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Preparation method of ceftezole sodium

A technology for ceftizole sodium and thiadiazole, which is applied in the field of preparation of ceftizole sodium, can solve problems such as low yield and purity, and achieve the effects of improved product yield and purity, and low related impurities

Active Publication Date: 2019-02-15
SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD +2
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] The prior art reports that the ceftezole sodium process mostly has the problems of low total product yield and purity, related substances, and high residual moisture content. It is very necessary to seek a process to solve the existing technical problems

Method used

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Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0025] Preparation of Intermediate 1

[0026] 11.81g (0.1mol) of 2-mercapto-1,3,4-thiadiazole, BF 3 -Dimethyl carbonate (0.25mol, according to BF 3 ), 180ml of dimethyl carbonate and 0.1mol of carbonic acid were added to the reactor, and then 27.23g (0.1mol) of 7-ACA was slowly added dropwise, and the reaction temperature was controlled at 0-10°C and stirred for 2h. After the reaction was complete, cold water was added, and the Adjust the pH to 5.5 with ammonia water, crystallize for 1 hour, grow crystals for 2-2.5 hours, centrifuge and dry to obtain 31.54 g of intermediate 1 with a yield of 95% and a purity of 99.4%.

[0027] Preparation of Ceftezole Sodium Crude Product

[0028] Add 12.80 g (0.1 mol) of tetrazolium acetic acid, 0.15 mol of 4-picoline and 200 ml of methylene chloride into the reactor, stir and dissolve, and control the temperature at -10 to -5 °C, then add pivaloyl chloride (0.1 mol) was added in batches and stirred for 1 h to obtain intermediate 2 with a ...

Embodiment 2

[0033] Preparation of Intermediate 1

[0034] 11.82g (0.1mol) of 2-mercapto-1,3,4-thiadiazole, BF 3 - Dimethyl carbonate (0.3mol, according to BF 3 ), 180ml of dimethyl carbonate, and 0.1mol of acetic acid were added to the reactor, and then 27.23g (0.1mol) of 7-ACA was slowly added dropwise, and the reaction temperature was controlled at 0-10°C and stirred for 2h. After the reaction was complete, cold water was added, and the Adjust the pH to 5.5 with ammonia water, crystallize for 1 hour, grow crystals for 2-2.5 hours, centrifuge and dry to obtain 30.94 g of intermediate 1 with a yield of 93% and a purity of 99.2%.

[0035] Preparation of Ceftezole Sodium Crude Product

[0036] Add 12.80g (0.1mol) of tetrazoleacetic acid, 0.20mol of 4-picoline and 200ml of dichloromethane into the reactor, stir and dissolve, control the temperature at -10~-5°C, and then add pivaloyl chloride (0.1 mol) was added in batches and stirred for 1 h to obtain intermediate 2 with a purity greater ...

Embodiment 3

[0041] Preparation of Intermediate 1

[0042] 11.82g (0.1mol) of 2-mercapto-1,3,4-thiadiazole, BF 3 -Dimethyl carbonate (0.25mol, according to BF 3 ), 180ml of dimethyl carbonate, and 0.1mol of acetic acid were added to the reactor, and then 27.23g (0.1mol) of 7-ACA was slowly added dropwise, and the reaction temperature was controlled at 0-10°C and stirred for 2h. After the reaction was complete, cold water was added, and the Adjust the pH to 5.5 with ammonia water, crystallize for 1 hour, grow crystals for 2-2.5 hours, centrifuge and dry to obtain 30.60 g of intermediate 1 with a yield of 92% and a purity of 99.2%.

[0043] Preparation of Ceftezole Sodium Crude Product

[0044] Add 12.80g (0.1mol) of tetrazoleacetic acid, 0.15mol of 2,6-lutidine and 200ml of dichloromethane into the reactor, stir and dissolve, control the temperature at -10~-5℃, and then Acid chloride (0.1 mol) was added in batches, and stirred for 1 h to obtain intermediate 2 with a purity greater than 9...

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PUM

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Abstract

The invention discloses a preparation method of ceftezole sodium, and belongs to the technical fields of pharmaceutical synthesis and refining. According to the method, 2-mercapto-1,3,4-thiadiazole and 7-aminocephalosporanic acid(ACA) are adopted to react and prepare an intermediate 1; and the obtained intermediate 1 reacts with tetrazolium anhydride(an intermediate 2) for acidation, salifying andrefining to prepare and obtain the ceftezole sodium. The preparation method provided by the invention is simple in operation, mild in reaction conditions, relatively high in yield and purity, low incontents of maximum single impurities and moisture and suitable for industrial production.

Description

technical field [0001] The invention belongs to the technical field of medicines, in particular to a preparation method of ceftezole sodium. Background technique [0002] Chemical name: (6R,7R)-3-[[(1,3,4-thiazol-2-yl)thio]methyl]-7-[(1H-tetrazol-1-yl)acetamido]-8 -Oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt. [0003] Ceftezole sodium is a cephalosporin derivative with antibacterial activity, and its mechanism of action is to inhibit the synthesis of bacterial cell walls to exert its antibacterial activity. Gram-positive bacteria, especially cocci, including penicillinase-producing and non-penicillinase-producing Staphylococcus aureus, Streptococcus pyogenes, pneumococcus, group B hemolytic streptococcus, viridans streptococcus, Staphylococcus epidermidis, and Diphtheria bacillus and Bacillus anthracis are more sensitive. Moderately sensitive to some Gram-negative bacteria, such as Escherichia coli, Klebsiella, Salmonella, Shigella, Proteus mirab...

Claims

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Application Information

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IPC IPC(8): C07D501/06C07D501/36
CPCC07D501/06C07D501/36
Inventor 宋丽丽朱全明卢少海
Owner SHANDONG LUOXIN PARMACEUTICAL GROUP STOCK CO LTD
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