A new method for synthesizing remdesivir

Abstract

The present invention discloses a novel synthesis method for remdesivir. The synthesis method of the present invention uses D-ribose as a raw material and synthesizes remdesivir through a series of reactions such as oxidation, cyclohexanone protection, silylation protection, substitution, substitution, deprotection, coupling, and deprotection. The present invention also optimizes the post-processing operation and has the advantages of short reaction time, high yield, low cost, and suitability for industrial production. The structure of remdesivir involved in the present invention is:

Description

Technical Field

[0001] The present invention belongs to the technical field of chemical synthesis, and specifically relates to a new synthesis method and process for synthesizing remdesivir. Background Art

[0002] Viruses are specialized organisms lacking a cellular structure, including DNA viruses, RNA viruses, and protein viruses. In recent years, RNA viruses have become more prevalent, and once they occur, they often spread widely. For example, the Ebola virus, which was prevalent in the 1970s, the SARS outbreak in 2003, and the novel coronavirus in 2019 have not only impacted human life to a certain extent, but have also significantly affected social development and human safety. Remdesivir (cas:1809249-37-3), a synthetic monomeric analog of nucleotides, has attracted widespread interest as an anti-RNA virus drug. For example, remdesivir targets the Ebola virus, the RdRp protein, an RNA-dependent RNA synthetase. However, current remdesivir synthesis reactions are small-scale, yield low, and the operation is very complex and costly. For example, the synthesis method reported in Journal of Medicinal Chemistry 2017, 60, 5, 1648-1661 has low yield, complex post-processing, and small preparation volume. Summary of the Invention

[0003] In order to overcome the above-mentioned defects of the prior art, the present invention provides a new synthesis method and process for synthesizing Remdesivir for the first time.

[0004] The synthesis method of the present invention uses D-ribose as a raw material and synthesizes remdesivir through a series of reactions such as oxidation, cyclohexanone protection, silylation protection, substitution, substitution, deprotection, coupling, and deprotection. The present invention also optimizes the post-processing operation and has the advantages of short reaction time, high yield (>35%), low cost, and suitability for industrial production. The remdesivir of the present invention is shown in Formula J, and its synthesis route is shown in the following route (I).

[0005]

[0006] The novel synthesis method and process of remdesivir described in the present invention comprises the following specific steps:

[0007] 1) In a solvent, the compound of formula A reacts with an oxidizing agent in the presence of an acid-binding agent to obtain a compound of formula B;

[0008] 2) In an organic solvent, the compound of formula B is subjected to a protection reaction under the action of a strong acid catalyst to obtain a compound of formula C;

[0009] 3) in an organic solvent, reacting the compound of formula C with a silane reagent in the presence of an acid-binding agent and a catalyst to obtain a compound of formula D;

[0010] 4) reacting the compound of formula D with a halogenated heterocyclic reagent in an organic solvent in the presence of an acid binding agent to obtain a compound of formula E;

[0011] 5) reacting the compound of formula E with a cyano reagent and a Lewis acid in an organic solvent to obtain a compound of formula F;

[0012] 6) reacting the compound of formula F with a deprotection agent in an organic solvent to obtain a compound of formula G;

[0013] 7) In an organic solvent, the compound of formula G undergoes a coupling reaction with an organophosphorus reagent under the action of an acid binding agent and a coupling agent to obtain a compound of formula H;

[0014] 8) In a solvent, the compound of formula H is deprotected under the action of a strong acid reagent to obtain a compound of formula J.

[0015] In step 1), the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, and water; preferably, water.

[0016] In step 1), the acid binding agent is one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, imidazole, triethylamine, DIPEA, pyridine or DBU; preferably, it is sodium bicarbonate.

[0017] In step 1), the oxidant is one of bromine, sodium hypochlorite, and chloric acid; preferably, it is bromine.

[0018] In step 1), the molar ratio of the compound of formula A, the acid binding agent, and the oxidizing agent is 1:(1-5):(1-5); preferably, 1:2.5:2.

[0019] In step 1), the temperature of the oxidation reaction is 0-100°C; preferably, 20°C.

[0020] In step 1), the oxidation reaction time is 1-10 hours; preferably, 1 hour.

[0021] In step 2), the solvent is one or more of cyclohexanone, toluene, and xylene; preferably, cyclohexanone.

[0022] In step 2), the acidic catalyst is one of p-toluenesulfonic acid, camphorsulfonic acid, and sulfuric acid; preferably, p-toluenesulfonic acid.

[0023] In step 2), the molar ratio of the compound of formula B to the acidic catalyst is 1:(0.05-5).

[0024] In step 2), the temperature of the cyclohexanone protection reaction is 0-100°C; preferably, 70°C

[0025] In step 2), the cyclohexanone protection reaction time is 1-24 hours; preferably, 12 hours.

[0026] In step 3), the organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, xylene, and chlorobenzene; but is not limited to the above organic solvents.

[0027] In step 3), the acid binding agent is one of imidazole, triethylamine, DIPEA, pyridine or DBU; preferably, it is imidazole.

[0028] In step 3), the catalyst is selected from one or more of DBU, DBN, imidazole, N-methylimidazole, DMAP, and 4-pyrrolidinopyridine; preferably, DMAP.

[0029] In step 3), the silanization agent is one of TBSCl, TMSCl, TBDPSCl or TBSOTf; preferably, TBSCl.

[0030] In step 3), the molar ratio of the compound of formula C, the acid binding agent, the catalyst, and the silanization agent is 1: (1-5): (0.05-0.5): (1-5); preferably, 1: 3: 0.1: 2.

[0031] In step 3), the temperature of the silanization reaction is 0-100°C; preferably, 30°C.

[0032] In step 3), the silanization reaction time is 1-12 hours; preferably, 10 hours.

[0033] In step 3), after obtaining the compound of formula D, a post-treatment process is further included, wherein the post-treatment process is filtration and recovery of the acid binding agent. The resulting filtrate is concentrated under reduced pressure, and the removed solvent and a small amount of TBSCl reagent mixture are recycled. After concentration, appropriate amounts of DCM and water are added to the residue, the liquids are separated, dried, and the dichloromethane phase is concentrated under reduced pressure to replace the solvent in the next step.

[0034] The silylation protection method used in step 3) of the present invention is simple, efficient, and employs mild conditions. The solvent is fully utilized, the acid-binding agent can also be recycled, and very little waste liquid is generated. It is scientific and environmentally friendly, has obvious advantages, and is suitable for industrial scale-up. It also avoids the methods described in existing literature that use highly irritating materials such as benzyl chloride or benzyl bromide, which are unsuitable for industrialization, difficult to operate, and expensive.

[0035] In step 4), the organic solvent is a commonly used organic solvent in the art, preferably tetrahydrofuran.

[0036] In step 4), the acid binding agent is one or more of DIPEA, triethylamine, pyridine, 2,6-lutidine, butyl lithium, and sodium hydrogen hydride; preferably, butyl lithium and sodium hydrogen hydride.

[0037] In step 4), the reaction time is 1-8 hours, preferably 6 hours.

[0038] In step 4), the reaction temperature is -80-50°C, preferably -70°C.

[0039] In step 4), the molar ratio of the compound of formula D, the halogenated heterocyclic reagent, and the acid-binding agent is 1:(1-5):(1-5); preferably, 1:1.1:(2:3).

[0040] In step 5), the organic solvent is one of ACN, THF, dichloromethane, and 1,2-dichloroethane; preferably, dichloromethane.

[0041] In step 5), the Lewis acid reagent is selected from one or more of boron trifluoride etherate, boron trifluoride acetonitrile, boron trifluoride tetrahydrofuran, and trimethylsilyl trifluoromethanesulfonate; preferably, trimethylsilyl trifluoromethanesulfonate.

[0042] In step 5), the cyano reagent is TMSCN.

[0043] In step 5), the reaction time is 2-10 hours; preferably, 4 hours.

[0044] In step 5), the reaction temperature is -20-50°C; preferably, 0-5°C.

[0045] In step 5), the molar ratio of the compound of formula E, Lewis acid reagent and cyano reagent is 1:(2-5):(2-10); preferably, 1:5:6.

[0046] In step 6), the organic solvent is one of THF, dichloromethane, and 1,2-dichloroethane; preferably, dichloromethane.

[0047] In step 6), the deprotection reagent is TBAF;

[0048] In step 6), the temperature of the deprotection reaction is 0-100°C, preferably 30°C.

[0049] In step 6), the deprotection reaction time is 2 to 16 hours; preferably, 12 hours.

[0050] In step 6), the molar ratio of the compound of formula F to the deprotection reagent is 1:(1-5); preferably, 1:5.

[0051] In step 6), after obtaining the compound of formula G, a post-treatment process is further included, wherein the post-treatment process is concentrated under reduced pressure, the removed solvent is recovered and reused, an appropriate amount of MTBE and a saturated aqueous sodium chloride solution are added to the obtained concentrate, stirred for a suitable time and then separated, the obtained MTBE phase is dried, concentrated to dryness under reduced pressure, and the solvent for the next step is added and set aside.

[0052] In step 7), the organic solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, and 1,2-dichloroethane; preferably, acetonitrile.

[0053] In step 7), the coupling reagent is magnesium chloride.

[0054] In step 7), the acid binding agent is one or more of DIPEA, triethylamine, pyridine, and 2,6-lutidine; preferably, DIPEA.

[0055] In step 7), the coupling reaction temperature is 20-80°C; preferably, 40-60°C.

[0056] In step 7), the coupling reaction time is 4-8 hours; preferably, 6 hours.

[0057] In step 7), the molar ratio of the compound of formula G, coupling reagent, acid-binding agent and organophosphorus reagent is 1:(1-5):(1-5):(1-5); preferably, 1:1:2.5:1.2.

[0058] In step 7), after obtaining the compound of formula H, a post-treatment process is further included, wherein the post-treatment process comprises adding a small amount of methanol for quenching, concentrating under reduced pressure, and subjecting the obtained concentrate to column chromatography to obtain the pure compound of formula H.

[0059] In step 8), the solvent is one of a mixed solvent of dichloromethane and water, a mixed solvent of 1,2-dichloroethane and water, and a mixed solvent of methanol and water; preferably, it is a mixed solvent of dichloromethane and water.

[0060] In step 8), the strong acid reagent is one of trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid; preferably, it is trifluoroacetic acid.

[0061] In step 8), the temperature of the deprotection reaction is 20-60°C; preferably, 30°C.

[0062] In step 8), the deprotection reaction time is 1-24 h; preferably, 12 h.

[0063] In step 8), the molar ratio of the compound of formula H to the strong acid reagent is 1:(1-5); preferably, 1:3.

[0064] The main innovations of the present invention compared to the prior art are as follows: 1. The silanization protection method used in step 3 has significant advantages over the existing benzyl protection method: (1) Silanization protection avoids the use of highly irritating materials such as benzyl chloride or benzyl bromide, which is scientific, environmentally friendly, and has mild reaction conditions; (2) Silanization protection is simple and efficient, fully utilizes the solvent, and the acid-binding agent can also be recycled, resulting in very little waste liquid and cost savings. 2. The TBAF deprotection method used in step 6 has significant advantages over the boron trichloride solution debenzylation method in the literature, with low raw material costs, high efficiency, simple operation, short processing time, and low production costs, which is conducive to industrialization.

[0065] In one embodiment, the industrial synthesis route of Remdesivir containing formula (J) is as follows:

[0066]

[0067] The present invention also proposes remdesivir, the structure of which is shown below:

[0068]

[0069] The present invention has the beneficial effects of short reaction time, simple operation, low wastewater production, high yield, and suitability for industrial-scale production. Most importantly, the invention utilizes silanization protection under mild conditions, which is economical and environmentally friendly, improves product yield, and reduces production costs. Furthermore, the invention avoids the need for debenzylation of boron trichloride, resulting in high efficiency, simple operation, and favorable industrialization.

[0070] Correspondence table of abbreviations used in the manual

[0071] Entry abbreviation Full name 1 DCM dichloromethane 2 THF Tetrahydrofuran 3 ACN Acetonitrile 4 TBSCl tert-Butyldimethylsilyl chloride 5 TMSCl trimethylchlorosilane 6 TBDPSCl tert-Butyldiphenylchlorosilane 7 DIPEA N,N-Diisopropylethylamine 8 DMAP 4-Dimethylaminopyridine 9 DBU 1,8-Diazabicycloundec-7-ene 10 DBN 1,5-Diazabicyclo[4.3.0]non-5-ene 11 TBSOTf tert-Butyldimethylsilyl trifluoromethanesulfonate 12 TMSCN Trimethylsilyl cyanide 13 TBAF Tetrabutylammonium fluoride 14 MTBE Methyl tert-butyl ether DETAILED DESCRIPTION

[0072] The present invention is further described in detail with reference to the following specific examples. Except for the contents specifically mentioned below, the processes, conditions, experimental methods, etc. for implementing the present invention are common knowledge and common common sense in the field and are not particularly limited by the present invention.

[0073] Example 1

[0074] Synthesis of compound B:

[0075] To a 100L reactor connected to a tail gas absorption device, water (45L), D-ribose (9kg, 60mol) and sodium bicarbonate (12.6kg, 150mol) were added, and bromine (19.2kg, 120mol) was added dropwise at 20°C. After the addition was complete, the mixture was reacted at 20°C for 1h. HPLC detection showed that the reaction of the raw materials was complete.

[0076] Cool to 0°C and add sodium sulfite to quench the reaction before proceeding to the next step.

[0077] Example 2

[0078] Synthesis of compound C:

[0079] To the above reaction solution, p-toluenesulfonic acid (catalytic amount) and cyclohexanone (40 L) were added, and the temperature was raised to 70° C. for reaction for 12 h. HPLC detection showed that the reaction of the raw materials was complete.

[0080] Concentrate to dryness, add ethyl acetate, wash with sodium bicarbonate, and then wash with saturated sodium chloride. The organic phase is concentrated to dryness to obtain the product compound C (13 kg). The two-step yield is 95%.

[0081] Example 3

[0082] Synthesis of compound D:

[0083] Under nitrogen protection, C (13 kg, 57 mol), imidazole (11.6 kg, 171 mol), DMAP (catalyst) and dichloromethane (65 L) were added to a 100 L reactor. TBSCl (17.2 kg, 114 mol) was added dropwise at 30°C. After completion of the addition, the mixture was reacted at 30°C for 10 h. The reaction was complete by HPLC.

[0084] Filter and recover the filter cake. The filtrate is concentrated, and the concentrated dichloromethane and TBSCl mixed solvent is recovered and reused. The light yellow solid obtained by concentration is added with 40L dichloromethane and 20L water and stirred for 0.5h. The liquid is separated, the organic phase is dried and concentrated to dryness, and the tetrahydrofuran is concentrated once to obtain a crude product D of about 20kg of light yellow solid (theoretical amount is 19.5kg, containing a small amount of solvent), with a yield of 100%. Tetrahydrofuran is then added and directly added to the next step. The feeding method of this step is simple and convenient. In the post-processing process, the catalyst and solvent can be recycled. Compared with the methods recorded in the existing literature, the present invention has obvious advantages and is very suitable for industrial production.

[0085] 1 H NMR (400MHz, CHLOROFORM-d) δppm 0.10 (s, 6H) 0.91 (s, 9H) 1.74 -1.51 (m, 10H) 3.97 (dd, J = 15.35, 6.58Hz, 2H) 4.54 - 4.47 (m, 1H) 4.80 (s, 2H).

[0086] Example 4

[0087] Synthesis of compound E:

[0088] Under nitrogen, a 500-L reactor was charged with a halogenated heterocyclic reagent (16.3 kg, 62.7 mol), THF (30 L), and 1,2-bis(chlorodimethylsilyl)ethane (13.5 kg, 62.7 mol). The mixture was stirred for 30 min, followed by the addition of sodium hydroxide (4.6 kg, 114 mol) in portions and stirring for 60 min. The system was cooled to -70°C, and n-butyllithium (68 L, 171 mol) was added dropwise. The reaction was incubated for 1 h. A solution of (D) in THF (30 L) was then added dropwise at -70°C, and the reaction was incubated for 6 h. HPLC analysis confirmed the complete reaction of the starting materials.

[0089] The system was poured into an aqueous solution of citric acid to quench the reaction, and EA was added for extraction. The organic phases were combined, washed with a saturated aqueous solution of sodium bicarbonate, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to obtain crude product E. Flash column chromatography gave pure product E (19 kg) with a yield of 70%.

[0090] Example 5

[0091] Synthesis of compound F:

[0092] Under nitrogen, add Compound E (19 kg, 39.9 mol) and dichloromethane (95 L) to a 500 L reactor. Cool to 0°C, then add TMSOTf (44.3 kg, 199 mol) dropwise. Stir for 0.5 h, then add TMSCN (23.7 kg, 239 mol) dropwise, and stir for 4 h. HPLC analysis indicates complete reaction.

[0093] The reaction was quenched by adding saturated aqueous sodium bicarbonate solution, the phases were separated, and compound F was extracted by adding DCM and recovered for reuse. The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated to give crude product F. Pure product F (17.4 kg) was obtained by flash column chromatography. The yield was 90%.

[0094] Example 6

[0095] Synthesis of compound G:

[0096] Under nitrogen protection, compound F (17.4 kg, 35.9 mol) and dichloromethane (85 L) were added to a 500 L reactor, and TBAF (46.9 kg, 179 mol) was added at 30° C. After addition, the mixture was kept warm and reacted for 12 h. HPLC detection showed that the reaction of the raw materials was complete.

[0097] The solvent was evaporated under reduced pressure, MTBE and saturated aqueous sodium chloride solution were added, stirred, separated, dried over anhydrous sodium sulfate, and concentrated to dryness to obtain about 14 kg of crude product G (theoretical amount is 13.3 kg, containing a small amount of solvent), which was directly used in the next step. The yield was 100%.

[0098] Example 7

[0099] Synthesis of compound H:

[0100] Under nitrogen, G (13.3 kg, 35.9 mol), organophosphorus reagent (19.4 kg, 43.1 mol), magnesium chloride (3.4 kg, 35.9 mol), and ACN (65 L) were added to a 500 L reactor. DIPEA (11.6 kg, 89.7 mol) was added dropwise at 60°C and allowed to react at room temperature. HPLC analysis confirmed the complete reaction of the starting materials.

[0101] The temperature was lowered to 0°C, methanol was added dropwise, and the solvent was concentrated to obtain crude product H. The crude product was purified by flash column chromatography to obtain pure product H (17.1 kg) with a yield of 70%.

[0102] 1 H-NMR (400MHz, METHANOL-d 4) δppm 0.86 (t, J=7.4Hz, 6H) 1.36– 1.23 (m, 7H) 1.50–1.42 (m, 1H) 1.51-1.65 (m, 10H) 1.70 (s, 3H) 3.84 (dq, J=9.7, 7.1Hz,1H)3.92(dd,J=10.9,5.7Hz,1H)4.02(dd,J=10.9,5.8Hz,1H)4.36–4. 24(m,2H)4.60–4.53(m,1H)4.99(dd,J=6.6,3.5Hz,1H)5.34(d,J=6.6Hz,1H) 6.89(q,J=4.6Hz,2H)7.17–7.10(m,3H)7.30–7.23(m,2H)7.86(s,1H).

[0103] Example 8

[0104] Synthesis of compound J:

[0105] Under nitrogen protection, H (17.1 kg, 25.1 mol), dichloromethane (85 L) and water (51 L) were added to a 500 L reactor. Trifluoroacetic acid (8.6 kg, 75.4 mol) was added dropwise at room temperature. The reaction was allowed to proceed at room temperature. HPLC detection showed that the reaction of the raw materials was complete.

[0106] The mixture was allowed to stand, separated, and the aqueous phase was extracted with dichloromethane. The organic phases were combined, washed with saturated aqueous sodium bicarbonate solution, dried over anhydrous sodium sulfate, and the solvent was concentrated to obtain crude product J. The crude product was purified by flash column chromatography to obtain pure product J (12.1 kg) with a yield of 80%.

[0107] 1 H-NMR(400MHz,METHANOL-d 4)δppm 0.85(t,J=7.4Hz,6H)1.35–1.27(m,8H)1.49–1.41(m,1H)3.96–3.85(m,2H)4.02(dd,J=10.9,5.8Hz,1H) 4.17(t,J=5.6Hz,1H)4.28(ddd,J=10.3,5.9,4.2Hz,1H)4.43–4.34(m,2H)4. 79(d,J=5.4Hz,1H)6.87(d,J=4.6Hz,1H)6.91(d,J=4.6Hz,1H)7.21–7.12(m, 3H)7.33–7.26(m,2H)7.86(s,1H).

[0108] The protection content of the present invention is not limited to the above embodiments. Without departing from the spirit and scope of the inventive concept, changes and advantages that can be thought of by those skilled in the art are included in the present invention and are protected by the appended claims.

Claims

1. A new method for synthesizing remdesivir, characterized in that: The remdesivir is shown in Formula J, and the synthesis route of the compound of Formula J is shown in the following route (I): The specific steps are as follows: 1) In a solvent, the compound of formula A reacts with an oxidizing agent in the presence of an acid-binding agent to produce a compound of formula B; 2) In an organic solvent, the compound of formula B is subjected to a protection reaction under the action of a strong acid catalyst to obtain a compound of formula C; 3) In an organic solvent, the compound of formula C reacts with a silane reagent in the presence of an acid-binding agent and a catalyst to obtain a compound of formula D; 4) In an organic solvent, the compound of formula D reacts with a halogenated heterocyclic reagent in the presence of an acid-binding agent to obtain a compound of formula E; the acid-binding agent is n-butyl lithium; and the reaction temperature is -80°C to -70°C; 5) reacting the compound of formula E with a cyano reagent and a Lewis acid in an organic solvent to obtain a compound of formula F; the reaction temperature is 0-5°C; 6) reacting the compound of formula F with a deprotection reagent in an organic solvent to obtain a compound of formula G; the deprotection reaction temperature is 0-100° C.; 7) In a solvent, the compound of formula G undergoes a coupling reaction with an organophosphorus reagent under the action of an acid binding agent and a coupling agent to obtain a compound of formula H; 8) In a solvent, the compound of formula H is deprotected under the action of a strong acid reagent to obtain a compound of formula J.

2. The synthesis method according to claim 1, wherein In step 1), the solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, and water; and / or the acid-binding agent is one of sodium bicarbonate, sodium carbonate, potassium bicarbonate, potassium carbonate, imidazole, triethylamine, DIPEA, pyridine, or DBU; and / or the oxidizing agent is one of bromine, sodium hypochlorite, and chloric acid; and / or the molar ratio of the compound of formula A, the acid-binding agent, and the oxidizing agent is 1:(1-5):(1-5).

3. The synthesis method according to claim 1, wherein In step 1), the temperature of the oxidation reaction is 0-100° C.; the time of the oxidation reaction is 1-10 hours.

4. The synthesis method according to claim 1, wherein In step 2), the organic solvent is cyclohexanone; and / or the strong acid catalyst is one of p-toluenesulfonic acid and sulfuric acid; and / or the molar ratio of the compound of formula B to the strong acid catalyst is 1:(0.05-5).

5. The synthesis method according to claim 1, wherein In step 2), the protection reaction temperature is 0-100° C.; the protection reaction time is 1-24 hours.

6. The synthesis method according to claim 1, wherein In step 3), the organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, toluene, xylene, and chlorobenzene.

7. The synthesis method according to claim 1, wherein In step 3), the acid-binding agent is one of imidazole, triethylamine, DIPEA, pyridine or DBU; the catalyst is selected from one or more of DBU, DBN, imidazole, N-methylimidazole, DMAP, and 4-pyrrolidinylpyridine; the silane reagent is one of TBSCl or TBSOTf; and / or the molar ratio of the compound of formula C, the acid-binding agent, the catalyst, and the silane reagent is 1:(1-5):(0.05-0.5):(1-5).

8. The synthesis method according to claim 1, wherein In step 3), the temperature of the silanization reaction is 0-100° C.; the time of the silanization reaction is 1-12 hours.

9. The synthesis method according to claim 1, wherein In step 4), the organic solvent is selected from one or more of dichloromethane, 1,2-dichloroethane, tetrahydrofuran, benzene, toluene, xylene, and chlorobenzene.

10. The synthesis method according to claim 1, wherein In step 4), the molar ratio of the compound of formula D, the halogenated heterocyclic reagent, and the acid binding agent is 1:(1-5):(1-5).

11. The synthesis method according to claim 1, wherein In step 5), the organic solvent is one of ACN, THF, dichloromethane, and 1,2-dichloroethane; the Lewis acid reagent is one or more selected from boron trifluoride etherate, boron trifluoride acetonitrile, boron trifluoride tetrahydrofuran, and trimethylsilyl trifluoromethanesulfonate; the cyano reagent is TMSCN; and / or the molar ratio of the compound of formula E, the Lewis acid reagent, and the cyano reagent is 1:(2-5):(2-10).

12. The synthesis method according to claim 1, wherein In step 6), the organic solvent is one of THF, dichloromethane, and 1,2-dichloroethane; the deprotection reagent is TBAF; and the molar ratio of the compound of formula F to the deprotection reagent is 1:(1-5).

13. The synthesis method according to claim 1, wherein In step 7), the solvent is selected from one or more of acetonitrile, tetrahydrofuran, dichloromethane, and 1,2-dichloroethane; and / or the coupling agent is magnesium chloride; and / or the acid-binding agent is one or more of DIPEA, triethylamine, pyridine, and 2,6-lutidine; and / or the temperature of the coupling reaction is 20-80°C; and / or the molar ratio of the compound of formula G, the coupling agent, the acid-binding agent, and the organophosphorus reagent is 1:(1-5):(1-5):(1-5).

14. The synthesis method according to claim 1, wherein In step 8), the solvent is one of a mixed solvent of dichloromethane and water, a mixed solvent of 1,2-dichloroethane and water, and a mixed solvent of methanol and water; and / or the strong acid reagent is one of trifluoroacetic acid, methanesulfonic acid, and trifluoromethanesulfonic acid; and / or the temperature of the deprotection reaction is 20-60°C; and / or the time of the deprotection reaction is 1-24h; and / or the molar ratio of the compound of formula H to the strong acid reagent is 1:(1-5).

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