of the present invention;

[0047] Fig.15 is the mass spectrum of product 6A in Comparative Example 1 of the present invention;

[0048] Fig.16 It is the NMR spectrum of product 6A in Comparative Example 1 of the present invention. DETAILED DESCRIPTION

[0049] The present invention will be further described in detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention. The experimental methods used in the following examples are generally conventional, unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available, unless otherwise specified.

[0050] Example 1

[0051] A synthetic method of AEEA-AEEA, the steps are as follows:

[0052] Step 1:

[0053] Triethylene glycol (630.17 g, 4.196 mol), TEA (583 mL, 4.196 mol) and solvent DCM (1 L) were added to a 5 L three-necked flask to obtain a colorless solution. After the reaction solution was cooled to 0 °C and stirred, the reactant p-toluenesulfonyl chloride (200 g, 1.049 mol) was dissolved in DCM (1 L) and added dropwise to the reaction solution. The temperature was kept at 0 °C to finally obtain a light yellow solution, which was stirred at room temperature for 1 h.

[0054] After the reaction was completed, the reaction solution was washed twice with 2L of water, and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain product 1 (320 g, 872.6 mmol) with a purity of 95.3% and a yield of 83.18%.

[0055] LCMS (ESI) calculation for C 13 H 20 O6S,+[M+H]+304.36,found[M+Na]+337.5.

[0056] Step 2:

[0057] Product 1 (320 g, 1.051 mol), potassium phthalimide (204.5 g, 1.103 mol) and solvent DMF (300 mL) were added to a 1 L eggplant-shaped bottle to obtain a white suspension. The reaction solution was heated to 100° C. and stirred for 12 h to finally obtain a light yellow suspension.

[0058] After the reaction was completed, 1 L of ethyl acetate was added to the reaction solution, stirred for half an hour, and the light yellow solid impurities were filtered out. The filtrate was poured into 2 L of saturated brine, and the aqueous layer was extracted with ethyl acetate (3×1 L). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated to obtain product 2 (260 g, 903.004 mmol) with a purity of 97.2% and a yield of 85.89%.

[0059] LCMS (ESI) calculation for C 14 H 17 NO5,+[M+H]+279.29,found 280.19.

[0060] 1H NMR (400MHz, CDCl3) δ7.85 (dd, J=5.5, 3.1Hz, 2H), 7.72 (dp, J=6.6, 3.3Hz, 2H), 3.91 (t, J=5. 7Hz,2H),3.76(t,J=5.7Hz,2H),3.66(q,J=3.3Hz,4H),3.63-3.58(m,2H),3.57-3.51(m,2H).

[0061] Step 3:

[0062] Add product 2 (240 g, 859.9 mmol), 2,2,6,6-tetramethylpiperidinyl oxide (TEMPO) (1.30 g, 0.97 mol%) and solvent DCM (500 mL) into a 3L three-necked flask to obtain a light yellow solution. Cool the reaction solution to 0°C and stir, add 86 mL of 10% sodium bromide solution (8.58 g, 83.4 mmol), then slowly add 7% sodium bicarbonate solution (7.0 g, 83.3 mmol, 104 mL) and measure the system pH to be 8.5, then slowly add sodium hypochlorite solution (1667 mmol, chlorine content: 7.5%), control the temperature at 2°C during the addition process, and the total addition time is 7 h. Continue stirring for half an hour after the addition is completed.

[0063] After the reaction was completed, 1 L of dichloromethane was added to the reaction system, and the aqueous phase was retained after separation. The pH of the aqueous phase was then adjusted to 6 with 1 M hydrochloric acid solution, and a large amount of white solid was precipitated. The pH was slowly adjusted to 2, and the aqueous layer was extracted with DCM (2×1 L). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to finally obtain product 3 (140 g, 453.507 mmol) with a purity of 95.4% and a yield of 54.4%.

[0064] LCMS (ESI) calculation for C 14 H 15 NO6,[M+H]+293.28,found 294.1.

[0065] 1H NMR (400MHz, CDCl3) δ7.90-7.85(m,2H),7.74(dd,J=5.5,3.0Hz,2H),4.12(s,2H),3.94(t,J=5.6Hz,2H),3.79(t,J=5.6Hz,2H),3.73(s,4H).

[0066] Step 4:

[0067] Product 3 (2 g, 6.820 mmol) and solvent water (10 mL) were added to a 100 mL eggplant-shaped bottle to obtain a colorless suspension. After adding the reactant hydrazine hydrate (0.829 mL, 13.639 mmol), the system became clear, and a small amount of white solid was precipitated after stirring at room temperature overnight.

[0068] After the reaction was completed, the pH of the system was adjusted to 5 with 1 M dilute sulfuric acid. During this process, a large amount of white solid was precipitated. The white solid was removed by filtration and the filtrate was concentrated to obtain product 4 (1.2 g, 6.619 mmol) with a purity of 90.54% and a yield of 97.05%, which was directly used in the next step.

[0069] LCMS (ESI) calculation for C6H 13 NO4,+[M+H] + 163.17, found 164.1.

[0070] 1 H NMR(400MHz,D2O)δ3.84(s,2H),3.69-3.65(m,2H),3.64-3.56(m,4H),3.13-3.08(m,2H).

[0071] Step 5:

[0072] Product 4 (1.2 g, 7.354 mmol) and methanol (10 mL) were added to a 50 mL eggplant-shaped bottle to obtain a colorless solution. Concentrated sulfuric acid (98%) (0.4 mL, 7.354 mmol) was added as a reactant and refluxed at 65°C overnight.

[0073] After the reaction was completed, the reaction solution was concentrated to obtain a crude product 5 (1.2 g, 6.095 mmol) with a purity of 89.85% and a yield of 82.87%.

[0074] LCMS (ESI) calculation for C7H 15 NO4,[M+H]+177.20, found 178.1.

[0075] Step 6:

[0076] Add product 3 (0.5 g, 1.705 mmol) and solvent thionyl chloride (1.2 mL, 17.049 mmol) to a 50 mL eggplant-shaped bottle to obtain a light yellow solution. Heat to 85 ° C and reflux for 1 h, add DCM (5 mL) to obtain a dilution. Add product 5 (0.34 g, 1.705 mmol) and reactant DIEA (1.1 mL, 6.820 mmol) and solvent DCM (5 mL) to a 50 mL eggplant-shaped bottle, slowly dropwise add the dilution obtained above to the system, and stir at room temperature for 1 h.

[0077] After the reaction was completed, the reaction solution was diluted with 100 mL DCM, washed with 100 mL saturated NH4Cl solution and water, respectively. The organic layer was dried over Na2SO4, filtered and concentrated to obtain product 6 (0.72 g, 1.512 mmol) with a purity of 95.1% and a yield of 88.76%.

[0078] LCMS (ESI) calculation for C 21 H 28 N2O9,+[M+H]+452.46,found 453.3.

[0079] 1H NMR (400MHz, CDCl3) δ7.87 (dd, J = 5.4, 3.1Hz, 2H), 7.78-7.71 (m, 2H), 7.15 (s, 1H), 4.18 (s, 2H), 3 .97-3.90(m,4H),3.80-3.71(m,7H),3.70-3.66(m,4H),3.66-3.58(m,4H),3.52(q,J=5.4Hz,2H).

[0080] Step 7:

[0081] Product 6 (700 mg, 1.547 mmol) and methanol (3 mL) were added to a 50 mL eggplant-shaped bottle to obtain a colorless solution. Sodium hydroxide (124 mg, 3.094 mmol) was added and stirred at 60 °C for 2 h for monitoring. After the hydrolysis was complete, the mixture was cooled to room temperature. Hydrazine hydrate (0.2 mL, 3.094 mmol) was added to the system and the system became clear. After stirring at room temperature overnight, a small amount of white solid was precipitated.

[0082] After the reaction was completed, the pH of the system was adjusted to 5 with 1 M dilute sulfuric acid. During this process, a large amount of white solid was precipitated. The white solid was removed by filtration. The filtrate was concentrated to obtain the final product AEEA-AEEA (450 mg, 1.314 mmol) with a content of 90.04% and a yield of 84.90%.

[0083] LCMS (ESI) calculation for C 12 H24 N2O7,+[M+H] + 308.33, found 309.2.

[0084] 1 H NMR (400MHz, D2O) δ3.97 (s, 2H), 3.82 (s, 2H), 3.66-3.61 (m, 6H), 3.58-3.52 (m, 6H), 3.34 (t, J = 5.2Hz, 2H), 3.09 (dd, J = 5.8, 4.5Hz, 2H).

[0085] Example 2

[0086] A synthetic method of AEEA-AEEA, the steps are as follows:

[0087] Step 1:

[0088] Triethylene glycol (525.60 g, 3.5 mol), TEA (626 mL, 3.5 mol) and solvent DCM (1 L) were added to a 5 L three-necked flask to obtain a colorless solution. The reaction solution was cooled to 0 °C and stirred, and then p-toluenesulfonyl chloride (200 g, 1.0 mol) was dissolved in DCM (1 L) and added dropwise to the reaction solution. The temperature was maintained at 5 °C to obtain a light yellow solution, which was heated to room temperature and stirred for 1 h.

[0089] After the reaction was completed, the reaction solution was washed twice with 2 L of water, and the organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain product 1 (318.5 g, 868.7 mmol) with a purity of 95.2% and a yield of 82.8%.

[0090] Example 3

[0091] Step 3:

[0092] Product 2 (240 g, 859.9 mmol), 2,2,6,6-tetramethylpiperidinyl oxide (TEMPO) (0.70 g, 0.52 mol%) and solvent DCM (500 mL) were added to a 3L three-necked flask to obtain a light yellow solution. The reaction solution was cooled to 3°C and stirred, 86 mL of 10% sodium bromide solution (8.58 g, 83.354 mmol) was added, and 104 mL of 7% sodium bicarbonate solution (7.0 g, 83.354 mmol) was slowly added. After the pH of the system was measured to be 8.5, sodium hypochlorite solution (1667 mmol, chlorine content: 7.5%) was slowly added dropwise. The temperature during the addition process was controlled at 2°C, and the total addition time was 7 h. After the addition was completed, stirring was continued for half an hour.

[0093] After the reaction was completed, 1 L of dichloromethane was added to the reaction system, and the aqueous phase was retained after separation. The pH of the aqueous phase was then adjusted to 6 with 1 M hydrochloric acid solution, and a large amount of white solid was precipitated. The pH was slowly adjusted to 2, and the aqueous layer was extracted with DCM (2×1 L). The organic layers were combined and dried over anhydrous Na2SO4, filtered and concentrated to finally obtain product 3 (136 g, 463.72 mmol) with a purity of 95.5% and a yield of 53.9%.

[0094] Comparative Example 1

[0095]

[0096] Product 3 (3 g, 10.229 mmol), product 4 (1.67 g, 10.229 mmol) and solvent DMF (20 mL) were added to a 100 mL three-necked flask to obtain a colorless suspension. EDCI (2.55 g, 13.298 mmol) and HOBT (1.80 g, 13.298 mmol) were added, the system was purged with nitrogen, and the reactant DIEA (5.072 mL, 30.687 mmol) was slowly added dropwise, and stirred at room temperature for 2 h.

[0097] After the reaction was completed, the reaction solution was diluted with 300 mL of ethyl acetate, and then the organic phase was washed with 300 mL of saturated brine. The organic layer was dried over anhydrous Na2SO4, filtered and concentrated to obtain a crude product, which was then subjected to reverse phase preparation to obtain product 6A (400 mg, 0.912 mmol) with a yield of 8.92%.

[0098] LCMS (ESI) calculation for C 20 H 26 N2O9,+[M+H] + 438.43, found 439.3.

[0099] 1 H NMR(400MHz,D2O)δ7.75-7.66(m,4H),3.80(s,2H),3.76(d,J=5.4Hz,4H),3.71-3.67(m,2H),3. 61-3.57(m,2H),3.52(ddd,J=8.3,3.7,2.0Hz,6H),3.46(t,J=5.5Hz,2H),3.22(t,J=5.5Hz,2H).

[0100] Comparative Example 2

[0101] The only difference between this comparative example and Example 1 is that the reaction temperature in step (2) is 80° C., and the remaining steps are the same as those in Example 1. Product 2 (153 g, 427.314 mmol) is obtained with a purity of 96.8% and a yield of 40.66%.

[0102] Comparative Example 3

[0103] The difference between this comparative example and Example 1 is that the solvent DCM (500 mL) in step (3) is replaced by tetrahydrofuran (500 mL), and the remaining steps are consistent with Example 1.

[0104] Finally, product 3 (25.14 g, 85.7 mmol) was obtained with a purity of 81.8% and a yield of 9.77%.

[0105] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing AEEA-AEEA, characterized in that: The following steps are involved: (1) After mixing triethylene glycol, triethylamine and solvent 1, p-toluenesulfonyl chloride solution is added to react to obtain product 1; (2) mixing product 1, potassium phthalimide and solvent 2, and reacting them to obtain product 2; (3) mixing the product 2, 2,2,6,6-tetramethylpiperidinyl oxide and the solvent 3, adding a sodium bromide solution, adjusting the pH, and then adding a sodium hypochlorite solution, stirring, and reacting to obtain a product 3; (4) mixing the product 3, hydrazine hydrate and solvent 4, and reacting them to obtain the product 4; (5) Mix product 4 and methanol, add concentrated sulfuric acid, and heat under reflux to obtain product 5; (6) mixing product 5, N,N-diisopropylethylamine and solvent 5, adding the refluxing solution of product 3, and reacting to obtain product 6; (7) After mixing the product 6, sodium hydroxide and solvent 6, hydrazine hydrate is added and reacted to obtain AEEA-AEEA.

2. The synthesis method according to claim 1, characterized in that The molar ratio of triethylene glycol, triethylamine and p-toluenesulfonyl chloride in step (1) is 3.5-4.5:3.5-4.5:1, the solvent 1 is dichloromethane, the mass volume ratio of triethylene glycol and solvent 1 is 1g:1.5-2mL, the solvent of the p-toluenesulfonyl chloride solution is dichloromethane, the concentration of the p-toluenesulfonyl chloride solution is 0.8-1.2mol / L, the reaction temperature is -5 to 5°C, the reaction time is 0.8-1.2h, and after the reaction, the steps of washing, drying, filtering and concentrating are also included.

3. The synthesis method according to claim 1, characterized in that In step (2), the molar ratio of the product 1 to potassium phthalimide is 1:0.8-1.2, the solvent 2 is N,N-dimethylformamide, the mass volume ratio of the product 1 to the solvent 2 is 1g:0.9-1.1mL, the reaction temperature is 95-105°C, the reaction time is 12-14h, and the reaction further includes extraction, drying, filtering and concentration steps.

4. The synthesis method according to claim 1, characterized in that The molar ratio of the product 2 to sodium hypochlorite in step (3) is 1:1.8-2.2, the amount of the 2,2,6,6-tetramethylpiperidinyl oxide is 0.5mol%-1.0mol%, the amount of sodium bromide is 0.8mol%-1.2mol%, the solvent 3 is dichloromethane, and the mass volume ratio of the product 2 to the solvent 3 is 1g:1.5-2.5mL.

5. The synthesis method according to claim 4, characterized in that The solution for adjusting the pH in step (3) is a sodium bicarbonate solution, and the pH is adjusted to 8-9. The chlorine content in the sodium hypochlorite solution is 7%-8%, the molar ratio of sodium hypochlorite to product 2 is 1.8-2:1, the reaction temperature is 0-5°C, and after the reaction, the steps of extraction, drying, filtering and concentration are also included.

6. The synthesis method according to claim 1, characterized in that The molar ratio of the product 3 to hydrazine hydrate in step (4) is 1:1.8-2.2, the solvent 4 is water, the mass volume ratio of the product 3 to the solvent 4 is 1g:4-6mL, the reaction temperature is room temperature, the reaction time is 12-14h, and the reaction also includes purification, filtering and concentration steps.

7. The synthesis method according to claim 1, characterized in that In step (5), the mass volume ratio of the product 4 to methanol is 1 g: 8-10 mL, the mass concentration of the concentrated sulfuric acid is 95%-99%, the molar ratio of the concentrated sulfuric acid to the product 4 is 0.8-1.2: 1, the heating reflux temperature is 60-70° C., the heating reflux time is 12-14 h, and the step of concentration is also included after heating reflux.

8. The synthesis method according to claim 1, characterized in that In step (6), the molar ratio of the product 5 to N,N-diisopropylethylamine is 1:3.5-4.5, the solvent 5 is dichloromethane, the mass volume ratio of the product 5 to dichloromethane is 1g:14-15mL, and the reflux solution of the product 3 is a mixture of the product 3 and thionyl chloride, heated to 80-90°C, refluxed for 0.8-1.2h, concentrated, and then added with dichloromethane to obtain a diluent.

9. The synthesis method according to claim 1, characterized in that The reaction temperature in step (6) is room temperature, the reaction time is 0.8-1.2h, and the reaction further includes extraction, drying, filtration and concentration steps.

10. The synthesis method according to any one of claims 1 to 9, characterized in that: The molar ratio of the product 6, sodium hydroxide and hydrazine hydrate in step (7) is 1:1.5-2.5:1.5-2.5, the solvent 6 is methanol, the mass volume ratio of the product 6 to the solvent 6 is 1g:4-5mL, the reaction temperature is room temperature, the reaction time is 10-12h, and the reaction also includes purification, filtering and concentration steps after the reaction.

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