阅读说明：本技术 一种硫酸头孢匹罗的合成方法 (Synthesis method of cefpirome sulfate ) 是由 徐志雄 张永飞 于 2021-07-23 设计创作，主要内容包括：本发明公开了一种硫酸头孢匹罗的合成方法,涉及生物医药合成技术领域,通过7-ACA与六甲基二硅烷胺、三甲基碘硅烷作用,得到保护氨基和羧基的7-ACA,然后与三甲基碘硅烷和2,3-环戊烯并吡啶作用,一锅法合成7-ACP中间体,7-ACP中间产物再和AE活性酯反应,通过酰化和成盐反应得到硫酸头孢匹罗,再进行溶解、析晶、养晶,最终得到硫酸头孢匹罗晶体。如此设置,通过本方案可以制备硫酸头孢匹罗晶体,且结晶性能好、纯度高、无杂色；在一锅法合成7-ACP中间产物的过程中以及酰化反应过程中均采用了微波法,微波的使用能够极大地加快有机合成反应速率,提高产物的收率和纯度,节省了很多繁琐的步骤,大大缩短了反应时间。(The invention discloses a method for synthesizing cefpirome sulfate, which relates to the technical field of biological medicine synthesis, and is characterized in that 7-ACA for protecting amino and carboxyl is obtained by the action of 7-ACA, hexamethyldisilazane and iodotrimethylsilane, then the 7-ACA reacts with iodotrimethylsilane and 2, 3-cyclopentenopyridine, a 7-ACP intermediate is synthesized by a one-pot method, the 7-ACP intermediate reacts with AE active ester, cefpirome sulfate is obtained by acylation and salt-forming reaction, and then the cefpirome sulfate crystal is obtained by dissolution, crystallization and crystal growth. By the arrangement, cefpirome sulfate crystals can be prepared, and the cefpirome sulfate crystals have the advantages of good crystallization performance, high purity and no variegated color; microwave methods are adopted in the process of synthesizing the 7-ACP intermediate product by the one-pot method and the acylation reaction process, the use of the microwaves can greatly accelerate the organic synthesis reaction rate, improve the yield and the purity of the product, save a plurality of complicated steps and greatly shorten the reaction time.)

1. A method for synthesizing cefpirome sulfate is characterized by comprising the following steps:

a. dissolving 7-ACA in a mixed solvent of dichloromethane and ethanol, adding hexamethyldisilazane and iodotrimethylsilane, mixing uniformly, adding 2, 3-cyclopentenopyridine at room temperature, and reacting the mixture for 2-4 minutes under 400W microwave condition to obtain a 7-ACP intermediate product;

b.7-ACP intermediate product and AE active ester are dissolved in a mixed solution of N, N-dimethylformamide and water, alkali liquor is added to make the mixed solution alkaline, acylation reaction is carried out under 600W microwave condition for 1-2 minutes to obtain cefpirome solution, sulfuric acid is added into the cefpirome solution, salt reaction is generated under acidic condition, and cefpirome sulfate is obtained by filtering, washing and drying;

c. dissolving cefpirome sulfate in acetone, adding activated carbon into the mixed solution under an acidic condition, carrying out decolorization treatment for 15-30 minutes, filtering after decolorization, taking the filtrate, heating the filtrate to 15-18 ℃, adding a sulfuric acid solution until the mixed solution is turbid, growing crystals for 1.5-2.5 hours, adding acetone into the mixed solution, growing crystals for 0.5-1.5 hours, and carrying out suction filtration to obtain crystals;

d. and filtering and washing the obtained crystal with acetone for multiple times, and drying in vacuum to obtain the cefpirome sulfate crystal.

2. The method for synthesizing cefpirome sulfate according to claim 1, wherein the ratio of the amounts of 7-ACA, hexamethyldisilazane and iodotrimethylsilane in step a is 1: 2-5: 4-8, and the ratio of the amounts of 7-ACA and 2, 3-cyclopentenopyridine is 1: 1-2.

3. The method for synthesizing cefpirome sulfate according to claim 1, wherein the amount of AE active ester added in step b is 1-1.2 times of the amount of the substance of 7-ACA.

4. The method for synthesizing cefpirome sulfate according to claim 1, wherein in step b, the pH value of the mixed solution is adjusted to 7.0-9.0 by one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and ammonia water.

5. The method for synthesizing cefpirome sulfate according to claim 1, wherein in step b, sulfuric acid is added to the solution of cefpirome so that the pH of the mixture is 1.5.

6. The method for synthesizing cefpirome sulfate according to claim 1, wherein in step c, cefpirome sulfate is dissolved in acetone, and a sulfurous acid solution is added thereto to adjust the pH of the mixed solution to 4.4-4.0.

Technical Field

The invention relates to the technical field of biological medicine preparation, and more particularly relates to a method for synthesizing cefpirome sulfate.

Background

Cefpirome is widely applied to clinical infection resistance as a fourth-generation cephalosporin antibiotic. Since cefpirome is in an amorphous state when it is precipitated from a solution, it is difficult to store it because of its poor stability, cefpirome is usually prepared in the form of a sulfate.

At present, cefpirome sulfate is mainly used as an intravenous injection in clinic, and plays an antibacterial role by blocking cell wall synthesis, and cefpirome sulfate also has a strong antibacterial effect on cells producing beta-lactamase. Cefpirome sulfate mainly appears in the form of injection, and is rarely prepared into powder, tablets and the like, so that the use scene of cefpirome sulfate is greatly limited. In addition, in the prior art, when cefpirome sulfate is prepared, the reaction conditions are harsh, the heating temperature, the stirring time, the reaction time and the like need to be controlled well, the stirring time and the reaction time are both long, the operation process is complicated, and the efficiency of mass production is limited.

Therefore, how to solve the problems of complicated preparation process and harsh preparation conditions of cefpirome sulfate in the prior art becomes an important technical problem to be solved by technical personnel in the field.

Disclosure of Invention

The invention aims to provide a method for synthesizing cefpirome sulfate, and solves the problems of complicated preparation process and harsh preparation conditions of cefpirome sulfate in the prior art. The technical effects that can be produced by the preferred technical scheme in the technical schemes provided by the invention are described in detail in the following.

In order to achieve the purpose, the invention provides the following technical scheme:

the invention provides a method for synthesizing cefpirome sulfate, which comprises the following steps:

a. dissolving 7-ACA (7-aminocephalosporanic acid) in a mixed solvent of dichloromethane and ethanol, adding hexamethyldisilazane and iodotrimethylsilane, uniformly mixing, adding 2, 3-cyclopentenopyridine at room temperature, and reacting the mixture for 2-4 minutes under 400W microwave condition to obtain a 7-ACP intermediate product;

b.7-ACP intermediate product and AE active ester are dissolved in a mixed solution of N, N-dimethylformamide and water, alkali liquor is added to make the mixed solution alkaline, acylation reaction is carried out under 600W microwave condition for 1-2 minutes to obtain cefpirome solution, sulfuric acid is added into the cefpirome solution, salt reaction is generated under acidic condition, and cefpirome sulfate is obtained by filtering, washing and drying;

c. dissolving cefpirome sulfate in acetone, adding activated carbon into the mixed solution under an acidic condition, carrying out decolorization treatment for 15-30 minutes, filtering after decolorization, taking the filtrate, heating the filtrate to 15-18 ℃, adding a sulfuric acid solution until the mixed solution is turbid, growing crystals for 1.5-2.5 hours, adding acetone into the mixed solution, growing crystals for 0.5-1.5 hours, and carrying out suction filtration to obtain crystals;

d. and filtering and washing the obtained crystal with acetone for multiple times, and drying in vacuum to obtain the cefpirome sulfate crystal.

Preferably, the ratio of the amounts of the 7-ACA, hexamethyldisilazane and trimethyliodosilane in step a is 1:2 to 5:4 to 8, and the ratio of the amounts of the 7-ACA and 2, 3-cyclopentenopyridine is 1:1 to 2.

Preferably, the amount of AE active ester added in step b is 1 to 1.2 times the amount of the substance of 7-ACA.

Preferably, in the step b, the pH value of the mixed solution is adjusted to 7.0-9.0 by one or more of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate and ammonia water.

Preferably, in step b, sulfuric acid is added to the cefpirome solution so that the pH of the mixture is 1.5.

Preferably, in step c, cefpirome sulfate is dissolved in acetone, and a sulfurous acid solution is added to the solution to adjust the pH value of the mixed solution to 4.4-4.0.

According to the technical scheme provided by the invention, 7-ACA with protected amino and carboxyl is obtained by the action of 7-ACA with hexamethyldisilane amine and trimethyl iodosilane, and then the 7-ACA is reacted with trimethyl iodosilane and 2, 3-cyclopentenopyridine to synthesize a 7-ACP intermediate product by a one-pot method. And reacting the 7-ACP intermediate product with AE active ester, performing acylation and salt-forming reaction to obtain cefpirome sulfate, and dissolving, crystallizing and growing crystals to finally obtain cefpirome sulfate crystals. The technical scheme provided by the invention has the following beneficial effects: the cefpirome sulfate crystal can be prepared by the scheme, and has good crystallization performance, high purity and no variegated color; microwave methods are adopted in the process of synthesizing the 7-ACP intermediate product by the one-pot method and the acylation reaction process, the use of the microwaves can greatly accelerate the organic synthesis reaction rate, improve the yield and the purity of the product, save a plurality of complicated steps and greatly shorten the reaction time.

Detailed Description

In order to make the objects, technical solutions and advantages of the present invention more apparent, the technical solutions of the present invention will be described in detail below. It is to be understood that the described embodiments are merely exemplary of the invention, and not restrictive of the full scope of the invention. All other embodiments, which can be derived by a person skilled in the art from the examples given herein without any inventive step, are within the scope of the present invention.

The purpose of the present embodiment is to provide a method for synthesizing cefpirome sulfate, which solves the problems of complex preparation process and harsh preparation conditions of cefpirome sulfate in the prior art.

Hereinafter, examples will be described. The embodiments described below do not limit the contents of the invention described in the claims. The entire contents of the configurations shown in the following embodiments are not limited to those required as solutions of the inventions described in the claims.

The present invention will be further illustrated with reference to the following examples, which are intended to be illustrative only and not limiting.

The first embodiment is as follows:

80ml of a mixture of methylene chloride and ethanol (V) was added to the flask_{Methylene dichloride}：V_Ethanol1:1), 27.2g (0.1mol) of 7-ACA was dissolved in the mixture, 32.2g (0.2mol) of hexamethyldisilazane and 84g (0.4mol) of iodotrimethylsilane were added dropwise thereto, 12.5g (0.1mol) of 2, 3-cyclopentenopyridine was further added at room temperature, and the mixture was reacted under 400W microwave conditions for 2 minutes.

After the reaction is finished, dropwise adding an acidic methanol-deionized water mixed solution into the mixed solution, separating the solution after stirring, extracting an organic phase by using 300ml of deionized water, slowly adding 750ml of acetone while stirring to generate a large amount of crystals, stirring for 1.5h, filtering, washing a filter cake, and drying to obtain 20.0g of a 7-ACP intermediate product.

The resulting 7-ACP intermediate was dissolved in 160ml of N,(V) in a mixture of N-Dimethylformamide (DMF) and water_DMF：V_{Water (W)}1: 5), adding 40.5g (0.1mol) of AE active ester, adding ammonia water to make the pH value of the mixed solution be 8.0, carrying out acylation reaction under 600W microwave condition for 1 minute to obtain a cefpirome solution, adding 6mol/L sulfuric acid into the cefpirome solution to make the mixed solution generate salt reaction under the condition that the pH value is 1.5, filtering, washing and drying to obtain 28.2g of cefpirome sulfate.

Dissolving 20g of cefpirome sulfate in 80ml of acetone, adding 35% of sulfurous acid solution into the mixed solution, adding activated carbon into the mixed solution under an acidic condition, decoloring for 15 minutes, filtering to obtain filtrate after decoloring, heating the filtrate to 15 ℃, adding 15% of sulfuric acid solution until the mixed solution is turbid, growing crystals for 1.5 hours, adding 40ml of acetone into the mixed solution, growing crystals for 0.5 hour, and performing suction filtration to obtain crystals. And filtering and washing the obtained crystal with acetone for multiple times, and drying in vacuum to obtain the cefpirome sulfate crystal.

Example two:

80ml of a mixture of methylene chloride and ethanol (V) was added to the flask_{Methylene dichloride}：V_Ethanol1:1), 27.2g (0.1mol) of 7-ACA was dissolved in the mixture, 80.5g (0.5mol) of hexamethyldisilazane and 84g (0.4mol) of iodotrimethylsilane were added dropwise thereto, 25g (0.2mol) of 2, 3-cyclopentenopyridine was further added at room temperature, and the mixture was reacted under 400W microwave conditions for 4 minutes.

After the reaction is finished, dropwise adding an acidic methanol-deionized water mixed solution into the mixed solution, separating the solution after stirring, extracting an organic phase by using 300ml of deionized water, slowly adding 750ml of acetone while stirring to generate a large amount of crystals, stirring for 1.5h, filtering, washing a filter cake, and drying to obtain 21.6g of a 7-ACP intermediate product.

The resulting 7-ACP intermediate was dissolved in 160ml of a mixture of N, N-Dimethylformamide (DMF) and water (V)_DMF：V_{Water (W)}5:1), adding 48.6g (0.12mol) of AE active ester, adding ammonia water to adjust the pH value of the mixed solution to 9.0, carrying out acylation reaction under 600W microwave condition,the reaction time is 2 minutes to obtain a cefpirome solution, then 6mol/L sulfuric acid is added into the cefpirome solution to enable the mixed solution to generate salt reaction under the condition that the pH value is 1.5, and 28.9g of cefpirome sulfate is obtained by filtering, washing and drying.

Dissolving 20g of cefpirome sulfate in 80ml of acetone, adding 35% of sulfurous acid solution into the mixed solution, adding activated carbon into the mixed solution under an acidic condition, decoloring for 30 minutes, filtering to obtain filtrate after decoloring, heating the filtrate to 18 ℃, adding 15% of sulfuric acid solution until the mixed solution is turbid, growing crystals for 2.5 hours, adding 80ml of acetone into the mixed solution, growing crystals for 1.5 hours, and performing suction filtration to obtain crystals. And filtering and washing the obtained crystal with acetone for multiple times, and drying in vacuum to obtain the cefpirome sulfate crystal.

According to the first and second examples, the yield of cefpirome sulfate crystals can be improved within a certain range by increasing the microwave reaction time. In addition, the product with low color grade index can be obtained by prolonging the decoloring treatment time, and the crystallization performance of the crystal can be adjusted by adjusting the crystal growing condition.

It is understood that the same or similar parts in the above embodiments may be mutually referred to, and the same or similar parts in other embodiments may be referred to for the content which is not described in detail in some embodiments. The multiple schemes provided by the invention comprise basic schemes, are independent from each other and are not restricted with each other, but can be combined with each other under the condition of no conflict, so that multiple effects are realized together.

The above description is only for the specific embodiments of the present invention, but the scope of the present invention is not limited thereto, and any person skilled in the art can easily conceive of the changes or substitutions within the technical scope of the present invention, and all the changes or substitutions should be covered within the scope of the present invention. Therefore, the protection scope of the present invention shall be subject to the protection scope of the appended claims.