The preparation method of cefhydroxime sodium crystal

Abstract

The invention belongs to the field of medicinal chemistry, and relates to a preparation method of cephalosporins hydroxyl oxime sodium crystal with high purity and good stability. The preparation method comprises the steps that cephalosporins hydroxyl oxime acid reacts with a salt forming agent sodium acetate through an emulsion interface to form salt, and then the cephalosporins hydroxyl oxime sodium crystal is separated out by adding an anti-solvent. According to the preparation method of the cephalosporins hydroxyl oxime sodium crystal, the prepared cephalosporins hydroxyl oxime sodium crystal is high in purity and good in stability, thus the safety performance can be better, the antibacterial action function is achieved for gram-positive and gram-negative bacteria, and the cephalosporins hydroxyl oxime sodium crystal might be used for infection of respiratory tract, urinary tract, skin, soft tissue and the like.

Description

technical field

[0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a broad-spectrum antibacterial compound 3-hydroxymethyl-7-[2-amino-4-thiazolyl-(methoxyimino)acetamido]-8-oxo A preparation method of generation-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (hereinafter referred to as cefhydroxime sodium) crystal. Background technique

[0002] Cephalosporin antibiotics are widely used antibiotics. Cephalosporins have a "β-lactam ring" in their molecular structure, which acts on the bacterial cell wall to act as an antibacterial agent with little toxic and side effects. They are all fungicides during the reproductive period, and their antibacterial effect is time-dependent and has good tissue penetration It is suitable for various tissue infections caused by sensitive bacteria.

[0003] In 1948, Italian scientist Giuseppe Brotzu extracted cephalosporin compounds for the first time from the acremonium cephal...

Examples

Embodiment 1

[0027] Add 3.6 grams of sodium acetate trihydrate into 14.4 ml of water, stir and dissolve, and prepare an aqueous sodium acetate solution of about 20 wt %;

[0028] At 15-20°C, add 20ml of ethyl acetate and 0.2ml of caprylic acid glyceride into the reaction vessel, stir well, add 10ml of water under stirring, and control the stirring speed at 60-70 rpm to form a uniform emulsion Then, 10 g of cefhydroxamic acid and the above-mentioned about 20 wt % sodium acetate aqueous solution are added to the emulsion in batches at the same time, so that the pH value remains between 6 and 8 for a salt-forming reaction, and the addition is stirred for 30 minutes;

[0029] After the salt-forming reaction, transfer to a centrifuge, centrifuge at a centrifugal speed of 15,000-20,000r / min to break the emulsion, then let it stand and separate the layers, remove the ethyl acetate layer, add 1g of activated carbon to the obtained water layer, and stir for 10 minutes , filtered, after the activate...

Embodiment 2

[0042] Add 3.3 grams of sodium acetate trihydrate into 10 ml of water, stir and dissolve, and prepare an aqueous sodium acetate solution of about 25 wt %;

[0043] At 25-30°C, add 15ml of ethyl acetate and 0.3ml of caprylic acid glyceride into the reaction vessel, stir well, then add 10ml of water while stirring, and control the stirring speed at 90-100 rpm to form a uniform emulsion ; Then 10g of cefhydroxamic acid and the above-mentioned about 25wt% sodium acetate aqueous solution are added to the emulsion in batches at the same time, so that the pH value remains between 6 and 8 for a salt-forming reaction, and the addition is completed and stirred for 25 minutes;

[0044] After the salt-forming reaction, transfer to a centrifuge, centrifuge at a centrifugal speed of 20,000-25,000r / min to break the emulsification, then let it stand and separate the layers, remove the ethyl acetate layer, add 2g of activated carbon to the obtained water layer, and stir for 10 minutes , filter...

Embodiment 3

[0047] Add 3.95 grams of sodium acetate trihydrate into 19.8 ml of water, stir and dissolve, and prepare an aqueous sodium acetate solution of about 16.6 wt %;

[0048] At 5-10°C, add 30ml of ethyl acetate and 1.5ml of caprylic acid glyceride into the reaction vessel, stir well, add 30ml of water under stirring, and control the stirring speed at 50-65 rpm to form a uniform emulsion ; Then 10g of cefhydroxamic acid and the above-mentioned about 16.6wt% sodium acetate aqueous solution are added to the emulsion in batches at the same time, so that the pH value remains between 6 and 8 for a salt-forming reaction, and the addition is stirred for 30 minutes;

[0049] After the salt-forming reaction, transfer to a centrifuge, centrifuge at a centrifugal speed of 15,000-20,000r / min to break the emulsification, then let it stand and separate the layers, remove the ethyl acetate layer, add 5g of activated carbon to the obtained water layer, and stir for 10 minutes , filtered, after the ...

technical field

[0001] The invention belongs to the field of medicinal chemistry, and more specifically relates to a broad-spectrum antibacterial compound 3-hydroxymethyl-7-[2-amino-4-thiazolyl-(methoxyimino)acetamido]-8-oxo A preparation method of generation-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid sodium salt (hereinafter referred to as cefhydroxime sodium) crystal. Background technique

[0002] Cephalosporin antibiotics are widely used antibiotics. Cephalosporins have a "β-lactam ring" in their molecular structure, which acts on the bacterial cell wall to act as an antibacterial agent with little toxic and side effects. They are all fungicides during the reproductive period, and their antibacterial effect is time-dependent and has good tissue penetration It is suitable for various tissue infections caused by sensitive bacteria.

[0003] In 1948, Italian scientist Giuseppe Brotzu extracted cephalosporin compounds for the first time from the acremonium cephal...

Examples

Embodiment 1

[0027] Add 3.6 grams of sodium acetate trihydrate into 14.4 ml of water, stir and dissolve, and prepare an aqueous sodium acetate solution of about 20 wt %;

[0028] At 15-20°C, add 20ml of ethyl acetate and 0.2ml of caprylic acid glyceride into the reaction vessel, stir well, add 10ml of water under stirring, and control the stirring speed at 60-70 rpm to form a uniform emulsion Then, 10 g of cefhydroxamic acid and the above-mentioned about 20 wt % sodium acetate aqueous solution are added to the emulsion in batches at the same time, so that the pH value remains between 6 and 8 for a salt-forming reaction, and the addition is stirred for 30 minutes;

[0029] After the salt-forming reaction, transfer to a centrifuge, centrifuge at a centrifugal speed of 15,000-20,000r / min to break the emulsion, then let it stand and separate the layers, remove the ethyl acetate layer, add 1g of activated carbon to the obtained water layer, and stir for 10 minutes , filtered, after the activate...

Embodiment 2

[0042] Add 3.3 grams of sodium acetate trihydrate into 10 ml of water, stir and dissolve, and prepare an aqueous sodium acetate solution of about 25 wt %;

[0043] At 25-30°C, add 15ml of ethyl acetate and 0.3ml of caprylic acid glyceride into the reaction vessel, stir well, then add 10ml of water while stirring, and control the stirring speed at 90-100 rpm to form a uniform emulsion ; Then 10g of cefhydroxamic acid and the above-mentioned about 25wt% sodium acetate aqueous solution are added to the emulsion in batches at the same time, so that the pH value remains between 6 and 8 for a salt-forming reaction, and the addition is completed and stirred for 25 minutes;

[0044] After the salt-forming reaction, transfer to a centrifuge, centrifuge at a centrifugal speed of 20,000-25,000r / min to break the emulsification, then let it stand and separate the layers, remove the ethyl acetate layer, add 2g of activated carbon to the obtained water layer, and stir for 10 minutes , filter...

Embodiment 3

[0047] Add 3.95 grams of sodium acetate trihydrate into 19.8 ml of water, stir and dissolve, and prepare an aqueous sodium acetate solution of about 16.6 wt %;

[0048] At 5-10°C, add 30ml of ethyl acetate and 1.5ml of caprylic acid glyceride into the reaction vessel, stir well, add 30ml of water under stirring, and control the stirring speed at 50-65 rpm to form a uniform emulsion ; Then 10g of cefhydroxamic acid and the above-mentioned about 16.6wt% sodium acetate aqueous solution are added to the emulsion in batches at the same time, so that the pH value remains between 6 and 8 for a salt-forming reaction, and the addition is stirred for 30 minutes;

[0049] After the salt-forming reaction, transfer to a centrifuge, centrifuge at a centrifugal speed of 15,000-20,000r / min to break the emulsification, then let it stand and separate the layers, remove the ethyl acetate layer, add 5g of activated carbon to the obtained water layer, and stir for 10 minutes , filtered, after the ...

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