A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit

Abstract

The invention provides a method for crystallizing phenylacetyl-7-amino-3-deacetoxycephalosporanic acid controllable in particle size and crystal habit. The method includes the following steps that a phenylacetyl-7-amino-3-deacetoxycephalosporanic acid crude product is added into ammonia water and uniformly mixed, and the mixture is filtered to obtain a phenylacetyl-7-amino-3-deacetoxycephalosporanic acid solution; hydrochloric acid is added into the phenylacetyl-7-amino-3-deacetoxycephalosporanic acid solution under the stirring condition at the temperature of 5-30 DEG C and at the speed of 90-180 r / min, the pH value is adjusted to be 1.5-3.0, crystal growing is conducted for 1-5 hours, and the phenylacetyl-7-ADCA is obtained. The purity of the phenylacetyl-7-ADCA prepared through the preparation method of the phenylacetyl-7-ADCA can reach 99.7%, the phenylacetyl-7-ADCA is in a long bar shape or a needle shape in the aspect of crystal habits, and the phenylacetyl-7-ADCA has the advantages of being complete in crystal habit, high in purity, good in liquidity, not prone to coalescence and the like, and has wide application prospects.

Description

technical field

[0001] The invention relates to the technical field of pharmaceutical and chemical production, in particular to a method for crystallizing phenylacetyl-7-amino-3-deacetoxycephalosporanic acid with controllable particle size and crystal habit. Background technique

[0002] Cephalosporin antibiotics are widely used in the treatment of bacterial infections due to their spectrum and low toxicity. 7-Amino-3-deacetoxycephalosporanic acid (7-ADCA) is an important intermediate of semi-synthetic cephalosporin antibiotics, and the demand is gradually increasing, and 7-ADCA is mainly obtained by deacylation of phenylacetyl-7-ADCA of. The traditional synthetic method of phenylacetyl-7-ADCA uses penicillin G sulfoxide as raw material, adopts chemical methods for esterification, rearrangement, ring expansion, hydrolysis, and alkaline hydrolysis to obtain an aqueous solution containing phenylacetyl-7-ADCA salt. Since the aqueous solution of phenylacetyl-7-ADCA salt in thi...

Examples

Embodiment 1

[0035] A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit:

[0036] Step 1. Weigh 3.02 g of fully dried crude phenylacetyl-7-ADCA and place it in a beaker, add 100 g of dilute ammonia solution with a mass fraction of 1%, stir to dissolve, and filter with a 0.45 μm mixed filter membrane to remove insoluble impurities. Obtain phenylacetyl-7-ADCA solution;

[0037] Step 2. Transfer the phenylacetyl-7-ADCA solution to the jacketed crystallizer, turn on the stirring device, control the rotation speed to 120r / min, turn on the constant temperature water bath device, and control the temperature of the crystallization environment in the jacketed crystallizer to 20°C. Add 0.5mol / L dilute hydrochloric acid solution dropwise to the phenylacetyl-7-ADCA solution at a dropping rate of 0.3mL / min. When the pH of the detection system is 2.1, stop adding dilute hydrochloric acid solution and start crystal growth. Th...

Embodiment 2

[0043] A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit:

[0044] Step 1. Weigh 1 g of fully dried phenylacetyl-7-ADCA crude product and place it in a beaker, add 100 g of dilute ammonia solution with a mass fraction of 0.25%, stir to dissolve, and filter with a 0.45 μm organic filter membrane to remove insoluble impurities to obtain Phenylacetyl-7-ADCA solution;

[0045] Step 2. Transfer the phenylacetyl-7-ADCA solution to the jacketed crystallizer, turn on the stirring device, control the rotation speed to 90r / min, turn on the constant temperature water bath device, and control the temperature of the crystallization environment in the jacketed crystallizer to 5°C. Add 0.25mol / L dilute hydrochloric acid solution dropwise to the phenylacetyl-7-ADCA solution at a rate of 0.1mL / min. When the pH of the detection system is 3.0, stop adding dilute hydrochloric acid solution and start growing crystals. ...

Embodiment 3

[0049] A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit:

[0050] Step 1. Weigh 5 g of fully dried phenylacetyl-7-ADCA crude product and place it in a beaker, add 100 g of dilute ammonia solution with a mass fraction of 3%, stir and dissolve, and filter with a 0.22 μm mixed filter membrane to remove insoluble impurities to obtain Phenylacetyl-7-ADCA solution;

[0051] Step 2. Transfer the phenylacetyl-7-ADCA solution to the jacketed crystallizer, turn on the stirring device, control the rotation speed to 180r / min, turn on the constant temperature water bath device, and control the temperature of the crystallization environment in the jacketed crystallizer to 30°C. Add 1.25mol / L dilute hydrochloric acid solution dropwise to the phenylacetyl-7-ADCA solution at a dropping rate of 0.5mL / min, stop adding dilute hydrochloric acid solution when the pH of the detection system is 1.5, start crystal growt...

technical field

[0001] The invention relates to the technical field of pharmaceutical and chemical production, in particular to a method for crystallizing phenylacetyl-7-amino-3-deacetoxycephalosporanic acid with controllable particle size and crystal habit. Background technique

[0002] Cephalosporin antibiotics are widely used in the treatment of bacterial infections due to their spectrum and low toxicity. 7-Amino-3-deacetoxycephalosporanic acid (7-ADCA) is an important intermediate of semi-synthetic cephalosporin antibiotics, and the demand is gradually increasing, and 7-ADCA is mainly obtained by deacylation of phenylacetyl-7-ADCA of. The traditional synthetic method of phenylacetyl-7-ADCA uses penicillin G sulfoxide as raw material, adopts chemical methods for esterification, rearrangement, ring expansion, hydrolysis, and alkaline hydrolysis to obtain an aqueous solution containing phenylacetyl-7-ADCA salt. Since the aqueous solution of phenylacetyl-7-ADCA salt in thi...

Examples

Embodiment 1

[0035] A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit:

[0036] Step 1. Weigh 3.02 g of fully dried crude phenylacetyl-7-ADCA and place it in a beaker, add 100 g of dilute ammonia solution with a mass fraction of 1%, stir to dissolve, and filter with a 0.45 μm mixed filter membrane to remove insoluble impurities. Obtain phenylacetyl-7-ADCA solution;

[0037] Step 2. Transfer the phenylacetyl-7-ADCA solution to the jacketed crystallizer, turn on the stirring device, control the rotation speed to 120r / min, turn on the constant temperature water bath device, and control the temperature of the crystallization environment in the jacketed crystallizer to 20°C. Add 0.5mol / L dilute hydrochloric acid solution dropwise to the phenylacetyl-7-ADCA solution at a dropping rate of 0.3mL / min. When the pH of the detection system is 2.1, stop adding dilute hydrochloric acid solution and start crystal growth. Th...

Embodiment 2

[0043] A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit:

[0044] Step 1. Weigh 1 g of fully dried phenylacetyl-7-ADCA crude product and place it in a beaker, add 100 g of dilute ammonia solution with a mass fraction of 0.25%, stir to dissolve, and filter with a 0.45 μm organic filter membrane to remove insoluble impurities to obtain Phenylacetyl-7-ADCA solution;

[0045] Step 2. Transfer the phenylacetyl-7-ADCA solution to the jacketed crystallizer, turn on the stirring device, control the rotation speed to 90r / min, turn on the constant temperature water bath device, and control the temperature of the crystallization environment in the jacketed crystallizer to 5°C. Add 0.25mol / L dilute hydrochloric acid solution dropwise to the phenylacetyl-7-ADCA solution at a rate of 0.1mL / min. When the pH of the detection system is 3.0, stop adding dilute hydrochloric acid solution and start growing crystals. ...

Embodiment 3

[0049] A crystallization method of phenylacetyl-7-amino-3-desacetoxycephalosporanic acid with controllable particle size and crystal habit:

[0050] Step 1. Weigh 5 g of fully dried phenylacetyl-7-ADCA crude product and place it in a beaker, add 100 g of dilute ammonia solution with a mass fraction of 3%, stir and dissolve, and filter with a 0.22 μm mixed filter membrane to remove insoluble impurities to obtain Phenylacetyl-7-ADCA solution;

[0051] Step 2. Transfer the phenylacetyl-7-ADCA solution to the jacketed crystallizer, turn on the stirring device, control the rotation speed to 180r / min, turn on the constant temperature water bath device, and control the temperature of the crystallization environment in the jacketed crystallizer to 30°C. Add 1.25mol / L dilute hydrochloric acid solution dropwise to the phenylacetyl-7-ADCA solution at a dropping rate of 0.5mL / min, stop adding dilute hydrochloric acid solution when the pH of the detection system is 1.5, start crystal growt...

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