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Synthesis method of ceftazidime

A technology of ceftazidime and synthetic method, which is applied in the field of synthesis of biomedicine and chemical technology, can solve problems such as low product yield, and achieve the effects of high yield, reduced ring damage, and reduced production cost

Active Publication Date: 2017-10-20
苏州盛达药业有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0011] Although in this patent, by transforming the active ester of ceftazidime, it is hydrolyzed and then condensed with the TA, which simplifies some operation steps and shortens the production cycle to a certain extent, but still needs to use more in the production process. Expensive iodine reagents are used to ensure that the iodine substitution can be completed. At the same time, through repeated tests by the applicant, more by-products are generated in the process of preparing ceftazidime, and the yield of the product is still low

Method used

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  • Synthesis method of ceftazidime
  • Synthesis method of ceftazidime
  • Synthesis method of ceftazidime

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: 7--ACP·2HCl·H 2 Preparation of O

[0042]In a dry 500ml four-necked flask, add 50g (0.184mol) of 7-ACA and 38g of hexamethyldisilazane amine, heat and reflux for 8 hours, then cool down to 8°C±2°C, add 10g (0.11mol) of aniline, and stir After 0.5 hours, add 42g (0.21mol) iodotrimethylsilane, stir and react for 3 hours, and measure the residue of 7-ACA by HPLC. , N-dimethylformamide, stirred and reacted for 0.5 hours, then below -10°C, added 18g (0.228mol) of pyridine, stirred and reacted for 4 hours under temperature control, cooled to -35°C after the reaction, and added dropwise 15% HCl / isopropanol solution 150ml, after the dropwise addition, stir the reaction for 30 minutes, then add 100ml of purified water, stir well, separate layers, in CH 2 Cl 2 Add 40ml of purified water to the phase for extraction once more, combine the water phases, then add 500ml of acetone to the water phase, control the temperature at 5°C to 10°C, stir, grow crystals for 1 hou...

Embodiment 2

[0043] Example 2: 7--ACP·2HCl·H 2 Preparation of O

[0044] In a dry 500ml four-neck flask, add 50g (0.184mol) of 7-ACA and 38g of hexamethyldisilazane amine, heat and reflux for 8 hours, cool down to 8°C±2°C, add 10g (0.093mol) of 2-formazolamide Aniline, stirred for 0.5 hours, added 40g (0.225mol) iodotrimethylsilane, stirred and reacted for 3 hours, HPLC determined 7-ACA residues, after passing the test, the temperature dropped to -3°C ~ -5°C, added 7ml (0.12mol ) tetrahydrofuran and 40ml N,N-dimethylacetamide, stirred and reacted for 1.0 hour, and then added 18g (0.228mol) of pyridine at a temperature below -5°C, and reacted with temperature controlled stirring for 4 hours. Add 120ml of 15% HCl / isopropanol solution, after the dropwise addition, stir the reaction for 30 minutes, then add 120ml of purified water, stir well, separate layers, and 2 Cl 2 Then add 50ml of purified water to extract once, combine the water phase, add 600ml of acetone to the water phase, control...

Embodiment 3

[0045] Embodiment 3: the preparation of ceftazidime dihydrochloride

[0046] In a dry 1000ml four-necked bottle, add 7-ACP·2HCl·H 2 O 40g (0.104mol), dichloromethane 400ml, ceftazidime active ester 55g (0.115mol), cool down at 0-5°C, add 40g (0.4mol) of triethylamine dropwise, add dropwise for about 15min, and time the reaction for 6h after the dropwise addition , the reaction was completed, filtered, washed with 100ml of dichloromethane, and dried at 45°C to obtain 62g of ceftazidime axetil as an intermediate.

[0047] In another 1000ml four-necked bottle, add 62g of ceftazidime axetil, 50g of formic acid, 50ml of concentrated hydrochloric acid, control the temperature at 20°C-25°C, stir for 3-4h for hydrolysis reaction, after the reaction is completed, add 600ml of acetone dropwise, crystallize, and grow the crystal for 1h. Cool down to 5°C-10°C, grow crystals for 1.5h, filter, wash with acetone, and vacuum-dry at 45°C to obtain 52g of ceftazidime dihydrochloride with a yie...

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Abstract

The invention provides a synthesis method of ceftazidime. The method includes: adopting 7-ACA as the starting material, and carrying out silanization reaction; then adding trimethyliodosilane and an acid-binding agent to carry out iodination reaction; then carrying out pyridine substitution reaction, then performing hydrolysis, acidification and crystallization separation, thus obtaining an intermediate 7-ACP.2HCl.H2O; reacting the intermediate with ceftazidime active ester under usual conditions to obtain ceftazidime dihydrochloride, dissolving ceftazidime dihydrochloride in water, adjusting the pH value, and performing crystallization separation to obtain ceftazidime. Specifically, the acid-binding agent is one of or a combination of several of aniline, 2-methylaniline and 4-toluidine, the feeding mole ratio of the acid-binding agent to 7-ACA is 0.2-0.8:1, tetrahydrofuran and an aprotic polar solvent are added into the reaction system, the aprotic polar solvent is N, N-dimethylformamide and / or N, N-dimethylacetamide. The method provided by the invention has the advantages of high yield, low cost and easy industrial production.

Description

technical field [0001] The invention belongs to the technical synthesis field of biomedicine and chemical engineering, and in particular relates to a synthesis method of ceftazidime. Background technique [0002] Ceftazidime is a third-generation broad-spectrum injectable cephalosporin antibiotic. It is usually mixed with co-solvent sodium carbonate or arginine to form injection powder. It is stable to various β-lactamases; Oxygen strains have a strong bactericidal effect and are highly effective against Pseudomonas aeruginosa. They are the only cephalosporin antibiotics that can replace aminoglycosides, so some people call them the fourth-generation cephalosporin antibiotics. Ceftazidime was created by the British Glaxo Company and launched in the market in 1984. Its structural formula is as follows: [0003] [0004] The chemical name is [(6R-[6α,7β(Z)]]-1-[[7-[[(2-amino-4-thiazolyl)[1-carboxy-1-methylethoxy)imino ]acetyl]amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2...

Claims

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Application Information

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IPC IPC(8): C07D501/46C07D501/04
Inventor 周自金罗新祖陈锋刘华建刘玉良王磊
Owner 苏州盛达药业有限公司
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