CN110423237B - Method for refining ertapenem sodium - Google Patents
Method for refining ertapenem sodium Download PDFInfo
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- CN110423237B CN110423237B CN201910852580.XA CN201910852580A CN110423237B CN 110423237 B CN110423237 B CN 110423237B CN 201910852580 A CN201910852580 A CN 201910852580A CN 110423237 B CN110423237 B CN 110423237B
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- C07D477/10—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2
- C07D477/12—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6
- C07D477/16—Heterocyclic compounds containing 1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. carbapenicillins, thienamycins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulphur-containing hetero ring with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached in position 4, and with a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 2 with hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, attached in position 6 with hetero atoms or carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. an ester or nitrile radical, directly attached in position 3
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Abstract
The invention discloses a method for refining ertapenem sodium, and relates to the technical field of ertapenem sodium refining. The method comprises the following steps: (1) dissolving ertapenem sodium crude product in water to prepare ertapenem sodium crude product solution; (2) adding the ertapenem sodium crude product solution into an alumina column, controlling the column temperature to be 0-10 ℃, receiving the feed liquid, adding a sodium acetate aqueous solution for desorption, and merging the feed liquid after the desorption is finished; (3) and extracting water from the feed liquid by using n-butyl alcohol, adjusting the volume of a water phase of the feed liquid, and adding an organic solvent into the water phase of the feed liquid for crystallization to obtain an ertapenem sodium refined product. The method has simple process and low cost, is mainly used for reducing the color grade and the heavy metal content of ertapenem sodium, and provides a refining way for unqualified ertapenem sodium.
Description
Technical Field
The invention relates to the technical field of ertapenem sodium refining.
Background
Ertapenem sodium (Etapenem sodium), chemical name (4R, 5S, 6S) -3- [ [ (3S, 5S) -5- [ [ (3-carboxyphenyl) carbamoyl ] pyrrolidin-3-yl ] thio-6- (1-hydroxyethyl) -4-methyl-7-oxo-1-azabicyclo [3.2.0] hept-2-ene-2-carboxylic acid sodium salt, structural formula:
ertapenem, a novel broad spectrum carbapenem antibiotic developed by merck and astrazen, was approved for clinical use in the united states and europe at 11 and 4 months 2001 and 2002, respectively, and was introduced to our country by the msandong corporation in 2005. Ertapenem has the characteristics of long acting, strong antibacterial activity, low bacterial drug resistance selectivity and the like, has obvious clinical treatment advantages compared with other drugs, is the first carbapenem drug approved by FDA for community-acquired pneumonia, and can be used for treating foot infection caused by diabetic complications. Ertapenem interferes with bacterial cell wall synthesis by binding to Penicillin Binding Protein (PBP), resulting in inhibition of bacterial growth and reproduction and lysis of a few cells. Ertapenem is stable to most penicillinases, cephalosporises and extended spectrum beta-lactamases (ESBLs), but is hydrolyzed by metalloenzymes. Ertapenem has high antibacterial activity against gram-positive bacteria such as methicillin-sensitive Staphylococcus aureus, Streptococcus pneumoniae, Streptococcus pyogenes, etc., and bacteria of Enterobacteriaceae; the bacteria of the genus Haemophilus, Moraxella catarrhalis, Neisseria meningitidis, etc. are highly sensitive to the product, but the bacteria of the genus methicillin-resistant Staphylococcus, enterococcus, Pseudomonas aeruginosa, Acinetobacter, etc. are resistant to the product. The product is stable to human kidney dehydropeptidase-I, and does not need to be combined with cilastatin and the like for application.
The color grade and heavy metal residue of the ertapenem sodium product prepared by the existing method are difficult to reach qualified indexes, so that the medicinal ertapenem sodium product with qualified color grade and heavy metal residue has important research significance.
Disclosure of Invention
The invention aims to solve the technical problem of providing a method for refining ertapenem sodium, which has the advantages of simple process and low cost, is mainly used for reducing the color grade and the heavy metal content of the ertapenem sodium, and provides a refining way for unqualified ertapenem sodium.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows: a method for refining ertapenem sodium comprises the following steps:
(1) dissolving ertapenem sodium crude product in water to prepare ertapenem sodium crude product solution;
(2) adding the ertapenem sodium crude product solution into an alumina column, controlling the column temperature to be 0-10 ℃, receiving the feed liquid, adding a sodium acetate aqueous solution for desorption, and merging the feed liquid after the desorption is finished;
(3) and extracting water from the feed liquid by using n-butyl alcohol, adjusting the volume of a water phase of the feed liquid, and adding an organic solvent into the water phase of the feed liquid for crystallization to obtain an ertapenem sodium refined product.
Preferably, in the step (1), the ertapenem sodium crude product is dissolved in water at 0-10 ℃ to prepare an ertapenem sodium crude product solution.
Preferably, in the step (1), the concentration of the ertapenem sodium crude product solution is 30-80 g/L.
Preferably, in the step (2), the preparation method of the alumina column comprises the following steps:
a. activating alumina: uniformly stirring acetic acid with the mass fraction of 10% and neutral alumina, standing for 8-12 hours, and washing with purified water until the liquid is not sour and the water is clear; wherein the ratio of the milliliter number of 10% acetic acid to the gram number of neutral alumina is 1.5-2.5: 3;
b. adding activated and cooled alumina and purified water suspension into chromatographic glass column, settling, washing with purified water of pH7.0 + -0.5 cooled to 0-5 deg.C until the pH of eluate is 6.5-7.5, and making into alumina column.
Preferably, in the step (2), the amount of the alumina in the alumina column is 3-6 times of the weight of the ertapenem sodium crude product.
Preferably, in the step (2), the ratio of the height to the diameter of the alumina column packing is 4-8.
Preferably, in the step (2), the aqueous solution of sodium acetate is prepared by: stirring sodium acetate and purified water until the sodium acetate is completely dissolved, adjusting the pH value to 6.5-7.5 by using glacial acetic acid, and cooling to 0-10 ℃ for later use; wherein the ratio of the milliliter number of the purified water to the gram number of the sodium acetate is 100: 3 to 5.
Preferably, in the step (2), the volume consumption of the sodium acetate aqueous solution is 4-6 times of the volume of the alumina in the alumina column.
Preferably, in the step (3), the feed liquid is extracted with n-butyl alcohol, and the volume consumption of the n-butyl alcohol is 4-8 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 30-80 g/L.
Preferably, in the step (3), adding an organic solvent into the feed liquid water phase for crystallization, wherein the organic solvent is a mixed solution of methanol and n-propanol, and the volume ratio of the methanol to the n-propanol is 1: 1-2; the volume consumption of the organic solvent is 2-3: 1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20 to 10 ℃.
The synthesis of ertapenem sodium used in the invention can refer to the synthesis research of ertapenem sodium [ J ]. J. antibiotic 2011, 36(7):519 and 522.) or other existing technological methods for synthesizing ertapenem sodium.
Adopt the produced beneficial effect of above-mentioned technical scheme to lie in:
(1) the method disclosed by the invention is simple in process and low in cost, is mainly used for reducing the color grade and the heavy metal content of ertapenem sodium, and provides a refining way for unqualified ertapenem sodium.
(2) After the method is refined, the original ertapenem sodium crude product has the color grade of 6#, heavy metal of 11.75ppm or 7# and heavy metal of 12.41ppm, and the ertapenem sodium refined product has the color grade of 1# or 2# and heavy metal of 2.61-3.82ppm and meets the quality requirement.
Detailed Description
The present invention will be described in further detail with reference to specific embodiments.
1. Synthesis of Ertapenem condensates (cf. Saint, Lekun, Zhao Lenz, et al. St. Synthesis of Ertapenem sodium [ J ]. J. China J. antibiotics 2011, 36(7): 519. 522.)
3.36L of anhydrous acetonitrile is added into a reaction kettle, bicyclic MAP (1kg, 1.68mol) is added, the temperature of a side chain (0.9kg, 2.02mol) is reduced to-30 ℃, DIPA (0.2kg, 2mol) is dropwise added to react for 3.5h, reaction liquid is poured into sodium dihydrogen phosphate buffer solution, white solid is separated out, and the white solid is filtered, washed and dried to obtain 1.33kg of white solid, the yield is 100 percent and the HPLC is 99.2 percent.
2. Ertapenem monosodium salt (see Saint, Likun, Zhao Len, et al. St. Synthesis of Ertapenem sodium [ J ]. J. Chinese antibiotics 2011, 36(7): 519. 522.)
Ertapenem condensate (1.33kg, 1.68mol), 10% Pd/C (0.2kg), NaHCO3(0.168kg, 2.0mol) THF (22L) and H had been added2Reacting in an O (44L) hydrogenation reaction kettle at 0-5 ℃ under 10 atmospheric pressures for 3h, filtering, washing palladium carbon, adjusting the pH of the filtrate to 7.5, purifying by a macroporous resin column, concentrating, and dropwise adding acetone into the concentrated solution to obtain 0.53kg of white powder, wherein the yield is 64.4%, and the HPLC (high performance liquid chromatography) is 98.5%.
3. Alumina activation method
80mL of 10% acetic acid and 120g of neutral alumina are added into a 500mL beaker and stirred uniformly, and after standing for 8-12 hours, the mixture is washed by purified water until the liquid is not sour and the water is clear.
4. Preparation method of alumina column
Washing clean chromatographic glass column (containing sand core) with purified water, closing the bottom valve of the alumina column, adding activated and cooled alumina and purified water suspension at 0-5 deg.C, settling, opening the valve to make the upper liquid level of the water phase about 1-2mm higher than the top of the alumina, adding filter paper sheet with proper diameter, and adding a quartz sand layer of about 0.5cm on the filter paper. Washing with purified water of pH7.0 + -0.5 cooled to 0-5 deg.C until the pH of the eluate is 6.5-7.5.
Alumina column # 1: 22mm 200mm, 32g of dry-basis neutral alumina, and the volume of the alumina is about 28 mL;
alumina column # 2: 22mm 200mm, filling 45g of dry-basis neutral alumina, and ensuring that the volume of the alumina is about 40 mL;
alumina column 3 #: 22mm 200mm, 60g of dry-basis neutral alumina, and the volume of the alumina is about 54 mL;
alumina column 4 #: 30mm 200mm, and 120g of dry-basis neutral alumina with the volume of about 107 mL;
5. preparation of sodium acetate desorption solution
1000mL of purified water, 30-50 g of sodium acetate is added, and the mixture is stirred until the sodium acetate is completely dissolved. Carefully adjusting the pH value to 6.5-7.5 by using glacial acetic acid. Cooling to 0-10 ℃ for later use.
Example 1 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 300mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the ertapenem sodium crude product solution into a No. 1 alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. Adding 120mL of 4% sodium acetate solution (1000 mL of purified water, 40g of sodium acetate, stirring until the sodium acetate is completely dissolved), and carefully adjusting the pH value to 6.5-7.5 with glacial acetic acid, and cooling to 0-10 ℃ for later use) to elute the product, wherein the elution speed is 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 8 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 30 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20 to-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 6.43g of white crystalline powder of ertapenem sodium product is obtained, the yield is 64.30 percent, the color grade is No. 2, and the heavy metal residue is 3.22 ppm.
Example 2 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 200mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a No. 1 alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 120mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase in the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 6.5 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 50 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 2; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-10 to 0 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 6.41g of white crystalline powder of ertapenem sodium product is obtained, the yield is 64.10%, the color grade is No. 2, and the heavy metal residue is 3.46 ppm.
Example 3 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 130mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a No. 1 alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 120mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 4 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 80 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1.5; the total volume of the methanol and the n-propanol is 3:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20 to 10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 6.15g of white crystalline powder of ertapenem sodium product is obtained, the yield is 61.50%, the color grade is No. 2, and the heavy metal residue is 3.82 ppm.
Example 4 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 300mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a No. 2 alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 200mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase in the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 7.5 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 35 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 2; the total volume of the methanol and the n-propanol is 2.5:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5-15 ℃, and 6.37g of white crystalline powder of ertapenem sodium product is obtained, the yield is 63.70%, the color grade is light, and the heavy metal residue is 3.01 ppm.
Example 5 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 200mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a No. 2 alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 200mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 6 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 55 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-10 to-0 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 6.31g of white crystalline powder of ertapenem sodium product is obtained, the yield is 63.10 percent, the color grade is light No. 2, and the heavy metal residue is 3.12 ppm.
Example 6 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 130mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a No. 2 alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 200mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase in the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 4.5 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 75 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 2; the total volume of the methanol and the n-propanol is 2.5:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5-15 ℃, and 6.11g of white crystalline powder of ertapenem sodium product is obtained, the yield is 61.10%, the color grade is light No. 2, and the heavy metal residue is 3.44 ppm.
Example 7 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 300mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a 3# alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 300mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 8 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 30 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20 to-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 6.32g of white crystalline powder of ertapenem sodium product is obtained, the yield is 63.20%, the color grade is light, and the heavy metal residue is 2.88 ppm.
Example 8 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 200mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a 3# alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 300mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase in the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 6.5 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 50 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 2; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-10-0 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5-15 ℃, and 6.26g of white crystalline powder of ertapenem sodium product is obtained, the yield is 62.60%, the color grade is light No. 2, and the heavy metal residue is 3.96 ppm.
Example 9 purification of ertapenem sodium
(1) 10.0g of ertapenem sodium crude product (color grade No. 7, heavy metal 12.41ppm) is taken and added into a beaker filled with 130mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a 3# alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 300mL of 4% sodium acetate solution was added to the alumina column for elution at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 4 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 80 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1.5; the total volume of the methanol and the n-propanol is 3:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5-15 ℃, and 6.13g of white crystalline powder of ertapenem sodium product is obtained, the yield is 61.30%, the color grade is light No. 2, and the heavy metal residue is 3.07 ppm.
Example 10 purification of ertapenem sodium
(1) 20.0g of ertapenem sodium crude product (color grade No. 6, heavy metal 11.75ppm) is taken and added into a beaker filled with 600mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a 4# alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 500mL of 4% sodium acetate solution was added to the alumina column to elute at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 8 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 30 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20 to-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 13.73g of white crystalline powder of ertapenem sodium product is obtained, the yield is 68.65 percent, the color grade is No. 1, and the heavy metal residue is 2.61 ppm.
Example 11 purification of ertapenem sodium
(1) 20.0g of ertapenem sodium crude product (color grade No. 6, heavy metal 11.75ppm) is taken and added into a beaker filled with 360mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a 4# alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 500mL of 4% sodium acetate solution was added to the alumina column to elute at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase of the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 6 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 55 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 1; the total volume of the methanol and the n-propanol is 2:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-10 to-0 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5 to 15 ℃, and 13.52g of white crystalline powder of ertapenem sodium product is obtained, the yield is 67.60 percent, the color grade is No. 1, and the heavy metal residue is 2.74 ppm.
Example 12 purification of ertapenem sodium
(1) 20.0g of ertapenem sodium crude product (color grade No. 6, heavy metal 11.75ppm) is taken and added into a beaker filled with 280mL of purified water precooled to 0-5 ℃, and the mixture is stirred and dissolved uniformly by a glass rod for later use.
(2) Closing a column bottom valve of the alumina column, adding the crude ertapenem sodium crude product solution into a 4# alumina column in several times, and controlling the column temperature to be 0-10 ℃. And opening a column bottom valve, controlling the flow rate, and finishing the material passing within about 5 +/-0.5 hours. The first 2BV of feed was tested for absence of ertapenem sodium product and the feed was received from the third BV. 500mL of 4% sodium acetate solution was added to the alumina column to elute at a rate of 1.5 BV/h. After the elution is finished, the feed liquid is combined.
(3) Adjusting the volume of the water phase in the feed liquid by using n-butyl alcohol, wherein the volume of the n-butyl alcohol is 4.5 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 75 g/L. Adding methanol and n-propanol into the water phase for crystallization, wherein the volume ratio of the methanol to the n-propanol is 1: 2; the total volume of the methanol and the n-propanol is 2.5:1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20-10 ℃, the filtration is carried out, the low-temperature vacuum drying is carried out at the temperature of 5-15 ℃, and 13.12g of white crystalline powder of ertapenem sodium product is obtained, the yield is 65.60%, the color grade is No. 1, and the heavy metal residue is 2.83 ppm.
Examples 1-12 ertapenem sodium refining experiments the results of the study are shown in table 1:
the quality requirements of the qualified medicinal ertapenem sodium have the indexes of color grade less than or equal to 4#, heavy metal less than 10ppm and content more than or equal to 90%.
As can be seen from Table 1, the original ertapenem sodium crude product has a color grade of 6#, heavy metals of 11.75ppm or 7# and heavy metals of 12.41ppm, and the color grade of the ertapenem sodium crude product refined by the method of the invention reaches 1# or 2#, the heavy metals of 2.61-3.82ppm, and in addition, the content is more than 90% by detection, thereby meeting the quality requirements.
The above is only a preferred embodiment of the present invention, and it should be understood that the present invention is not limited thereto, and those skilled in the art can make various modifications, decorations and equivalents without departing from the principle of the present invention, and therefore, the present invention is to be covered within the protection scope of the present invention.
Claims (1)
1. A method for refining ertapenem sodium is characterized by comprising the following steps:
(1) dissolving ertapenem sodium crude product in water to prepare ertapenem sodium crude product solution;
(2) adding the ertapenem sodium crude product solution into an alumina column, controlling the column temperature to be 0-10 ℃, receiving the feed liquid, adding a sodium acetate aqueous solution for desorption, and merging the feed liquid after the desorption is finished;
(3) extracting water from the feed liquid by using n-butanol, adjusting the volume of the water phase of the feed liquid, and adding an organic solvent into the water phase of the feed liquid for crystallization to obtain an ertapenem sodium refined product;
in the step (1), dissolving ertapenem sodium crude product in water at 0-10 ℃ to prepare ertapenem sodium crude product solution; in the step (1), the concentration of the ertapenem sodium crude product solution is 30-80 g/L;
in the step (2), the preparation method of the alumina column comprises the following steps:
a. activating alumina: uniformly stirring acetic acid with the mass fraction of 10% and neutral alumina, standing for 8-12 hours, and washing with purified water until the liquid is not sour and the water is clear; wherein the ratio of the milliliter number of 10% acetic acid to the gram number of neutral alumina is 1.5-2.5: 3;
b. adding activated and cooled alumina and purified water suspension into chromatographic glass column, settling, washing with purified water of pH7.0 + -0.5 cooled to 0-5 deg.C until the pH of eluate is 6.5-7.5 to obtain alumina column; in the step (2), the amount of aluminum oxide in the aluminum oxide column is 3-6 times of the weight of the ertapenem sodium crude product; in the step (2), the height-diameter ratio of the alumina column filler is 4-8; in the step (2), the sodium acetate aqueous solution is prepared by: stirring sodium acetate and purified water until the sodium acetate is completely dissolved, adjusting the pH value to 6.5-7.5 by using glacial acetic acid, and cooling to 0-10 ℃ for later use; wherein the ratio of the milliliter number of the purified water to the gram number of the sodium acetate is 100: 3-5; in the step (2), the volume consumption of the sodium acetate aqueous solution is 4-6 times of the volume of the alumina in the alumina column; in the step (3), the feed liquid is used for extracting water by using n-butyl alcohol, and the volume consumption of the n-butyl alcohol is 4-8 times of the volume of the feed liquid; extracting water with n-butanol to adjust water phase volume of the feed liquid to 30-80 g/L; in the step (3), adding an organic solvent into the feed liquid water phase for crystallization, wherein the organic solvent is a mixed solution of methanol and n-propanol, and the volume ratio of the methanol to the n-propanol is 1: 1-2; the volume consumption of the organic solvent is 2-3: 1 of the volume of the water phase of the feed liquid; the crystallization temperature is-20 to 10 ℃.
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