CN115232150A - Preparation method of piperacillin sodium impurity - Google Patents
Preparation method of piperacillin sodium impurity Download PDFInfo
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- CN115232150A CN115232150A CN202210930496.7A CN202210930496A CN115232150A CN 115232150 A CN115232150 A CN 115232150A CN 202210930496 A CN202210930496 A CN 202210930496A CN 115232150 A CN115232150 A CN 115232150A
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- 239000012535 impurity Substances 0.000 title claims abstract description 76
- WCMIIGXFCMNQDS-IDYPWDAWSA-M piperacillin sodium Chemical compound [Na+].O=C1C(=O)N(CC)CCN1C(=O)N[C@H](C=1C=CC=CC=1)C(=O)N[C@@H]1C(=O)N2[C@@H](C([O-])=O)C(C)(C)S[C@@H]21 WCMIIGXFCMNQDS-IDYPWDAWSA-M 0.000 title claims abstract description 74
- 229960005264 piperacillin sodium Drugs 0.000 title claims abstract description 73
- 238000002360 preparation method Methods 0.000 title claims abstract description 21
- 238000000034 method Methods 0.000 claims abstract description 24
- 238000006243 chemical reaction Methods 0.000 claims abstract description 20
- 239000012043 crude product Substances 0.000 claims abstract description 20
- AVKUERGKIZMTKX-NJBDSQKTSA-N ampicillin Chemical compound C1([C@@H](N)C(=O)N[C@H]2[C@H]3SC([C@@H](N3C2=O)C(O)=O)(C)C)=CC=CC=C1 AVKUERGKIZMTKX-NJBDSQKTSA-N 0.000 claims abstract description 12
- 238000005917 acylation reaction Methods 0.000 claims abstract description 3
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- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 claims description 15
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 claims description 13
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- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 claims description 9
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- 239000003513 alkali Substances 0.000 claims description 7
- 239000000843 powder Substances 0.000 claims description 7
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- 239000003153 chemical reaction reagent Substances 0.000 claims description 6
- 238000004108 freeze drying Methods 0.000 claims description 6
- BWHMMNNQKKPAPP-UHFFFAOYSA-L potassium carbonate Chemical compound [K+].[K+].[O-]C([O-])=O BWHMMNNQKKPAPP-UHFFFAOYSA-L 0.000 claims description 6
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 claims description 6
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 claims description 6
- 239000003960 organic solvent Substances 0.000 claims description 5
- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 claims description 4
- 239000003795 chemical substances by application Substances 0.000 claims description 4
- 239000002904 solvent Substances 0.000 claims description 4
- 150000007945 N-acyl ureas Chemical group 0.000 claims description 3
- PFKFTWBEEFSNDU-UHFFFAOYSA-N carbonyldiimidazole Chemical compound C1=CN=CN1C(=O)N1C=CN=C1 PFKFTWBEEFSNDU-UHFFFAOYSA-N 0.000 claims description 3
- 238000006555 catalytic reaction Methods 0.000 claims description 3
- 229910000027 potassium carbonate Inorganic materials 0.000 claims description 3
- UCPYLLCMEDAXFR-UHFFFAOYSA-N triphosgene Chemical compound ClC(Cl)(Cl)OC(=O)OC(Cl)(Cl)Cl UCPYLLCMEDAXFR-UHFFFAOYSA-N 0.000 claims description 3
- GSNUFIFRDBKVIE-UHFFFAOYSA-N DMF Natural products CC1=CC=C(C)O1 GSNUFIFRDBKVIE-UHFFFAOYSA-N 0.000 claims description 2
- 230000010933 acylation Effects 0.000 claims description 2
- 238000004587 chromatography analysis Methods 0.000 claims description 2
- 238000011068 loading method Methods 0.000 claims description 2
- 229910000029 sodium carbonate Inorganic materials 0.000 claims description 2
- OAKJQQAXSVQMHS-UHFFFAOYSA-N Hydrazine Chemical compound NN OAKJQQAXSVQMHS-UHFFFAOYSA-N 0.000 claims 1
- 239000002585 base Substances 0.000 claims 1
- 238000004811 liquid chromatography Methods 0.000 claims 1
- 229960002292 piperacillin Drugs 0.000 claims 1
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- 238000003756 stirring Methods 0.000 description 15
- 239000012071 phase Substances 0.000 description 10
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 9
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 9
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- 238000001228 spectrum Methods 0.000 description 4
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- 239000012065 filter cake Substances 0.000 description 3
- 238000004128 high performance liquid chromatography Methods 0.000 description 3
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- OKTJSMMVPCPJKN-UHFFFAOYSA-N Carbon Chemical compound [C] OKTJSMMVPCPJKN-UHFFFAOYSA-N 0.000 description 1
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- 241000588724 Escherichia coli Species 0.000 description 1
- 241000606768 Haemophilus influenzae Species 0.000 description 1
- UFHFLCQGNIYNRP-UHFFFAOYSA-N Hydrogen Chemical compound [H][H] UFHFLCQGNIYNRP-UHFFFAOYSA-N 0.000 description 1
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- 241000588653 Neisseria Species 0.000 description 1
- 229930182555 Penicillin Natural products 0.000 description 1
- JGSARLDLIJGVTE-MBNYWOFBSA-N Penicillin G Chemical compound N([C@H]1[C@H]2SC([C@@H](N2C1=O)C(O)=O)(C)C)C(=O)CC1=CC=CC=C1 JGSARLDLIJGVTE-MBNYWOFBSA-N 0.000 description 1
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- 210000000988 bone and bone Anatomy 0.000 description 1
- 229910052799 carbon Inorganic materials 0.000 description 1
- OKBVVJOGVLARMR-QSWIMTSFSA-N cefixime Chemical compound S1C(N)=NC(C(=N\OCC(O)=O)\C(=O)N[C@@H]2C(N3C(=C(C=C)CS[C@@H]32)C(O)=O)=O)=C1 OKBVVJOGVLARMR-QSWIMTSFSA-N 0.000 description 1
- 229960002129 cefixime Drugs 0.000 description 1
- 210000002421 cell wall Anatomy 0.000 description 1
- 238000011097 chromatography purification Methods 0.000 description 1
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- 229940047650 haemophilus influenzae Drugs 0.000 description 1
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- 229940049954 penicillin Drugs 0.000 description 1
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- 210000001635 urinary tract Anatomy 0.000 description 1
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Images
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D499/00—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
- C07D499/21—Heterocyclic compounds containing 4-thia-1-azabicyclo [3.2.0] heptane ring systems, i.e. compounds containing a ring system of the formula:, e.g. penicillins, penems; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring with a nitrogen atom directly attached in position 6 and 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
- C07D499/80—Compounds with a nitrogen-containing hetero ring, attached with the ring nitrogen atom in position 6
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
Abstract
The invention discloses a preparation method of piperacillin sodium impurities. The method comprises the following steps: a. taking ampicillin as an initial material, and obtaining a piperacillin sodium impurity crude product through acylation reaction; b. the crude product is purified by a preparation liquid phase to obtain the pure piperacillin sodium impurity. The invention has the advantages of cheap and easily obtained synthetic materials, short synthetic route, simple reaction operation, low requirement on reaction equipment and high reaction conversion rate. Under the condition that the piperacillin sodium impurity reference substance is high in price and not easy to buy at present, a relatively convenient and reliable impurity reference substance acquisition channel is provided for the piperacillin sodium quality research, the cost of the impurity reference substance acquisition channel is greatly reduced, and the piperacillin sodium impurity reference substance acquisition channel has a great promotion effect on the more extensive research on the safety, reliability and stability of the piperacillin sodium medicine and the quality control in the production process of the piperacillin sodium medicine.
Description
Technical Field
The invention relates to the technical field of organic synthesis and preparation liquid phase purification, in particular to a synthesis and purification method of piperacillin sodium impurities.
Background
Piperacillin sodium is a semisynthetic penicillin antibiotic approved to be on the market in 1985, and has the characteristics of broad spectrum, high efficiency and good stability, so that the piperacillin sodium has wide clinical application in more than 80 countries and regions around the world at present. The piperacillin sodium plays a role in sterilization by inhibiting the synthesis of bacterial cell walls, and has good antibacterial effects on enterobacteriaceae bacteria such as escherichia coli, proteus, serratia, klebsiella, enterobacteriaceae, citrobacter, salmonella and shigella, and other gram-negative bacteria such as pseudomonas aeruginosa, acinetobacter, haemophilus influenzae and neisseria. The traditional Chinese medicine composition is mainly used for treating infections of lower respiratory tract, abdominal cavity, gynecology, urinary tract, skin, soft tissue, bone, joint and other parts in clinic.
The quality of the medicine is an important standard for measuring the quality of the medicine, and the quality of the medicine is determined by the curative effect and the toxic and side effect of the medicine, namely the effectiveness and the safety of the medicine. It is therefore desirable that the drug be within the therapeutic range without producing severe toxic effects and with little or no side effects. The content of the effective components of the medicine is an important mark for reflecting the purity of the medicine, and impurities in the medicine directly influence the curative effect of the medicine and can cause non-therapeutic toxic and side effects and must be controlled.
Through research, a specific impurity (2S, 5R, 6R) -6- (2, 5-dioxane-4-benzimidazoline-1-yl) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid) is generated in the cefixime production process, the impurity has no CAS number, the structural formula is shown as follows, and the preparation method is not reported in documents to date.
In order to control the quality of the medicine, the impurity content of the piperacillin sodium is definitely required in the registration and declaration process of the medicine. However, the current internationally popular method is to carry out research analysis and verification on the impurity reference substance in the medicine, and the evaluation of the consistency of the imitation pharmacy in China requires that the content of the specific impurity is not higher than that of the original medicine. Meanwhile, in order to ensure the safety of the medicine, the toxicity of the piperacillin sodium impurity is required to be researched, and the toxicity and the possible side effects of the piperacillin sodium impurity are specifically researched and evaluated. However, the piperacillin sodium impurity is a specific impurity, and the impurity is rarely sold in the market, so that the method has important value for quality control and safety evaluation of piperacillin sodium medicaments based on the specific impurity, and has very important practical significance for researching synthesis of the piperacillin sodium impurity.
Disclosure of Invention
The invention provides a preparation method of piperacillin sodium impurities aiming at the defects of the prior art. The invention has the advantages of easily obtained synthetic reaction materials, short synthetic route, low requirement on reaction equipment, mild reaction conditions and high purity of prepared pure products. Under the condition that the piperacillin sodium impurity is high in market price and difficult to buy at present, a relatively convenient and reliable acquisition channel is provided for the piperacillin sodium impurity research, the cost of the piperacillin sodium impurity is greatly reduced, and the piperacillin sodium impurity quality control method has a great promotion effect on the deeper and wider research on the safety, reliability and stability of related drugs of the piperacillin sodium and the quality control in the production process.
The above object of the present invention is achieved by the following means.
In a first aspect, a method for preparing piperacillin sodium impurities comprises the following steps:
a. ampicillin acid reacts with acylating reagent in solvent under the catalysis of alkali to form an inner ureide structure, and crude (2S, 5R, 6R) -6- (2, 5-dioxane-4-phenylimidazoline-1-yl) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid is obtained.
b. And (b) dissolving the crude product obtained in the step (a), loading the crude product into a preparative liquid chromatography column, eluting the crude product by using a mobile phase for chromatographic purification, and then freeze-drying the crude product to obtain a pure product of (2S, 5R, 6R) -6- (2, 5-dioxane-4-phenylimidazoline-1-yl) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid.
The synthetic reaction scheme of step a is expressed by the structural formula:
as an embodiment of the preparation method of piperacillin sodium impurity provided by the invention, one of tetrahydrofuran, acetonitrile, DMF and DMSO is used in the step a.
As an embodiment of the preparation method of piperacillin sodium impurity provided by the present invention, the alkali used in step a is one or two of potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.
In one embodiment of the preparation method of the piperacillin sodium impurity provided by the invention, in the step a, the molar ratio of alkali to ampicillin acid is (1.9 to 2.1): 1.
In one embodiment of the preparation method of piperacillin sodium impurity provided by the present invention, the acylating agent used in step a is one of triphosgene, thionyl chloride and carbonyldiimidazole.
In the step a, the molar ratio of the acylating agent to the ampicillin acid is 1 to 1.5) to 1.
As an embodiment of the preparation method of the piperacillin sodium impurity provided by the invention, the step a is a reaction at 0 to 10 ℃.
As an embodiment of the preparation method of the piperacillin sodium impurity, the reaction time of the step a is 4 to 5 hours.
As an embodiment of the preparation method of piperacillin sodium impurity provided by the present invention, the organic solvent for preparing the mobile phase in step b is one of methanol and acetonitrile.
As an embodiment of the preparation method of the piperacillin sodium impurity provided by the invention, the ratio of the organic solvent to the water in the mobile phase in the step b is (15 to 25): (85 to 75).
In a second aspect, a piperacillin sodium impurity is prepared by the above preparation method of piperacillin sodium impurity.
Compared with the prior art, the invention has the beneficial effects that:
the synthetic reaction materials are easy to obtain, the reaction route is short, the reaction operation is simple, the requirement on reaction equipment is not high, the reaction condition is mild, the content of the synthetic target product is high, a relatively convenient and reliable acquisition channel is provided for the piperacillin sodium impurity research under the condition that the piperacillin sodium impurity is high in market price and is difficult to buy at present, the cost is greatly reduced, and the method has a great promotion effect on the deeper and extensive research on the safety, reliability and stability of the piperacillin sodium related medicament and the quality control in the production process.
Step a, at low temperature and constant temperature, catalyzing amino and amide of ampicillin acid to react with an acylation reagent by using alkali to form an inner ureide structure, generating piperacillin sodium impurities, and extracting and crystallizing after the reaction is finished to obtain crude products with gram-grade more than 73%; and b, using a mobile phase prepared from methanol or acetonitrile and water, purifying by preparative liquid chromatography, and freeze-drying to obtain the target impurity with the purity of 99%, thereby providing a reliable method for obtaining the piperacillin sodium impurity with high purity.
Drawings
FIG. 1 is a synthetic scheme of the piperacillin sodium impurity prepared in example 1.
FIG. 2 is a nuclear magnetic hydrogen spectrum of the piperacillin sodium impurity prepared in example 1.
FIG. 3 is a nuclear magnetic carbon spectrum of the piperacillin sodium impurity prepared in example 1.
FIG. 4 is a mass spectrum of the piperacillin sodium impurity prepared in example 1.
Detailed Description
In order to overcome the technical problems described in the background art, the invention provides a piperacillin sodium impurity and a synthesis method thereof. Specifically, the piperacillin sodium impurity is specifically (2S, 5R, 6R) -6- (2, 5-dioxane-4-benzimidazolin-1-yl) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid, and the preparation method comprises the following steps:
step a: mixing ampicillin acid with an acylating reagent at 0-10 ℃, and adding alkali for catalysis to react to obtain a crude product of (2S, 5R, 6R) -6- (2, 5-dioxane-4-benzimidazol-1-yl) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid.
Step b: the crude product was purified by preparative liquid chromatography to give a pure product of (2S, 5R, 6R) -6- (2, 5-dioxan-4-benzimidazolin-1-yl) -3, 3-dimethyl-7-oxo-4-thia-1-azabicyclo [3.2.0] heptane-2-carboxylic acid.
Specifically, the synthesis process of the piperacillin sodium impurity is expressed by a structural formula as follows:
the invention is described in further detail below with reference to the drawings and specific examples, but the examples are not intended to limit the invention in any way. Reagents, methods and apparatus used in the present invention are conventional in the art unless otherwise indicated. The materials, reagents and the like used in the examples of the present invention are commercially available.
Example 1
The embodiment provides a preparation method of piperacillin sodium impurities, which comprises the following steps:
a1. synthesis of piperacillin sodium impurity crude product
The method comprises the following specific steps: adding 3.50g of ampicillin acid into a clean and dry single-mouth bottle, adding 25mL of tetrahydrofuran and 10mL of DMSO, controlling the temperature to be minus 7.5 to minus 2.5 ℃, stirring for 5min, adding 2.76g of potassium carbonate powder, and slowly dropwise adding a tetrahydrofuran solution of triphosgene (3.7 g of solution in 10mL of tetrahydrofuran). After dripping, stirring for 4 hours at the temperature of 0 to 10 ℃, adding 30mL of water to carry out quenching reaction, carrying out rotary evaporation to remove tetrahydrofuran, washing for three times by using an ethyl acetate 40mL-3 extraction method, removing an organic phase, stirring a water phase at the temperature of 0 to 10 ℃, slowly adjusting the pH value by using 3M dilute hydrochloric acid until a reaction system becomes turbid, stirring for 20 minutes at the temperature of 0 to 10 ℃, adjusting the pH value to 3 by using 3M hydrochloric acid, stirring for 20 minutes at the temperature of 0 to 10 ℃, carrying out suction filtration, and collecting a filter cake, namely a piperacillin sodium impurity crude product.
b1. Purification and drying of piperacillin sodium impurities
The method comprises the following specific steps: the crude product obtained in step a1 was dissolved in 15mL of methanol and applied to a preparative liquid C18 column, which was purified using methanol: pure water =25: and (3) carrying out isocratic elution on 75 mobile phases, collecting elution fractions of main peaks with the retention time of a prepared liquid phase online spectrum of 37 to 41min, freezing and icing the collected elution fractions in a refrigerator at the temperature of-40 ℃, then placing the elution fractions in a freeze dryer for freeze drying, and collecting dried white-like powder to obtain 1.73g of a pure product. HPLC purity 99.46%.
Example 2
The embodiment provides a synthetic method of piperacillin sodium impurities, which comprises the following steps:
a2. synthesis of piperacillin sodium impurity crude product
The method comprises the following specific steps: adding 3.50g of ampicillin acid into a clean and dry single-mouth bottle, adding 25mL of acetonitrile and 10mL of DMSO, controlling the temperature to be minus 7.5 to minus 2.5 ℃, stirring for 5min, adding 0.8g of sodium hydroxide powder, and slowly dropwise adding an acetonitrile solution of thionyl chloride (3.7 g of acetonitrile dissolved in 10mL of acetonitrile). After dripping, controlling the temperature to be 0 to 5 ℃, stirring for 4.5h, adding 30mL of water for quenching reaction, carrying out rotary evaporation to remove acetonitrile, washing for three times by using an ethyl acetate 40mL-3 extraction method, removing an organic phase, slowly adjusting the pH of a water phase at 0 to 10 ℃ under stirring until a reaction system becomes turbid by using 3M dilute hydrochloric acid, controlling the temperature to be 0 to 10 ℃, stirring for 20min, adjusting the pH to be 3 by using 3M hydrochloric acid, controlling the temperature to be 0 to 10 ℃, stirring for 20min, carrying out suction filtration, and collecting a filter cake, namely a piperacillin sodium impurity crude product.
b2. Purification and drying of piperacillin sodium impurities
The method comprises the following specific steps: the crude product obtained in step a1 was dissolved in 15mL of acetonitrile and applied to a preparative liquid C18 column, which was purified using acetonitrile: pure water =15: and (2) performing isocratic elution on the mobile phase of 85, collecting elution fractions of a main peak of which the retention time of the prepared liquid phase on-line chromatogram is 35-37.5 min, freezing and freezing the collected elution fractions in a refrigerator at the temperature of-40 ℃, freeze-drying the elution fractions in a freeze dryer, and collecting dried white-like powder to obtain 1.81g of a pure product. HPLC purity 99.11%.
Example 3
The embodiment provides a synthetic method of piperacillin sodium impurities, which comprises the following steps:
a3. synthesis of piperacillin sodium impurity crude product
The method comprises the following specific steps: adding 3.50g of ampicillin acid into a clean and dry single-neck bottle, adding 30mL of DMF, controlling the temperature to be 7.5 to 2.5 ℃, stirring for 5min, adding 0.48g of lithium hydroxide powder, and then adding 2.4g of carbonyldiimidazole. Stirring for 5 hours at the temperature of 0 to 10 ℃, adding 30mL of water to quench the reaction, extracting with ethyl acetate 40mL/3 for three times, removing the organic phase, stirring the water phase at the temperature of 0 to 10 ℃, slowly adjusting the pH value with 3M dilute hydrochloric acid until the reaction system becomes turbid, stirring for 20 minutes at the temperature of 0 to 10 ℃, adjusting the pH value to 3 with 3M hydrochloric acid, stirring for 20 minutes at the temperature of 0 to 10 ℃, performing suction filtration, and collecting a filter cake, namely the piperacillin sodium impurity crude product.
b3. Purification and drying of piperacillin sodium impurities
The method comprises the following specific steps: the crude product obtained in step a1 was dissolved in 15mL of acetonitrile and loaded onto a preparative liquid C18 chromatography column, which was purified using acetonitrile: pure water =15: and (2) eluting with 85 mobile phases at equal degrees, collecting elution fractions of a main peak of which the retention time of a prepared liquid phase online spectrum is 35-37.5 min, freezing and icing the collected elution fractions in a refrigerator at the temperature of-40 ℃, then placing the elution fractions in a freeze drier for freeze drying, and collecting dried white-like powder to obtain 1.68g of a pure product. HPLC purity 98.27%.
The above embodiments are preferred embodiments of the present invention, but the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications which do not depart from the spirit and principle of the present invention should be construed as equivalents thereof, and all such changes, modifications, substitutions, combinations, and simplifications are intended to be included in the scope of the present invention.
Claims (11)
1. A preparation method of piperacillin sodium impurities is characterized by comprising the following steps:
dissolving ampicillin acid in a solvent, and reacting amino, amide and an acylation reagent under the catalysis of alkali to form an inner ureide structure to obtain the piperacillin sodium impurity crude product.
2. According to the description of claim 1, the crude product is dissolved by a solvent, a liquid chromatography column is prepared by loading, a mobile phase is prepared by an organic solvent and water according to a proper proportion, the piperacillin sodium impurity is purified by chromatography, and the purified piperacillin sodium impurity powder with high purity is obtained by freeze drying.
3. The method for preparing piperacillin sodium impurity according to claim 1, wherein the solvent used in the step a is one or two of tetrahydrofuran, acetonitrile, DMF, DMSO.
4. The method for preparing piperacillin sodium impurity according to claim 1, wherein the base used in the step a is one or two of potassium carbonate, sodium carbonate, lithium hydroxide, sodium hydroxide and potassium hydroxide.
5. The method for preparing piperacillin sodium impurity according to claim 1, wherein in the step a, the molar ratio of the alkali to the ampicillin acid is (1.9 to 2.1): 1.
6. The method for preparing piperacillin sodium impurity according to claim 1, wherein the acylating agent used in step a is one of triphosgene, thionyl chloride and carbonyldiimidazole.
7. The method for preparing piperacillin sodium impurity according to claim 1, wherein in the step a, the molar ratio of the acylating agent to ampicillin acid is (1 to 1.5): 1.
8. The method for preparing piperacillin sodium impurity according to claim 1, wherein the reaction in step a is carried out at 0 to 10 ℃ for 4 to 5 hours.
9. The method for preparing piperacillin sodium impurity according to claim 1, wherein in the step b, the organic solvent for preparing the mobile phase is one of methanol and acetonitrile.
10. The process for the preparation of piperacillin sodium impurity according to claim 1, wherein in the step b, the ratio of the organic solvent to water in the mobile phase is (15 to 25): (85 to 75).
11. Piperacillin impurities, characterized in that they are obtained by the preparation process according to claims 1 to 9.
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Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3926956A (en) * | 1973-02-16 | 1975-12-16 | Rhone Poulenc Sa | Process for the preparation of ampicillin |
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Patent Citations (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US3926956A (en) * | 1973-02-16 | 1975-12-16 | Rhone Poulenc Sa | Process for the preparation of ampicillin |
Non-Patent Citations (1)
| Title |
|---|
| 樊长莹: "哌拉西林杂质及其制备方法研究", 《医药化工》, vol. 46, no. 9, pages 151 - 152 * |
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