Synthesis method of ceftaroline fosamil polymer impurity U4

Abstract

The invention relates to the technical field of chemical synthesis, in particular to a synthesis method of a ceftaroline fosamil polymer impurity U4. The synthesis method comprises the following steps: dissolving 4-(2-(((6R, 7R)-7-amino-2-carboxyl-8-oxo-5-thia-1-azabicyclo [4.2. 0] oct-2-ene-3-yl) thio) thiazole-4-yl)-1-methylpyridine-1-onium chloride hydrochloride into a solvent A, and adding a condensing agent, so as to obtain a mixture C; dissolving (Z)-2-(5-((dichlorophosphoryl) amino)-1, 2, 4-thiadiazole-3-yl)-2-(ethyoxyl imino) acetyl chloride into a solvent D, adding into the mixture C, and sequentially adding alkali and water to react, so as to obtain sodium salt of a polymer impurity U4; and dissolving in water, adjusting the pH value to be acidic, and separating out a solid, thereby obtaining the product. The method has the advantages of high purity and high yield.

Description

Technical Field

[0001] The invention relates to the technical field of chemical synthesis, and in particular to a method for synthesizing a ceftaroline fosamil polymer impurity U4. Background Art

[0002] The chemical name of ceftaroline fosamil is (6R,7R)-7-{(2Z)-2-(ethoxyimino)-2-[5-(phosphoramido)-1,2,4-thiadiazol-3-yl]acetamido}-3-{[4-(1-methyl-4-pyridinyl)-1,3-thiazol-2-yl]thio}-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid acetate monohydrate, with a CAS number of 866021-48-9. The drug was developed by Takeda Pharmaceutical of Japan and approved by the FDA for marketing on October 29, 2010 after Forest Laboratories of the United States obtained market authorization. It is mainly used to treat community-acquired cellular pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI), including infections caused by methicillin-resistant Staphylococcus aureus (MRSA).

[0003] Impurities in medicines are substances that have no medicinal effects in the medicines, and impurities will affect the stability and safety of the medicines. Since impurities have no therapeutic effects and may even be harmful to human health, they must be strictly controlled.

[0004] U.S. Patent Publication No. US2011 / 0152311 A1 discloses a polymer impurity U4 of ceftaroline fosamil, the structural formula of which is as follows:

[0005]

[0006] Ceftaroline fosamil polymer impurity U4 (CAS: 1286218-68-5) is a dimer impurity of ceftaroline fosamil. The polymer impurity is very likely to cause allergic reactions and threaten the life and health of patients during clinical medication. Therefore, it is very important to obtain a reference substance for this impurity. Ceftaroline fosamil polymer impurity U4 is the main impurity in the production and storage of ceftaroline fosamil. This impurity is difficult to remove. However, due to the poor stability of the antibiotic itself, it is easy to decompose. The impurity U4 present in a small amount in the reaction solution is difficult to separate, and the purity is very low and the quality is poor, so it cannot be used as a reference substance.

[0007] There is currently no report on the synthesis of ceftaroline fosamil polymer impurity U4.

[0008] Therefore, it is very necessary to develop a synthesis method of ceftaroline fosamil polymer impurity U4 that can solve the above technical problems. Summary of the invention

[0009] The purpose of the present invention is to overcome the deficiencies of the prior art and provide a method for synthesizing ceftaroline fosamil polymer impurity U4 with higher purity and yield.

[0010] The present invention is achieved through the following technical solutions:

[0011] A method for synthesizing ceftaroline fosamil polymer impurity U4 comprises the following steps:

[0012] (1) dissolving compound 1 in solvent A to obtain a mixture B; the compound 1 is 4-(2-(((6R,7R)-7-amino-2-carboxyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride;

[0013] (2) adding a condensing agent to mixture B to obtain mixture C;

[0014] (3) Compound 2 is dissolved in solvent D and added to mixture C to obtain mixture E; the compound 2 is (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride;

[0015] (4) adding alkali and water to the mixture E in sequence for reaction, filtering, and obtaining the sodium salt of the polymer impurity U4;

[0016] (5) The sodium salt of polymer impurity U4 is dissolved in water, the pH is adjusted to be acidic, and a solid is precipitated to obtain.

[0017] Preferably, the molar ratio of compound 1 to compound 2 is 1:1-5; the molar ratio of compound 1 to the condensing agent is 1:0.5-10; and the molar ratio of compound 1 to the base is 1:2-40.

[0018] More preferably, the molar ratio of compound 1 to compound 2 is 1:1-2; the molar ratio of compound 1 to the condensing agent is 1:2-4; and the molar ratio of compound 1 to the base is 1:5-10.

[0019] Preferably, the solvent A in step (1) comprises at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0020] More preferably, the solvent A comprises a mixed solvent of acetonitrile and N,N-dimethylacetamide.

[0021] More preferably, the volume ratio of acetonitrile to N,N-dimethylacetamide is 100:1-5:1.

[0022] More preferably, the volume ratio of acetonitrile to N,N-dimethylacetamide is 10:1-5:1.

[0023] Preferably, the temperature of the mixture B is 15-25°C.

[0024] Preferably, the condensing agent in step (2) includes at least one of N,O-bis(trimethylsilyl)acetamide (BSA), N,N'-bis(trimethylsilyl)urea (BSU), and N-methyl-N-(trimethylsilyl)acetamide (MSA). N,O-bis(trimethylsilyl)acetamide is further preferred.

[0025] Preferably, after adding the condensing agent in step (2), the temperature is controlled at 0-50° C. and stirred for 0.5-5 h.

[0026] More preferably, after adding the condensing agent in step (2), the temperature is controlled at 15-25° C. and stirred for 1-3 h.

[0027] Preferably, the solvent D in step (3) is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.

[0028] Preferably, after adding the mixture C in step (3), the temperature is controlled at -10 to 20°C and stirred for 10 min to 3 h.

[0029] More preferably, after adding into mixture C in step (3), the temperature is controlled at -5 to 5°C and stirred for 0.5 to 1.5 h.

[0030] The temperature of the mixture C in step (3) is not particularly limited, as long as it can dissolve the material.

[0031] Preferably, the base in step (4) comprises at least one of sodium acetate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate and dipotassium hydrogen phosphate.

[0032] Preferably, the reaction temperature in step (4) is -5 to 5°C, the reaction time after adding the base is 2 to 4 hours, and the reaction time after adding water is 10 to 20 hours.

[0033] Preferably, step (4) further comprises washing the solid obtained after filtration, dissolving it with water, adding acetone to precipitate the solid, cooling it to -5 to 5°C and stirring it for 1 to 3 hours, filtering it, washing the obtained solid with acetone, and purifying it with a chromatographic column to obtain the sodium salt of the polymer impurity U4.

[0034] Preferably, in step (5), after the sodium salt of the polymer impurity U4 is dissolved in water, the temperature is adjusted to 0-10°C.

[0035] Preferably, in step (5), the pH is adjusted to 0.5-1.0.

[0036] Preferably, step (5) further comprises filtering the precipitated solid, washing it with water, and drying it in an inert atmosphere to obtain the product. The inert atmosphere includes but is not limited to nitrogen, argon, etc.

[0037] The beneficial effects of the present invention are:

[0038] The invention provides a method for synthesizing a ceftaroline fosamil polymer impurity U4. By screening reaction reagents and reaction parameters thereof, the prepared impurity U4 has high yield and purity. BRIEF DESCRIPTION OF THE DRAWINGS

[0039] Figure 1 This is the mass spectrum of the impurity U4 of the ceftaroline fosamil polymer in Example 1.

[0040] Figure 2 Example 1 Cefuroxime polymer impurity U4 1 H-NMR spectrum. DETAILED DESCRIPTION

[0041] The present invention will be further described below in conjunction with specific embodiments, and the advantages and features of the present invention will become clearer as the description proceeds. However, these embodiments are exemplary only and do not constitute any limitation to the scope of the present invention. It should be understood by those skilled in the art that the details and forms of the technical solution of the present invention may be modified or replaced without departing from the spirit and scope of the present invention, but these modifications and replacements all fall within the scope of protection of the present invention.

[0042] Example 1

[0043] (1) Preparation of sodium salt of ceftaroline fosamil polymer impurity U4: At 20°C, 5 g of 4-(2-(((6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride was dissolved in a mixed solvent of 50 mL of acetonitrile and 10 mL of N,N-dimethylacetamide, the temperature was controlled at 20°C, 6.4 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, and the temperature was controlled at 20°C and stirred for 2 h. The temperature was lowered to 0°C, and a solution of 4.4 g of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride in 50 mL of acetonitrile was added dropwise, and the mixture was stirred for 1 h after the addition was completed. Then the temperature was controlled at 0°C, 6.0 g of sodium acetate solid was added in batches, stirred at 0°C for 3 h, then 0.8 g of water was added dropwise, reacted at 0°C for 15 h, filtered, the solid was washed with 2 mL of water, the crude solid was dissolved with 100 mL of water, then 200 mL of acetone was added dropwise to precipitate the solid, the temperature was lowered to 0°C and stirred for 2 h, filtered, and the solid was washed with 5 mL of acetone to obtain a crude sodium salt of ceftaroline fosamil polymer impurity U4, which was then separated and purified by column chromatography to obtain a sodium salt product of ceftaroline fosamil polymer impurity U4 (chromatographic column: C18, 250 mm×20 mm, 10 μm; mobile phase: 0.1% formic acid: methanol = 75:25 (0 min), 0.1% formic acid: methanol = 15:85 (18.0 min), 0.1% formic acid: methanol = 75:25 (20.0-23.0 min); flow rate: 20 mL / min; wavelength: 245 nm).

[0044] (2) Preparation of Ceftaroline Fosamil Polymer Impurity U4: The sodium salt of the Ceftaroline Fosamil Polymer Impurity U4 was dissolved in 50 mL of water, the temperature was controlled at 5° C., 3.6 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 0.8, a solid was precipitated, and the solid was filtered and washed with 2 mL of water to obtain Ceftaroline Fosamil Polymer Impurity U4. The wet product was dried in a nitrogen stream for 24 h to obtain 5.4 g of Ceftaroline Fosamil Polymer Impurity U4, with a yield of 76% and a purity of 96.1%.

[0045] MS (m / z, C 44 H 40 N 16 O 15 P2S8):[(M+2) / 2] + =676.1; Exp: 1350.0. The mass spectrum of the ceftaroline fosamil polymer impurity U4 is shown in Figure 1 shown.

[0046] 1H NMR (400 MHz, DMSO-d6) δ9.14 (dt, J = 8.4, 0.7 Hz, 4H), 8.32 (d, J = 8.5 Hz, 4H), 7.66 (s, 2H), 5.65 (d, J = 6.7 Hz, 2H), 5.17 (d, J = 6.7 Hz, 2H), 4.42-4.38 (m, 6H), 4.12 (p, J = 6.4 Hz, 4H), 3.85 (s, 2H), 1.29 (t, J = 6.4 Hz, 6H). The nuclear magnetic resonance (NMR) hydrogen spectrum of the ceftaroline fosamil polymer impurity U4 is shown in Figure 2 shown.

[0047] The reaction route is as follows:

[0048]

[0049] Example 2

[0050] The only difference from Example 1 is that the composition of solvent A (mixed solvent of acetonitrile and N,N-dimethylacetamide) is replaced, the total volume remains unchanged, and the other conditions are the same, as follows:

[0051]

[0052]

[0053] Example 3

[0054] The only difference from Example 1 is that the type of condensing agent is replaced, and the other conditions are the same, as follows:

[0055]

[0056] Example 4

[0057] The only difference from Example 1 is that the type of alkali (sodium acetate) is replaced, and the other conditions are the same, as follows:

[0058]

[0059] Example 5

[0060] (1) Preparation of sodium salt of ceftaroline fosamil polymer impurity U4: 5 g of 4-(2-(((6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride was dissolved in a mixed solvent of 54.5 mL of acetonitrile and 5.5 mL of N,N-dimethylacetamide at 15° C. The temperature was controlled at 15° C., 4.2 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, and the temperature was controlled at 15° C. and stirred for 3 h. The temperature was lowered to 5°C, and a solution of 3.7 g of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride in 50 mL of tetrahydrofuran was added dropwise. After the addition was complete, the mixture was stirred for 1.5 h. Then the temperature was controlled at 5°C, 4.3 g of sodium acetate solid was added in batches, stirred at 5°C for 4 h, then 0.8 g of water was added dropwise, reacted at 0°C for 20 h, filtered, the solid was washed with 2 mL of water, the crude solid was dissolved with 100 mL of water, then 200 mL of acetone was added dropwise to precipitate the solid, the temperature was lowered to 5°C and stirred for 3 h, filtered, and the solid was washed with 10 mL of acetone to obtain a crude sodium salt of ceftaroline fosamil polymer impurity U4, which was then separated and purified by column chromatography to obtain a sodium salt product of ceftaroline fosamil polymer impurity U4 (chromatographic column: C18, 250 mm×20 mm, 10 μm; mobile phase: 0.1% formic acid: methanol = 75:25 (0 min), 0.1% formic acid: methanol = 15:85 (18.0 min), 0.1% formic acid: methanol = 75:25 (20.0-23.0 min); flow rate: 20 mL / min; wavelength: 245 nm).

[0061] (2) Preparation of Ceftaroline Fosamil Polymer Impurity U4: The sodium salt of the above-mentioned Ceftaroline Fosamil Impurity U4 was dissolved in 50 mL of water, the temperature was controlled at 10° C., 4.6 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 0.5, a solid was precipitated, and the solid was filtered and washed with 2 mL of water to obtain Ceftaroline Fosamil Polymer Impurity U4. The wet product was dried in a nitrogen stream for 24 h to obtain 5.1 g of Ceftaroline Fosamil Polymer Impurity U4, with a yield of 73% and a purity of 95.6%.

[0062] Example 6

[0063] (1) Preparation of sodium salt of ceftaroline fosamil polymer impurity U4: 5 g of 4-(2-(((6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride was dissolved in a mixed solvent of 54.5 mL of acetonitrile and 5.5 mL of N,N-dimethylacetamide at 25° C. The temperature was controlled at 25° C., 8.7 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, and the temperature was controlled at 25° C. and stirred for 1 h. The temperature was lowered to -5°C, and a solution of 7.3 g of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride in 50 mL of ethyl acetate was added dropwise. After the addition was complete, the mixture was stirred for 0.5 h. Then the temperature was controlled at -5°C, 8.6 g of sodium acetate solid was added in batches, the mixture was stirred at -5°C for 2 h, and then 0.8 g of water was added dropwise, the mixture was reacted at -5°C for 10 h, filtered, the solid was washed with 2 mL of water, the crude solid was dissolved with 100 mL of water, and then 200 mL of acetone was added dropwise to precipitate the solid, the temperature was lowered to -5°C and stirred for 1 h, filtered, and the solid was washed with 10 mL of acetone to obtain a crude sodium salt of ceftaroline fosamil polymer impurity U4, which was then separated and purified by column chromatography to obtain a sodium salt product of ceftaroline fosamil polymer impurity U4 (chromatographic column: C18, 250 mm×20 mm, 10 μm; mobile phase: 0.1% formic acid: methanol = 75:25 (0 min), 0.1% formic acid: methanol = 15:85 (18.0 min), 0.1% formic acid: methanol = 75:25 (20.0-23.0 min); flow rate: 20 mL / min; wavelength: 245 nm).

[0064] (2) Preparation of Ceftaroline Fosamil Polymer Impurity U4: The sodium salt of the Ceftaroline Fosamil Polymer Impurity U4 was dissolved in 50 mL of water, the temperature was controlled at 0°C, 3.3 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 1.0, a solid was precipitated, and the solid was filtered and washed with 2 mL of water to obtain Ceftaroline Fosamil Polymer Impurity U4. The wet product was dried in a helium stream for 12 h to obtain 5.0 g of Ceftaroline Fosamil Polymer Impurity U4 (4.4 g), with a yield of 71% and a purity of 94.5%.

[0065] Example 7

[0066] (1) Preparation of sodium salt of ceftaroline fosamil polymer impurity U4: 5 g of 4-(2-(((6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride was dissolved in a mixed solvent of 55 mL of acetonitrile and 0.5 mL of N,N-dimethylacetamide at 0°C, and 21.2 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise at 0°C. The mixture was stirred at 0°C for 5 h. The mixture was cooled to -10°C, and a solution of 18.3 g of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride in 50 mL of acetonitrile was added dropwise. After the addition was complete, the mixture was stirred for 3 h. Then the temperature was controlled at 0°C, 34.2 g of sodium acetate solid was added in batches, stirred at 0°C for 4 h, then 4.0 g of water was added dropwise, reacted at 0°C for 20 h, filtered, the solid was washed with 2 mL of water, the crude solid was dissolved with 100 mL of water, then 200 mL of acetone was added dropwise to precipitate the solid, the temperature was lowered to 0°C and stirred for 3 h, filtered, and the solid was washed with 10 mL of acetone to obtain a crude sodium salt of ceftaroline fosamil polymer impurity U4, which was then separated and purified by column chromatography to obtain a sodium salt product of ceftaroline fosamil polymer impurity U4 (chromatographic column: C18, 250 mm×20 mm, 10 μm; mobile phase: 0.1% formic acid: methanol = 75:25 (0 min), 0.1% formic acid: methanol = 15:85 (18.0 min), 0.1% formic acid: methanol = 75:25 (20.0-23.0 min); flow rate: 20 mL / min; wavelength: 245 nm).

[0067] (2) Preparation of Ceftaroline Fosamil Polymer Impurity U4: The sodium salt of the above-mentioned Ceftaroline Fosamil Impurity U4 was dissolved in 50 mL of water, the temperature was controlled at 5° C., 3.8 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 0.8, a solid was precipitated, and the solid was filtered and washed with 2 mL of water to obtain Ceftaroline Fosamil Polymer Impurity U4. The wet product was dried in a nitrogen stream for 24 h to obtain 4.3 g of Ceftaroline Fosamil Polymer Impurity U4, with a yield of 61% and a purity of 94.6%.

[0068] Example 8

[0069] (1) Preparation of sodium salt of ceftaroline fosamil polymer impurity U4: 5 g of 4-(2-(((6R,7R)-7-amino-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride was dissolved in a mixed solvent of 55 mL of acetonitrile and 5 mL of N,N-dimethylacetamide at 50°C, and the temperature was controlled at 50°C. 1.1 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, and the temperature was controlled at 50°C and stirred for 0.5 h. The temperature was lowered to 20°C, and a solution of 3.7 g of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride in 50 mL of acetonitrile was added dropwise. After the addition was completed, the mixture was stirred for 10 min. Then the temperature was controlled at 0°C, 1.7 g of sodium acetate solid was added in batches, stirred at 0°C for 2 h, then 0.2 g of water was added dropwise, reacted at 0°C for 10 h, filtered, the solid was washed with 2 mL of water, the crude solid was dissolved with 100 mL of water, then 200 mL of acetone was added dropwise to precipitate the solid, the temperature was lowered to 0°C and stirred for 2 h, filtered, and the solid was washed with 10 mL of acetone to obtain a crude sodium salt of ceftaroline fosamil polymer impurity U4, which was then separated and purified by column chromatography to obtain a sodium salt product of ceftaroline fosamil polymer impurity U4 (chromatographic column: C18, 250 mm×20 mm, 10 μm; mobile phase: 0.1% formic acid: methanol = 75:25 (0 min), 0.1% formic acid: methanol = 15:85 (18.0 min), 0.1% formic acid: methanol = 75:25 (20.0-23.0 min); flow rate: 20 mL / min; wavelength: 245 nm).

[0070] (2) Preparation of Ceftaroline Fosamil Polymer Impurity U4: The sodium salt of the Ceftaroline Fosamil Polymer Impurity U4 was dissolved in 50 mL of water, the temperature was controlled at 0° C., 3.1 mL of concentrated hydrochloric acid was added dropwise to adjust the pH to 1.0, a solid was precipitated, and the solid was filtered and washed with 2 mL of water to obtain Ceftaroline Fosamil Polymer Impurity U4. The wet product was dried in a nitrogen stream for 12 h to obtain 3.7 g of Ceftaroline Fosamil Polymer Impurity U4, with a yield of 56% and a purity of 94.5%.

[0071] The above detailed description is a specific description of one feasible embodiment of the present invention. The embodiment is not intended to limit the patent scope of the present invention. Any equivalent implementation or modification that does not deviate from the present invention should be included in the scope of the technical solution of the present invention.

Claims

1. A method for synthesizing ceftaroline fosamil polymer impurity U4, characterized in that: The steps include: (1) dissolving compound 1 in solvent A to obtain a mixture B; the compound 1 is 4-(2-(((6R,7R)-7-amino-2-carboxyl-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-en-3-yl)thio)thiazol-4-yl)-1-methylpyridin-1-ium chloride hydrochloride; (2) adding a condensing agent to mixture B to obtain mixture C; (3) Compound 2 is dissolved in solvent D and added to mixture C to obtain mixture E; the compound 2 is (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride; (4) adding alkali and water to the mixture E in sequence for reaction, filtering, and obtaining the sodium salt of the polymer impurity U4; (5) The sodium salt of polymer impurity U4 is dissolved in water, the pH is adjusted to be acidic, and a solid is precipitated to obtain.

2. The synthesis method according to claim 1, characterized in that In step (1), the solvent A comprises at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; and the temperature of the mixture B is 15-25°C.

3. The synthesis method according to claim 2, characterized in that The solvent A comprises a mixed solvent of acetonitrile and N,N-dimethylacetamide.

4. The synthesis method according to claim 3, characterized in that The volume ratio of acetonitrile to N,N-dimethylacetamide is 100:1-5:

1.

5. The synthesis method according to claim 4, characterized in that The volume ratio of acetonitrile to N,N-dimethylacetamide is 10:1-5:

1.

6. The synthesis method according to claim 1, characterized in that The condensing agent in step (2) includes at least one of N,O-bis(trimethylsilyl)acetamide, N,N'-bis(trimethylsilyl)urea, and N-methyl-N-(trimethylsilyl)acetamide; The solvent D in step (3) is at least one of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide; The base in step (4) includes at least one of sodium acetate, sodium carbonate, sodium bicarbonate, sodium hydroxide, sodium phosphate, disodium hydrogen phosphate, potassium carbonate, potassium bicarbonate, potassium hydroxide, potassium phosphate and dipotassium hydrogen phosphate; The reaction temperature in step (4) is -5 to 5°C, the reaction time after adding the base is 2 to 4 hours, and the reaction time after adding water is 10 to 20 hours; Step (4) further comprises washing the solid obtained after filtering, dissolving it with water, adding acetone to precipitate the solid, cooling it to -5 to 5°C, stirring it for 1 to 3 hours, filtering it, washing the obtained solid with acetone, and purifying it with a chromatographic column to obtain the sodium salt of the polymer impurity U4; After the sodium salt of the polymer impurity U4 in step (5) is dissolved in water, the temperature is adjusted to 0-10°C; In step (5), the pH is adjusted to 0.5-1.0; Step (5) further comprises filtering the precipitated solid, washing it with water, and drying it in an inert atmosphere to obtain the product.

7. The synthesis method according to claim 1, characterized in that The molar ratio of compound 1 to compound 2 is 1:1-5; the molar ratio of compound 1 to the condensing agent is 1:0.5-10; and the molar ratio of compound 1 to the base is 1:2-40.

8. The synthesis method according to claim 7, characterized in that The molar ratio of compound 1 to compound 2 is 1:1-2; the molar ratio of compound 1 to the condensing agent is 1:2-4; and the molar ratio of compound 1 to the base is 1:5-10.

9. The synthesis method according to claim 1, characterized in that After adding the condensing agent in step (2), the temperature is controlled at 0-50°C and stirred for 0.5-5h; After adding the mixture C in step (3), the temperature is controlled at -10 to 20°C and stirred for 10 min to 3 h.

10. The synthesis method according to claim 9, characterized in that After adding the condensing agent in step (2), the temperature is controlled at 15-25° C. and stirred for 1-3 hours; After adding the mixture C in step (3), the temperature is controlled at -5 to 5°C and stirred for 0.5h to 1.5h.

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