Synthesis method of upatinib and intermediate Up-3 thereof

Abstract

The invention belongs to the technical field of medicine synthesis, and particularly relates to a synthesis method of upatinib and an intermediate Up-3 thereof. The preparation method comprises the following steps: dissolving a compound Up-1 and a compound Up-2 in a solvent A, adding alkali 1, and reacting to obtain an intermediate Up-3; dissolving the intermediate Up-3 in a solvent B, adding an acid a, removing Boc protection and closing a ring to obtain an intermediate Up-6, and reacting under the action of an acid b to obtain a compound Up-14; the preparation method comprises the following steps: dissolving carbonyl diimidazole, trifluoroethylamine hydrochloride and alkali 2 in a solvent C, stirring, mixing with a compound Up-14 solution, reacting to obtain a compound Up-13, adding an alkali 3 solution, and removing Tos protecting groups to obtain upatinib. According to the method disclosed by the invention, the upatinib crude product is simply synthesized by taking Up-3 as a starting material through a two-pot method for the first time, the time of the whole process is saved, the total yield is relatively high, the purity of the obtained product is also relatively high, and the method is suitable for large-scale production.

Description

Technical Field

[0001] This invention belongs to the field of drug synthesis technology, specifically relating to a method for synthesizing utpatinib and its intermediate Up-3. Background Technology

[0002] Atopic dermatitis (AD) is a common chronic skin disease characterized by recurrent eczematous rashes and itching, and can occur in all age groups. Upadacitinib is a reversible ATP-competitive inhibitor with significantly higher selectivity for JAK1 than for JAK2, JAK3, or TYK2. Clinical trials have demonstrated its sustained efficacy over a 140-week treatment period, with good long-term safety, avoiding the adverse effects of AD on adolescent growth and development. The compound structure of upadacitinib is as follows: .

[0003] Chinese invention patent application CN108368121A discloses the following synthetic route for utpatinib: .

[0004] This invention uses Up-11 and Up-2 as starting materials, undergoes nucleophilic substitution under basic conditions with lithium tert-butoxide, followed by cyclization with trifluoroacetic anhydride, removal of the Tos protecting group under basic conditions, removal of the Cbz protecting group by palladium-catalyzed hydrogenation reduction, and finally addition of CDI and trifluoroethylamine to obtain utpatinib. The reaction materials... t BuOLi and Pd / C are relatively expensive, involve hydrogenation reactions which are quite dangerous, and require lengthy and cumbersome steps for amidation after hydrogenation, making them unsuitable for industrial production.

[0005] Chinese invention patent application CN115151529A alters the reaction sequence, and its synthetic route is as follows: .

[0006] This invention uses Up-1 as a starting material and nucleophilically substitutes it with Up-2 under alkaline conditions with sodium hydride. Following a ring-closure reaction, intermediate Up-6 is obtained. Then, concentrated hydrochloric acid is added to remove the Cbz protecting group, yielding intermediate Up-14. This intermediate is then condensed with trifluoroethylamine to generate intermediate Up-13. Finally, under alkaline conditions, the Tos protecting group is removed to obtain crude utpatinib. This route has a low yield (less than 20% overall) due to its cumbersome operation. While the use of concentrated hydrochloric acid to remove the Cbz group avoids the dangerous hydrogenation reaction, the first step uses the hazardous chemical sodium hydride, posing a certain safety hazard.

[0007] Therefore, there is still a need to optimize the process of utpatinib to make it more suitable for industrial production. Summary of the Invention

[0008] To address the shortcomings of existing technologies, this invention provides a method for synthesizing utpatinib and its intermediate Up-3. This method has a simple process route, low cost, and is suitable for industrial production.

[0009] To achieve the above-mentioned objectives of this invention, the specific technical solution adopted by this invention is as follows: This invention first provides a method for synthesizing Up-3, an intermediate of utpatinib, comprising the following steps: Compounds Up-1 and Up-2 were dissolved in solvent A, and base 1 was added. The reaction yielded intermediate Up-3. The synthetic route is as follows: .

[0010] Preferably, solvent A is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and acetone, and is more preferably N,N-dimethylformamide.

[0011] Preferably, the alkali 1 is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, DIPEA and DMAP, and is preferably sodium hydroxide.

[0012] Preferably, the mass ratio of compound Up-1 to compound Up-2 is 1:1-1.2, the mass ratio of solvent A to compound Up-1 is 4-6:1, and the molar ratio of base 1 to compound Up-1 is 1.5-2.5:1.

[0013] Preferably, the reaction temperature is -10~35℃, the reaction time is 3-5h, and the reaction also includes the steps of quenching the reaction, crystallization, filtration, washing and drying.

[0014] More preferably, the quenching reagent is glacial acetic acid, the temperature is raised to room temperature after quenching, the crystallization solvent is a mixed solution of anhydrous ethanol and water, and the crystallization time is 6-12 hours.

[0015] This invention also relates to a method for synthesizing utpatinib, which uses Up-3, an intermediate obtained by the above-described synthesis method, as a starting material and includes the following steps: (1) Intermediate Up-3 was dissolved in solvent B, acid a was added, Boc protection was removed and the ring was closed to obtain intermediate Up-6, which was then reacted under the action of acid b to obtain compound Up-14. The synthetic route is as follows: ; (2) Carbonyl diimidazole, trifluoroethylamine hydrochloride and base 2 were dissolved in solvent C, stirred and mixed with solution of compound Up-14 to react and give compound Up-13. Then, solution of base 3 was added to remove the Tos protecting group to give utpatinib. The synthetic route is as follows: .

[0016] Preferably, the solvent B in step (1) is selected from one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone and ethyl acetate, and is preferably acetonitrile.

[0017] Preferably, acid a is selected from one or more of glacial acetic acid, trifluoroacetic acid, trifluoroacetic anhydride, thionyl chloride, polyphosphoric acid and p-toluenesulfonic acid, and is preferably trifluoroacetic anhydride.

[0018] Preferably, acid b is selected from one or more of concentrated hydrochloric acid, hydrobromic acid, and concentrated sulfuric acid, and is preferably hydrobromic acid.

[0019] Preferably, in step (1), the mass ratio of intermediate Up-3 to solvent B is 1:4-6, and the molar ratio of acid a to intermediate Up-3 is 3-4.5:1.

[0020] Preferably, the conditions for de-Boc protection and ring closure in step (1) include: heating to 70-80℃ and stirring under reflux for 2.5-3.5h; after de-Boc protection and ring closure, the step further includes removing solvent B by vacuum distillation.

[0021] Preferably, in step (1), the molar ratio of acid b to intermediate Up-3 is 9-10:1, the mass concentration of acid b is 35%-45%, the reaction temperature is 70-85℃, and the reaction time is 4-5h.

[0022] Preferably, step (1) further includes cooling, extraction, adjusting the pH of the aqueous phase to 8-9, adding dichloromethane to extract the aqueous phase, separating the liquid, and concentrating the organic phase after the reaction.

[0023] Preferably, the alkali 2 and alkali 3 mentioned in step (2) are selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate, and are preferably sodium hydroxide.

[0024] Preferably, the solvent C is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane, and ethyl acetate.

[0025] Preferably, in step (2), the molar ratio of carbonyl diimidazole, trifluoroethylamine and base 2 is 1:1-1.2:1-1.5, the mass ratio of solvent C to carbonyl diimidazole is 7-10:1, the stirring temperature is 0-5℃, and the stirring time is 0.5-1.5h.

[0026] Preferably, the solvent of the Up-14 solution in step (2) is selected from one or more of water, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and ethyl acetate, and the molar ratio of Up-14 to carbonyl diimidazole is 0.4-0.6:1.

[0027] Preferably, the reaction temperature in step (2) is 25-35℃, the reaction time is 1.5-2.5h, and the reaction also includes the steps of separating the aqueous phase and washing the organic phase with saturated brine.

[0028] Preferably, the mass concentration of the alkali 3 solution in step (2) is 20%-30%, the pH is adjusted to 12-13 by adding alkali 3 solution, the temperature for removing the Tos protecting group is 30-55℃, and the time for removing the Tos protecting group is 2-3h; after removing the Tos protecting group, the steps also include separating the aqueous phase, washing the organic phase with saturated brine and concentrating it to dryness, pulping, filtration and drying.

[0029] Compared with the prior art, the present invention has the following beneficial effects: (1) In the synthesis of the key intermediate Up-3 of utpatinib, the present invention optimizes the reaction base compared with the traditional process, avoids the use of expensive bases such as sodium hydride and lithium tert-butoxide, and reduces material costs.

[0030] (2) In the process of synthesizing utpatinib, the present invention pioneered a simple two-pot method for synthesizing crude utpatinib using Up-3 as the starting material. The advantage of the first pot (step (1)) over the traditional process route is that it avoids the removal of intermediate Up-6, and the second pot (step (2)) avoids the removal of intermediate Up-13, which simplifies the operation process, avoids the problem of low yield caused by multiple separation and purification operations, and saves the time of the entire process. This method not only has a higher overall yield, but also a higher purity of the product, which is suitable for large-scale production. Attached Figure Description

[0031] Figure 1 It is compound Up-3 from Example 1. 1 H-NMR spectrum; Figure 2 This is the high-resolution mass spectrum of compound Up-3 from Example 1; Figure 3 It is compound Up-14 from Example 1. 1 H-NMR spectrum; Figure 4 This is the high-resolution mass spectrum of compound Up-14 from Example 1; Figure 5 It is utpatinib in Example 1 1 H-NMR spectrum; Figure 6 This is the high-resolution mass spectrum of utpatinib from Example 1. Detailed Implementation

[0032] The present invention will be further described in detail below with reference to specific embodiments. The following embodiments are not intended to limit the present invention, but only to illustrate the present invention. Unless otherwise specified, the experimental methods used in the following embodiments are generally performed under conventional conditions. Unless otherwise specified, the materials and reagents used in the following embodiments are commercially available.

[0033] Example 1 The synthesis method of Up-3, an intermediate of utpatinib, is as follows:

[0034] Up-1 (80.0 g, 0.206 mol) and Up-2 (80.8 g, 0.228 mol) were added to a 2000 mL four-necked flask. 320.0 g of N,N-dimethylformamide was added to dissolve the mixture. The system temperature was maintained at 0 °C. Sodium hydroxide (16.0 g, 0.4 mol) was slowly added. After the addition was complete, 80.0 g of N,N-dimethylformamide was added for rinsing. The mixture was stirred at 200 rpm for 3 hours. After the reaction was completed under HPLC monitoring, glacial acetic acid (25.2 g, 0.42 mol) was added to quench the reaction. The system temperature was raised to room temperature. 600.0 g of anhydrous ethanol and 200.0 g of water were added. The mixture was stirred at 300 rpm for 12 hours to induce crystallization. The crystals were filtered, and the filter cake was rinsed with a small amount of anhydrous ethanol and dried to obtain 113.1 g of white Up-3 solid. The yield was 83.0%, and the purity was 99.845% according to HPLC analysis.

[0035] intermediate Up-3 1 The H-NMR spectrum and high-resolution mass spectrum are shown below. Figure 1 and Figure 2 High-resolution mass spectrum of intermediate Up-3, HRMS-ESI (m / z) theoretical value calculated C 34 H 40 N5O7S [M+H] + The value was 662.2648, but the actual value found was 662.2652.

[0036] The synthesis method of utpatinib is as follows: (1) Synthesis of compound Up-14

[0037] Up-3 (20.0 g, 30.2 mmol) was added to a 500 mL four-necked flask and dissolved in 100.0 g acetonitrile. Trifluoroacetic anhydride (25.2 g, 120 mmol) was slowly added dropwise while stirring at 200 rpm. The mixture was heated to 70 °C and refluxed at 200 rpm for 3 hours with stirring. Acetonitrile was removed by vacuum distillation. Hydrobromic acid (57.8 g, 285.8 mmol, with a mass concentration of 40.0%) was added while stirring at 200 rpm. The mixture was heated to 80 °C and reacted for 4 hours. After the reaction was completed by HPLC monitoring, the system temperature was lowered to room temperature. 100.0 g water and 60.0 g ethyl acetate were added for extraction. The organic phase was removed by separation. The aqueous phase was slowly adjusted to pH 8-9 by adding 10% sodium hydroxide aqueous solution. Dichloromethane was then added to extract the aqueous phase. The organic phase obtained by separation was concentrated to dryness to give 8.78 g of Up-14 pale yellow solid, yield: 71.0%.

[0038] Compound Up-14 1 The H-NMR spectrum and high-resolution mass spectrum are shown below. Figure 3 and Figure 4 High-resolution mass spectrum of compound Up-14, calculated C from theoretical HRMS-ESI (m / z) values. 21 H 24 N5O2S [M+H] + The value was 410.1651, but 410.1656 was actually found.

[0039] (2) Synthesis of utpatinib

[0040] Carbonyl diimidazole (CDI) (6.3 g, 39.0 mmol) and anhydrous potassium carbonate (5.5 g, 39.8 mmol) were added to a 250 mL single-necked flask. 50.0 g of 2-methyltetrahydrofuran was added and stirred. The mixture was cooled to 0 °C and 2,2,2-trifluoroethylamine hydrochloride (5.3 g, 39.1 mmol) was added. The mixture was then heated to room temperature and stirred at 200 rpm for 1 hour to obtain a suspension.

[0041] In another 250 mL four-necked flask, intermediate Up-14 (8.0 g, 19.6 mmol) was added, followed by 25.0 g of 2-methyltetrahydrofuran, which was stirred and dissolved. The suspension was then added dropwise. After the addition was complete, 25 mL of water was added and the mixture was stirred at 200 rpm for 2 hours at room temperature. After the reaction was completed under HPLC monitoring, the aqueous phase was separated and the organic phase was washed with saturated brine. The pH was then adjusted to 12 with 20% sodium hydroxide solution, and the mixture was heated to 50 °C for 2 hours. After the reaction was completed under HPLC monitoring, the aqueous phase was separated and the organic phase was washed with saturated brine and concentrated to dryness. The mixture was then stirred with 15 mL of ethyl acetate and 90 mL of n-heptane at 300 rpm for 0.5 hours, filtered, and dried to obtain 6.8 g of utpatinib-like white solid, with a yield of 91.3% and a purity of 99.281% as determined by HPLC.

[0042] Upatinib 1 The H-NMR spectrum and high-resolution mass spectrum are shown below. Figure 5 and Figure 6 High-resolution mass spectrum of utpatinib, HRMS-ESI (m / z) theoretical value calculated C 17 H 20 F3N6O [M+H] + The value was 381.1651, but the actual value found was 381.1660.

[0043] Example 2 The synthesis method of Up-3, an intermediate of utpatinib, is as follows: Up-1 (80.0 g, 0.206 mol) and Up-2 (80.8 g, 0.228 mol) were added to a 2000 mL four-necked flask. 320.0 g of N,N-dimethylformamide was added to dissolve the mixture. The system temperature was controlled at -5 °C. Potassium tert-butoxide (44.9 g, 0.4 mol) was slowly added. After the addition was complete, 80.0 g of N,N-dimethylformamide was added for rinsing. The mixture was stirred at 200 rpm for 4 hours. After the reaction was completed by HPLC monitoring, glacial acetic acid (25.2 g, 0.42 mol) was added to quench the reaction. The system temperature was raised to room temperature, and 300.0 g of anhydrous ethanol and 300 g of water were added. The mixture was stirred at 300 rpm for 12 hours to induce crystallization. The crystals were filtered, and the filter cake was rinsed with a small amount of anhydrous ethanol and dried to obtain 105.9 g of white Up-3 solid. The yield was 77.7%, and the purity was 99.287% according to HPLC analysis.

[0044] The synthesis method of utpatinib is as follows: (1) Synthesis of compound Up-14 Up-3 (20.0 g, 30.2 mmol) was added to a 500 mL four-necked flask and dissolved in 100.0 g acetonitrile. Trifluoroacetic anhydride (25.2 g, 120 mmol) was slowly added dropwise with stirring. The mixture was heated to 70 °C and refluxed with stirring for 3 hours. Acetonitrile was removed by vacuum distillation. Hydrogen bromide glacial acetic acid solution (60.9 g, 285.8 mmol, with a mass concentration of 38.0%) was added with stirring at 200 r / min. The mixture was heated to 82 °C and reacted for 4 hours. After the reaction was completed by HPLC monitoring, the system temperature was lowered to room temperature. 100.0 g water and 60.0 g ethyl acetate were added for extraction. The organic phase was removed by separation. Sodium carbonate aqueous solution was slowly added to the aqueous phase to adjust the pH to 8. Dichloromethane was then added to extract the aqueous phase. The organic phase obtained by separation was concentrated to dryness to give 9.58 g of Up-14 pale yellow solid, yield: 77.5%.

[0045] (2) Synthesis of utpatinib 2,2,2-trifluoroethylamine hydrochloride (5.3 g, 39.1 mmol) and anhydrous potassium carbonate (5.5 g, 39.8 mmol) were added to a 250 mL single-necked flask. 50.0 g of 2-methyltetrahydrofuran was added and stirred. The temperature was controlled at -5 °C. CDI (6.3 g, 39.0 mmol) was added. After the addition was complete, the temperature was raised to 30 °C and stirred at 200 r / min for 1 hour to obtain a suspension.

[0046] In another 250 mL four-necked flask, intermediate Up-14 (8.0 g, 19.6 mmol) was added, along with 25.0 g of 2-methyltetrahydrofuran and 25 mL of water. The mixture was stirred and dissolved. The suspension was then added dropwise, and the mixture was stirred at 200 rpm for 1 hour at room temperature. After the reaction was completed under HPLC monitoring, the aqueous phase was removed by separation. The organic phase was washed with saturated brine, and the pH was adjusted to 12 with 30% sodium hydroxide solution. The mixture was heated to 50 °C and reacted for 2 hours. After the reaction was completed under HPLC monitoring, the aqueous phase was removed by separation, and the organic phase was washed with saturated brine and concentrated to dryness. The crude solid obtained was dissolved in 15 mL of ethyl acetate, and 100 mL of n-heptane was added dropwise at 300 rpm for 1 hour while maintaining the temperature at 5 °C. After filtration and drying, 6.9 g of Up-15, a white solid, was obtained, with a yield of 92.8% and a purity of 99.129% as determined by HPLC.

[0047] Comparative Example 1 The only difference between this comparative example and Example 1 is that the reaction time in the synthesis of the utpatinib intermediate Up-3 was extended to 5.5 hours, and the yield of the final compound Up-3 was 55.6%.

[0048] The experimental data from Example 1 and Comparative Example 1 show that during the preparation of the utpatinib intermediate Up-3, a prolonged reaction time leads to a significant decrease in the yield of the final product. This is because a prolonged reaction time results in the removal of Boc and Tos from Up-1, thus affecting the yield.

[0049] Comparative Example 2 The only difference between this comparative example and Example 1 is that the amount of solvent N,N-dimethylformamide was reduced to 280.0 g during the synthesis of the utpatinib intermediate Up-3, and the final yield of compound Up-3 was 64.9%.

[0050] The experimental data from Example 1 and Comparative Example 2 show that reducing the amount of solvent during the preparation of Up-3, an intermediate of utpatinib, leads to a significant decrease in the yield of the final product. The possible reason is that, for the same reaction time, reducing the amount of solvent results in slow dissolution of the raw material, ultimately leading to a large amount of raw material remaining and thus a decrease in yield.

[0051] Comparative Example 3 The only difference between this comparative example and Example 1 is that, in the process of synthesizing the utpatinib intermediate Up-14, after the addition of trifluoroacetic anhydride, the temperature of the reaction system was raised to 85°C, and the final yield of the compound Up-14 was 47.2%.

[0052] The experimental data from Example 1 and Comparative Example 3 show that during the preparation of the utpatinib intermediate Up-14, an increase in reaction temperature leads to a significant decrease in the yield of the final product. This is because an increase in temperature generates a large number of byproducts: the amino group on Up-3 does not close after the Boc protecting group is removed, but reacts with trifluoroacetic anhydride, thus affecting the yield.

[0053] Comparative Example 4 The only difference between this comparative example and Example 1 is that the amount of anhydrous potassium carbonate added during the synthesis of utpatinib was reduced to (2.3 g, 20.0 mmol), and the final yield of the compound utpatinib was 51.0%.

[0054] The experimental data from Example 1 and Comparative Example 4 show that reducing the amount of anhydrous potassium carbonate used in the preparation of utpatinib leads to a significant decrease in the yield of the final product. This is because the role of anhydrous potassium carbonate in the reaction system is to adjust the pH to a weakly alkaline state so that trifluoroethylamine hydrochloride can be released. Reducing the amount of anhydrous potassium carbonate results in a large amount of trifluoroethylamine raw material remaining, thus affecting the yield.

[0055] The above detailed description is a specific description of one of the feasible embodiments of the present invention. This embodiment is not intended to limit the patent scope of the present invention. All equivalent implementations or modifications that do not depart from the present invention should be included within the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing Up-3, an intermediate of utpatinib, characterized in that, Includes the following steps: Compounds Up-1 and Up-2 were dissolved in solvent A, and base 1 was added. The reaction yielded intermediate Up-3. The synthetic route is as follows: 。 2. The synthesis method according to claim 1, characterized in that, Solvent A is selected from any one of N,N-dimethylformamide, N,N-dimethylacetamide, acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, and acetone, and base 1 is selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate, sodium carbonate, potassium tert-butoxide, sodium tert-butoxide, triethylamine, pyridine, DIPEA, and DMAP.

3. The synthesis method according to claim 2, characterized in that, The mass ratio of compound Up-1 to compound Up-2 is 1:1-1.2, the mass ratio of solvent A to compound Up-1 is 4-6:1, the molar ratio of base 1 to compound Up-1 is 1.5-2.5:1, the reaction temperature is -10~35℃, the reaction time is 3-5h, and the reaction also includes the steps of quenching reaction, crystallization, filtration, washing and drying.

4. A method for synthesizing utpatinib, characterized in that, Using the intermediate Up-3 obtained by the synthesis method according to any one of claims 1-3 as the starting material, the method includes the following steps: (1) Intermediate Up-3 was dissolved in solvent B, acid a was added, Boc protection was removed and the ring was closed to obtain intermediate Up-6, which was then reacted under the action of acid b to obtain compound Up-14. The synthetic route is as follows: ； (2) Carbonyl diimidazole, trifluoroethylamine hydrochloride and base 2 were dissolved in solvent C, stirred and mixed with solution of compound Up-14 to react and give compound Up-13. Then, solution of base 3 was added to remove the Tos protecting group to give utpatinib. The synthetic route is as follows: 。 5. The synthesis method according to claim 4, characterized in that, In step (1), solvent B is selected from one or more of acetonitrile, tetrahydrofuran, 2-methyltetrahydrofuran, acetone and ethyl acetate; acid a is selected from one or more of glacial acetic acid, trifluoroacetic acid, trifluoroacetic anhydride, thionyl chloride, polyphosphoric acid and p-toluenesulfonic acid; and acid b is selected from one or more of concentrated hydrochloric acid, hydrobromic acid and concentrated sulfuric acid.

6. The synthesis method according to claim 4, characterized in that, In step (1), the mass ratio of intermediate Up-3 to solvent B is 1:4-6, the molar ratio of acid a to intermediate Up-3 is 3-4.5:1, and the conditions for de-Boc protection and cyclization include: heating to 70-80℃ and stirring under reflux for 2.5-3.5h; after de-Boc protection and cyclization, the step of removing solvent B by vacuum distillation is also included.

7. The synthesis method according to claim 4, characterized in that, In step (1), the molar ratio of acid b to intermediate Up-3 is 9-10:1, the mass concentration of acid b is 35%-45%, the reaction temperature is 70-85℃, the reaction time is 4-5h, and the reaction also includes the steps of cooling, extraction, adjusting the pH of the aqueous phase to 8-9, adding dichloromethane to extract the aqueous phase, separating the liquid, and concentrating the organic phase.

8. The synthesis method according to claim 4, characterized in that, In step (2), both base 2 and base 3 are selected from one or more of sodium hydroxide, potassium hydroxide, potassium carbonate and sodium carbonate. Solvent C is selected from one or more of tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and ethyl acetate. The molar ratio of carbonyl diimidazole, trifluoroethylamine and base 2 is 1:1-1.2:1-1.

5. The mass ratio of solvent C to carbonyl diimidazole is 7-10:

1. The stirring temperature is 0-5℃ and the stirring time is 0.5-1.5h.

9. The synthesis method according to claim 4, characterized in that, The solvent of the Up-14 solution in step (2) is selected from one or more of water, tetrahydrofuran, 2-methyltetrahydrofuran, dichloromethane and ethyl acetate. The molar ratio of Up-14 to carbonyl diimidazole is 0.4-0.6:

1. The reaction temperature is 25-35℃ and the reaction time is 1.5-2.5h. After the reaction, the aqueous phase is removed by separation and the organic phase is washed with saturated brine.

10. The synthesis method according to claim 9, characterized in that, The mass concentration of the alkali 3 solution in step (2) is 20%-30%. The pH is adjusted to 12-13 by adding alkali 3 solution. The temperature for removing the Tos protecting group is 30-55℃, and the time for removing the Tos protecting group is 2-3h. After removing the Tos protecting group, the steps also include separating the aqueous phase, washing the organic phase with saturated brine and concentrating it to dryness, pulping, filtration and drying.

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