阅读说明：本技术 氨基噻唑乙酰肟酸粒径可控的制备方法 (Preparation method of aminothiazole acetohydroxamic acid with controllable particle size ) 是由 余成 刘承平 彭亮 王雅琦 于 2020-12-26 设计创作，主要内容包括：本发明涉及一种氨基噻唑乙酰肟酸粒径可控的制备方法,属于化学制药技术领域。所述的制备方法包括以去甲氨噻肟酸乙酯为原料,经水解生成化合物1的水解步骤；向体系内滴加酰化剂进行酰化反应,得到化合物2的酰化步骤；向反应体系中加入活性炭脱色,然后通过在不同温度下向体系中滴加酸性溶液控制体系pH值,待固体析出后,离心烘干,得到粒度可控的化合物3的析晶步骤。本发明通过控制不同的酸液加入温度,使得制备的氨基噻唑乙酰肟酸粒径可控；工艺流程操作简单,适合工业化生产。(The invention relates to a preparation method of aminothiazole acetohydroxamic acid with controllable particle size, belonging to the technical field of chemical pharmacy. The preparation method comprises a hydrolysis step of hydrolyzing ethyl noraminothiazolyloximate serving as a raw material to generate a compound 1; an acylation step of dropping an acylating agent into the system to carry out an acylation reaction to obtain a compound 2; adding activated carbon into the reaction system for decolorization, then dropwise adding an acidic solution into the system at different temperatures to control the pH value of the system, and after solid is separated out, centrifugally drying to obtain a compound 3 with controllable granularity. The particle size of the prepared aminothiazole acetoxime acid is controllable by controlling the adding temperature of different acid solutions; the process flow is simple to operate and is suitable for industrial production.)

1. A preparation method of aminothiazole acetohydroxamic acid with controllable particle size is characterized by comprising the following steps:

(1) hydrolysis: taking ethyl noraminothiazolyloximate as a raw material, and hydrolyzing to generate a compound 1;

(2) acylation: dropwise adding an acylating agent into the system for acylation reaction to obtain a compound 2;

(3) and (3) crystallization: after the acylation reaction is finished, adding activated carbon into a reaction system for decolorization, then dropwise adding an acidic solution into the system at different temperatures to control the pH value of the system, and after solid is separated out, centrifugally drying to obtain a compound 3 with controllable particle size;

the temperature ranges are as follows:

maintaining the temperature of the system at 10-15 deg.C, and the D50% particle diameter is 55-70 μm;

maintaining the temperature of the system at 20-25 deg.C, and D50% particle size at 75-90 μm;

the system temperature is maintained at 30-35 ℃, and the D50% particle size is 100-120 μm.

2. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1, wherein: the hydrolysis step is carried out in a solvent, wherein the solvent is water or an organic solvent or a mixed solvent consisting of the organic solvent and the water.

3. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 2, wherein: the organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran or tert-butanol.

4. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 2 or 3, wherein: the concentration of the organic solvent in the mixed solvent is 5-95 wt.%.

5. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1, wherein: the hydrolysis step adopts inorganic base or organic base to promote the reaction, wherein the inorganic base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate, and the organic base is one or more of sodium methoxide, potassium ethoxide, sodium ethoxide or potassium tert-butoxide.

6. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1 or 5, wherein: the molar ratio of the inorganic base to the ethyl noraminothiazolime carboxylate is 1.5-4.0: 1.

7. the method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1, wherein: the acylating agent is one or more of acetic acid, acetyl chloride or acetic anhydride.

8. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1 or 7, wherein: the molar ratio of acylating agent to compound 1 is 1.2-1.8: 1.

9. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1, wherein: the acidic solution is one or more of sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid.

10. The method for preparing aminothiazole acetohydroxamic acid with controllable particle size according to claim 1 or 9, wherein: the concentration of the acidic solution is 5-30 wt.%, and the pH value of the system is controlled to be 3-4 in the crystallization step.

Technical Field

The invention relates to a preparation method of aminothiazole acetohydroxamic acid with controllable particle size, belonging to the technical field of chemical pharmacy.

Background

Aminothiazole acetoxime acid, chemical name: (Z) -2- (2-aminothiazol-4-yl) -2-acetyloxyiminoacetic acid CAS:110130-88-6 molecular weight: 229.21300 molecular formula: c₇H₇N₃O₄The molecular structure of S is:

the aminothiazole acetohydroxamic acid is used as an intermediate product of cefdinir activated thioester, and the production process and the control of related quality standards of the aminothiazole acetohydroxamic acid are quite critical to the quality of the cefdinir activated thioester. Cefdinir is an excellent third-generation oral cephalosporin antibiotic, is clinically used for treating infectious diseases caused by sensitive bacteria, has broad-spectrum antibacterial activity, high safety, less side effect and good clinical application effect, and belongs to one of the varieties with large market demand at home and abroad. Compared with the cyclization method and the acyl chloride method, the method for synthesizing cefdinir by the active ester method has the advantages of mild reaction conditions, fewer steps, high yield and reduction of the generation of impurity E-isomer. The current industrialized activated thioester method is characterized in that 7-AVCA and CAEM are acylated and then acetoxyl protecting group is removed to obtain cefdinir, which gradually replaces the method using S-2-benzothiazole- (Z) -2- (2-aminothiazole-4-yl) -2-triphenylmethoxyimino thioacetate (BAEM) as raw material.

Chinese patent CN 103301081A discloses a cefdinir dispersible tablet and a preparation method thereof, wherein the particle size of cefdinir is controlled by controlling micronization, d50 is less than or equal to 30 μm, d90 is less than or equal to 30 μm, and d100 is less than or equal to 30 μm; the obtained cefdinir dispersible tablet has good dissolution effect and high bioavailability, and the obtained product has low impurity content.

Chinese patent CN 105503853A discloses a method for synthesizing cefdinir activated thioester, which uses demethyl aminothiazoly loximate ethyl ester as raw material to realize hydrolysis and acylation in one step, and then the addition product is esterified in proper solvent to synthesize the cefdinir activated thioester. The method omits the dehydration process, and the quality of the intermediate process and the indexes of subsequent products are uncontrollable. It is difficult to control the relevant indexes of the intermediate products during the esterification process.

Disclosure of Invention

The invention aims to provide a preparation method of aminothiazole acetohydroxamic acid with controllable particle size, which can control the particle size, has simple process route, mild conditions and low production cost and is suitable for industrial production.

The preparation method of the aminothiazole acetohydroxamic acid with controllable particle size comprises the following steps:

(1) hydrolysis: taking ethyl noraminothiazolyloximate as a raw material, and hydrolyzing to generate a compound 1;

(2) acylation: dropwise adding an acylating agent into the system for acylation reaction to obtain a compound 2;

(3) and (3) crystallization: after the acylation reaction is finished, adding activated carbon into a reaction system for decolorization, then dropwise adding an acidic solution into the system at different temperatures to control the pH value of the system, and after solid is separated out, centrifugally drying to obtain a compound 3 with controllable particle size;

the temperature ranges are as follows:

maintaining the temperature of the system at 10-15 deg.C, and the D50% particle diameter is 55-70 μm;

maintaining the temperature of the system at 20-25 deg.C, and D50% particle size at 75-90 μm;

the system temperature is maintained at 30-35 ℃, and the D50% particle size is 100-120 μm.

Wherein:

the hydrolysis step is carried out in a solvent, and the solvent is water or an organic solvent or a mixed solvent consisting of the organic solvent and the water. A mixed solvent of an organic solvent and water is preferred.

The organic solvent is one or more of methanol, ethanol, acetone, tetrahydrofuran or tert-butyl alcohol, and preferably one of methanol, ethanol or tetrahydrofuran.

The concentration of the organic solvent in the mixed solvent is 5-95 wt.%, preferably 5-10 wt.%.

The hydrolysis step adopts inorganic base or organic base to promote the reaction, and the inorganic base is one or more of sodium hydroxide, potassium hydroxide, lithium hydroxide, potassium carbonate, sodium carbonate or cesium carbonate; the organic base is one or more of sodium methoxide, potassium ethoxide, sodium ethoxide or potassium tert-butoxide; one of sodium hydroxide, potassium carbonate or lithium hydroxide is preferred.

The molar ratio of the inorganic base to the ethyl noraminothiazoly loximate is 1.5-4.0: 1, preferably 2.0 to 3.0: 1.

the acylating agent is one or more of acetic acid, acetyl chloride or acetic anhydride, and preferably acetyl chloride or acetic anhydride.

The mol ratio of the acylating agent to the compound 1 is 1.2-1.8: 1.

The acidic solution is one or more of sulfuric acid, hydrochloric acid, phosphoric acid or acetic acid, preferably hydrochloric acid or acetic acid.

The concentration of the acidic solution is 5-30 wt.%, preferably 20-30 wt.%.

In the crystallization step, the pH value of the system is controlled to be 3-4.

The intermediate in the invention is not required to be separated, and the compound 3 is directly obtained.

The invention has the following beneficial effects:

the invention discloses a preparation method of aminothiazole acetohydroxamic acid with controllable particle size, which comprises the steps of hydrolysis, acylation, crystallization and the like, wherein the total yield is more than 73%.

Compared with the prior art, the invention has the advantages that: the particle size of the prepared aminothiazole acetohydroxamic acid is controllable by controlling the adding temperature of different acid solutions and the pH value of a system; the process flow is simple to operate and is suitable for industrial production. The invention realizes effective control of product quality through controllable particle size, and can select the particle size of the obtained product according to actual conditions.

Drawings

FIG. 1 is an electron microscope photograph of the products of examples 1-4.

Wherein a is the electron microscope picture of example 1; b is an electron microscope picture of example 2; c is the electron microscope picture of example 3; d is the electron microscope picture of example 4;

FIG. 2 is a graph of particle size for the products of examples 1-4.

Detailed Description

The present invention is further illustrated by the following specific examples.

Example 1

And (3) hydrolysis process: ethyl noraminothiazolime 50.00g, 150ml of tap water and 50ml of methanol were placed in a 500ml three-necked flask, and 27.00g of sodium hydroxide was added to the system at room temperature, followed by stirring overnight after dropping to obtain Compound 1.

And (3) acylation process: 97.0g of acetic anhydride was added dropwise to the system, and the mixture was stirred for 4 hours after completion of the addition of the acetic anhydride, whereby Compound 2 was obtained.

A crystallization process: adding 1100ml of tap water and 2g of activated carbon for decolorization, maintaining the system temperature at 10-15 ℃, dropwise adding 20 wt.% of hydrochloric acid aqueous solution until the pH value is 3-4, and controlling dropwise adding for 45 min. Suction filtration, rinsing 3 times with 50ml water respectively to obtain a wet product of the compound 3, and vacuum drying to obtain 135.28g of a dry product of the compound 3 with the yield of 78.5 percent. The particle size detection shows that the D50% particle size is 57.559 mu m.

Example 2

And (3) hydrolysis process: ethyl noraminothiazolime 50.00g, 150ml of tap water and 50ml of methanol were placed in a 500ml three-necked flask, and 27.01g of sodium hydroxide was added to the system at room temperature, followed by stirring overnight after dropping to obtain Compound 1.

And (3) acylation process: 97.0g of acetic anhydride was added dropwise to the system, and the mixture was stirred for 4 hours after completion of the addition of the acetic anhydride, whereby Compound 2 was obtained.

A crystallization process: adding 1100ml of tap water and 2g of activated carbon for decolorization, maintaining the system temperature at 10-15 ℃, dropwise adding 20 wt.% of hydrochloric acid aqueous solution until the pH value is 3-4, and controlling dropwise adding for 45 min. Suction filtration, rinsing 3 times with 50ml water respectively to obtain a wet product of the compound 3, and vacuum drying to obtain 132.69g of a dry product of the compound 3 with the yield of 77.0 percent. The particle size detection shows that the D50% particle size is 67.902 mu m.

Example 3

And (3) hydrolysis process: ethyl noraminothiazolyloximate 50.00g, water 150ml, tetrahydrofuran 30ml, potassium carbonate 192.40g was added to the system at room temperature, and the mixture was stirred overnight after the addition, to obtain Compound 1.

And (3) acylation process: 97.0g of acetic anhydride was added dropwise to the system, and the mixture was stirred for 4 hours after completion of the addition of the acetic anhydride, whereby Compound 2 was obtained.

A crystallization process: adding 1100ml of tap water and 2g of activated carbon for decolorization, maintaining the temperature of the system at 20-25 ℃, dropwise adding 30 wt.% of acetic acid aqueous solution until the pH value is 3-4, and dropwise adding for 45min in a time-controlled manner. Suction filtration, rinsing 3 times with 50ml water respectively to obtain a wet product of the compound 3, and vacuum drying to obtain 119.42g of a dry product of the compound 3 with the yield of 73.5 percent. The particle size detection shows that the D50% particle size is 76.004 mu m.

Example 4

And (3) hydrolysis process: 50.00g of ethyl noraminothiazolime, 150ml of water and 30ml of tetrahydrofuran are placed in a 500ml three-necked flask, 192.40g of potassium carbonate is added into the system at room temperature, and the mixture is stirred overnight after the addition is finished, so that the compound 1 is obtained.

And (3) acylation process: 97.0g of acetyl anhydride is added dropwise into the system, and the mixture is stirred for 4 hours after the addition of the acetyl anhydride, so that the compound 2 is obtained.

A crystallization process: adding 1100ml of tap water and 2g of activated carbon for decolorization, maintaining the temperature of the system at 30-35 ℃, dropwise adding 30 wt.% of acetic acid aqueous solution until the pH value is 3-4, and controlling the time and dropwise adding for 45 min. Suction filtration, rinsing 3 times with 50ml water respectively to obtain a wet product of the compound 3, and vacuum drying to obtain 125.97g of a dry product of the compound 3 with the yield of 73.1 percent. The particle size detection shows that the D50% particle size is 118.825 mu m.

The invention also makes a comparison experiment, and the experimental result proves that the particle size of the aminothiazole acetoxime acid which is not prepared by the method is unstable, and the particle size distribution has no any rule. The method for controlling the particle size of the invention is fully demonstrated to realize effective monitoring of the product quality.