Refining method of ertapenem sodium

Abstract

The invention belongs to the technical field of refining of raw material medicines, and particularly relates to a refining method of ertapenem sodium. According to the refining method of the ertapenem sodium provided by the invention, the crude ertapenem sodium product is treated by using the adsorption material, so that palladium and dimers in the refined ertapenem sodium product can be remarkably reduced, the color grade of the refined ertapenem sodium product is improved, the quality of the refined ertapenem sodium product is improved, and the refining effect of the ertapenem sodium is improved; meanwhile, the refining effect of the ertapenem sodium can be further improved by improving the variety and proportion of the adsorption material; the refining effect of the ertapenem sodium can be improved by improving the technological parameters such as the stirring rotating speed and time in the refining process; therefore, the technical problem of poor refining effect of the ertapenem sodium crude product in the prior art is solved.

Description

Technical Field

[0001] The present application belongs to the technical field of raw material drug refining, and in particular relates to a method for refining ertapenem sodium. Background Art

[0002] Ertapenem sodium, chemical name: (4R,5R,6S)-3-[(3S,5S)-5-[(3-carboxyphenyl)carbamoyl]-3-pyrrolidinyl]sulfur-6-(1-hydroxyethyl)-4-methyl-7-oxo-1-azabicyclo[3.2.0]hept-2-ene-2-carboxylic acid monosodium salt; Ertapenem sodium has good antibacterial activity and pharmacokinetic properties, long half-life, and can achieve satisfactory results with one dose every 24 hours. It also has obvious effects on moderate to severe infections caused by secondary abdominal infections, complicated skin and appendage infections, community-acquired pneumonia, complicated urinary tract infections, acute pelvic infections, bacteremia, etc.

[0003] After the crude ertapenem sodium is prepared, it is necessary to purify the crude ertapenem sodium, because the residual palladium and dimer content in the crude ertapenem sodium is high, and the color grade is also poor, which leads to the safety and quality of the crude ertapenem sodium failing to meet the qualified requirements; the purification effect of the crude ertapenem sodium by filtering with a Buchner funnel is poor. The current mainstream technical solution is to dissolve the crude ertapenem sodium, add anion resin column and alumina column for elution, and then crystallize / crystallize the eluted filtrate to obtain the refined product of ertapenem sodium, thereby improving Purity of ertapenem sodium; however, the addition of anion resin columns, alumina columns and other column processes requires specific complex operating steps, and operators need to be trained. At the same time, the refining effect of column processes such as anion resin columns and alumina columns is related to the adsorption components filled in the column. The adsorption components filled in the column are single, and it is difficult to take into account the effects of palladium removal, color removal and dimer removal. In addition, column processes such as anion resin columns and alumina columns have a small processing capacity and are difficult to meet the requirements of improving production efficiency in the industrial field; thus, the existing process has a poor refining effect on the crude ertapenem sodium. Summary of the invention

[0004] In view of this, the present application provides a method for refining ertapenem sodium, which is used to solve the technical problem of poor refining effect of crude ertapenem sodium in the prior art.

[0005] The first aspect of the present application provides a method for refining ertapenem sodium, comprising the following steps:

[0006] Step S1, adding a crude aqueous solution of ertapenem sodium into a methanol solvent to obtain an ertapenem sodium methanol aqueous solution at a temperature not exceeding -5°C;

[0007] Step S2, adding the adsorption material into the methanol aqueous solution of ertapenem sodium and stirring to obtain a refined suspension of ertapenem sodium;

[0008] Step S3, filtering the refined suspension of ertapenem sodium to obtain a refined solution of ertapenem sodium;

[0009] Step S4, adding an organic solvent to the refined ertapenem sodium solution for crystallization to obtain a refined ertapenem sodium product.

[0010] Preferably, in step S2, the adsorption material is selected from at least one of LSC-340 resin, MOPA-20-2680 material, polymer chromatographic filler NM200, and iMoLboX-LMat-NH material.

[0011] Preferably, in step S2, the adsorption material is selected from at least one composite adsorption material of iMoLboX-LMat-NH material and LSC-340 resin, iMoLboX-LMat-NH material and MOPA-20-2680 material, iMoLboX-LMat-NH material and polymer chromatography filler NM200, LSC-340 resin and MOPA-20-2680 material, LSC-340 resin and polymer chromatography filler NM200, MOPA-20-2680 material and polymer chromatography filler NM200.

[0012] Preferably, calculated by parts by mass, the mass ratio of iMoLboX-LMat-NH material to LSC-340 resin in the composite adsorption material is 1:1-3;

[0013] The mass ratio of iMoLboX-LMat-NH material and MOPA-20-2680 material in the composite adsorption material is 1:1-3;

[0014] The mass ratio of iMoLboX-LMat-NH material and polymer chromatographic filler NM200 in the composite adsorption material is 1:1-3;

[0015] The mass ratio of LSC-340 resin and MOPA-20-2680 material in the composite adsorption material is 1:1-3;

[0016] The mass ratio of LSC-340 resin and polymer chromatographic filler NM200 in the composite adsorption material is 1:1-3;

[0017] In the composite adsorption material, the mass ratio of MOPA-20-2680 material and polymer chromatographic filler NM200 is 1:1-3.

[0018] Preferably, in step S1 and step S2, the mass ratio of the crude ertapenem sodium to the adsorption material is 1:0.02-0.2.

[0019] Preferably, in step S2, the stirring speed is 200-500 rpm / min, and the time is 20-200 min.

[0020] Preferably, in step S1, the temperature of the ertapenem sodium methanol aqueous solution is -15 to -5°C.

[0021] Preferably, in step S3, the filtering process is performed by filtering using a 0.45 μm filter membrane.

[0022] Preferably, in step S4, the crystallization process is to drop n-propanol into the ertapenem sodium refined solution twice for crystallization.

[0023] Preferably, in step S4, the step of adding n-propanol dropwise to the ertapenem sodium refined solution twice for crystallization is specifically as follows:

[0024] Step S41, for the first time, 75 L of n-propanol was added at a dropping speed of 0.8-2.5 L / min within 1.5 h, and after the addition was completed, the crystal was stirred and grown for 2 h;

[0025] Step S41, adding 105 L of n-propanol at a dropping speed of 0.4-0.6 L / min for the second time within 3-5 hours, stirring and growing the crystal for 15-30 minutes after the dropping is completed, to obtain a crystalline refined product of ertapenem sodium.

[0026] Compared with the prior art, the method for refining ertapenem sodium provided in the present application has at least the following beneficial effects:

[0027] 1. In a method for refining ertapenem sodium provided in the present application, the crude ertapenem sodium is treated with an adsorption material, which can significantly reduce the palladium and dimer in the refined ertapenem sodium and improve the color grade; at the same time, the refining process is simple, ertapenem sodium can be refined on a large scale, and it is convenient to replace the type of adsorption material.

[0028] 2. In the method for refining ertapenem sodium provided in the present application, by flexibly selecting different adsorption materials and improving the types and ratios of adsorption materials as needed, the performance in multiple aspects or one aspect such as palladium residue, total amount of dimers and color grade can be significantly improved.

[0029] 3. In the method for refining ertapenem sodium provided in the present application, the refining effect of ertapenem sodium can be further improved by improving process parameters such as stirring speed and time during the refining process. BRIEF DESCRIPTION OF THE DRAWINGS

[0030] In order to more clearly illustrate the specific implementation methods of the present application or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present application. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0031] Figure 1 A schematic flow chart of a method for refining ertapenem sodium provided in this application. DETAILED DESCRIPTION

[0032] The present application provides a method for refining ertapenem sodium, which is used to solve the technical problem of poor refining effect of crude ertapenem sodium in the prior art.

[0033] The technical solution of the present application will be described clearly and completely below in conjunction with the accompanying drawings. Obviously, the described embodiments are part of the embodiments of the present application, rather than all of the embodiments. Based on the embodiments in the present application, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present application.

[0034] In view of the current defect of poor refining effect of crude ertapenem sodium, the present application provides a method for refining ertapenem sodium, which comprises: firstly adding an aqueous solution of crude ertapenem sodium into a methanol solvent to obtain an aqueous solution of ertapenem sodium in methanol at a temperature not exceeding -5°C; then adding an adsorbent material into the aqueous solution of ertapenem sodium in methanol and stirring to obtain a refined suspension of ertapenem sodium; next filtering the refined suspension of ertapenem sodium to obtain a refined solution of ertapenem sodium; and then adding an organic solvent into the refined solution of ertapenem sodium for crystallization to obtain a refined product of ertapenem sodium.

[0035] In a method for refining ertapenem sodium provided in the present application, various adsorption materials are added to an aqueous solution of ertapenem sodium in methanol and stirred, so that the adsorption materials can be fully dispersed in the aqueous solution of ertapenem sodium in methanol, and the adsorption effect of the adsorption materials is exerted to remove the residual palladium and dimer in the aqueous solution of ertapenem sodium in methanol, while improving the color grade of the ertapenem sodium product; experimental results show that the total amount of residual palladium and dimer of the refined ertapenem sodium obtained by filtering the crude ertapenem sodium product with a Buchner funnel is high, and the color grade is poor, while the method for refining ertapenem sodium provided in the present application uses adsorption materials to significantly reduce the total amount of residual palladium and dimer of the refined ertapenem sodium product, and improve the color grade of the refined ertapenem sodium product, thereby achieving a better refining effect; Moreover, the process is simple and does not require specific complex operation steps like the traditional column process. The refining method of ertapenem sodium provided in the present application can simplify the steps of the refining process; at the same time, it is also unnecessary to process a small amount of ertapenem sodium like the traditional column process, which is difficult to meet the defects of large-scale refining process requirements of pharmaceutical companies. The refining method of ertapenem sodium provided in the present application can meet the requirements of the industrial field to improve production efficiency; in addition, it is also unnecessary to fill alumina and anion adsorption resin into the column like the traditional column process. The refining method of ertapenem sodium provided in the present application is more convenient to select adsorption materials, and suitable adsorption materials can be selected according to needs, thereby overcoming the current defect of poor refining effect of crude ertapenem sodium.

[0036] Preferably, for the adsorption material used in the method for refining ertapenem sodium provided in the present application, a single adsorption material or a composite adsorption material can be selected; for example, any one of LSC-340 resin, MOPA-20-2680 material, polymer chromatographic filler NM200, iMoLboX-LMat-NH material can be selected, or these adsorption materials can be compounded, such as iMoLboX-LMat-NH material and LSC-340 resin, iMoLboX-LMat-NH material and MOPA-20-2680 material. -2680 material, iMoLboX-LMat-NH material and polymer chromatographic filler NM200, LSC-340 resin and MOPA-20-2680 material, LSC-340 resin and polymer chromatographic filler NM200, MOPA-20-2680 material and polymer chromatographic filler NM200 and other composite adsorption materials; the composite adsorption material can greatly improve the refining effect of ertapenem sodium because it can utilize the synergistic effect of two adsorption materials, and the ratio of the two adsorption materials in the composite adsorption material can be controlled in the range of 1:1~3.

[0037] Preferably, for the mass ratio of the adsorption material used in the method for refining ertapenem sodium provided in the present application and the crude ertapenem sodium to be refined, the present application controls the addition of 0.02kg to 0.2kg of adsorption material to every 1kg of crude ertapenem sodium to be refined, for example, 0.35kg of adsorption material is added to 5kg of crude ertapenem sodium to be refined.

[0038] Preferably, for the method for refining ertapenem sodium provided in the present application, after adding the adsorption material to the methanol aqueous solution of ertapenem sodium, controlling the stirring speed and time can also improve the refining effect of the crude ertapenem sodium. The present application selects a stirring speed of 200~500rpm / min and a time of 20~200min.

[0039] The following is a detailed description of the method for refining ertapenem sodium provided in the present application in combination with embodiments and experimental examples.

[0040] Example 1

[0041] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0042] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0043] The step of refining the methanol aqueous solution of ertapenem sodium includes: adding 0.35 kg of LSC-340 resin as an adsorption material into a reaction kettle, controlling the temperature at -15 to -5°C, and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0044] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0045] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0046] Example 2

[0047] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0048] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0049] The step of refining the methanol aqueous solution of ertapenem sodium includes: adding 0.35 kg of MOPA-20-2680 as an adsorption material into a reaction kettle, controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0050] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0051] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0052] Example 3

[0053] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0054] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0055] The step of refining the methanol aqueous solution of ertapenem sodium includes: adding 0.35 kg of polymer chromatographic filler NM200 as an adsorption material into a reaction kettle, controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0056] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0057] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0058] Example 4

[0059] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0060] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0061] The step of refining the methanol aqueous solution of ertapenem sodium comprises: adding 0.35 kg of iMoLboX-LMat-NH material as an adsorption material into a reaction kettle, controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0062] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0063] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0064] Example 5

[0065] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0066] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0067] The step of refining the methanol aqueous solution of ertapenem sodium comprises: adding 0.175 kg of iMoLboX-LMat-NH material and 0.175 kg of LSC-340 resin as a composite adsorption material into a reaction kettle, and then controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0068] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0069] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0070] Example 6

[0071] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0072] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0073] The step of refining the ertapenem sodium methanol aqueous solution comprises: adding 0.175 kg of iMoLboX-LMat-NH material and 0.175 kg of MOPA-20-2680 material as a composite adsorption material into a reactor, controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0074] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0075] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0076] Example 7

[0077] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0078] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0079] The step of refining the methanol aqueous solution of ertapenem sodium comprises: adding 0.175 kg of iMoLboX-LMat-NH material and 0.175 kg of polymer chromatographic filler NM200 as a composite adsorption material into a reaction kettle, and then controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0080] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0081] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0082] Example 8

[0083] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0084] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0085] The step of refining the ertapenem sodium methanol aqueous solution comprises: adding 0.175 kg of iMoLboX-LMat-NH material and 0.175 kg of polymer chromatographic filler NM200 as a composite adsorption material into a reactor, and then controlling the temperature at -15 to -5°C and stirring for 30 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0086] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0087] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0088] Example 9

[0089] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0090] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0091] The step of refining the methanol aqueous solution of ertapenem sodium comprises: adding 0.175 kg of iMoLboX-LMat-NH material and 0.175 kg of polymer chromatographic filler NM200 as a composite adsorption material into a reaction kettle, and then controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 50 rpm / min to obtain a refined suspension of ertapenem sodium.

[0092] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0093] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0094] Example 10

[0095] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0096] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0097] The step of refining the ertapenem sodium methanol aqueous solution includes: adding 0.175 kg of LSC-340 resin and 0.175 kg of MOPA-20-2680 material as a composite adsorption material into a reaction kettle, and then controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0098] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0099] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0100] Embodiment 11

[0101] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0102] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0103] The step of refining the methanol aqueous solution of ertapenem sodium includes: adding 0.175 kg of LSC-340 resin and 0.175 kg of polymer chromatographic filler NM200 as a composite adsorption material into a reaction kettle, and then controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0104] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0105] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0106] Example 12

[0107] The embodiment of the present application provides a method for refining ertapenem sodium, and the preparation method includes the steps of preparing an aqueous solution of ertapenem sodium in methanol, refining the aqueous solution of ertapenem sodium in methanol, filtering, and crystallizing.

[0108] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0109] The step of refining the ertapenem sodium methanol aqueous solution comprises: adding 0.175 kg of MOPA-20-2680 material and 0.175 kg of polymer chromatographic filler NM200 as a composite adsorption material into a reaction kettle, and then controlling the temperature at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min to obtain a refined suspension of ertapenem sodium.

[0110] The filtering step includes: filtering the refined suspension of ertapenem sodium with a filter membrane having a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into a reaction kettle to obtain a refined solution of ertapenem sodium.

[0111] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0112] Comparative Example 1

[0113] The comparative example of the present application provides a method for refining ertapenem sodium, and the preparation method comprises the steps of preparing an aqueous solution of ertapenem sodium in methanol, filtering and refining, and crystallizing.

[0114] The steps of preparing the methanol aqueous solution of ertapenem sodium include: cooling 50L of purified water to 0-5°C, adding 5kg of crude ertapenem sodium and stirring to dissolve, transferring the crude solution after dissolution to another reactor containing 40L of methanol cooled to -25--15°C, controlling the speed and amount of adding -25--15°C methanol from the 0-5°C crude solution so that the liquid temperature in the reactor does not exceed -5°C, and controlling the temperature in the reactor at -15--5°C after the transfer is completed to obtain the methanol aqueous solution of ertapenem sodium.

[0115] The steps of filtering and refining include: controlling the temperature in the reactor at -15 to -5°C and stirring for 90 minutes at a stirring speed of 250 rpm / min, then filtering with a filter membrane with a pore size of 0.45 microns, washing the filter cake with 10L of pre-cooled methanol, and transferring the filtrate into the reactor to obtain a refined solution of ertapenem sodium.

[0116] The crystallization step includes: adding 75L of n-propanol to the refined solution of ertapenem sodium, controlling the dropping speed to complete the dropping within 1.5 hours, and stirring and growing the crystal for 2 hours after the dropping is completed; continuing to add 105L of n-propanol, controlling the dropping speed to complete the dropping within 3-5 hours, and stirring and growing the crystal for 15-30 minutes after the dropping is completed, filtering and drying under reduced pressure to obtain the refined ertapenem sodium.

[0117] Experimental Example 1

[0118] Experimental Example 1 of the present application performs performance tests on the refined ertapenem sodium provided in Examples 1-12 and Comparative Example 1 to evaluate the refining effects of different methods on the crude ertapenem sodium. The results are shown in Table 1.

[0119] Table 1: Performance test results of refined ertapenem sodium provided in Examples 1-12 and Comparative Example 1

[0120]

[0121] As can be seen from Table 1, the refining method provided in Comparative Example 1 has a poor refining effect on ertapenem sodium, the residual palladium concentration of ertapenem sodium is 8.29ppm, the total amount of dimers is 0.7%, and the color grade is only 4~5; while the refining method provided in Examples 1-12 significantly reduces the content of impurities such as residual palladium and the total amount of dimers due to the addition of adsorption materials and stirring, and the color grade is also improved; and the refining method of ertapenem sodium provided in Examples 1-12 has a simple refining process, can purify ertapenem sodium on a large scale, and it is convenient to replace the type of adsorption materials, thereby improving the refining effect of ertapenem sodium.

[0122] It can be further seen from Table 1 that after the addition of the adsorbent material, under the same stirring speed and time, the refining effect of ertapenem sodium is different due to the different adsorbent materials; when a single adsorbent material is used, the polymer chromatographic filler NM200 has a better effect in reducing the total amount of dimers in the refined ertapenem sodium and improving the color grade, and the iMoLboX-LMat-NH material has a better effect in reducing the palladium concentration in the refined ertapenem sodium; and compared with a single adsorbent material, the refining effect of the composite adsorbent material can be further improved. When the iMoLboX-LMat-NH material and the polymer chromatographic filler NM200 are used as composite adsorbent materials, the quality of the refined ertapenem sodium can be improved in terms of palladium residue, total amount of dimers and color grade.

[0123] It can also be seen from Table 1 that after adding the same adsorption material, under different stirring speeds and times, the refining effect of Ertapenem Sodium is different due to the different stirring time and speed; when iMoLboX-LMat-NH material and polymer chromatographic filler NM200 are used as composite adsorption materials, after the stirring time is reduced from 90min to 30min, more palladium is likely to remain in the Ertapenem Sodium refined product, and after the stirring speed is reduced from 250rpm / min to 50rpm / min, more palladium and dimer are likely to remain in the Ertapenem Sodium refined product, and the color grade is reduced.

[0124] The above embodiments are only used to illustrate the technical solutions of the present application, rather than to limit them. Although the present application has been described in detail with reference to the aforementioned embodiments, a person skilled in the art should understand that the technical solutions described in the aforementioned embodiments may still be modified, or some or all of the technical features thereof may be replaced by equivalents. However, these modifications or replacements do not deviate the essence of the corresponding technical solutions from the scope of the technical solutions of the embodiments of the present application.

Claims

1. A method for refining ertapenem sodium, characterized in that: The following steps are involved: Step S1, adding a crude aqueous solution of ertapenem sodium into a methanol solvent to obtain an ertapenem sodium methanol aqueous solution at a temperature not exceeding -5°C; Step S2, adding the adsorption material into the methanol aqueous solution of ertapenem sodium and stirring to obtain a refined suspension of ertapenem sodium; Step S3, filtering the refined suspension of ertapenem sodium to obtain a refined solution of ertapenem sodium; Step S4, adding an organic solvent to the refined ertapenem sodium solution for crystallization to obtain a refined ertapenem sodium product.

2. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S2, the adsorption material is selected from at least one of LSC-340 resin, MOPA-20-2680 material, polymer chromatographic filler NM200, and iMoLboX-LMat-NH material.

3. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S2, the adsorption material is selected from at least one composite adsorption material of iMoLboX-LMat-NH material and LSC-340 resin, iMoLboX-LMat-NH material and MOPA-20-2680 material, iMoLboX-LMat-NH material and polymer chromatography filler NM200, LSC-340 resin and MOPA-20-2680 material, LSC-340 resin and polymer chromatography filler NM200, MOPA-20-2680 material and polymer chromatography filler NM200.

4. The method for refining ertapenem sodium according to claim 3, characterized in that: Calculated by parts by mass, the mass ratio of iMoLboX-LMat-NH material and LSC-340 resin in the composite adsorption material is 1:1-3; The mass ratio of iMoLboX-LMat-NH material and MOPA-20-2680 material in the composite adsorption material is 1:1-3; The mass ratio of iMoLboX-LMat-NH material and polymer chromatographic filler NM200 in the composite adsorption material is 1:1-3; The mass ratio of LSC-340 resin and MOPA-20-2680 material in the composite adsorption material is 1:1-3; The mass ratio of LSC-340 resin and polymer chromatographic filler NM200 in the composite adsorption material is 1:1-3; In the composite adsorption material, the mass ratio of MOPA-20-2680 material and polymer chromatographic filler NM200 is 1:1-3.

5. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S1 and step S2, the mass ratio of the crude ertapenem sodium to the adsorption material is 1:0.02-0.

2.

6. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S2, the stirring speed is 200-500 rpm / min, and the time is 20-200 min.

7. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S1, the temperature of the ertapenem sodium methanol aqueous solution is -15 to -5°C.

8. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S3, the filtering process is performed by filtering using a 0.45 μm filter membrane.

9. The method for refining ertapenem sodium according to claim 1, characterized in that: In step S4, the crystallization process is to drop n-propanol into the ertapenem sodium refined solution twice for crystallization.

10. The method for refining ertapenem sodium according to claim 9, characterized in that: In step S4, the step of adding n-propanol dropwise twice to the ertapenem sodium refined solution for crystallization is specifically as follows: Step S41, for the first time, 75 L of n-propanol was added at a dropping speed of 0.8-2.5 L / min within 1.5 h, and after the addition was completed, the crystal was stirred and grown for 2 h; Step S41, adding 105 L of n-propanol at a dropping speed of 0.4-0.6 L / min for the second time within 3-5 hours, stirring and growing the crystal for 15-30 minutes after the dropping is completed, to obtain a crystalline refined product of ertapenem sodium.

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