Synthesis method of ceftaroline fosamil diphosphate U2 impurity reference substance
Patent Information
- Application Number
- CN202411209129.3
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-08-30
- Publication Date
- 2025-01-14
AI Technical Summary
[0006]头孢洛林酯二磷酸U2杂质，属于头孢洛林酯的降解产物，在储存及生产过程中均会产生，为了有效控制头孢洛林酯二磷酸U2杂质在头孢洛林酯中的含量，获得该杂质的对照品是一项非常重要的工作，但是目前没有针对头孢洛林酯二磷酸U2杂质的合成研究报道
（1）本发明开发出了制备头孢洛林酯二磷酸U2杂质对照品的方法，可以合成出该杂质对照品，对头孢洛林酯质量控制有着重要的意义；
Smart Images
Figure SMS_1 
Figure SMS_2 
Figure SMS_3
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of preparation of impurities of pharmaceutical compounds, and particularly relates to a method for synthesizing a ceftaroline fosamil diphosphate U2 impurity reference substance. Background Art
[0002] Ceftaroline fosamil is a prodrug of ceftaroline. It is a fifth-generation cephalosporin antibiotic that is administered by injection and has a broad spectrum of bactericidal activity. It is mainly used to treat community-acquired bacterial pneumonia (CABP) and acute bacterial skin and skin structure infections (ABSSSI) in adults, including methicillin-resistant Staphylococcus aureus (MRSA) infections. Compared with other cephalosporins, ceftaroline fosamil has milder adverse reactions, better safety, and good prospects. The structure of ceftaroline fosamil is shown below.
[0003]
[0004] The U2 impurity of cefuroxime diphosphate is an important impurity that needs to be studied in the quality control of cefuroxime fosamil. Its name is: (6R,7R)-7-((Z)-2-(ethoxyimino)-2-(5-((hydroxy(phosphonooxy)phosphoryl)amino)-1,2,4-thiadiazol-3-yl)acetamido)-3- ((4-(1-methylpyridin-1-ium-4-yl)thiazol-2-yl)thio)-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylate, the molecular formula is: C 22 H 22 N8O 11 P2S4, the structure is shown below.
[0005]
[0006] The U2 impurity of ceftaroline fosamil diphosphate is a degradation product of ceftaroline fosamil and is produced during storage and production. In order to effectively control the content of the U2 impurity of ceftaroline fosamil diphosphate in ceftaroline fosamil, it is very important to obtain a reference substance for the impurity. However, there is currently no report on the synthesis of the U2 impurity of ceftaroline fosamil diphosphate.
[0007] Based on this, it is necessary to develop a synthesis method for cefuroxime diphosphate U2 impurity reference substance. Summary of the invention
[0008] In view of the deficiencies in the prior art, the present invention provides a method for synthesizing a ceftaroline fosamil diphosphate U2 impurity reference substance.
[0009] The present invention is achieved through the following technical solutions: A method for synthesizing a ceftaroline fosamil diphosphate U2 impurity reference substance comprises the following steps: (1) 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, a condensation agent and an organic solvent A are mixed and stirred, and a mixed solution of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride and an organic solvent B is added and reacted to obtain a mixture 1; (2) adding a phosphoric acid aqueous solution and a base to the mixture 1 to react and obtain a crude product of DIPEA salt of ceftaroline fosamil diphosphate U2; (3) Dissolve the crude DIPEA salt of ceftaroline fosamil diphosphate U2 in water and adjust the pH to obtain the ceftaroline fosamil diphosphate U2 impurity reference substance.
[0010] Preferably, in step (1), the molar ratio of 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, the condensation agent and (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride is 1:0.5-10:1-5, preferably 1:2.5-3.5:1-1.5.
[0011] Preferably, the condensing agent in step (1) is selected from any one of N,O-bis(trimethylsilyl)acetamide, N,N'-bis(trimethylsilyl)urea and N-methyl-N-(trimethylsilyl)acetamide, preferably N,O-bis(trimethylsilyl)acetamide.
[0012] Preferably, the organic solvent A and the organic solvent B in step (1) are each independently selected from one or more of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.
[0013] Further preferably, the organic solvent A and the organic solvent B in step (1) are both acetonitrile.
[0014] Preferably, in step (1), the mass volume ratio 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 to organic solvent A is 80-120 mg / mL.
[0015] Preferably, the mass volume ratio of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride and organic solvent B in step (1) is 70-130 mg / mL.
[0016] Preferably, in step (1), the stirring temperature is 0°C-50°C, the stirring time is 0.5-5h, the stirring speed is 600-800rpm, the reaction temperature is -10°C~20°C, and the reaction time is 10min-3h.
[0017] Further preferably, in step (1), the stirring temperature is 15°C-25°C, the stirring time is 2.5-3.5h, the stirring speed is 600-800rpm, the reaction temperature is -5°C~5°C, and the reaction time is 0.5-1.5h.
[0018] Preferably, the molar ratio of the 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, phosphoric acid and base is 1:2-40:0-80, preferably 1:15-25:35-45.
[0019] Preferably, the mass concentration of the aqueous phosphoric acid solution in step (2) is 20%-100%, preferably 85%, and the base is selected from any one of N,N-diisopropylethylamine, triethylamine, tributylamine and pyridine, preferably N,N-diisopropylethylamine.
[0020] Preferably, the reaction temperature in step (2) is -20°C to 20°C, preferably -5°C to 0°C, and the reaction time is 1-20h, preferably 7-9h; after the reaction, the steps of purification, crystallization, filtration and washing are also included.
[0021] More preferably, water and acetonitrile are added during purification crystallization, the crystallization temperature is 0-5°C, the crystallization time is 1.5-2.5 h, and the washing solvent is acetonitrile.
[0022] Preferably, the environment for adjusting the pH in step (3) is an ice water bath, the solution for adjusting the pH is concentrated hydrochloric acid, and the pH is adjusted to 0.5-1.0, and after the pH is adjusted, the steps of filtering, washing with water and drying are also included.
[0023] More preferably, the drying method is drying in a nitrogen flow, the drying temperature is 5-15° C., and the drying time is 20-30 h, preferably 24 h.
[0024] Compared with the prior art, the present invention has the following beneficial effects: (1) The present invention develops a method for preparing the U2 impurity reference substance of ceftaroline fosamil diphosphate, which can synthesize the impurity reference substance and has important significance for the quality control of ceftaroline fosamil; (2) The U2 impurity reference substance of ceftaroline fosamil diphosphate prepared by the present invention has a yield of about 60% and a purity of about 95%; (3) The synthesis route of the present invention is short and the preparation is simple. DETAILED DESCRIPTION
[0025] The present invention will be further described in detail below in conjunction with specific examples. The following examples are not intended to limit the present invention, but are only intended to illustrate the present invention. The experimental methods used in the following examples are generally conventional, unless otherwise specified, and the materials, reagents, etc. used in the following examples are commercially available, unless otherwise specified.
[0026] Example 1 A method for synthesizing a ceftaroline fosamil diphosphate U2 impurity reference substance, the synthesis route of which is as follows:
[0027] The specific steps are as follows: (1) At room temperature, 5 g of 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 was dissolved in 50 mL of acetonitrile, the temperature was controlled at 20°C, 6.4 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, the temperature was controlled at 20°C, and the mixture was stirred at 700 rpm for 3 h. The mixture was cooled to 0°C, and a solution of 4.2 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, stirring was continued at 700 rpm for 1 h to obtain a mixture 1; (2) Under stirring, 28.2 g of commercially available H3PO4 solution (85%) and 53.9 g of N,N-diisopropylethylamine (DIPEA) were added dropwise to the mixture 1, and the mixture was reacted at -5°C for 8 h. The mixture was filtered and the solid was washed with 10 mL of acetonitrile to obtain 8.6 g of crude DIPEA salt of ceftaroline fosamil U2. The crude solid was dissolved in 100 mL of water, and then 200 mL of acetonitrile was added dropwise to precipitate the solid. The mixture was cooled to 0°C, stirred for 2 h, filtered, and the solid was washed with 10 mL of acetonitrile to obtain 5.9 g of DIPEA salt of ceftaroline fosamil diphosphate U2 with an HPLC purity of 93.4%; (3) Dissolve 5.9 g of the purified ceftaroline fosamil U2 DIPEA salt in 50 mL of water, add 7.4 mL of concentrated hydrochloric acid dropwise under an ice-water bath to adjust the pH to 0.8, precipitate a solid, filter, and wash the solid with 10 mL of water to obtain ceftaroline fosamil diphosphate U2 impurity. Dry the wet product in a nitrogen stream at 10°C for 24 h to obtain 4.9 g of ceftaroline fosamil U2 impurity, with a yield of 62% and a purity of 98.6%.
[0028] 1 HNMR (CDCl3) δ 9.67 (dd, J = 7.4, 1.4 Hz, 2H), 8.40 (dd, J = 7.5, 1.6Hz, 1H), 8.26 (dd, J = 7.5, 1.5 Hz, 1H), 7.01 (s, 1H), 6.76 (s, 1H), 6.13 (s,1H), 5.47 (d, J = 7.1 Hz, 1H), 5.39 (d, J = 7.0 Hz, 1H), 4.35 (s, 3H), 4.16(dd, J = 12.4, 8.0 Hz, 1H), 3.69 – 3.60 (m, 2H), 3.54 (d, J = 17.6 Hz, 1H),1.12 (t, J = 8.0 Hz, 3H).
[0029] Example 2 A method for synthesizing a ceftaroline fosamil diphosphate U2 impurity reference substance, the specific steps of which are as follows: (1) At room temperature, 5 g of 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 was dissolved in 50 mL of acetonitrile, the temperature was controlled at 25°C, 5.3 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, the temperature was controlled at 25°C, and the mixture was stirred at 800 rpm for 3.5 h. The mixture was cooled 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 acetonitrile was added dropwise. After the addition was completed, the mixture was stirred at 800 rpm for 1.5 h to obtain a mixture 1; (2) Under stirring, 21.1 g of commercially available H3PO4 solution (85%) and 47.2 g of N,N-diisopropylethylamine (DIPEA) were added dropwise to the mixture 1 in sequence, and the mixture was reacted at 0°C for 9 h, filtered, and the solid was washed with 10 mL of acetonitrile to obtain 7.8 g of crude DIPEA salt of ceftaroline fosamil U2. The crude solid was dissolved in 90 mL of water, and then 180 mL of acetonitrile was added dropwise to precipitate a solid. The mixture was cooled to 2°C, stirred at 800 rpm for 1.5 h, filtered, and the solid was washed with 10 mL of acetonitrile to obtain 5.5 g of DIPEA salt of ceftaroline fosamil diphosphate U2 with an HPLC purity of 90.6%.
[0030] (3) Dissolve 5.5 g of the purified ceftaroline fosamil diphosphate U2 DIPEA salt in 46 mL of water, add 5.1 mL of concentrated hydrochloric acid dropwise under an ice-water bath to adjust the pH to 0.5, precipitate a solid, filter, and wash the solid with 5 mL of water to obtain ceftaroline fosamil diphosphate U2 impurity. Dry the wet product in a nitrogen stream at 15°C for 20 h to obtain 4.5 g of ceftaroline fosamil diphosphate U2 impurity, with a yield of 56% and a purity of 95.2%.
[0031] Example 3 A method for synthesizing a ceftaroline fosamil diphosphate U2 impurity reference substance, the specific steps of which are as follows: (1) At room temperature, 5 g of 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 was dissolved in 50 mL of acetonitrile, the temperature was controlled at 15°C, 7.4 g of N,O-bis(trimethylsilyl)acetamide (BSA) was added dropwise, the temperature was controlled at 15°C, and the mixture was stirred at 600 rpm for 2.5 h. The mixture was cooled to -5°C, and a solution of 5.5 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 at 600 rpm for 0.5 h to obtain a mixture 1; (2) Under stirring, 35.4 g of commercially available H3PO4 solution (85%) and 60.7 g of N,N-diisopropylethylamine (DIPEA) were added dropwise to the mixture 1 in sequence, and the mixture was reacted at -5°C for 7 h, filtered, and the solid was washed with 10 mL of acetonitrile to obtain 7.2 g of crude DIPEA salt of ceftaroline fosamil diphosphate U2. The crude solid was dissolved in 84 mL of water, and then 168 mL of acetonitrile was added dropwise to precipitate a solid. The mixture was cooled to 5°C, stirred for 2.5 h, filtered, and the solid was washed with 10 mL of acetonitrile to obtain 5.0 g of DIPEA salt of ceftaroline fosamil diphosphate U2 with an HPLC purity of 95.6%.
[0032] (3) Dissolve 5.0 g of the purified ceftaroline fosamil diphosphate U2 DIPEA salt in 50 mL of water, add 5.3 mL of concentrated hydrochloric acid dropwise under an ice-water bath to adjust the pH to 1.0, precipitate a solid, filter, and wash the solid with 10 mL of water to obtain ceftaroline fosamil diphosphate U2 impurity. Dry the wet product in a nitrogen stream at 5°C for 30 h to obtain 4.2 g of ceftaroline fosamil diphosphate U2 impurity, with a yield of 53% and a purity of 97.8%.
[0033] Example 4 All acetonitrile in step (1) of Example 1 was replaced by tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide, respectively, and the rest of the preparation process was the same as that of Example 1. The yield and purity of the prepared ceftaroline fosamil diphosphate U2 impurity are shown in Table 1.
[0034] Table 1 Yield and purity of ceftaroline fosamil diphosphate U2 impurity
[0035] Example 5 The N,O-bis(trimethylsilyl)acetamide (BSA) in step (1) of Example 1 was replaced by N,N'-bis(trimethylsilyl)urea (BSU) and N-methyl-N-(trimethylsilyl)acetamide (MSA), respectively, and the rest of the preparation process was the same as that of Example 1. The yield and purity of the prepared ceftaroline fosamil diphosphate U2 impurity are shown in Table 2.
[0036] Table 2 Yield and purity of ceftaroline fosamil diphosphate U2 impurity
[0037] Example 6 The N,N-diisopropylethylamine (DIPEA) in step (2) of Example 1 was replaced by triethylamine (TEA), tributylamine (TBA), and pyridine (Py), respectively, and the rest of the preparation process was the same as that of Example 1. The yield and purity of the prepared ceftaroline fosamil diphosphate U2 impurity are shown in Table 3.
[0038] Table 3 Yield and purity of ceftaroline fosamil diphosphate U2 impurity
[0039] Example 7 The mass concentration of the H3PO4 aqueous solution in step (2) of Example 1 was replaced by 20% and 100% phosphoric acid crystals, respectively, and the rest of the preparation process was the same as that of Example 1. The yield and purity of the prepared ceftaroline fosamil diphosphate U2 impurity are shown in Table 4.
[0040] Table 4 Yield and purity of ceftaroline fosamil diphosphate U2 impurity
[0041] 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 a ceftaroline fosamil diphosphate U2 impurity reference substance, characterized in that: The following steps are involved: (1) 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, a condensation agent and an organic solvent A are mixed and stirred, and a mixed solution of (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride and an organic solvent B is added and reacted to obtain a mixture 1; (2) adding a phosphoric acid aqueous solution and a base to the mixture 1 to react and obtain the DIPEA salt of ceftaroline fosamil diphosphate U2; (3) Dissolve the DIPEA salt of ceftaroline fosamil diphosphate U2 in water and adjust the pH to obtain the ceftaroline fosamil diphosphate U2 impurity reference substance.
2. The synthesis method according to claim 1, characterized in that In step (1), the molar ratio of 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, the condensation agent and (Z)-2-(5-((dichlorophosphoryl)amino)-1,2,4-thiadiazol-3-yl)-2-(ethoxyimino)acetyl chloride is 1:0.5-10:1-5.
3. The synthesis method according to claim 1, characterized in that The condensing agent in step (1) is selected from any one of N,O-bis(trimethylsilyl)acetamide, N,N'-bis(trimethylsilyl)urea and N-methyl-N-(trimethylsilyl)acetamide.
4. The synthesis method according to claim 1, characterized in that The organic solvent A and the organic solvent B in step (1) are each independently selected from one or more of acetonitrile, tetrahydrofuran, 1,4-dioxane, ethyl acetate, dichloromethane, N,N-dimethylformamide, N,N-dimethylacetamide and dimethyl sulfoxide.
5. The synthesis method according to claim 1, characterized in that In step (1), the stirring temperature is 0°C-50°C, the stirring time is 0.5-5h, the stirring speed is 600-800rpm, the reaction temperature is -10°C~20°C, and the reaction time is 10min-3h.
6. The synthesis method according to claim 5, characterized in that In step (1), the stirring temperature is 15°C-25°C, the stirring time is 2.5-3.5h, the stirring speed is 600-800rpm, the reaction temperature is -5°C~5°C, and the reaction time is 0.5-1.5h.
7. The synthesis method according to claim 1, characterized in that The molar ratio of the 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, phosphoric acid and base is 1:2-40:0-80.
8. The synthesis method according to any one of claims 1 to 7, characterized in that The mass concentration of the phosphoric acid aqueous solution in step (2) is 20%-100%, and the base is selected from any one of N,N-diisopropylethylamine, triethylamine, tributylamine and pyridine.
9. The synthesis method according to claim 1, characterized in that The reaction temperature in step (2) is -20°C to 20°C, the reaction time is 1-20h, and after the reaction, the steps of purification, crystallization, filtration and washing are also included.
10. The synthesis method according to claim 1, characterized in that The environment for adjusting the pH in step (3) is an ice water bath, and the solution for adjusting the pH is concentrated hydrochloric acid, which is adjusted to a pH of 0.5-1.
0. After adjusting the pH, the steps of filtering, washing with water and drying are also included.