Preparation method of compound

Abstract

The invention discloses a preparation method for synthesizing a compound, belongs to the field of chemical synthesis, and aims to provide a novel route for synthesizing methyl 6-((3-(4-(tert-butoxarbonyl) piperizin-1-yl) propyl) (methyl) amine) quinine-4-carboxylate, which is more novel, practical, economical and high in reproducibility, and a preparation method for synthesizing the compound is provided, so that the method has the advantages of high yield, high yield and the like, and is suitable for industrial production and application of the novel route for synthesizing the methyl 6-((3-(4-(tert-butoxarbonyl) piperizin-1-yl) propyl) (methyl) amine) quinine-4-carboxylate. Therefore, a reference is provided and a foundation is laid for large-scale preparation of the FAPI-46.

Description

Technical Field

[0001] The present invention relates to the field of pharmaceuticals, and specifically to a new preparation method of methyl 6-((3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)(methyl)amino)quinoline-4-carboxylate. Methyl 6-((3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)(methyl)amino)quinoline-4-carboxylate can be used as an intermediate for the preparation of FAPI-46. FAPI-46 can be used as a precursor for the preparation of a radioactive probe. The probe obtained by labeling it with a radionuclide can be used for the diagnosis and internal radiotherapy of diseases with overexpression of fibroblast activation protein (FAP) such as cancer, local inflammation, and tissue organ fibrosis. The preparation method of methyl 6-((3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)(methyl)amino)quinoline-4-carboxylate described in the present invention has the advantages of a shorter synthesis route, high and stable yield, and can lay a good foundation for the large-scale preparation of FAPI-46. Background Art

[0002] FAP-targeted molecular imaging is gradually becoming a powerful diagnostic and therapeutic tool for diseases such as cancer, inflammation, and fibrosis. In previous research work, we reported a new synthetic route for FAPI-46 (Compound 1) (CN118791466A). This compound can be used to prepare an FAP-targeted radioactive probe by labeling with a radionuclide.

[0003]

[0004] The synthesis method of FAPI-46 reported in Patent CN118791466A uses 5-bromoindirubin and sodium pyruvate as raw materials, and FAPI-46 can be prepared through 20 steps of reactions such as Pfitzinger reaction, high-temperature decarboxylation, tert-butyl protection of carboxyl group, C-N coupling reaction, removal of tert-butyl protection, methyl protection of tert-butyl, removal of methyl protection, and condensation reaction. The synthesis route is as follows:

[0005]

[0006] In the above route, in the process of preparing compound (12) (i.e., compound (H-8)) from compound (4) (i.e., compound (H-1)), if the route of (4) → (8) → (9) → (10) → (11) → (7) → (12) is adopted, the carboxyl group in (4) needs to be protected with tert-butyl first, then C-N coupling is carried out, and then the tert-butyl protection is removed to obtain (11) with an exposed carboxyl group. Finally, the carboxyl group in (11) is protected to form a methyl ester to obtain (7). This route involves the operations of protecting the carboxyl group with tert-butyl, then removing the tert-butyl protection and then protecting it with a methyl group, resulting in it being rather lengthy; if the route of (4) → (5) → (6) → (7) → (12) is adopted, (6) needs to be prepared from (5) through a C-N coupling reaction. The yield of this coupling step is less than 15% whether a palladium catalyst or a copper catalyst is used. Summary of the Invention

[0007] The problem to be solved by the present invention is to overcome the problems of a lengthy route or a low yield of the single-step reaction C-N coupling reaction when synthesizing methyl 6-((3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)(methyl)amino)quinoline-4-carboxylate (compound (H-8), a key intermediate in the preparation of FAPI-46) reported in patent (CN118791466A). The aim is to provide a newer, more practical, economical and highly reproducible method for synthesizing methyl 6-((3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)(methyl)amino)quinoline-4-carboxylate, providing a reference and laying a foundation for the large-scale preparation of FAPI-46.

[0008]

[0009] The synthesis route is as follows:

[0010]

[0011] In some specific technical solutions, the steps of the method are as follows:

[0012] 1) The carboxyl group of the compound of formula (H-1) is protected with a methyl group to obtain the compound of formula (H-2);

[0013] 2) The hydroxyl group of the compound of formula (H-3) is protected with a silicon group to obtain the compound of formula (H-4);

[0014] 3) The compound of formula (H-2) and the compound of formula (H-4) are subjected to C-N coupling to obtain the compound of formula (H-5);

[0015] 4) The compound of formula (H-5) is deprotected by desilylation to obtain the compound of formula (H-6);

[0016] 5) The compound of formula (H-6) is mesylated at the hydroxyl group to obtain the compound of formula (H-7);

[0017] 6) The compound of formula (H-7) reacts with N-Boc piperazine through nucleophilic substitution to obtain the compound of formula (H-8).

[0018] In the technical solution of the present invention, in step 1), the reaction conditions are as follows :

[0019] The methyl donor for methyl protecting the carboxyl group is methyl iodide, methyl bromide, methyl chloride, dimethyl sulfate, preferably methyl iodide;

[0020] A basic reagent is added during the reaction, and the base selected is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide, preferably the base selected is potassium carbonate;

[0021] The solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, acetone, methanol, ethanol or water, preferably the solvent is N,N-dimethylformamide;

[0022] Among them, the molar ratio of compound H-1, methyl donor, and basic reagent is 1:1 to 5:1 to 5;

[0023] The reaction temperature is 0 - 100 °C, preferably 20 - 40 °C; the reaction time is 2 - 8 h, preferably: the reaction time is 1 - 3 h.

[0024] In the technical solution of the present invention, in step 2), the reaction conditions are as follows:

[0025] The silyl protecting group donor for silyl protecting the hydroxyl group is trimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, chlorotriethylsilane, preferably tert-butyldiphenylchlorosilane;

[0026] A basic reagent is added during the reaction, and the basic reagent selected is imidazole, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate, sodium methoxide, preferably the basic reagent is sodium hydride;

[0027] The solvent is N,N-dimethylformamide, dichloromethane, tetrahydrofuran or acetonitrile, preferably: the solvent is N,N-dimethylformamide;

[0028] Among them, the molar ratio of compound H-3, silyl protecting group donor, and basic reagent is 1 - 3:1 - 3:1 - 3;

[0029] The reaction temperature is 0 - 40 °C, preferably the temperature is 20 - 40 °C; the reaction time is 1 - 8 h; preferably the reaction time is 2 - 3 h.

[0030] In the technical solution of the present invention, in step 3), the reaction conditions are as follows:

[0031] The solvent is methanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, water or toluene. Preferably, the selected solvent is 1,4-dioxane;

[0032] A palladium catalyst is added during the reaction. The palladium catalyst is palladium acetate, dichlorobis(ferrocenylphenylphosphine)palladium(II), palladium(III) triphenylphosphine, dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0). Preferably, tris(dibenzylideneacetone)dipalladium(0);

[0033] A ligand is added during the reaction. The ligand is triphenylphosphine, dibenzyldimethylphosphine, ferrocenylphenylphosphine, derivatives of ferrocenylphenylphosphine, tris(2-pyridyl)phosphine, tetrakis(triphenylphosphine)palladium(0), 3-amino-4-(2-pyridyl)benzoic acid, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl. Preferably, 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl;

[0034] A basic reagent needs to be added during the reaction. The basic reagent is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, potassium hydroxide, sodium hydroxide or potassium tert-butoxide. Preferably, the basic reagent is cesium carbonate;

[0035] The molar ratio of compound H-2, compound H-4, basic reagent, ligand, and palladium catalyst is 0.5 - 1.5:0.5 - 1.5:1 - 3:0.05 - 0.25:0.01 - 0.1;

[0036] The reaction is protected by an inert gas; the reaction temperature is 70°C - 150°C; the reaction time is 4 - 12 h; preferably, the reaction temperature is 100 - 110°C and the reaction time is 8 - 10 h.

[0037] In the technical solution of the present invention, in step 4), the reaction conditions are as follows:

[0038] The conditions for the reaction are as follows: The desilylating reagent is at least one of tetrabutylammonium fluoride, acetic acid in tetrahydrofuran solution, sodium hydroxide in ethanol solution, potassium hydroxide in methanol solution, and pyridine hydrogen fluoride complex. Preferably, tetrabutylammonium fluoride;

[0039] The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide. Preferably, the solvent is tetrahydrofuran;

[0040] The molar ratio of compound H-5 to the desilylating reagent is 1:1 - 5.

[0041] The reaction temperature is 0 - 40°C. Preferably, the reaction temperature is 20 - 40°C; the reaction time is 1 - 5 h. Preferably, the reaction time is 1 - 3 h.

[0042] In the technical solution of the present invention, in step 5), the reaction conditions are as follows:

[0043] During the reaction process, the mesyl donor is mesyl chloride or mesyl anhydride, preferably mesyl chloride;

[0044] The base reagent is triethylamine or N,N-diisopropylethylamine, preferably triethylamine as the mesyl donor;

[0045] The solvent is dichloromethane, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide, preferably dichloromethane as the selected solvent;

[0046] The molar ratio of compound H-6, the mesyl donor, and the base reagent is 1:1 to 5:3 to 8.

[0047] The reaction temperature is 0 - 40 °C, and the reaction time is 1 - 8 h; preferably the reaction time is 1 - 3 h.

[0048] In the technical solution of the present invention, in step 6), the reaction conditions are as follows:

[0049] The reaction conditions are as follows: it is carried out under basic conditions, and the base reagent used is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, potassium hydroxide or sodium hydroxide, preferably potassium carbonate as the base;

[0050] A catalyst is added during the reaction process, and the catalyst used is potassium iodide or sodium iodide, preferably sodium iodide as the catalyst;

[0051] The reaction solvent is N,N-dimethylformamide, dimethyl sulfoxide, acetone, methanol, ethanol or water, preferably N,N-dimethylformamide as the reaction solvent;

[0052] The molar ratio of compound H-6, 1-Boc-piperazine, the catalyst, and the base reagent is 1:0.5 to 1.5:1 to 2:1 to 3.

[0053] The reaction temperature is 50 - 100 °C, preferably 65 - 75 °C; the reaction time is 2 - 10 h, preferably 2 - 3 h.

[0054] The key steps of this invention include obtaining the compound of formula (H-2) by methyl protecting the carboxyl group of the compound of formula (H-1), obtaining the compound of formula (H-4) by silyl protecting the hydroxyl group of the compound of formula (H-3), obtaining the compound of formula (H-5) by C-N coupling of the compound of formula (H-3) and the compound of formula (H-4), obtaining the compound of formula (H-6) by removing the silyl protection of the compound of formula (H-5), obtaining the compound of formula (H-7) by mesylation of the hydroxyl group of the compound of formula (H-6), and obtaining the compound of formula (H-8) by nucleophilic substitution reaction of the compound of formula (H-7) with N-Boc piperazine. This route avoids the long operation of protecting the carboxyl group with tert-butyl and then removing the tert-butyl protection and then protecting with methyl as reported in the existing patent when preparing 12 by the route of (4) → (8) → (9) → (10) → (11) → (7) → (12), or the problem of low yield when preparing compound (12) by the route of (4) → (5) → (6) → (7) → (12) in the preparation of compound (6) from compound (5) through C-N coupling reaction. This synthetic route has a short route, simple operation, high yield, few by-products, convenient purification, has practical application significance, and is conducive to mass production. Description of the Drawings

[0055] Figure 1 is the 1H NMR spectrum of the compound of formula (H-2).

[0056] Figure 2 is the 1H NMR spectrum of the compound of formula (H-4).

[0057] Figure 3 is the 1H NMR spectrum of the compound of formula (H-5).

[0058] Figure 4 is the 1H NMR spectrum of the compound of formula (H-6).

[0059] Figure 5 is the 1H NMR spectrum of the compound of formula (H-7).

[0060] Figure 6 is the 1H NMR spectrum of the compound of formula (H-8). Detailed Description of the Invention

[0061] The content of the present invention will be specifically described below by way of examples. In the present invention, the following examples are for better explaining the present invention and are not used to limit the scope of the present invention.

[0062] Example 1

[0063] Methyl 6-bromoquinoline-4-carboxylate

[0064]

[0065] 6-Bromoquinoline-2,4-dicarboxylic acid (500 mg, 2 mmol) was dissolved in N,N-dimethylformamide (10 mL). Potassium carbonate (1.1 g, 8 mmol) and iodomethane (852 mg, 6 mmol) were added to the mixture and stirred at room temperature for 2 h. After completion of the reaction, as monitored by TLC, 20 mL of water was added to dilute the reaction solution. The aqueous phase was then extracted with ethyl acetate (10 mL x 3). The combined organic phases were washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. Flash column chromatography afforded 387 mg of a pale yellow solid with a purity of 97% and a yield of 73%. 1 H NMR (400MHz, CDCl3) δ9.02 (t, 2H), 8.02 (d, J = 8.99Hz, 1H), 7.94 (d, J = 4.49Hz, 1H), 7.84 (dd, J1 = 2.12Hz, J2 = 8.99Hz, 1H), 4.04 (s, 3H). MS (ESI): m / z 251.96[M+H] + .

[0066] Example 2

[0067] 3-((tert-Butyldiphenylsilyloxy)oxy)-N-methylpropylamine

[0068]

[0069] 3-(Methylamino)-1-propanol (5.0 g, 21.73 mmol) was dissolved in anhydrous tetrahydrofuran (20 mL) on an ice bath. 60% sodium hydride (869.3 mg, 21.73 mmol) was then slowly added portionwise to the mixture, stirring on ice for 30 min. Tert-butyldiphenylsilyl chloride (5.97 g, 21.73 mmol) was then added to the mixture, and the mixture was allowed to warm to room temperature and stirred for 3 h. After completion of the reaction, as monitored by TLC, the reaction mixture was poured into 80 mL of water. The aqueous phase was extracted with ethyl acetate (40 mL x 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent evaporated under reduced pressure. Flash column chromatography afforded 5.45 g of a yellow oil with a purity of 98% and a yield of 77%. 1 H NMR(400MHz,Chloroform-d)δ7.70-7.64(m,4H),7.39(q,J=8.2,7.1Hz,6H),3.74(t,J=6.0Hz,2H) ,2.70(t,J=6.8Hz,2H),2.41(s,3H),1.97(s,1H),1.76(p,J=6.3Hz,2H),1.06(s,9H).MS(ESI):m / z 328.20[M+H] + .

[0070] Example 3

[0071] Methyl 6-((3-((tert-butyldiphenylsilyloxy)oxy)propyl)(methyl)amino)quinoline-4-carboxylate

[0072]

[0073] Methyl 6-bromoquinoline-4-carboxylate (3.7 g, 13.91 mmol), 3-((tert-butyldiphenylsilyloxy)oxy)-N-methylpropylamine (5.0 g, 15.3 mmol), cesium carbonate (9.06 g, 27.82 mmol), 2-dicyclohexylphosphino-2,4,6-triisopropylbiphenyl (650 mg, 1.391 mmol) were placed in a pressure tube. 20 mL of anhydrous 1,4-dioxane was injected into the flask, and then tris(dibenzylideneacetone)dipalladium (635 mg, 0.6955 mmol) was added to the flask. The pressure tube was evacuated for 4 - 5 min and stirred at 105 °C for 10 h. After monitoring the completion of the reaction by TLC, the reaction solution was poured into 70 mL of water, and the aqueous phase was extracted with ethyl acetate (30 mL × 3). The organic phases were combined, washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. 5.54 g of a yellow oil was obtained by flash column chromatography, with a purity of 98% and a yield of 77.7%. 1 H NMR (400 MHz, Chloroform-d) δ 8.66 (d, J = 4.5 Hz, 1H), 7.98 (d, J = 9.4 Hz, 1H), 7.92 (d, J = 2.7 Hz, 1H), 7.83 (d, J = 4.5 Hz, 1H), 7.73 - 7.69 (m, 4H), 7.48 (dd, J = 9.4, 2.8 Hz, 1H), 7.43 - 7.36 (m, 6H), 3.97 (s, 3H), 3.78 (t, J = 5.7 Hz, 2H), 3.68 (t, J = 7.0 Hz, 2H), 3.10 (s, 3H), 1.89 (p, J = 6.2 Hz, 2H), 1.14 (s, 9H). MS (ESI): m / z 513.25 [M + H] + .

[0074] Example 4

[0075] Methyl 6-((3-hydroxypropyl)(methyl)amino)quinoline-4-carboxylate

[0076]

[0077] Dissolve methyl 6-((3-((tert-butyldiphenylsilyloxy)oxy)propyl)(methyl)amino)quinoline-4-carboxylate (6.6 g, 11.92 mmol) in tetrahydrofuran (15 mL), add a tetrahydrofuran solution of tetrabutylammonium fluoride (1 M, 23.83 mL, 23.83 mmol), and stir at room temperature for 2 h. After monitoring the completion of the reaction by TLC, evaporate the solvent under reduced pressure and use it directly for the next step, with a yield of 99%. 1 H NMR (400 MHz, CDCl3) δ 8.65 (d, J = 9.41 Hz, 1H), 7.98 (d, J = 9.28 Hz, 1H), 7.94 (d, J = 2.89 Hz, 1H), 7.83 (d, J = 4.46 Hz, 1H), 7.43 (dd, J1 = 2.84 Hz, J2 = 9.44 Hz, 1H), 4.00 (s, 3H), 3.77 (t, 2H), 3.65 (t, 2H), 1.96 - 1.90 (m, 2H). MS (ESI): m / z 275.13

[0078] [M+H] + .

[0079] Example 5

[0080] Methyl 6-(methyl(3-((methylsulfonyl)oxy)propyl)amino)quinoline-4-carboxylate

[0081]

[0082] Add triethylamine (304 mL, 2.2 mmol) to a dichloromethane solution (5 mL) of methyl 6-(3-hydroxymethylpropylamino)quinoline-4-carboxylate (100 mg, 0.37 mmol), and stir at 0 °C for 10 min. While maintaining 0 °C, slowly add methanesulfonyl chloride (84 mg, 0.73 mmol) to the system. After addition, stir at 0 °C for 30 min and then allow it to warm to room temperature naturally. The system reacts at room temperature for 1 h. After monitoring the completion of the reaction by TLC, add saturated ammonium chloride solution to the system at 0 °C and stir for 10 min to quench the reaction. After quenching, perform liquid separation and collect the organic phase. Wash the organic phase twice with water and then once with saturated brine, dry over anhydrous sodium sulfate, evaporate the solvent under reduced pressure, and obtain 120 mg of an orange-red oily substance by flash column chromatography, with a purity of 99% and a yield of 94%. 11H NMR (400 MHz, Chloroform-d) δ 8.67 (d, J = 4.5 Hz, 1H), 8.02 - 7.95 (m, 2H), 7.84 (d, J = 4.5 Hz, 1H), 7.37 (dd, J = 9.4, 2.6 Hz, 1H), 4.33 (t, J = 5.9 Hz, 2H), 3.99 (s, 3H), 3.66 (t, J = 6.9 Hz, 2H), 3.13 (s, 3H), 3.02 (s, 3H), 2.13 (p, J = 6.2 Hz, 2H). MS (ESI): m / z 253.11 [M+H] + .

[0083] Example 6

[0084] Methyl 6-((3-(4-(tert-butoxycarbonyl)piperazin-1-yl)propyl)(methyl)amino)quinoline-4-carboxylate

[0085]

[0086] Potassium carbonate (3.92 g, 28.4 mmol), sodium iodide (2.98 g, 19.9 mmol), and 1-Boc piperazine (2.91 g, 15.6 mmol) were successively added to a solution of methyl 6-(methyl(3-((methylsulfonyl)oxy)propyl)amino)quinoline-4-carboxylate (5.0 g, 14.2 mmol) in anhydrous N,N-dimethylformamide (30 mL). The mixture was stirred at 70 °C for 2.5 h. After monitoring the completion of the reaction by TLC, 70 mL of water was added for dilution, and the aqueous phase was extracted with ethyl acetate (30 mL x 3). The organic phase was washed with saturated brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. 5.2 g of an orange-yellow oil was obtained by flash column chromatography, with a purity of 98% and a yield of 83%. 1 1H NMR (400 MHz, CDCl3) δ 8.62 (d, J = 4.49 Hz, 1H), 7.93 (d, J = 9.31 Hz, 1H), 7.89 (d, J = 2.74 Hz, 1H), 7.81 (d, J = 4.56 Hz, 1H), 7.41 (dd, J1 = 2.82 Hz, J2 = 9.42 Hz, 1H), 3.97 (s, 3H), 3.54 (t, 2H), 3.43 (t, 4H), 3.07 (s, 3H), 2.40 - 2.36 (m, 4H), 1.85 - 1.78 (m, 2H), 1.43 (s, 9H). MS (ESI): m / z 443.26 [M+H] + .

Claims

1. A method for preparing a compound, characterized in that:

2. The method according to claim 1, wherein The steps of the method are as follows: 1) The compound of formula (H-1) is subjected to carboxyl protection with a methyl group to obtain a compound of formula (H-2); 2) The compound of formula (H-3) is subjected to hydroxyl protection with a silicon group to obtain a compound of formula (H-4); 3) The compound of formula (H-2) and the compound of formula (H-4) are subjected to C-N coupling to obtain a compound of formula (H-5); 4) The compound of formula (H-5) is subjected to desilylation protection to obtain a compound of formula (H-6); 5) The compound of formula (H-6) is subjected to mesylation of the hydroxyl group to obtain a compound of formula (H-7); 6) The compound of formula (H-7) reacts with N-Boc piperazine through nucleophilic substitution to obtain a compound of formula (H-8).

3. The method according to claim 2, characterized in that, In step 1), the reaction conditions are as follows: The methyl donor for carboxyl protection with a methyl group is methyl iodide, methyl bromide, methyl chloride, dimethyl sulfate, preferably methyl iodide; A basic reagent is added during the reaction, and the selected base is potassium carbonate, sodium carbonate, cesium carbonate, potassium hydroxide or sodium hydroxide, preferably the selected base is potassium carbonate; The solvent is selected from N,N-dimethylformamide, dimethyl sulfoxide, acetone, methanol, ethanol or water, preferably the solvent is N,N-dimethylformamide; The molar ratio of compound H-1, methyl donor, and basic reagent is 1:1 to 5:1 to 5; The reaction temperature is 0 - 100 °C, preferably 20 - 40 °C; the reaction time is 2 - 8 h, preferably: the reaction time is 1 - 3 h.

4. The method according to claim 2, wherein In step 2), the silicon protecting group donor for hydroxyl protection with a silicon group is trimethylchlorosilane, tert-butyldimethylchlorosilane, tert-butyldiphenylchlorosilane, chlorotriethylsilane, preferably tert-butyldiphenylchlorosilane; A basic reagent is added during the reaction, and the selected basic reagent is imidazole, triethylamine, diisopropylethylamine, 4-dimethylaminopyridine, pyridine, potassium carbonate, sodium methoxide, preferably the basic reagent is sodium hydride; The solvent is N,N-dimethylformamide, dichloromethane, tetrahydrofuran or acetonitrile, preferably: the solvent is N,N-dimethylformamide; The molar ratio of compound H-3, silicon protecting group donor, and basic reagent is 1 - 3:1 - 3:1 - 3; The reaction temperature is 0 - 40 °C, preferably the temperature is 20 - 40 °C; the reaction time is 1 - 8 h; preferably the reaction time is 2 - 3 h.

5. The method according to claim 2, wherein In step 3), the solvent is methanol, N,N-dimethylformamide, tetrahydrofuran, 1,4-dioxane, water or toluene, preferably the selected solvent is 1,4-dioxane; A palladium catalyst is added during the reaction, and the palladium catalyst is palladium acetate, dichlorobis(η5-cyclopentadienyl)iron(II)palladium(II), palladium(III) triphenylphosphine, dichlorobis(triphenylphosphine)palladium(II), tris(dibenzylideneacetone)dipalladium(0), preferably tris(dibenzylideneacetone)dipalladium(0); A ligand is added during the reaction, and the ligand is triphenylphosphine, dibenzyldimethylphosphine, ferrocenediphenylphosphine, derivatives of ferrocenediphenylphosphine, tris(2-pyridyl)phosphine, tetrakis(triphenylphosphine)palladium(0), 3-amino-4-(2-pyridyl)benzoic acid, 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl, preferably 2-dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl; During the reaction, a basic reagent needs to be added. The basic reagent is potassium carbonate, sodium carbonate, cesium carbonate, potassium phosphate, sodium phosphate, potassium acetate, sodium acetate, potassium hydroxide, sodium hydroxide or potassium tert-butoxide. Preferably, the basic reagent is cesium carbonate; Among them, the molar ratio of compound H-2, compound H-4, basic reagent, ligand, and palladium catalyst is 0.5-1.5:0.5-1.5:1-3:0.05-0.25:0.01-0.1; The reaction is protected by an inert gas; the reaction temperature is 70°C - 150°C; the reaction time is 4-12 h; preferably, the reaction temperature is 100-110°C, and the reaction time is 8-10 h.

6. The method according to claim 2, wherein In step 4), the reaction conditions are as follows: the desilylation reagent is at least one of tetrabutylammonium fluoride, acetic acid tetrahydrofuran solution, sodium hydroxide ethanol solution, potassium hydroxide methanol solution, and pyridine hydrogen fluoride complex. Preferably, the desilylation reagent is tetrabutylammonium fluoride; The solvent is dichloromethane, tetrahydrofuran, N,N-dimethylformamide. Preferably, the solvent is tetrahydrofuran; Among them, the molar ratio of compound H-5 to the desilylation reagent is 1:1-5. The reaction temperature is 0-40°C. Preferably, the reaction temperature is 20-40°C; the reaction time is 1-5 h. Preferably, the reaction time is 1-3 h.

7. The method according to claim 2, characterized in that, In step 5), the mesyl group donor during the reaction is methanesulfonyl chloride, methanesulfonic anhydride. Preferably, the mesyl group donor is methanesulfonyl chloride; The basic reagent is triethylamine or N,N-diisopropylethylamine. Preferably, the mesyl group donor is triethylamine; The solvent is dichloromethane, tetrahydrofuran, dimethyl sulfoxide or N,N-dimethylformamide. Preferably, the selected solvent is dichloromethane; Among them, the molar ratio of compound H-6, mesyl group donor, and basic reagent is 1:1-5:3-8. The reaction temperature is 0-40°C, and the reaction time is 1-8 h; preferably, the reaction time is 8. The method according to claim 2, wherein ​ ​ ​ ​ ​

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