CN110590814A - Synthetic method of dimer impurity generated in production of cefazolin sodium - Google Patents
Synthetic method of dimer impurity generated in production of cefazolin sodium Download PDFInfo
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- CN110590814A CN110590814A CN201910929372.5A CN201910929372A CN110590814A CN 110590814 A CN110590814 A CN 110590814A CN 201910929372 A CN201910929372 A CN 201910929372A CN 110590814 A CN110590814 A CN 110590814A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/04—Preparation or injection of sample to be analysed
- G01N30/06—Preparation
Abstract
The invention discloses a dimer impurity D generated by cefazolin sodium and a synthetic method of the dimer impurity generated by producing the cefazolin sodium. The method comprises the following steps: reacting the starting material A and sodium hydroxide in ethanol and water as solvents, adjusting the pH value with dilute hydrochloric acid, extracting, and distilling to obtain an intermediate B; adding the intermediate B into dichloromethane, adding a dess-martin reagent, quenching the reaction solution, and filtering to obtain a mother solution of the compound C for later use; and sequentially adding the compound A and sodium triacetyl borohydride into dichloromethane, adding the mother liquor of the product C, quenching, extracting and purifying by using a chromatographic silica gel column to obtain a dimer impurity D after the reaction is finished. The dimeric impurity D synthesized may provide an impurity control for the reaction.
Description
Technical Field
The invention belongs to the technical field of pharmaceutical chemistry synthesis, and particularly relates to a synthetic method of dimer impurities in a production process of cefazolin sodium.
Background
Cefazolin sodium is a semi-synthetic third-generation cephalosporin. The product is free acid (pentahydrate), and is added with a certain amount of anhydrous sodium carbonate to prepare injection for use. Is suitable for treating septicemia caused by sensitive gram-negative bacilli, lower respiratory system infection, celiac and biliary system infection, complicated urinary tract infection and severe skin soft tissue infection.
Cefazolin sodium was discovered in 1978. In 1983, the british pueraria lanuginosa company first developed it on the market. In 1992, cefazolin sodium is first marketed in China, and is formally listed in the basic medicine catalog in China in 1993. Clinical application for 10 years proves that the cefazolin sodium has the characteristics of wide antibacterial spectrum, enzyme resistance and the like, has strong antibacterial activity on pseudomonas aeruginosa, is widely used for treating various moderate and severe infections, and is a preferred medicine for treating critical patients infected with gram-negative bacteria. The antibacterial action mechanism of cefazolin sodium is to influence the synthesis of bacterial cell walls. Similar to other cephalosporins, the product can inhibit transpeptidation of transpeptidase in the final step of cell wall synthesis, so that cross-linking can not be formed, thereby affecting cell wall synthesis and leading to bacterial lysis and death.
The main synthetic route is mainly as follows:
CN105541870, 2016, reports to disclose preparation of cefazolin sodium from 7-aminocephalosporanic acid; wherein the reaction equation is as follows:
the dimer compound is an impurity MS (M + H) appearing in the synthesis process of cefazolin sodium]+=485.1, but studies on the synthesis method of the impurity have not been reported so far.
Disclosure of Invention
The present invention provides a dimer and a simple method for synthesizing the dimer.
In order to achieve the purpose, the invention provides the following technical scheme:
a dimeric impurity D produced by cefazolin sodium, characterized in that it has the following structure:
the invention further discloses a synthetic method of dimer impurity D generated by cefazolin sodium, which is characterized by comprising the following steps:
1) reacting the starting material A and sodium hydroxide in ethanol and water as solvents under the reaction condition of 30 ℃ for 12 hours, adjusting the pH value with dilute hydrochloric acid, extracting, and distilling to obtain an intermediate B; the starting material A: the molar ratio of sodium hydroxide is 1: 2.5 to 4;
2) adding the intermediate B obtained in the step 1) into dichloromethane, adding a dess-martin reagent, using quenching reaction liquid, and filtering to obtain mother liquid of a compound C for later use; the intermediate B: ratio of dess martin reagent 1: 1 to 3;
3) sequentially adding the compound A and sodium triacetyl borohydride into dichloromethane, adding the mother liquor of the product C in the step 2), quenching and extracting after the reaction is finished, and purifying by using a chromatographic silica gel column to obtain a dimer impurity D;
the ratio of the compound C to the sodium triacetyl borohydride is 1: 1 to 3;
the solvent used by the chromatographic column in the step 3) is ethyl acetate: petroleum ether = 5: 1- -3
The invention further discloses application of the dimer impurity D generated by the cefazolin sodium in preparation of a reference substance for detecting the cefazolin sodium impurity, and experimental results show that the synthesis method is simple and effective.
The invention is described in more detail below:
the synthetic route of the synthetic method of the cefazolin sodium dimeric impurity D disclosed by the invention is as follows:
1) reacting the starting material A and sodium hydroxide in ethanol and water as solvents, adjusting the pH value with dilute hydrochloric acid, extracting, and distilling to obtain an intermediate B;
2) adding the intermediate B obtained in the step 1) into dichloromethane, adding a dess-martin reagent, using quenching reaction liquid, and filtering to obtain mother liquid of a compound C for later use;
3) and (3) sequentially adding the compound A and sodium triacetyl borohydride into dichloromethane, adding the mother liquor of the product C in the step 2), and reacting. Quenching, extracting and purifying by a chromatographic silica gel column to obtain a dimer impurity D.
In the synthesis method of the present invention, compound B: ratio of dess martin reagent 1: 1.05.
in the synthesis method, the preferable ratio of the compound C to the sodium triacetyl borohydride is 1: 1.05.
in the synthesis method of the invention, the reaction condition temperature in the step 1) is preferably 30 ℃ and the time is 12 hours.
In the synthesis method, the solvent used in the chromatographic column in the step 3) is preferably ethyl acetate: petroleum ether = 5: 1.
the synthesis method of the dimer impurity generated in the production of cefazolin sodium disclosed by the invention has the positive effects that:
(1) a simple method for synthesizing a dimer is provided.
(2) The synthesized dimeric impurity D can provide impurity contrast for reaction, and the problem of impurity analysis control of cefazolin sodium is solved.
Detailed Description
For the sake of simplicity and clarity, descriptions of well-known techniques are omitted appropriately below to avoid unnecessary detail affecting the description of the present solution. The synthesis of dimeric impurity D in the production of cefazolin sodium according to the present invention is further illustrated below with reference to preferred examples, in particular compound a can be synthesized by the method provided in US5552542, 1996 or commercially available; the sodium hydroxide, dess-martin reagent and sodium triacetoxyborohydride are commercially available.
Example 1
A method for synthesizing dimeric impurity D produced in the production of cefazolin sodium, comprising the steps of:
1) 50.00 g (0.183 mol) of Compound A, 250 ml of ethanol and 125ml of water are respectively added into a 1000ml three-necked flask with a thermometer and a mechanical stirrer, 18.30 g (0.457mol) of sodium hydroxide is slowly added at the temperature of 30 ℃, the temperature is kept at 30 ℃, the reaction is kept at the temperature for 12 hours, the TLC is used for monitoring the reaction, after the reaction is finished, the ethanol in the reaction solution is distilled off, the pH is adjusted to be approximately equal to 7 by 5 percent of hydrochloric acid aqueous solution, the ethyl acetate is extracted by ethyl acetate, and the ethyl acetate is distilled off under reduced pressure to obtain 34.50 g of compound B, the yield is 82 percent, and the content is 98.2 percent.
2) To a 2000 ml three-necked flask equipped with a thermometer and mechanical stirring under nitrogen atmosphere was added 34.50 g (0.15 mol) of Compound B, 1000ml of dry dichloromethane, 66.80g (0.158mol) of dess Martin reagent was slowly added at 20 ℃ and the reaction was monitored by TLC for 1 hour, after completion of the reaction, the reaction solution was filtered through a Buchner funnel lined with diatomaceous earth and the filter cake was rinsed with a small amount of dry dichloromethane. The mother liquor does not need to be treated.
3) To a 2000 ml three-necked flask equipped with a thermometer and mechanically stirred, 28.59 g (0.105 mol) of Compound A, 24.47 g (0.115ml) of sodium triacetoxyborohydride and 300 ml of dried methylene chloride were added dropwise, 1000ml of the mother liquor of the previous step C was added dropwise, the temperature was controlled at 25 ℃ with an ice water bath, the reaction was kept at an incubation temperature for 1.5 hours, the reaction was monitored by TLC, after completion of the reaction, the reaction was quenched with 500 ml of water, extracted with methylene chloride to obtain 85.0 g of a crude product, and purified by a column chromatography silica gel (200 mesh silica gel, using ethyl acetate as a solvent: the petroleum ether proportion is 5: 1) purification gave 24.23 g of dimer D in 33.21% yield over two steps, content 93.1%.1H NMR(DMSO-d 6 )δ10.54(br,2H),8.25(br,4H),4.85(s,2H), 4.3-4.5(m,2H), 4.3-4.5(m,4H), 3.44(d, 2H), 3.20-3.25(m,5H), 2.21(s,3H). [M+H]+=485.1.
The dimeric impurity D can be efficiently synthesized according to the formula. However, the synthesis yield of the two steps is low, and finally, the reductive amination reaction contains more impurities. Purification is difficult.
Example 2
1) Respectively adding 50.00 g (0.183 mol) of compound A, 250 ml of ethanol and 125ml of water into a 1000ml three-neck flask provided with a thermometer and a mechanical stirrer, slowly adding 18.30 g (0.457mol) of sodium hydroxide at the temperature of 30 ℃, keeping the temperature for reaction for 12 hours, monitoring the reaction by TLC, evaporating ethanol in a reaction solution after the reaction is finished, adjusting the pH to be approximately 7 by 5 percent of hydrochloric acid aqueous solution, extracting by ethyl acetate, distilling under reduced pressure to remove the ethyl acetate to obtain 34.50 g of compound B, wherein the yield is 82 percent, and the content is 98.2 percent
2) To a 2000 ml three-necked flask equipped with a thermometer and mechanical stirring under nitrogen atmosphere was added 34.50 g (0.15 mol) of Compound B, 1000ml of dry methylene chloride, the reaction temperature was lowered to 0 ℃ with an ice-water bath, 66.80g (0.158mol) of dess Martin reagent was slowly added, the reaction was incubated for 1 hour, the reaction was monitored by TLC, after completion of the reaction, the reaction solution was filtered through a Buchner funnel lined with diatomaceous earth, and the filter cake was rinsed with a small amount of dry methylene chloride. The mother liquor C is directly used in the next step without being treated.
3) To a 2000 ml three-necked flask equipped with a thermometer and mechanically stirred, 28.59 g (0.105 mol) of Compound A, 24.47 g (0.115ml) of sodium triacetoxyborohydride and 300 ml of dried methylene chloride were added dropwise, 1000ml of the mother liquor of the previous step C was added dropwise, the temperature was controlled at 10 ℃ in an ice water bath, the reaction was kept at an elevated temperature for 2 hours, the reaction was monitored by TLC, after the completion of the reaction, the reaction was quenched with 500 ml of water, and the crude product was extracted with methylene chloride to give 80.0 g, which was purified by column chromatography on silica gel (200 mesh silica gel, using ethyl acetate as a solvent: the petroleum ether proportion is 5: 1) purification gave 32.11 g of dimer D in 44% yield over the two steps, content 95.1%.1H NMR(DMSO-d6)δ10.54(br,2H),8.25(br,4H),4.85(s,2H), 4.3-4.5(m,2H), 4.3-4.5(m,4H), 3.44(d, 2H), 3.20-3.25(m,5H), 2.21(s,3H). [M+H]+=485.1.
The dimer impurity D can be synthesized efficiently and high-quality according to the formula. The reductive amination reaction process has few impurities, the reaction is fast, the purification is simple, and the synthetic dimeric impurity D is easily obtained.
Example 3
An Agilent 1200 high performance liquid chromatograph, a semi-preparative column (10mm multiplied by 250mm, 10 μm) with octadecylsilane chemically bonded silica as a filler, a 5mmol/L ammonium acetate solution-methanol (the volume ratio of the two is 700-. Under the chromatographic conditions, cefazolin sodium peaks for about 20 minutes and impurities peaks for about 15 minutes.
Taking a proper amount of the impurity monomer, preparing a solution of 0.5mg/ml by using a diluent, determining according to a method for checking related substances of cefazolin sodium, and calculating the purity of a main peak to be 99.2% by using an area normalization method. No peak was observed at 15 minutes. For further verification, the test solution is added into a cefazolin sodium sample solution to be used as a mixed solution for HPLC determination, a peak appears in 15 minutes, and a chromatogram proves that the cefazolin sodium sample has no target impurity peak.
It will be apparent to those skilled in the art that various changes and modifications can be made in the above embodiments without departing from the spirit and scope of the invention, and it is intended that all such changes and modifications as fall within the true spirit and scope of the invention be interpreted in accordance with the principles of the invention. And the invention is not limited to the example embodiments set forth in the description.
Claims (4)
1. A dimeric impurity D produced by cefazolin sodium, characterized in that it has the following structure:
2. a process for the synthesis of dimeric impurity D produced by cefazolin sodium according to claim 1, comprising the steps of:
1) reacting the starting material A and sodium hydroxide in ethanol and water as solvents under the reaction condition of 30 ℃ for 12 hours, adjusting the pH value with dilute hydrochloric acid, extracting, and distilling to obtain an intermediate B; the starting material A: the molar ratio of sodium hydroxide is 1: 2.5 to 4;
2) adding the intermediate B obtained in the step 1) into dichloromethane, adding a dess-martin reagent, using quenching reaction liquid, and filtering to obtain mother liquid of a compound C for later use; the intermediate B: ratio of dess martin reagent 1: 1 to 3;
3) sequentially adding the compound A and sodium triacetyl borohydride into dichloromethane, adding the mother liquor of the product C in the step 2), quenching and extracting after the reaction is finished, and purifying by using a chromatographic silica gel column to obtain a dimer impurity D;
the ratio of the compound C to the sodium triacetyl borohydride is 1: 1 to 3;
3. the method for synthesizing cefazolin sodium dimer impurity of claim 1, wherein the solvent used in the chromatographic column of step 3) is ethyl acetate: petroleum ether = 5: 1- -3.
4. Use of the dimeric impurity D produced by cefazolin sodium according to claim 1 for the preparation of a control for detecting cefazolin sodium impurity.
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Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478433A (en) * | 2021-12-08 | 2022-05-13 | 河北合佳创新医药科技有限公司 | Preparation method of 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer |
Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1186494A (en) * | 1995-05-11 | 1998-07-01 | 生化企业 | Antibacterial cephalosporins |
| CN103012437A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing cefoxitin acid as antibacterial medicament |
| CN104844623A (en) * | 2015-05-22 | 2015-08-19 | 齐鲁安替制药有限公司 | Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid |
| CN105541870A (en) * | 2016-02-01 | 2016-05-04 | 中山市金城道勃法制药有限公司 | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium |
| WO2016109259A2 (en) * | 2014-12-30 | 2016-07-07 | Merck Sharp & Dohme Corp. | Synthesis of cephalosporin compounds |
-
2019
- 2019-09-29 CN CN201910929372.5A patent/CN110590814A/en active Pending
Patent Citations (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1186494A (en) * | 1995-05-11 | 1998-07-01 | 生化企业 | Antibacterial cephalosporins |
| CN103012437A (en) * | 2012-12-04 | 2013-04-03 | 山东鑫泉医药有限公司 | Method for preparing cefoxitin acid as antibacterial medicament |
| WO2016109259A2 (en) * | 2014-12-30 | 2016-07-07 | Merck Sharp & Dohme Corp. | Synthesis of cephalosporin compounds |
| CN104844623A (en) * | 2015-05-22 | 2015-08-19 | 齐鲁安替制药有限公司 | Synthesis method of high-purity 7-amino-3-propylene-1-yl-3-cephem-4-carboxylic acid |
| CN105541870A (en) * | 2016-02-01 | 2016-05-04 | 中山市金城道勃法制药有限公司 | Preparation method of cefazolin sodium with previous research quality and medicine preparation of cefazolin sodium |
Cited By (1)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114478433A (en) * | 2021-12-08 | 2022-05-13 | 河北合佳创新医药科技有限公司 | Preparation method of 2-methyl-5-mercapto-1, 3, 4-thiadiazole dimer |
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