CN111393455A - Preparation method of cefmetazole impurity - Google Patents
Preparation method of cefmetazole impurity Download PDFInfo
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- CN111393455A CN111393455A CN202010352207.0A CN202010352207A CN111393455A CN 111393455 A CN111393455 A CN 111393455A CN 202010352207 A CN202010352207 A CN 202010352207A CN 111393455 A CN111393455 A CN 111393455A
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- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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- C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
- C07D403/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
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- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
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Abstract
The invention discloses a preparation method of cefmetazole impurity, which comprises the steps of taking cefmetazole intermediate 7-MAC as an initial raw material, hydrolyzing under a proper acidic condition to obtain cefmetazole impurity 2, and carrying out ring-opening reaction on the cefmetazole impurity 2 under an alkaline condition to generate cefmetazole impurity 1. The method for synthesizing cefmetazole has the advantages that the two cefmetazole impurities are prepared by the synthetic method, the synthetic steps are simple, and the purity of the obtained product is high. Because the research and control of the impurities of the raw material medicines are one of the key factors for ensuring the quality of the raw material medicines, the invention provides two novel preparation methods of the cefmetazole impurities, and the two preparation methods have important significance for the quality research of the cefmetazole raw material medicines.
Description
Technical Field
The invention belongs to the field of fine organic synthesis, and particularly relates to a preparation method of cefmetazole impurity.
Background
Cefmetazole, developed by sango corporation and iprjohn corporation in the U.S., is a semisynthetic cefuromycin, has a broad antibacterial spectrum, and has good antibacterial activity against gram-negative bacteria, gram-positive bacteria and anaerobic bacteria, cefmetazole is highly stable against β -lactamase, has good tolerance, small side effects, and wide adaptation diseases.
In 2019, 10 and 15 days, the State drug administration has publicly asked technical requirements (survey draft) for evaluation of the quality of simulated drugs for chemical injections and the consistency of therapeutic effects, and data requirements (survey draft) for evaluation and declaration of the quality of simulated drugs for chemical injections on the market and the consistency of therapeutic effects, and long-term evaluation of consistency of injections has been expected to be formally started in the industry. Therefore, the research on the process impurities and degradation impurities of the cefmetazole bulk drug is particularly important.
The preparation of impurities is one of the important links of the quality research of raw material medicaments and preparations. Impurities can affect the quality of the raw material drugs and further affect the safety of the drugs. Impurities should be well studied and the more comprehensive, the more sufficient the better. The main reasons are: the main factor affecting the safety of drugs is impurities, which must be studied thoroughly in order to ensure the safety of drugs. In addition, insufficient research of impurities cannot prove that the product is free of impurities and that the detection method can detect impurities. Furthermore, the situation of impurities is complex, and particularly highly toxic impurities, at very low limits (possibly as low as a few ppm) can cause serious injury to the human body, and need to be thoroughly studied and controlled. The original research has already carried out sufficient clinical research on the bulk drug prepared by the production process, the imitation drugs are not subjected to clinical tests, and due to the difference of the impurity spectra, some high-toxicity impurities which are not concerned can cause serious consequences, so the risk of the situation is very high. In the process of evaluating cefmetazole consistency, the applicant finds that the cefmetazole impurity sold in the market is not comprehensive, and in order to further research the cefmetazole impurity, the applicant self-prepares two cefmetazole impurities different from those in the same research.
Disclosure of Invention
The invention aims to provide two novel preparation methods of cefmetazole impurities.
In order to achieve the purpose, the invention adopts the following technical scheme:
the preparation method of cefmetazole impurity comprises the following steps:
1) adding 1 part by weight of 7-MAC into 30-60 parts by weight of organic solvent, and uniformly stirring;
2) then, controlling the temperature to be 0-10 ℃, slowly dropwise adding 60-120 parts by weight of 1-3M inorganic acid into the system for 1-3 hours, adjusting the pH to 1-3, raising the temperature to 20-30 ℃, and continuously stirring for 3-5 hours;
3) after the reaction is finished, carrying out extraction and layering, concentrating and spin-drying the organic phase under reduced pressure under the conditions that the temperature is 0-10 ℃ and the vacuum degree is-0.08-0.10 MPa, wherein cefmetazole impurity 2, namely (Z) -benzyl 2- (2, 3-dioxazetidin-1-yl) -4-hydrosulfinyl-3- (((1-methyl-1H-tetrazol-5-yl) thio) but-2-enoate, has the following structural formula:
4) taking 1 part by weight of the prepared cefmetazole impurity 2, adding the cefmetazole impurity into 10-30 parts by weight of aliphatic alcohol, adding 3-5 parts by weight of 10% inorganic alkali solution by mass concentration, controlling the temperature to be 0-10 ℃, and stirring for 2-3 hours;
5) after the reaction is finished, extracting and layering, concentrating and spin-drying the organic phase under reduced pressure under the conditions that the temperature is 0-10 ℃ and the vacuum degree is-0.08 to-0.10 MPa, wherein cefmetazole impurity 1, namely (R) -benzyl-7, 7-dihydroxy-3- (((1-methyl-1H-tetrazol-5-yl) thio) methyl) -8-oxo-5-thia-1-azabicyclo [4.2.0] oct-2-ene-2-carboxylate, has the following structural formula:
the reaction route is as follows:
the reaction mechanism is as follows:
7-MAC carries out the hydrolysis under acid condition and generates cefmetazole impurity 2, and the structure of two hydroxyl groups of cefmetazole impurity 2 is unstable, forms the structure similar to acetal, loses a water easily and forms carbonyl, then carries out ring opening reaction under alkaline condition again, forms cefmetazole impurity 1.
Further, the organic solvent is one of dichloromethane, ethyl acetate, acetone, acetonitrile, n-hexane or tetrahydrofuran.
The inorganic acid is one of hydrochloric acid, sulfuric acid, glacial acetic acid, phosphoric acid or hydrobromic acid.
The aliphatic alcohol is one of ethanol, methanol, isopropanol, n-butanol or isoamylol.
The inorganic base is selected from one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or calcium hydroxide.
According to the technical scheme, cefmetazole intermediate 7-MAC is used as an initial raw material and is hydrolyzed under a proper acidic condition to obtain cefmetazole impurity 2, and the cefmetazole impurity 2 generates a ring-opening reaction under an alkaline condition to generate cefmetazole impurity 1. The method for synthesizing cefmetazole has the advantages that the two cefmetazole impurities are prepared by the synthetic method, the synthetic steps are simple, and the purity of the obtained product is high. The invention simultaneously carries out structural confirmation on two impurities and carries out detection of mass spectrum and nuclear magnetic resonance. Because the research and control of the impurities of the raw material medicines are one of the key factors for ensuring the quality of the raw material medicines, the invention provides two novel preparation methods of the cefmetazole impurities, and the two preparation methods have important significance for the quality research of the cefmetazole raw material medicines.
Drawings
Fig. 1 is a high performance liquid chromatogram of cefmetazole impurity 1.
Fig. 2 is a HNMR picture of cefmetazole impurity 1.
Fig. 3 is a mass spectrum of cefmetazole impurity 1.
Fig. 4 is a high performance liquid chromatogram of cefmetazole impurity 2.
Fig. 5 is a HNMR picture of cefmetazole impurity 2.
Fig. 6 is a mass spectrum of cefmetazole impurity 2.
Detailed Description
The present invention will be further described with reference to specific examples in order to explain the technical contents of the present invention in detail.
Example 1
The preparation method of cefmetazole impurity comprises the following steps:
1) adding 100g of DCM and 2g of 7-MAC into a reaction bottle, starting stirring for 10min to dissolve a solid, controlling the temperature to be 5 ℃, slowly dripping 150g of 3M HCl, adjusting the pH to 1.0 after about 2h, naturally heating to 25 ℃ after dripping is finished, continuously stirring for 3h, extracting for layering after the reaction is finished, concentrating and spin-drying organic phase under reduced pressure, controlling the temperature to be 5 ℃ and controlling the vacuum degree to be-0.10 MPa to obtain cefmetazole impurity 2, wherein a liquid phase map, an HNMR map and a mass spectrum of the cefmetazole impurity are shown in figures 1-3.
2) 1.5g of the impurity 2 prepared above was added to a reaction flask, dissolved in 50g of ethanol, stirred, 5g of 10% NaOH solution was added dropwise over a period of about 0.5h, the temperature was controlled at 5 ℃ after the addition was completed, and stirred for 2 h. And after the reaction is finished, carrying out extraction layering, carrying out vacuum concentration and spin-drying on the organic phase, controlling the temperature to be 5 ℃ and the vacuum degree to be-0.10 MPa, and obtaining cefmetazole impurity 1, wherein a liquid phase spectrogram, an HNMR (hydrogen peroxide magnetic resonance) diagram and a mass spectrogram of the cefmetazole impurity are shown in figures 4-6.
Example 2
The preparation method of cefmetazole impurity comprises the following steps:
1) adding acetonitrile 100g and 7-MAC2g into a reaction bottle, starting stirring for 10min to dissolve the solid, then controlling the temperature to be 0 ℃, and slowly dropwise adding 150g of 3M H2And (3) adjusting the pH value to 1.0 by using SO4 for about 2 hours, naturally heating to 20 ℃ after the dropwise addition, continuously stirring for 3 hours, extracting and layering after the reaction is finished, concentrating and spin-drying the organic phase under reduced pressure, controlling the temperature to be 0 ℃, and controlling the vacuum degree to be-0.08 MPa to obtain cefmetazole impurity 2.
2) 1.5g of the impurity 2 prepared above was added to a reaction flask, dissolved in 50g of methanol, stirred, and then 5g of 10% KOH solution was added dropwise over about 0.5 hour, and after the addition, the temperature was controlled at 0 ℃ and stirred for 2 hours. After the reaction is finished, extracting and layering, concentrating and spin-drying the organic phase under reduced pressure, controlling the temperature at 0 ℃ and the vacuum degree at-0.08 MPa, and obtaining cefmetazole impurity 1.
Example 3
The preparation method of cefmetazole impurity comprises the following steps:
1) adding 100g of n-hexane and 2g of 7-MAC into a reaction bottle, starting stirring for 10min to dissolve the solid, then controlling the temperature to be 10 ℃, and slowly dropwise adding 150g of 3M H3PO4Adjusting the pH to 2.0 after about 2 hours of use, naturally heating to 30 ℃ after the dropwise addition, continuously stirring for 3 hours, extracting and layering after the reaction is finished, concentrating and spin-drying the organic phase under reduced pressure, controlling the temperature to 10 ℃, and controlling the vacuum degree to be-0.10 MPa to obtain cefmetazole impurity 2.
2. 1.5g of impurity 2 prepared as described above was added to a reaction flask, dissolved in 50g of isopropyl alcohol, stirred, and then 5g of 10% Na was added dropwise2CO3The solution took about 0.5h, and after the dropwise addition, the temperature was controlled at 10 ℃ and the solution was stirred for 2 h. After the reaction is finished, extracting and layering, concentrating and spin-drying the organic phase under reduced pressure, controlling the temperature at 10 ℃ and the vacuum degree at-0.10 MPa, and obtaining cefmetazole impurity 1.
Example 4
The preparation method of cefmetazole impurity comprises the following steps:
1) adding 100g of EA and 7-MAC2g into a reaction bottle, starting stirring for 10min to dissolve the solid clearly, controlling the temperature to be 6 ℃, slowly dropwise adding 150g of 3M HOAc, adjusting the pH to be 2.0 after about 2h, naturally heating to 28 ℃ after the dropwise adding is finished, continuously stirring for 3h, extracting and layering after the reaction is finished, concentrating and spin-drying the organic phase under reduced pressure, controlling the temperature to be 6 ℃, and controlling the vacuum degree to be-0.09 MPa to obtain cefmetazole impurity 2.
2) Adding 1.5g of impurity 2 prepared above into a reaction bottle, dissolving in 50g of n-butanol, stirring, and adding 5g of 10% NaHCO dropwise3The solution took about 0.5h, and after the dropwise addition, the temperature was controlled at 6 ℃ and the solution was stirred for 2 h. After the reaction is finished, extracting and layering, concentrating and spin-drying the organic phase under reduced pressure, controlling the temperature to be 6 ℃ and the vacuum degree to be-0.09 MPa, and obtaining cefmetazole impurity 1.
The above description is only an embodiment of the present invention, and not intended to limit the scope of the present invention, and all equivalent modifications made by the present invention in the specification or directly or indirectly applied to the related technical field are included in the scope of the present invention.
Claims (10)
1. The preparation method of cefmetazole impurity is characterized by comprising the following steps: which comprises the following steps:
1) adding 1 part by weight of 7-MAC into 30-60 parts by weight of organic solvent, and uniformly stirring;
2) slowly dripping 60-120 parts by weight of inorganic acid into the system at the temperature of 0-10 ℃, adjusting the pH to 1-3, raising the temperature to 20-30 ℃, and continuously stirring for 3-5 hours;
3) after the reaction is finished, extracting and layering, and concentrating and spin-drying the organic phase under reduced pressure to obtain cefmetazole impurity 2, wherein the structural formula of the cefmetazole impurity 2 is as follows:
2. the method for preparing cefmetazole impurity according to claim 1, wherein the method comprises the following steps: the organic solvent in the step 1) is one of dichloromethane, ethyl acetate, acetone, acetonitrile, normal hexane or tetrahydrofuran.
3. The method for preparing cefmetazole impurity according to claim 1, wherein the method comprises the following steps: and in the step 2), the inorganic acid is one of hydrochloric acid, sulfuric acid, glacial acetic acid, phosphoric acid or hydrobromic acid.
4. The method for preparing cefmetazole impurity according to claim 1, wherein the method comprises the following steps: the molar concentration of the inorganic acid in the step 2) is 1-3M, and the dropping time of the inorganic acid is 1-3 hours.
5. The method for preparing cefmetazole impurity according to claim 1, wherein the method comprises the following steps: the conditions of the reduced pressure concentration and spin drying of the organic phase in the step 3) are as follows: the temperature is 0-10 ℃, and the vacuum degree is-0.08 to-0.10 MPa.
6. The preparation method of cefmetazole impurity is characterized by comprising the following steps: which comprises the following steps:
1) taking 1 part by weight of cefmetazole impurity 2 prepared in claim 1, adding the cefmetazole impurity into 10-30 parts by weight of aliphatic alcohol, adding 3-5 parts by weight of inorganic alkali solution, controlling the temperature to be 0-10 ℃, and stirring for 2-3 hours;
2) after the reaction is finished, extracting and layering, and concentrating and spin-drying the organic phase under reduced pressure under the conditions that the temperature is 0-10 ℃ and the vacuum degree is-0.08-0.10 MPa to obtain cefmetazole impurity 1, wherein the structural formula of the cefmetazole impurity 1 is as follows:
7. the method for preparing cefmetazole impurity according to claim 6, wherein the method comprises the following steps: the aliphatic alcohol in the step 1) is one of ethanol, methanol, isopropanol, n-butanol or isoamylol.
8. The method for preparing cefmetazole impurity according to claim 6, wherein the method comprises the following steps: the inorganic base in the step 1) is one of sodium hydroxide, potassium hydroxide, sodium carbonate, sodium bicarbonate, potassium carbonate or calcium hydroxide.
9. The method for preparing cefmetazole impurity according to claim 6, wherein the method comprises the following steps: the mass concentration of the inorganic alkali solution in the step 1) is 10%.
10. The method for preparing cefmetazole impurity according to claim 6, wherein the method comprises the following steps: the organic phase decompression concentration spin-drying conditions in the step 2) are as follows: the temperature is 0-10 ℃, and the vacuum degree is-0.08 to-0.10 MPa.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114249751A (en) * | 2021-12-28 | 2022-03-29 | 苏州东瑞制药有限公司 | Preparation method of high-purity cefmetazole lactone |
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| CN108299471A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of improvement preparation process of cefmetazole intermediate |
| WO2018219189A1 (en) * | 2017-05-27 | 2018-12-06 | 上海颢峰医药科技有限公司 | Application of cefmetazole in preparation of medicine for preventing/treating pulmonary hypertension |
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- 2020-04-28 CN CN202010352207.0A patent/CN111393455A/en active Pending
Patent Citations (3)
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| CN105646545A (en) * | 2016-03-17 | 2016-06-08 | 重庆福安药业集团庆余堂制药有限公司 | Cefmetazole sodium for reducing anaphylaxis and preparation thereof |
| CN108299471A (en) * | 2017-01-12 | 2018-07-20 | 重庆常捷医药有限公司 | A kind of improvement preparation process of cefmetazole intermediate |
| WO2018219189A1 (en) * | 2017-05-27 | 2018-12-06 | 上海颢峰医药科技有限公司 | Application of cefmetazole in preparation of medicine for preventing/treating pulmonary hypertension |
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114249751A (en) * | 2021-12-28 | 2022-03-29 | 苏州东瑞制药有限公司 | Preparation method of high-purity cefmetazole lactone |
| CN114249751B (en) * | 2021-12-28 | 2023-10-13 | 苏州东瑞制药有限公司 | Preparation method of high-purity cefmetazole lactone |
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