Synthesis method of dimer impurity D produced by cefazolin sodium production

A technology of cefazolin sodium and a synthetic method, which is applied in the field of synthesis of dimer impurities, can solve problems such as no very effective synthetic methods, and achieve the effect of solving the problem of impurity analysis and control and a simple synthetic method

Inactive Publication Date: 2019-12-20
TIANJIN LISHENG PHARM CO LTD
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  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0007] The dimer compound is an impurity that occurs during the synthesis of cefazolin sodium MS: [M+H] + =485.1, but this impurity has not been reported on a very effective synthetic method so far

Method used

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  • Synthesis method of dimer impurity D produced by cefazolin sodium production
  • Synthesis method of dimer impurity D produced by cefazolin sodium production
  • Synthesis method of dimer impurity D produced by cefazolin sodium production

Examples

Experimental program
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Effect test

Embodiment 1

[0036] A kind of synthetic method of the dimeric impurity D that produces cefazolin sodium comprises the following steps:

[0037] 1) Add 50.00 g (0.183 mol) of compound A, 250 ml of ethanol, and 125 ml of water to a 1000 ml three-necked flask equipped with a thermometer and mechanical stirring, and slowly add 18.30 g (0.457 mol) of hydrogen hydroxide at a temperature of 30°C Sodium, keep warm at 30 ℃, keep warm for 12 hours, monitor the reaction by TLC, after the reaction, distill off the ethanol in the reaction solution, adjust the pH ≈ 7 with 5% hydrochloric acid aqueous solution, extract with ethyl acetate, and distill off the acetic acid under reduced pressure Ethyl ester was used to obtain 34.50 g of compound B with a yield of 82% and a content of 98.2%.

[0038] 2) Add 34.50 g (0.15 mol) of compound B and 1000 ml of dry dichloromethane into a 2000 ml three-neck flask equipped with a thermometer and mechanical stirring under nitrogen protection, and slowly add 66.80 g (0...

Embodiment 2

[0042] 1) Add 50.00 g (0.183 mol) of compound A, 250 ml of ethanol, and 125 ml of water to a 1000 ml three-necked flask equipped with a thermometer and mechanical stirring, and slowly add 18.30 g (0.457 mol) of hydrogen hydroxide at a temperature of 30°C Sodium, keep warm at 30 ℃, keep warm for 12 hours, monitor the reaction by TLC, after the reaction, distill off the ethanol in the reaction solution, adjust the pH ≈ 7 with 5% hydrochloric acid aqueous solution, extract with ethyl acetate, and distill off the acetic acid under reduced pressure Ethyl ester obtained 34.50 g of compound B, the yield was 82%, and the content was 98.2%

[0043] 2) Add 34.50 g (0.15 mol) of compound B and 1000 ml of dry dichloromethane into a 2000 ml three-necked flask equipped with a thermometer and mechanical stirring under nitrogen protection, and reduce the reaction temperature to 0 °C with an ice-water bath, slowly Add 66.80g (0.158mol) Dess.Martin reagent, keep warm for 1 hour, TLC monitors th...

Embodiment 3

[0047] Agilent 1200 high-performance liquid chromatography, octadecylsilane bonded silica gel as a semi-preparative column (10mm × 250mm, 10μm) as a filler, 5mmol / L ammonium acetate solution-methanol (the volume ratio of the two is 700-900 :300-100) as the mobile phase, take an appropriate amount of sample, dissolve it in water, and prepare the test solution for impurities of 10-200mg / ml. The injection volume is 100μl, the flow rate is 1-3ml / min, the detection wavelength is 246nm, and the column temperature is 30℃ . Under this chromatographic condition, the peak of cefazolin sodium is about 20 minutes, and the peak of impurities is about 15 minutes.

[0048] Get this impurity monomer proper amount, be prepared as the solution of 0.5mg / ml with diluent, measure by cefazolin sodium related substance inspection method, calculate the purity of main peak with area normalization method and be 99.2%. No peak was found at 15 minutes. For further verification, the test solution was ad...

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Abstract

The invention discloses a dimer impurity D produced by cefazolin sodium, and a synthesis method of the dimer impurity D produced by cefazolin sodium production. The method comprises: carrying out a reaction on an initial raw material A and sodium hydroxide in a solvent ethanol and water, adjusting the pH value with diluted hydrochloric acid, extracting, and distilling to obtain an intermediate B;adding the intermediate B into dichloromethane, adding a Dess-Martin Periodinane reagent, quenching the reaction solution, and filtering to obtain the mother liquor of a compound C so as to be spare;and sequentially adding a compound A and sodium triacetoxyborohydride into dichloromethane, adding the mother liquor of the product C, quenching after completing the reaction, extracting, and purifying by using a chromatographic silica gel column to obtain a dimer impurity D. According to the present invention, the synthesized dimer impurity D can provide impurity control for the reaction.

Description

technical field [0001] The invention belongs to the technical field of pharmaceutical chemical synthesis, and more specifically relates to a synthesis method for dimer impurities in the production process of cefazolin sodium. Background technique [0002] Cefazolin sodium is a semi-synthetic third-generation cephalosporin. The product is free acid (pentahydrate), and a certain amount of anhydrous sodium carbonate is added to make injection for use. It is suitable for sepsis caused by sensitive Gram-negative bacilli, lower respiratory system infection, abdominal cavity and biliary system infection, complicated urinary tract infection and severe skin and soft tissue infection. [0003] Cefazolin sodium was discovered in 1978. In 1983, the British Glaxo Company first developed it and listed it on the market. In 1992, cefazolin sodium was listed in my country for the first time, and in 1993, it was officially included in the list of essential medicines in my country. After m...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07D519/00G01N30/02G01N30/06
CPCC07D519/00G01N30/02G01N30/06
Inventor 姚志雄霍志甲姜根华张瑜
Owner TIANJIN LISHENG PHARM CO LTD
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