阅读说明：本技术 头孢克肟侧链酸结晶工艺 (Crystallization process of cefixime side chain acid ) 是由 侯卫 韩扬 王君伟 李剑 于 2020-12-28 设计创作，主要内容包括：本发明涉及一种头孢克肟侧链酸结晶工艺,属于化学制药技术领域。本发明所述的工艺是向反应釜中加入水、碱液和硫脲,再加入头孢克肟开环侧链酸,加入过程中控制pH值在2.0～7.0范围内；头孢克肟开环侧链酸加毕,将搅拌速度降至70～150r/min,加入晶种,继续反应；反应完毕,再调pH值至0.5～1.8,过滤、洗涤后得到头孢克肟侧链酸晶体。本发明通过限定反应物的最佳浓度配比、加料方式、转速以及控制析晶条件,使得析出的产品为立方体形状的晶体。相比于现有技术得到的无定形的头孢克肟侧链酸晶体,本发明的立方体形状的晶体纯度高,稳定性好,有利于产品质量的提升。(The invention relates to a cefixime side chain acid crystallization process, and belongs to the technical field of chemical pharmacy. Adding water, alkali liquor and thiourea into a reaction kettle, adding cefixime ring-opening side chain acid, and controlling the pH value within the range of 2.0-7.0 in the adding process; after the addition of the cefixime ring-opening side chain acid is finished, reducing the stirring speed to 70-150 r/min, adding seed crystals, and continuing the reaction; after the reaction is finished, adjusting the pH value to 0.5-1.8, filtering and washing to obtain the cefixime side chain acid crystal. The invention ensures that the precipitated product is cubic crystal by limiting the optimal concentration ratio, feeding mode and rotating speed of reactants and controlling the crystallization condition. Compared with the amorphous cefixime side chain acid crystal obtained in the prior art, the cubic crystal has high purity and good stability, and is beneficial to the improvement of the product quality.)

1. A cefixime side chain acid crystallization process is characterized in that water, alkali liquor and thiourea are added into a reaction kettle, the cefixime ring-opening side chain acid is added under the conditions that the temperature is 0-40 ℃, the stirring speed is 230-280 r/min, and the pH value is controlled within the range of 2.0-7.0 in the adding process; after the addition of the cefixime ring-opening side chain acid is finished, reducing the stirring speed to 70-150 r/min, adding seed crystals, keeping the temperature at 0-40 ℃, and continuing to react for 2-3 hours; after the reaction is finished, adjusting the pH value to 0.5-1.8, filtering and washing to obtain the cefixime side chain acid crystal.

2. The cefixime side chain acid crystallization process according to claim 1, characterized in that the cefixime side chain acid is added under the conditions of 20-30 ℃ and stirring speed of 240-260 r/min, and the pH value is controlled within the range of 4.0-6.0 during the addition process.

3. The cefixime side chain acid crystallization process according to claim 1, wherein the cefixime side chain acid is added in 6 batches, and the time for adding the cefixime side chain acid in batches is controlled to be 1-4 hours.

4. A process for the crystallization of cefixime side chain acid according to claim 3, wherein the time for adding the cefixime side chain acid in batches is controlled to be 2-3 hours.

5. The cefixime side chain acid crystallization process according to claim 1, characterized in that the mass of thiourea accounts for 10-20% of the total mass of water, alkali solution, thiourea and cefixime side chain acid.

6. The cefixime side chain acid crystallization process according to claim 1, characterized in that the mass of the alkali liquor accounts for 10-48% of the total mass of water, the alkali liquor, thiourea and the cefixime side chain acid.

7. The cefixime side chain acid crystallization process according to claim 1, wherein the cefixime side chain acid accounts for 5-10% of the total mass of water, alkali liquor, thiourea and cefixime side chain acid.

8. The cefixime side chain acid crystallization process according to claim 1, characterized in that the stirring speed is reduced to 80-120 r/min, seed crystals are added, the temperature is maintained at 20-30 ℃, and the reaction is continued for 2-3 hours.

9. The cefixime side chain acid crystallization process according to claim 1 or 8, characterized in that the seed crystal is a cefixime side chain acid finished product, and the mass of the seed crystal accounts for 0.5-2% of the total mass of the cefixime side chain acid after ring opening.

10. The method for preparing the novel crystal form of cefixime side chain acid according to claim 1, characterized in that after the reaction is finished, 5-10 wt.% of dilute hydrochloric acid solution is used for adjusting the pH value to 1.0-1.5, and after filtering and washing, the cefixime side chain acid crystal with the purity of more than 99.8% is obtained.

Technical Field

The invention relates to a cefixime side chain acid crystallization process, and belongs to the technical field of chemical pharmacy.

Background

Cefixime is a third-generation oral cephalosporin antibiotic drug, has wide antibacterial range and strong antibacterial action, has excellent antibacterial activity on most enterobacteriaceae bacteria, and has wide application in clinical medicine.

Chinese patent CN106632136A discloses a method for preparing cefixime side chain acid, which comprises the step of reacting cefixime side chain acid with thiourea in aqueous solution to prepare the cefixime side chain acid. The method adopts the aqueous phase solution for reaction, does not need to use an organic solvent, has simple post-treatment operation of the product, does not need a solvent recovery process, can improve the production yield of the product, reduces the production cost and brings remarkable economic benefit. However, the above method has many steps and increases the cost.

In addition, cefixime side chain acid is an important intermediate for synthesizing cefixime antibiotics, and the synthesis of cefixime side chain acid in the prior art generally has the defects of low purity and poor stability.

Disclosure of Invention

The invention aims to provide a cefixime side chain acid crystallization process, and the obtained cefixime side chain acid crystal has high purity and strong stability.

The cefixime side chain acid crystallization process comprises the steps of adding water, alkali liquor and thiourea into a reaction kettle, adding cefixime ring-opening side chain acid under the conditions that the temperature is 0-40 ℃ and the stirring speed is 230-280 r/min, and controlling the pH value in the adding process to be within the range of 2.0-7.0; after the addition of the cefixime ring-opening side chain acid is finished, reducing the stirring speed to 70-150 r/min, adding seed crystals, keeping the temperature at 0-40 ℃, and continuing to react for 2-3 hours; after the reaction is finished, adjusting the pH value to 0.5-1.8, filtering and washing to obtain the cefixime side chain acid crystal.

The preferable technical scheme is as follows:

adding cefixime ring-opening side chain acid at the temperature of 20-30 ℃ and the stirring speed of 240-260 r/min, and controlling the pH value within the range of 4.0-6.0 in the adding process.

And in the adding process, adding alkali liquor to control the pH value to be within the range of 4.0-6.0.

The cefixime ring-opening side chain acid is added in 6 batches, and the time for adding the cefixime ring-opening side chain acid in batches is controlled to be 1-4 hours, preferably 2-3 hours.

The mass of the thiourea accounts for 10-20% of the total mass of the water, the alkali liquor, the thiourea and the cefixime ring-opening side chain acid.

The mass of the alkali liquor accounts for 10-48% of the total mass of the water, the alkali liquor, the thiourea and the cefixime ring-opening side chain acid.

The alkali liquor is sodium hydroxide.

The cefixime ring-opening side chain acid accounts for 5-10% of the total mass of water, alkali liquor, thiourea and the cefixime ring-opening side chain acid.

And reducing the stirring speed to 80-120 r/min, adding seed crystals, maintaining the temperature at 20-30 ℃, and continuing to react for 2-3 hours.

The seed crystal is a cefixime side chain acid finished product, and the mass of the seed crystal accounts for 0.5-2% of the total mass of the cefixime ring-opening side chain acid.

After the reaction is finished, adjusting the pH value to 1.0-1.5 by using 5-10 wt.% of dilute hydrochloric acid solution, filtering and washing to obtain the cefixime side chain acid crystal with the purity of more than 99.8%.

The invention has the following beneficial effects:

according to the invention, the pH value is controlled within the range of 2.0-7.0 in the process of adding the cefixime ring-opening side chain acid, the cefixime ring-opening side chain acid is added, the stirring speed is reduced from 230-280 r/min to 70-150 r/min, and then seed crystal is added to carry out the process of reaction and crystallization. After the reaction is finished, adjusting the pH value to 0.5-1.8 to obtain the cubic cefixime side chain acid crystal. Through experiments, the purity of the cubic cefixime side chain acid crystal is more than 99.8 percent, and the purity change in 90 days is only 0.03 percent.

The invention ensures that the precipitated product is a cubic crystal by limiting the optimal concentration ratio, feeding mode and rotating speed of reactants and controlling crystallization conditions, while the crystal of cefixime side chain acid obtained by the prior art is a non-shaped crystal. Compared with the prior art, the cubic crystal has high purity and good stability, and is beneficial to improving the product quality.

Drawings

FIG. 1 is an electron microscope photograph of the product of example 1.

FIG. 2 is a chromatogram of the product of example 1.

Fig. 3 is an electron microscope picture of the product of comparative example 1.

Detailed Description

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

Example 1

Adding 1000ml of water, 200.00g of 5 wt.% NaOH solution and 180.01g of thiourea into a reaction bottle, adding 100.00g of cefixime ring-opening side chain acid in 6 batches under the conditions of 26 ℃ and 250r/min of stirring speed, finishing the addition after 2h, adjusting the pH value to be 4.2-4.6 by adding 5 wt.% NaOH solution in the adding process, reducing the stirring speed to 100r/min after the addition is finished, adding 0.5g of seed crystal, continuing the reaction for 2.5h at 22 ℃, finishing the reaction, adjusting the pH value to 1.21 by using 5.5 wt.% of dilute hydrochloric acid solution, and obtaining 88.31g of cubic cefixime side chain acid crystal product after centrifugal material throwing, wherein the yield is 80.98% and the purity is 99.86%. Fig. 1 and 2 are an electron microscope picture and a chromatogram, respectively, of a product. As can be seen from fig. 1, the product is a cubic crystal.

Example 2

Adding 1000ml of water, 466g of 5 wt.% NaOH solution and 365.02g of thiourea into a reaction bottle, adding 150.00g of cefixime ring-opening side chain acid in 6 batches under the conditions of 20 ℃ and stirring speed of 240r/min, finishing the feeding after 3h, adjusting the pH value to be 4.8-5.1 by adding 5 wt.% NaOH solution in the feeding process, reducing the stirring speed to 80r/min after the feeding is finished, adding 1.5g of seed crystal, continuing to react for 2 hours at 28 ℃, finishing the reaction, adjusting the pH value to 1.33 by using 10 wt.% of dilute hydrochloric acid solution, and centrifugally throwing the oxime to obtain 134.12g of cubic cefixime side chain acid crystal product, wherein the yield is 81.99%, and the purity is 99.84%.

Example 3

Adding 1000ml of water, 582g of 5 wt.% NaOH solution and 263g of thiourea into a reaction bottle, adding 200.00g of cefixime ring-opening side chain acid in 6 batches under the conditions of 22 ℃ and a stirring speed of 260r/min, finishing the addition after 2h, adding 5 wt.% NaOH solution in the adding process to adjust the pH value to be 5.5-5.8, reducing the stirring speed to 120r/min after the addition is finished, adding 3g of seed crystal, continuing to react for 3 hours at 20 ℃, adjusting the pH value to 1.38 by using 10 wt.% of dilute hydrochloric acid solution after the reaction is finished, and obtaining 175.62g of cubic cefixime side chain acid crystal product after centrifugal material throwing, wherein the yield is 80.52%, and the purity is 99.85%.

Example 4

Adding 1500ml of water, 276.00g of 5 wt.% NaOH solution and 451g of thiourea into a reaction bottle, adding 170.00g of cefixime ring-opening side chain acid in 6 batches under the conditions of 22 ℃ and a stirring speed of 250r/min, finishing the feeding after 2.5h, adjusting the pH value to be 5.2-5.5 by adding 5 wt.% of NaOH solution in the feeding process, reducing the stirring speed to 90r/min after the feeding is finished, adding 3.4g of seed crystal, continuing the reaction for 2 hours at 26 ℃, adjusting the pH value to 1.44 by using 6 wt.% of dilute hydrochloric acid solution after the reaction is finished, and obtaining 152.34g of cubic cefixime side chain acid crystal product after centrifugal material throwing, wherein the yield is 82.17% and the purity is 99.82%.

Comparative example 1

Adding 200ml of water, 700ml of methanol and 519.00g of 5 wt.% NaOH solution into a reaction bottle, adding 200.1g of cefixime ring-opening side chain acid into the reaction bottle at 50 ℃, adding 375.00g of thiourea into the reaction bottle in 6 batches at 50 ℃, controlling the rotating speed at 250r/min after the addition of 6h, continuing to react for 8 hours at 55 ℃, adjusting the pH value to 3.22 by using 25 wt.% hydrochloric acid solution after the reaction is finished, and obtaining 162.49g of cefixime side chain acid product after centrifugal material throwing, wherein the yield is 74.50% and the purity is 99.68%. Fig. 3 is an electron microscope picture of the product. As can be seen from FIG. 3, the product was an amorphous crystal.

The experimental process for detecting the stability of the cefixime side chain acid crystal is as follows: samples of cefixime side chain acid prepared in examples 1-5 and comparative example 1 were sealed in a stability test chamber. Samples were taken at 40 ℃ and 55% humidity for 0, 30, 45, 60, 75 and 90 days to determine the HPLC purity of the crystals, as shown in Table 1.

TABLE 1 HPLC purities data sheet for the crystals of examples 1-4 and comparative example 1

As can be seen from table 1, the purity of examples 1 to 4 varied slightly, varying most by 0.06% within 90 days for the cefixime side chain acid crystals of example 4, and by only 0.03% within 90 days for the cefixime side chain acid crystals of example 1, while the purity of comparative example 1 varied by 0.30%. So that the cefixime side chain acid crystals prepared in examples 1 to 4 of the present invention were more stable than the cefixime side chain acid crystals of comparative example 1.

In conclusion, the cubic cefixime side chain acid crystal prepared by the method has better stability.