Preparation method of meropenem dimer impurity

Abstract

The invention discloses a preparation method of meropenem dimer impurities, which comprises the following steps: (1) adding meropenem into methanol, then adding acetic acid into the methanol, and stirring at 40-80 DEG C for 3-6 hours; (2) continuously adding meropenem and a water removal agent into the reaction liquid in the step (1), and stirring at-10 to 10 DEG C for 10 to 12 hours; and (3) filtering, cooling the filtrate to-20 to-15 DEG C, dropwise adding tetrahydrofuran into the filtrate for crystallization, and filtering to obtain the meropenem dimer impurity. The method is simple to operate, the raw material conversion rate can reach 99% or above, the product purity is 95% or above, and the method can be directly used as a reference substance for qualitative and quantitative research on meropenem dimerization impurities, so that the product quality is more effectively controlled.

Description

Technical Field

[0001] This invention belongs to the field of medicinal chemistry technology, specifically relating to a method for preparing a meropenem dimer impurity. Background Technology

[0002] Meropenem is a semi-synthetic broad-spectrum carbapenem antibiotic with strong antibacterial activity, stability against β-lactamases, and few side effects. It exhibits strong antibacterial activity against both Gram-positive and Gram-negative bacteria and is clinically used for mixed infections and various severe infections. This product has relatively few toxic side effects on the central nervous system and kidneys, and the incidence of adverse reactions in clinical application is low. However, as a β-lactam antibiotic, it is unstable in aqueous solution and easily forms dimer impurities. Therefore, when analyzing the purity of meropenem trihydrate, a reference standard of the dimer impurity is required to qualitatively and quantitatively study the impurities in the active pharmaceutical ingredient to ensure that the product meets requirements. Currently, commercially available standards for this dimer impurity have a purity of over 95%, but they are expensive.

[0003] CN105061284A discloses a method for preparing ring-opening impurities of carbapenem antibiotics, including a method for preparing meropening impurities, which can be obtained by stirring under alkaline conditions and is simple to operate. Currently, there are no reported methods for preparing meropening impurities. Therefore, developing a method for preparing high-purity dimer impurities would be of great significance. Summary of the Invention

[0004] To address the shortcomings of existing technologies, this invention provides a method for preparing meropenem dimer impurities. The method is simple to operate, has a high raw material conversion rate, and yields meropenem dimer impurities with high purity. It can be directly used as a reference standard for qualitative and quantitative studies of meropenem dimer impurities.

[0005] A method for preparing a meropenem dimer impurity includes the following steps: (1) Add meropenem to methanol, then add acetic acid to it, and stir at 40~80℃ for 3~6h; (2) Add meropenem and dehydrating agent to the reaction solution in step (1) and stir at -10 ~ 10℃ for 10-12h; (3) Filter the filtrate and cool it to -20 ~ -15℃. Then add tetrahydrofuran dropwise to it to crystallize. Filter to obtain meropenem dimer impurity.

[0006] Preferably, in step (1), the ratio of meropenem to methanol is 1g:(20~60)mL, and the volume ratio of acetic acid to methanol is (0.02~0.1):1.

[0007] Preferably, the mass ratio of meropenem in step (2), dehydrating agent, and meropenem in step (1) is (0.9 ~ 1): (5 ~ 20): 1.

[0008] Preferably, the volume ratio of tetrahydrofuran in step (3) to methanol in step (1) is (2 ~ 4): 1.

[0009] Preferably, the dehydrating agent is anhydrous sodium sulfate, anhydrous magnesium sulfate, 4A molecular sieve, or 5A molecular sieve.

[0010] Preferably, in step (1), the mixture is stirred at 55-60°C for 3-6 hours.

[0011] Preferably, in step (2), the mixture is stirred at -5 ~ 0℃ for 10-12 hours.

[0012] More preferably, in step (1), the ratio of meropenem to methanol is 1g:40mL, and the volume ratio of methanol to acetic acid is 0.05:1.

[0013] More preferably, the mass ratio of meropenem in step (2), dehydrating agent, and meropenem in step (1) is 0.95: 10: 1.

[0014] More preferably, the volume ratio of tetrahydrofuran in step (3) to methanol in step (1) is 3:1.

[0015] More preferably, the dehydrating agent is a 4A molecular sieve.

[0016] The structural formula of the meropenem dimer impurity described in this invention is as follows: .

[0017] The principle of this invention: Meropenem undergoes a ring-opening reaction under acidic conditions, resulting in a ring-opening impurity that is less stable under acidic conditions than under alkaline conditions. This impurity undergoes a dehydration reaction with meropenem to generate a dimer impurity. This dehydration reaction is reversible. By controlling the appropriate pH and dehydrating agent, the raw material meropenem can be almost completely converted into a dimer impurity.

[0018] Advantages of this invention: This invention is simple to operate, with a raw material conversion rate of over 99% and a product purity of over 95%. It can be directly used as a reference standard for qualitative and quantitative research on meropenem dimer impurities, thereby more effectively controlling product quality. Detailed Implementation

[0019] Example 1 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g of meropenem to 80mL of methanol, then add 4mL of acetic acid and stir at 60℃ for 4h; (2) Add 1.9g meropenem and 20g 4A molecular sieve to the reaction solution in step (1) and stir at -5℃ for 10h; (3) Filtration, cooling the filtrate to -20℃, and then adding 240mL of tetrahydrofuran to crystallize it. After filtration, 3.6g of meropenem dimer impurity was obtained. The raw material conversion rate was 99.7%, and the purity was 99.2% as determined by HPLC. The obtained meropenem dimer impurity was detected by NMR, and the results are as follows: 1 HNMR(400MHz, D2O:4.79 ppm): δ = 4.97-4.93 (m, 1H); 4.66-4.69 (m, 1H); 4.16-3.87 (m, 5H); 3.68-3.61 (m, 3H); 3.36-3.32 (m, 3H); 3.25-2.52 (m, 17H); 1.88-1.83 (m, 1H); 1.72-1.66 (m, 1H); 1.49-0.76 (m, 12H).

[0020] Example 2 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 120mL methanol, then add 12mL acetic acid and stir at 50℃ for 6h; (2) Add 1.8g meropenem and 40g 4A molecular sieve to the reaction solution in step (1) and stir at 0℃ for 12h; (3) Filtration, cooling the filtrate to -15℃, and then adding 480mL of tetrahydrofuran to crystallize it. After filtration, 3.3g of meropenem dimer impurity was obtained. The raw material conversion rate was 99.1%, and the purity was 98.9% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0021] Example 3 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 60mL methanol, then add 5mL acetic acid and stir at 45℃ for 6h; (2) Add 1.9g meropenem and 30g 4A molecular sieve to the reaction solution in step (1) and stir at -10℃ for 10h; (3) Filtration, cooling the filtrate to -20℃, and then adding 180mL of tetrahydrofuran to crystallize it. After filtration, 3.4g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.7%, and the purity was 97.1% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0022] Example 4 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 80mL methanol, then add 1.6mL acetic acid and stir at 70℃ for 6h; (2) Add 1.9g meropenem and 40g 4A molecular sieve to the reaction solution in step (1) and stir at 10℃ for 10h; (3) Filtration, cooling the filtrate to -15℃, and then adding 240mL of tetrahydrofuran to crystallize it. After filtration, 3.1g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.8%, and the purity was 98.2% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0023] Example 5 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 100mL methanol, then add 4mL acetic acid and stir at 80℃ for 3h; (2) Add 1.9g meropenem and 30g 4A molecular sieve to the reaction solution in step (1) and stir at -10℃ for 12h; (3) Filtration, cooling the filtrate to -20℃, and then adding 200mL of tetrahydrofuran to crystallize it. After filtration, 3.5g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.1%, and the purity was 97.0% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0024] Example 6 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 110mL methanol, then add 10mL acetic acid and stir at 40℃ for 6h; (2) Add 1.9g meropenem and 20g 4A molecular sieve to the reaction solution in step (1) and stir at 10°C for 11h; (3) Filtration, cooling the filtrate to -18℃, and then adding 350mL of tetrahydrofuran to it to crystallize. After filtration, 3.3g of meropenem dimer impurity was obtained. The raw material conversion rate was 99.2%, and the purity was 98.5% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0025] Example 7 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g of meropenem to 50mL of methanol, then add 5mL of acetic acid and stir at 60℃ for 4h; (2) Add 1.9g meropenem and 40g 4A molecular sieve to the reaction solution in step (1) and stir at -5℃ for 10h; (3) Filtration, cooling the filtrate to -15℃, and then adding 100mL of tetrahydrofuran to crystallize it. After filtration, 3.2g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.9%, and the purity was 97.7% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0026] Example 8 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 70mL methanol, then add 6mL acetic acid and stir at 55℃ for 4h; (2) Add 1.9g meropenem and 20g 5A molecular sieve to the reaction solution in step (1) and stir at 5°C for 10h; (3) Filtration, cooling the filtrate to -20℃, and then adding 200mL of tetrahydrofuran to crystallize it. After filtration, 3.5g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.2%, and the purity was 97.1% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0027] Example 9 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 100mL methanol, then add 10mL acetic acid and stir at 80℃ for 6h; (2) Add 1.9g meropenem and 40g anhydrous magnesium sulfate to the reaction solution in step (1) and stir at -10℃ for 12h; (3) Filtration, cooling the filtrate to -15℃, and then adding 400mL of tetrahydrofuran to crystallize it. After filtration, 3.6g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.7%, and the purity was 97.9% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0028] Example 10 A method for preparing a meropenem dimer impurity includes the following steps: (1) Add 2.0g meropenem to 100mL methanol, then add 10mL acetic acid and stir at 80℃ for 6h; (2) Add 2.0 g meropenem and 10 g anhydrous sodium sulfate to the reaction solution in step (1) and stir at -5°C for 12 h; (3) Filtration, cooling the filtrate to -15℃, and then adding 400mL of tetrahydrofuran to it to crystallize. After filtration, 3.2g of meropenem dimer impurity was obtained. The raw material conversion rate was 98.3%, and the purity was 98.0% as determined by HPLC. The results of NMR detection were similar to those in Example 1.

[0029] Comparative Example 1 Acetic acid is not added; otherwise, it is the same as in Example 1, as follows: (1) Add 2.0g of meropenem to 80mL of methanol and stir at 60℃ for 4h; (2) Add 1.9g meropenem and 20g 4A molecular sieve to the reaction solution in step (1) and stir at -5℃ for 10h; (3) Filtration, cooling the filtrate to -20℃, and then adding 240mL of tetrahydrofuran to crystallize it. After filtration, 0.1g of meropenem dimer impurity was obtained. The raw material conversion rate was 3.3%. The purity was 95.1% as determined by HPLC. The results of NMR were similar to those in Example 1.

[0030] Comparative Example 2 (1) Add 2.0g of meropenem to 80mL of methanol, then add 4mL of acetic acid and stir at 60℃ for 4h; (2) Add 1.9 g of meropenem to the reaction solution from step (1) and stir at -5°C for 10 h; (3) Filtration, cooling the filtrate to -20℃, and then adding 240mL of tetrahydrofuran to crystallize it. After filtration, 0.8g of meropenem dimer impurity was obtained. The raw material conversion rate was 7.5%. The purity was 97.6% as determined by HPLC. The results of NMR were similar to those in Example 1.

Claims

1. A method for preparing a meropenem dimer impurity, characterized in that: Includes the following steps: (1) Add meropenem to methanol, then add acetic acid to it, and stir at 40~80℃ for 3~6h; (2) Add meropenem and dehydrating agent to the reaction solution in step (1) and stir at -10 ~ 10℃ for 10-12h; (3) Filter the filtrate and cool it to -20 ~ -15℃. Then add tetrahydrofuran dropwise to it to crystallize. Filter to obtain meropenem dimer impurity.

2. The method for preparing meropenem dimer impurities according to claim 1, characterized in that: In step (1), the ratio of meropenem to methanol is 1g:(20~60)mL, and the volume ratio of acetic acid to methanol is (0.02~0.1):

1.

3. The method for preparing meropenem dimer impurities according to claim 2, characterized in that: The mass ratio of meropenem in step (2), dehydrating agent, and meropenem in step (1) is (0.9 ~ 1): (5 ~ 20):

1.

4. The method for preparing meropenem dimer impurities according to claim 3, characterized in that: The volume ratio of tetrahydrofuran in step (3) to methanol in step (1) is (2 ~ 4):

1.

5. The method for preparing meropenem dimer impurities according to claim 1, characterized in that: The dehydrating agent is anhydrous sodium sulfate, anhydrous magnesium sulfate, 4A molecular sieve, or 5A molecular sieve.

6. The method for preparing meropenem dimer impurities according to claim 4, characterized in that: In step (1), stir at 55-60℃ for 3-6 hours.

7. The method for preparing meropenem dimer impurities according to claim 6, characterized in that: In step (2), stir for 10-12 hours at -5 to 0°C.

8. The method for preparing meropenem dimer impurities according to claim 7, characterized in that: In step (1), the ratio of meropenem to methanol is 1g:40mL, and the volume ratio of methanol to acetic acid is 0.05:

1.

9. The method for preparing meropenem dimer impurities according to claim 8, characterized in that: The mass ratio of meropenem in step (2), dehydrating agent, and meropenem in step (1) is 0.95: 10:

1.

10. The method for preparing meropenem dimer impurities according to claim 9, characterized in that: The volume ratio of tetrahydrofuran in step (3) to methanol in step (1) is 3:1.