An intermediate of ERDRP-0519 and its preparation method

Abstract

This invention belongs to the field of medicinal chemistry, specifically relating to a method for synthesizing ERDRP-0519 and its novel intermediates. The method includes the following five steps: substitution reaction, oxidation to aldehyde, reductive amination, reductive nitro group reduction, and coupling, to prepare ERDRP-0519 in a high yield. The reaction formula is shown below. Compared with existing technologies, the preparation method of ERDRP-0519 in this application overcomes the problems of lengthy routes, cumbersome operations, and low yields, bringing the advantages of simple operation, high yield, and suitability for industrial production, thereby further expanding the application of ERDRP-0519 in the field of medicinal chemistry.

Description

Technical Field

[0001] This invention relates to the field of medicinal chemistry, and in particular to a novel intermediate of ERDRP-0519 and its preparation method. Background Technology

[0002] ERDRP-0519 (Formula I) has the chemical name 1-methyl-N-[4-[[(2S)-2-[2-(4-morpholinyl)ethyl]-1-piperidinyl]sulfonyl]phenyl]-3-(trifluoromethyl)-1H-pyrazole-5-carboxamide, and its structural formula is as follows:

[0003]

[0004] ERDRP-0519 is a non-nucleoside inhibitor targeting viral RNA polymerase, effective against measles virus both in vitro and in vivo. It is the first drug specifically developed against measles virus (MeV). The antiviral efficacy of ERDRP-0519 against type II feline infectious peritonitis (FIPV) was evaluated in vitro in feline kidney cells (CRFK). ERDRP significantly inhibited FIPV replication in a dose-dependent manner, reducing viral infectivity by up to 3-fold. Antiviral effects were observed even at a concentration of 30 μM without cytotoxicity, thus suggesting its potential as a treatment for feline infectious peritonitis (FIP).

[0005] The synthetic routes for the analogue and ERDRP-0519 are disclosed in the Journal of Medicinal Chemistry, 2012, vol. 55, 9, pp. 4220-4230. The reaction route for the preparation of the analogue is as follows:

[0006]

[0007] Reagents and conditions: (a) PCC, CH2Cl2. (b) Morpholine, NaBH(OAc)3, CH2Cl2. (c) SnCl2·2H2O, CH2Cl2 / MeOH. (d) i-Pr2NEt,CH2Cl2;

[0008] The main problems with applying this approach to large-scale production are as follows:

[0009] (1) Step a of this route uses PCC oxidation, which is complicated in post-treatment and puts great pressure on environmental protection.

[0010] (2) Each step bd requires silica gel column chromatography, which requires a large amount of mixed organic solvents for elution, which is not environmentally friendly and waste silica gel is difficult to dispose of.

[0011] (3) Product yield and purity need to be improved;

[0012] (4) This route is complex and not suitable for industrial production.

[0013] The synthesis of ERDRP-0519 also requires ten steps, is quite lengthy, and has a low yield (approximately 25.5%). The synthetic route is as follows:

[0014]

[0015] Therefore, there is an urgent need to develop a new method that is simple in process, low in cost, and suitable for industrial production. Summary of the Invention

[0016] This invention provides an industrially feasible and simple method for preparing ERDRP-0519 and a novel ERDRP-0519 intermediate. The preparation method is simple, economical, environmentally friendly, and uses readily available raw materials. Compared with existing publicly available synthetic routes, the preparation process is simple, the reaction conditions are mild, the equipment requirements are not high, the reaction time is short, the yield is high, the by-products are reduced, and the post-processing is easy. It is suitable for large-scale industrial production and has good industrialization prospects.

[0017] The first aspect of this invention provides a method for preparing a novel intermediate compound of formula 6, comprising the following steps:

[0018] (1) Compound of Formula 3 was subjected to the action of Des Martin oxidant to obtain intermediate compound of Formula 4;

[0019]

[0020] (2) The compound of formula 4 was reduced and aminationed with morpholine to obtain the intermediate compound of formula 5;

[0021]

[0022] (3) Compound of Formula 5 was subjected to a reducing agent to obtain compound of Formula 6;

[0023]

[0024] Preferably, in step (1), the molar ratio of the Dys-Martin oxidant to the compound 3 is (1.0 to 2.0):1, for example, 1.0:1, 1.1:1, 1.2:1, 1.3:1, 1.4:1, 1.5:1, 1.6:1, 1.7:1, 1.8:1, 1.9:1, or 2.0:1.

[0025] As a further improvement of the present invention, the reaction solvent in step (1) is selected from dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile, preferably dichloromethane.

[0026] As a further improvement of the present invention, the reaction temperature in step (1) is -10℃ to 50℃, preferably 15℃ to 30℃.

[0027] As a further improvement of the present invention, the reductive amination reaction in step (2) is a compound of formula 4, which undergoes a reduction reaction with borohydride in an organic solvent.

[0028] As a further improvement of the present invention, the borohydride in step (2) is selected from potassium borohydride, sodium borohydride, sodium cyanoborohydride, potassium borohydride acetate or sodium borohydride acetate, preferably sodium borohydride acetate.

[0029] As a further improvement of the present invention, the molar ratio of the compound of Formula 4 to the borohydride is 1:0.5 to 5, preferably 1:1.4 to 1.8.

[0030] As a further improvement of the present invention, the organic solvent in step (2) is selected from dichloromethane, dichloroethane, toluene, tetrahydrofuran or methanol, preferably dichloromethane.

[0031] As a further improvement of the present invention, the reaction temperature in step (2) is -20℃ to 35℃, preferably -5℃ to 25℃.

[0032] As a further improvement of the present invention, the nitro reduction reaction in step (3) is a compound of formula 5, which reacts with a reducing agent in an organic solvent.

[0033] As a further improvement of the present invention, the reducing agent in step (3) is selected from SnCl2, Pd / C, Fe / NH4Cl, Zn / NH4Cl, Raney Ni or Pb(OH)2, preferably SnCl2.

[0034] As a further improvement of the present invention, the molar ratio of the compound of Formula 5 to the reducing agent is 1:1 to 10, preferably 1:5 to 7.

[0035] As a further improvement of the present invention, the organic solvent in step (3) is selected from hydrocarbon solvents such as benzene, toluene or xylene; ether solvents such as tetrahydrofuran or dioxane; alcohol solvents such as methanol, ethanol or isopropanol; or dimethylformamide, dimethyl sulfoxide, acetonitrile, ethyl acetate and mixtures of the above solvents, preferably ethyl acetate.

[0036] As a further improvement of the present invention, the reaction temperature in step (3) is 40°C to 120°C, preferably 70°C to 90°C.

[0037] As a further improvement of the present invention, the preparation of the compound of formula 3 includes the following steps:

[0038]

[0039] Compound of Formula 1 and compound of Formula 2 were subjected to a substitution reaction under DIPEA conditions to obtain compound of Formula 3.

[0040] A second aspect of this invention provides a method for preparing compound ERDRP-0519 of formula I, wherein the reaction formula is shown below:

[0041]

[0042] Includes the following steps:

[0043] (1) The compound of formula 7 was reacted with oxalyl chloride to give a crude mixture of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxyl chloride;

[0044] (2) Evaporate the mixture in (1) to remove the solvent and excess oxaloyl chloride, and obtain 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxyl chloride as a white solid;

[0045] (3) The compound of formula 6 was reacted with a white solid solution of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxyl chloride under the action of an acid-binding agent to obtain ERDRP-0519.

[0046] As a further improvement of the present invention, the reaction in step (1) is carried out in a solvent, which is selected from aprotic solvents, preferably dichloromethane or tetrahydrofuran;

[0047] As a further improvement of the present invention, the reaction temperature in step (1) is selected from -10℃ to 30℃, preferably 0℃ to 10℃;

[0048] As a further improvement of the present invention, a catalyst is added to the reaction in step (1), the catalyst being selected from 4-dimethylaminopyridine or DMF, wherein the amount of catalyst used is 0.01% eq to 1% eq.

[0049] As a further improvement of the present invention, the evaporation in step (2) is selected from vacuum distillation or direct evaporation, preferably vacuum distillation, and the distillation temperature is selected from 50℃~70℃.

[0050] As a further improvement of the present invention, the yield of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxyl chloride, a white solid, is almost quantitative.

[0051] The acid-binding agent in step (3) is selected from triethylamine, pyridine, N,N-dimethylamine, DIPEA or K2CO3, preferably DIPEA.

[0052] The molar ratio of compound 6 in step (3) to compound 7 in step (1) is 1:(1-3), preferably 1:(1.2-1.8).

[0053] In step (3), the molar ratio of compound 6 to the acid-binding agent is 1:0.5 to 5, preferably 1:2 to 4.

[0054] The reaction in step (3) is carried out in a solvent selected from toluene, dichloromethane, chloroform, 1,2-dichloroethane or tetrahydrofuran, preferably dichloromethane.

[0055] The reaction temperature in step (3) is -20℃ to 35℃, preferably -5℃ to 25℃.

[0056] This invention also provides a method for preparing compound ERDRP-0519 of formula I, comprising the method for preparing compound ERDRP-0519 of formula I provided by the second aspect of this invention and / or the method for preparing a novel intermediate of formula 6 provided by the first aspect of this invention. All the preferred conditions for the above reaction steps can be referenced.

[0057] A third aspect of the present invention provides an intermediate compound of formula 4, formula 5, or formula 6, the structure of which is shown below:

[0058]

[0059] As a further improvement of the present invention, the compound of formula (4), formula (5), or formula (6) is used in the preparation of ERDRP-0519. The main advantages of the method of the present invention are:

[0060] This invention provides a novel synthetic route for the compound ERDRP-0519, which, through a clever design, prepares ERDRP-0519 from starting materials in only 5 reaction steps. The route is simple to operate, short, with mild reaction conditions, low equipment requirements, low cost, and simple post-processing. It avoids racemization during the reaction process, eliminates the need for resolution, and achieves high yield and high chiral purity, which is beneficial for industrial production.

[0061]

[0062] PCC oxidation: The next step does not proceed directly. PCC requires anhydrous conditions, and the oxidation of compound 3 to carboxylic acid by PCC is uncontrollable, thus preventing the subsequent reaction from taking place.

[0063] Swern oxidation: The operation is cumbersome and produces odorous gases. The reaction requires -78°C and liquid nitrogen, making it difficult to operate. The two-step yield is only 43.3%, which is not high. The final product is Des Martin oxidation, which is simple to operate, with a yield of 77.4%. The yield is improved, the reaction operation is simple, the requirements for laboratory equipment are low, and the safety factor is high. Detailed Implementation

[0064] To facilitate understanding of the present invention by those skilled in the art, the technical solution of the present invention is further described below with reference to specific embodiments. It should be understood that these embodiments are not intended to limit the scope and spirit of the claims. Unless otherwise specified, all raw materials, reagents, or solvents used in the present invention are commercially available, and experimental methods without specific conditions are generally performed under conventional conditions in the art.

[0065] Example 1: Synthesis of Compound 3:

[0066]

[0067] Add 500 mL of dichloromethane, compound 1 (10 g, 77.4 mmol), and DIPEA (15 g, 116 mmol) to a 1 L three-necked flask. Then add compound 2 (18.88 g, 85.2 mmol) at 0 °C. After the addition is complete, bring the mixture to room temperature and stir overnight. Monitor the reaction by TLC. Once the reaction is complete, wash with sodium bicarbonate solution, extract with dichloromethane, wash with water, dry over anhydrous sodium sulfate, concentrate, and pass the crude product through a silica gel column (ethyl acetate / petroleum ether = 1 / 5–1 / 3) to give a white solid compound 3 (19.8 g, yield: 81.5%). Comparative Example 1: Synthesis of Compound 3:

[0068] Add 50 mL of pyridine and compound 1 (1 g, 7.7 mmol) to a 100 mL three-necked flask. Then add compound 2 (1.88 g, 8.52 mmol) at 0 °C. After the addition is complete, bring the temperature to room temperature and stir overnight. Monitor the reaction by TLC. After the reaction is complete, wash with dilute hydrochloric acid solution, extract with dichloromethane, wash with water, dry with anhydrous sodium sulfate, concentrate, and pass the crude product through a silica gel column (ethyl acetate / petroleum ether = 1 / 10 to 1 / 3) to give a white solid compound (1.3 g, yield: 53.4%).

[0069] Example 2: Synthesis of Compound 4:

[0070]

[0071] Add 700 mL of dichloromethane, compound 3 (11.24 g, 35.8 mmol), and Dysmart reagent (15.16 g, 35.8 mmol) to a 1 L three-necked flask, and stir at room temperature for 2–3 h. Monitor the reaction by TLC (DCM / MeOH = 50 / 1, Rf = 0.3). After the reaction is complete, wash with saturated sodium thiosulfate solution, extract with dichloromethane, wash with water, dry with anhydrous sodium sulfate, and concentrate to obtain 10.63 g of crude compound 4, which can be used directly in the next step.

[0072] Synthesis of compound 4 in Comparative Example 2:

[0073] Method 1: (PCC oxidation) Add 50 mL of dichloromethane, compound 3 (1 g, 3.18 mmol), and PCC (0.88 g, 4.1 mmol) to a 100 mL three-necked flask and stir at room temperature for 3 h. Monitor the reaction by TLC (DCM / MeOH = 50 / 1, Rf = 0.4). After the reaction is complete, extract with dichloromethane, wash with water, dry with anhydrous sodium sulfate, concentrate, and use directly in the next step.

[0074] 50 mL of dichloromethane and crude compound 4 (1.3 g, 4.17 mmol) were added to a 100 mL three-necked flask to dissolve crude compound 4. After dissolution, morpholine (0.435 g, 5.01 mmol) and sodium triacetoxyborohydride (1.41 g, 6.67 mmol) were added at 0 °C and the mixture was reacted at room temperature for 3-4 h. The reaction was monitored by TLC (DCM / MeOH = 50 / 1), but no product was obtained.

[0075] Method 2: (Swern Oxidation) Add oxaloyl chloride (1.82 mL, 20.9 mmol) to a 100 mL round-bottom flask containing 15 mL of dry dichloromethane. Cool the solution to -78°C and add dimethyl sulfoxide (4.94 mL, 69.7 mmol) dropwise using a syringe (Caution! Gas release). Stir at -78°C for 5 minutes, then slowly add a solution of compound 3 (4.33 g, 13.9 mmol) in 5 mL of dichloromethane (dropwise over at least 5 minutes). Maintain the solution at -78°C for another 25 minutes, then add triethylamine (19.4 mL, 139 mmol) using a syringe to produce a bright yellow solution. Stir the solution for another 5 minutes, then heat to 0°C for 20 minutes. At this point, pour the reaction mixture into saturated ammonium chloride (20 mL) and stir for 30 minutes. Wash with water, dry with anhydrous sodium sulfate, concentrate, and use directly for the next step.

[0076] Add 500 mL of dichloromethane and crude compound 4 (4.5 g, 14.4 mmol) to a 1 L three-necked flask to dissolve the crude compound 4. After dissolution, add morpholine (1.51 g, 17.3 mmol) and sodium triacetoxyborohydride (4.88 g, 23.1 mmol) at 0 °C and react at room temperature for 3-4 h. Monitor the reaction by TLC. After the reaction is complete, extract with dichloromethane, wash with water, dry with anhydrous sodium sulfate, concentrate, and crudely pass through a silica gel column (dichloromethane / methanol = 100 / 1 to 50 / 1) to obtain a pale yellow oily compound 5 (2.31 g, yield of 43.3% in two consecutive steps).

[0077] Example 3: Synthesis of Compound 5:

[0078]

[0079] Add 500 mL of dichloromethane and crude compound 4 (10.63 g, 34 mmol) obtained in Example 2 to a 1 L three-necked flask. After stirring and dissolving, add morpholine (3.56 g, 40.8 mmol) and sodium triacetoxyborohydride (11.52 g, 54.4 mmol) at 0 °C and react at room temperature for 3-4 h. Monitor the reaction by TLC. After the reaction is complete, extract with dichloromethane, wash with water, dry with anhydrous sodium sulfate, concentrate, and crudely pass through a silica gel column (dichloromethane / methanol = 100 / 1 to 50 / 1) to obtain a pale yellow oily compound 5 (10.6 g, yield of 77.4% in two consecutive steps).

[0080] 1 H NMR (400MHz, Chloroform-d) δ8.32(d,J=8.8Hz,2H),8.01(d,J=8.8Hz,2H),4.20-4.07(m,1H),3.77(t,J=4.7Hz,4H),3.15-3.05(m,1H),2.70-2.57(m, 4H),2.57-2.49(m,2H),2.13-1.96(m,2H),1.71(ddd,J=13.4,8.7,4.1Hz,1 H),1.53-1.44(m,4H),1.31-1.21(m,1H),1.05(dq,J=12.3,6.0,4.0Hz,1H).

[0081] Example 4: Synthesis of Compound 6:

[0082]

[0083] 1000 mL of ethyl acetate and compound 5 (10.6 g, 27.6 mmol) were added to a 2 L three-necked flask. After stirring until dissolved, stannous chloride (31.4 g, 165.6 mmol) was added, and the mixture was heated to 80 °C and refluxed for 2 h. The reaction was monitored by TLC (DCM / MeOH = 20 / 1Rf = 0.3). The mixture was cooled to room temperature, quenched with saturated sodium bicarbonate solution, filtered, and the mother liquor was extracted with ethyl acetate, washed with water, dried over anhydrous sodium sulfate, and concentrated to give a white solid compound 6 (8.4 g, yield: 86.6%).

[0084] 1 H NMR(400MHz,Chloroform-d)δ7.60(d,J=8.6Hz,2H),6.67(d,J=8.7Hz,2H),4.10-4.01(m,2H),3.76(d,J=10.8Hz,5H),3.01( d,J=27.6Hz,1H),2.66-2.27(m,6H),2.01-1.86(m,1H),1.73-1.55(m,2H),1.46(dt,J=11.6,7.3Hz,5H),1.23-1.14(m,1H).

[0085] Synthesis of Compound 6 in Comparative Example 3:

[0086] Dichloromethane (20 mL) and methanol (5 mL) were added to a 100 mL three-necked flask, followed by compound 5 (1 g, 2.6 mmol). The mixture was stirred until dissolved. After dissolution, stannous chloride (2.4 g, 13 mmol) was added, and the mixture was reacted overnight at room temperature. The reaction was monitored by TLC (DCM / MeOH = 20 / 1, Rf = 0.3). The starting material was not completely reacted, and the product spot was small. Column purification (DCM / MeOH = 100 / 1 to 10 / 1) yielded a white solid compound 6 (0.095 g, yield: 10.3%).

[0087] Dichloromethane (20 mL) and methanol (5 mL) were added to a 100 mL three-necked flask, followed by compound 5 (1 g, 2.6 mmol), which was allowed to dissolve completely. Stannous chloride (2.4 g, 13 mmol) was then added, and the mixture was refluxed overnight. TLC monitoring showed that the starting material was not completely reacted. Column purification (DCM / MeOH = 100 / 1–10 / 1) yielded a white solid, compound 6 (0.139 g, yield: 15.2%).

[0088] THF (20 mL) was added to a 100 mL three-necked flask, followed by compound 5 (1 g, 2.6 mmol), which was allowed to dissolve completely. Then, Pd / C (0.05 g) was added, and the gas was replaced with hydrogen. The reaction was carried out overnight at 35 °C. The reaction was monitored by TLC (DCM / MeOH = 20 / 1, Rf = 0.3), and the starting material was not completely reacted. Column purification (DCM / MeOH = 100 / 1 to 10 / 1) yielded a white solid compound 6 (0.536 g, yield: 58.5%).

[0089] Example 5: Synthesis of ERDRP-0519:

[0090]

[0091] Add 500 mL of dichloromethane and compound 7 (7.5 g, 38.6 mmol) to a 1 L three-necked flask. After stirring and dissolving, slowly add oxalyl chloride (5.88 g, 46.3 mmol) at 0 °C. After the addition is complete, add 2 drops of DMF and stir at room temperature for 2-3 h. After the reaction is complete, evaporate to dryness to remove the solvent and excess oxalyl chloride. The residue (acyl chloride) is a white solid.

[0092] Add 1000 mL of dichloromethane and compound 6 (8.4 g, 23.7 mmol) to a 2 L three-necked flask until compound 6 is completely dissolved. Then add DIPEA (9.2 g, 71.3 mmol). At 0 °C, add the above-mentioned dichloromethane solution of the acyl chloride. After the addition is complete, stir at room temperature for 2-3 h. Monitor the reaction by TLC until complete. Extract with dichloromethane, wash with water, dry to anhydrous sodium sulfate, concentrate, and pass through a silica gel column (dichloromethane / methanol = 250 / 1 to 50 / 1) to obtain a white solid compound ERDRP-0519 (10.8 g, yield: 86.4%, purity 99.8%).

[0093] Comparative Example 4: Synthesis of ERDRP-0519:

[0094] Add 50 mL of dichloromethane and compound 7 (1 g, 5.16 mmol) to a 100 mL three-necked flask to dissolve the crude compound 7. After dissolution, slowly add oxaloyl chloride (1.3 g, 10.3 mmol) at 0 °C. After the addition is complete, add 2 drops of DMF and stir at room temperature for 2-3 h. After the reaction is complete, add compound 6 (1.21 g, 3.44 mmol) and DIPEA (3.55 g, 27.5 mmol). Stir at room temperature for 2-3 h and monitor the reaction by TLC. After the reaction is complete, extract with dichloromethane, wash with water, dry with anhydrous sodium sulfate, concentrate, and crudely pass through a silica gel column (dichloromethane / methanol = 250 / 1 to 50 / 1) to give a white solid compound ERDRP-0519 (0.76 g, yield: 41.7%).

[0095] The embodiments described above are merely examples of several implementations of the present invention, and while the descriptions are relatively specific and detailed, they should not be construed as limiting the scope of the present invention. It should be noted that those skilled in the art can make various modifications and improvements without departing from the concept of the present invention, and these modifications and improvements all fall within the scope of protection of the present invention.

Claims

1. A process for the preparation of the compound ERDRP-0519, characterized in that, The method comprises the following steps: (1) the compound of formula 3 is oxidized by the des-martin periodinane to obtain the intermediate compound of formula 4; (2) the compound of formula 4 is subjected to reductive amination with morpholine to obtain the intermediate compound of formula 5; (3) the compound of formula 5 is subjected to nitro reduction to obtain the compound of formula 6; The nitro reduction in the step (3) is that the compound of formula 5 is reacted with a reducing agent in an organic solvent; The reducing agent is SnCl2; The organic solvent is ethyl acetate; (4) the compound of formula 7 is reacted with oxalyl chloride to obtain the crude mixture of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid chloride; (5) the mixture in the step (4) is evaporated to remove the solvent and excess oxalyl chloride to obtain the white solid of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid chloride; (6) the compound of formula 6 is reacted with the solution of the white solid of 1-methyl-3-(trifluoromethyl)-1H-pyrazole-5-carboxylic acid chloride in the presence of an acid binding agent to obtain ERDRP-0519; 2. The production method according to claim 1, characterized by, The molar ratio of the des-martin periodinane to the compound of formula 3 in the step (1) is (1.0-2.0):

1.

3. The preparation method according to claim 1, characterized in that, The reaction in the step (1) is carried out in a solvent selected from dichloromethane, toluene, tetrahydrofuran, 2-methyltetrahydrofuran or acetonitrile.

4. The production method according to claim 3, characterized by, The solvent is dichloromethane.

5. The preparation method according to claim 1, characterized in that, The reaction temperature in the step (1) is -10-50°C.

6. The production method according to claim 5, wherein The reaction temperature is 15-30°C.

7. The preparation method according to claim 1, characterized in that, The reductive amination in the step (2) is that the compound of formula 4 is subjected to reduction with a borohydride in an organic solvent.

8. The production method according to claim 7, characterized by, The borohydride is selected from potassium borohydride, sodium borohydride, sodium cyanoborohydride, potassium borohydride acetate or sodium borohydride acetate.

9. The production method according to claim 8, characterized by, The borohydride is sodium borohydride acetate.

10. The preparation method according to claim 7, characterized in that, The molar ratio of the compound of formula 4 to the borohydride is 1:0.5-5.

11. The method of claim 10, wherein, The molar ratio of the compound of formula 4 to the borohydride is 1:1.4-1.

8.

12. The method of claim 7, wherein, The organic solvent is selected from dichloromethane, dichloroethane, toluene, tetrahydrofuran or methanol.

13. The method of claim 12, wherein, The solvent is dichloromethane.

14. The method of claim 7, wherein, The reaction temperature in the step (2) is -20-35°C.

15. The preparation method according to claim 14, wherein the reaction temperature is -5-25°C.

16. The method of claim 1, wherein, The molar ratio of the compound of formula 5 to the reducing agent is 1:1-10.

17. The method of claim 16, wherein the method further comprises, The molar ratio of the compound of formula 5 to the reducing agent is 1:5-7.

18. The method of claim 1, wherein, The reaction temperature in the step (3) is 40-120°C.

19. The method of claim 18, wherein, The reaction temperature is 70-90°C.

20. The method of claim 1, wherein, The reaction in the step (4) is carried out in a solvent selected from an aprotic solvent.

21. The method of claim 20, wherein, The solvent is dichloromethane or tetrahydrofuran.

22. The method of claim 1, wherein, A catalyst is added in the reaction in the step (4), and the catalyst is selected from 4-dimethylaminopyridine or DMF.

23. The method of claim 1, wherein, The reaction temperature in the step (4) is selected from -10-30°C.

24. The method of claim 23, wherein, The reaction temperature is 0-10°C.

25. The method of claim 1, wherein, The evaporation to dryness in the step (5) is selected from vacuum distillation or direct evaporation to dryness.

26. The method of claim 25, wherein, The evaporation to dryness is vacuum distillation, and the distillation temperature is 50-70°C.

27. The method of claim 1, wherein, The acid binding agent in the step (6) is selected from triethylamine, pyridine, N,N-dimethylaniline, DIPEA or K2CO3.

28. The method of claim 27, wherein, The acid binding agent is DIPEA.

29. The method of claim 1, wherein, The molar ratio of the compound of formula 6 to the acid binding agent is 1:0.5-5.

30. The method of claim 29, wherein, The molar ratio of the compound of formula 6 to the acid binding agent is 1:2-4.

31. The method of claim 1, wherein, The molar ratio of the compound of formula 6 in step (6) to the compound of formula 7 in step (4) is 1:(1-3).

32. The method of claim 31, wherein, The molar ratio of the compound of formula 6 in step (6) to the compound of formula 7 in step (4) is 1:(1.2-1.8).

33. The method of claim 1, wherein, The reaction in step (6) is carried out in a solvent selected from toluene, dichloromethane, chloroform, 1,2-dichloroethane or tetrahydrofuran.

34. The preparation method according to claim 33, characterized in that, The solvent is dichloromethane.

35. The method of claim 1, wherein, The reaction temperature in step (6) is -20°C-35°C.

36. The preparation method according to claim 35, characterized in that, The reaction temperature is -5-25°C.

37. The method of any one of claims 1 to 36, wherein The preparation of the compound of formula 3 comprises the following steps: The substitution reaction of the compound of formula 1 with the compound of formula 2 under the condition of DIPEA gives the compound of formula 3.

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