Recovery method of tazobactam crude product mother liquor

Abstract

The invention discloses a tazobactam crude product mother liquor recovery method, which belongs to the technical field of chemical process, and comprises the following steps: S1, pretreatment: adjusting the pH value of the tazobactam crude product mother liquor to 2.5-4.0; s2, adsorption: adsorbing the pretreated crude product mother liquor through an ion exchange resin column at the temperature of 5-20 DEG C; s3, desorption: using absolute ethyl alcohol as a desorption agent, carrying out desorption on the ion exchange resin column after adsorption, and collecting a desorption solution; s4, crystallization: concentrating the desorption solution at the temperature of not more than 35 DEG C, adding a tazobactam seed crystal, cooling to 0-5 DEG C, and growing the crystal for 20-40 minutes; and S4, suction filtration and drying: performing suction filtration on the material after crystal growing to obtain wet powder, and drying the wet powder to constant weight under the conditions that the temperature is 30-35 DEG C and the pressure is lower than-0.080 MPa to obtain a tazobactam product.

Description

TECHNICAL FIELD

[0001] The present application relates to a method for recovering tazobactam crude mother liquor, belonging to the technical field of chemical engineering. BACKGROUND

[0002] Tazobactam acid, also known as tazobactam, is a derivative of sulbactam, and is an irreversible competitive beta-lactamase inhibitor. It has strong inhibitory effect on penicillinase produced by Staphylococcus aureus, plasmid-mediated beta-lactamase produced by gram-negative bacilli, and chromosome-mediated beta-lactamase produced by bacteria such as Proteus, Bacteroides, and Klebsiella. It is widely used for the treatment of severe systemic and local infections, abdominal infections, lower respiratory tract infections, soft tissue infections, septicemia, etc. Compared with other antibacterial complex agents in use, it has a wider antibacterial spectrum and indications, and overcomes drug resistance, showing great advantages.

[0003] As an important beta-lactamase inhibitor, the recovery of the crude mother liquor produced during the production of tazobactam is of great significance. At present, there are many technical paths for the recovery of tazobactam crude mother liquor. For example, the patent technology of Shanghai Saiyao (CN120025348A) uses an ultrafiltration ceramic membrane system to remove solid particles in the mother liquor to obtain pretreated liquid, and then concentrates it through a nanofiltration system. The nanofiltration concentrated liquid is cooled and mixed with the ceramic membrane concentrated liquid, and then static, crystallization, filtration and drying are carried out to realize product recovery. This method can effectively improve the product yield, reduce energy consumption, and the operation system is simple, space is closed, and occupational hazards can be reduced. However, membrane fouling is still a key factor restricting its widespread application, and frequent cleaning or replacement of membrane components will increase costs.

[0004] Overall, although there has been some technical progress in the recovery of tazobactam crude mother liquor, there is still much room for improvement in reducing costs, improving safety and stability, and other aspects, and more efficient, environmentally friendly and safe recovery technologies need to be developed. SUMMARY

[0005] To solve the above technical problems, the present application provides a method for recovering tazobactam crude mother liquor, comprising the following steps: S1, pretreatment: adjust the pH value of the tazobactam crude mother liquor to the range of 2.5-4.0; Adjusting the pH of the crude mother liquor to the isoelectric point of tazobactam allows it to exist in molecular form, so that more efficient molecular adsorption is achieved on the cation exchange resin, including van der Waals force, hydrogen bond and other physical adsorption, rather than ion exchange, reducing impurity competition and improving the selectivity of the resin to tazobactam. From the source, the co-adsorption of impurities is reduced, laying a foundation for obtaining high-purity products in the subsequent process; S2, Adsorption: At a temperature of 5-20℃, the pretreated crude mother liquor is adsorbed through an ion exchange resin column; S3. Analysis: Anhydrous ethanol was used as the desorbent to desorb the adsorbed ion exchange resin column, and the eluent was collected. S4. Crystallization: After concentrating the eluent at a temperature not exceeding 35°C, add tazobactam seed crystals, cool to 0-5°C, and grow crystals for 20-40 minutes. To prepare tazobactam with a stable crystal form, seed crystals can induce the solute to grow in an orderly manner on a specific crystal face, reduce impurity entrapment, and obtain crystals with a more concentrated particle size distribution, which is convenient for subsequent filtration and washing. S5. Filtering and drying: Filter the crystallized material to obtain wet powder. Dry the wet powder to constant weight at 30-35℃ and pressure below -0.080 MPa to obtain tazobactam product.

[0006] Furthermore, in step S1, dilute hydrochloric acid or dilute sulfuric acid is used for pH adjustment.

[0007] Furthermore, in step S2, the pretreated crude mother liquor is adsorbed through an ion exchange resin column at a flow rate of 1-3 BV / h at a temperature of 5-20°C.

[0008] Furthermore, in step S3, the adsorbed ion exchange resin column is desorbed at a temperature of 50-60°C and a flow rate of 0.3-0.7 BV / h.

[0009] Furthermore, in step S4, after concentrating the eluent at a temperature not exceeding 35°C, tazobactam seed crystals are added, and the temperature is lowered to 0-5°C at a rate of 0.2-0.8°C / min, and crystallization is carried out at a rotation speed of 70-100 rpm for 20-40 minutes; the cooling rate of 0.2-0.8°C / min can prevent the solution from becoming too supersaturated instantaneously, thereby avoiding the formation of a large number of small crystals and promoting the formation of large and uniform crystals.

[0010] Furthermore, the ion exchange resin is a 001X7 resin column.

[0011] Furthermore, in step S4, the amount of tazobactam seed crystals added is 1%-3% of the theoretical mass of tazobactam in the eluent.

[0012] Compared with the prior art, the beneficial effects of the present invention are as follows: 1. The present invention provides a method for recovering crude tazobactam mother liquor. Through a combination of a series of processes, including pH pretreatment (adjusting to 2.5-4.0), low-temperature adsorption, anhydrous ethanol desorption, temperature-controlled crystallization (adding seed crystals and controlling the cooling rate), and low-temperature and low-pressure drying, the recovery yield of tazobactam is stably increased to over 70%, with a maximum of 78.4%, while the product purity is as high as 98.8%-99.7%.

[0013] 2. The present invention provides a method for recovering crude tazobactam mother liquor, using anhydrous ethanol as the eluent. Experimental data show that its eluent effect is significantly better than that of traditional eluents such as aqueous ethanol solution, sodium bicarbonate or sodium carbonate solution. It can elute tazobactam from the resin more efficiently and completely, and effectively reduce the co-elution of impurities, thereby improving the yield while ensuring the high purity of the product.

[0014] 3. The present invention provides a method for recovering crude tazobactam mother liquor. In the crystallization step, by adding tazobactam seed crystals and controlling the cooling rate of 0.2-0.8℃ / min, the orderly growth of crystals is effectively induced, avoiding the formation of fine crystals caused by instantaneous supersaturation. This not only makes the crystal particle size more uniform and facilitates subsequent filtration, but also significantly reduces the residual content of tazobactam in the mother liquor, further improving the overall yield. Detailed Implementation

[0015] The present invention will now be described in detail through specific embodiments, but this description is not intended to limit the scope of protection of the present invention. It should be noted that, unless otherwise specified, the experimental methods used in the experimental operations involved in this invention are conventional methods in the relevant field, and the equipment, materials, reagents, etc., used in the experiments can all be obtained through commercial channels, so that those skilled in the art can understand and implement the technical solutions of the present invention based on existing conditions. The scope of protection of the present invention will be determined in accordance with the claims and relevant legal provisions, and is not limited by the specific embodiments.

[0016] Example 1 S1. Pretreatment: Adjust the pH of the crude tazobactam mother liquor to 2.5 with dilute hydrochloric acid. S2. Take 20 L of crude mother liquor containing 1.6 g / L of tazobactam. When the water bath temperature is 10℃, the crude mother liquor begins to adsorb. Select 001X7 resin and control the flow rate to 1 BV. After the adsorption is completed, take the adsorbed liquid to detect the tazobactam content. S3. At a water bath temperature of 55°C, the resin column was desorbed using ethanol at a flow rate of 0.5 BV. After the desorption was completed, 17 L of eluent was obtained. S4. Concentrate 17 L of the eluent at 25°C to obtain 3.4 L of concentrate. Add tazobactam seed crystals, begin cooling at 80 rpm at a rate of 0.2°C / min to 4°C, then stop cooling and begin crystal growth for 30 min. The amount of tazobactam seed crystals added is 1% of the theoretical mass of tazobactam in the eluent. S5. After crystal growth is completed, the mixture is filtered to obtain wet powder. The wet powder is then dried at 35°C and -0.060 MPa to obtain 25.2 g of tazobactam product and 3.3 L of mother liquor, with a total yield of 72.5%.

[0017] Example 2 S1. Pretreatment: Adjust the pH of the crude tazobactam mother liquor to 4.0 with dilute sulfuric acid. S2. Take 30 L of crude mother liquor containing 1.3 g / L of tazobactam. When the water bath temperature is 15℃, the crude mother liquor begins to adsorb. Select 001X10 resin and control the flow rate at 1.5 BV. After the adsorption is completed, take the adsorbed liquid to detect the tazobactam content. S3. At a water bath temperature of 50°C, the resin column was desorbed using ethanol at a flow rate of 0.5 BV. After the desorption was completed, 23 L of eluent was obtained. S4. Concentrate 23 L of the eluent at 25°C to obtain 4.6 L of concentrate. Add tazobactam seed crystals, begin cooling at 80 rpm at a rate of 0.8°C / min to 1°C, then stop cooling and begin crystal growth for 25 min. The amount of tazobactam seed crystals added is 3% of the theoretical mass of tazobactam in the eluent. S5. After crystal growth, the mixture is filtered to obtain wet powder. The wet powder is then dried at 33°C and -0.050 MPa to obtain 27.4 g of tazobactam product and 4.5 L of mother liquor, with a total yield of 70.2%.

[0018] Example 3 S1. Pretreatment: Adjust the pH of the crude tazobactam mother liquor to 3.0 with dilute sulfuric acid. S2. Take 25 L of crude mother liquor containing 1.5 g / L of tazobactam. When the water bath temperature is 15℃, the crude mother liquor begins to adsorb. Select D001 resin and control the flow rate at 1.5 BV. After the adsorption is completed, take the adsorbed liquid to detect the tazobactam content. S3. At a water bath temperature of 50°C, the resin column was desorbed using an ethanol solution with a flow rate of 0.5 BV. After the desorption was completed, 18 L of eluent was obtained. S4. Concentrate 18 L of the eluent at 25°C to obtain 3.6 L of concentrate. Add tazobactam seed crystals, begin cooling at 80 rpm at a rate of 0.5°C / min to 5°C, then stop cooling and begin crystal growth for 40 min. The amount of tazobactam seed crystals added is 2% of the theoretical mass of tazobactam in the eluent. S5. After crystal growth, the mixture is filtered to obtain wet powder. The wet powder is then dried at 30°C and -0.050 MPa to obtain 28.1 g of tazobactam product and 3.5 L of mother liquor, with a total yield of 74.9%.

[0019] Example 4 S1. Pretreatment: Adjust the pH of the crude tazobactam mother liquor to 3.5 with dilute hydrochloric acid. S2. Take 25 L of crude mother liquor containing 1.1 g / L of tazobactam. When the water bath temperature is 15℃, start loading the crude mother liquor onto the column for adsorption. Control the flow rate at 1.5 BV. After the adsorption is completed, take the adsorbed liquid to detect the tazobactam content. S3. At a water bath temperature of 53°C, the resin column was desorbed using ethanol at a flow rate of 0.5 BV. After the desorption was completed, 19 L of eluent was obtained. S4. Concentrate 19 L of the eluent at 25°C to obtain 3.8 L of concentrate. Add tazobactam seed crystals, begin cooling at 80 rpm at a rate of 0.6°C / min to 5°C, then stop cooling and begin crystal growth for 40 min. The amount of tazobactam seed crystals added is 1.5% of the theoretical mass of tazobactam in the eluent. S5. After crystal growth is completed, the mixture is filtered to obtain wet powder. The wet powder is then dried at 30°C and -0.050 MPa to obtain 19.9 g of tazobactam product and 3.7 L of mother liquor, with a total yield of 72.3%.

[0020] Comparative Examples 1-3 Based on Example 1, the pH of the crude tazobactam mother liquor was adjusted to 2.0, 2.4, and 4.1 respectively using dilute sulfuric acid during pretreatment. The remaining steps were the same as in Example 1. The tazobactam content in the adsorbent, the tazobactam content in the mother liquor, and the tazobactam purity were measured, and the tazobactam yield was calculated.

[0021] Comparative Examples 4-6 Based on Example 1, the eluent was changed to a 4.5% NaHCO3, 4.5% Na2CO3, and 50% ethanol aqueous solution, while the remaining steps were the same as in Example 1. The tazobactam content in the adsorbent, the tazobactam content in the mother wash, and the tazobactam purity were measured, and the tazobactam yield was calculated.

[0022] Comparative Examples 7-9 Based on Example 2, the eluent was changed to a 4.5% NaHCO3, 4.5% Na2CO3, and 50% ethanol aqueous solution, and the remaining steps were the same as in Example 2.

[0023] Comparative Examples 10-12 Based on Example 3, the eluent was changed to a 4.5% NaHCO3, 4.5% Na2CO3, and 50% ethanol aqueous solution, and the remaining steps were the same as in Example 3.

[0024] Comparative Examples 13-15 Based on Example 4, the eluent was changed to a 4.5% NaHCO3, 4.5% Na2CO3, and 50% ethanol aqueous solution, and the remaining steps were the same as in Example 4.

[0025] The tazobactam content in the adsorbent solution, the tazobactam content in the mother wash solution, and the tazobactam purity in Examples 1-4 and Comparative Examples 1-12 were tested respectively, and the tazobactam yield was calculated. The results are shown in Table 1 below.

[0026] Table 1. Results of Tazobactam detection

[0027] As shown in Table 1, the recovery method provided by this invention can effectively improve the yield of tazobactam, with a yield greater than 70%, reaching as high as 78.4%, and high purity, greater than 98.8%, reaching as high as 99.7%. The results of Comparative Examples 1-3 demonstrate that deviations from a specific pH range in the pretreatment lead to a decrease in tazobactam yield and losses, while stabilizing the pH in the 2.5-4.0 range yields a higher tazobactam yield. The results of Comparative Examples 4-15 show that when the eluent is changed, the yield decreases significantly, and the loss of tazobactam is substantial. Ethanol has a better eluenting effect than ethanol-water, ethanol-water has a better eluenting effect than 4.5% NaHCO3, and 4.5% NaHCO3 solution has a better eluenting effect than 4.5% Na2CO3. Using anhydrous ethanol as the eluent and the specific process conditions of this invention, tazobactam can be eluted from the resin more efficiently, reducing product losses during the recovery process.

[0028] The purity of the tazobactam product obtained by this invention (98.8%-99.7%) is significantly higher than that of the comparative example, demonstrating that the recovery method of this invention has better selectivity, effectively reducing the introduction of impurities and co-elution, thereby obtaining a purer final product. Meanwhile, the tazobactam content in the mother liquor of each embodiment of this invention (2.01-2.61 g / L) is relatively low, indicating that the crystallization process of this invention is more complete and effectively reduces the product's dissolved residue in the mother liquor, especially compared to the comparative example using sodium bicarbonate and sodium carbonate solutions, showing a significant advantage.

Claims

1. A method for recovering a crude ceftazidime mother liquor, characterized by, The method comprises the following steps: S1, pretreatment: adjusting the pH value of the crude mother liquor of the heptazobatan to the range of 2.5-4.0; S2, adsorption: the pretreated crude mother liquor is adsorbed by the ion exchange resin column at a temperature of 5-20℃; S3, elution: using anhydrous ethanol as the desorbent, the ion exchange resin column after adsorption is eluted, and the eluate is collected; S4, crystallization: after the eluate is concentrated at a temperature not exceeding 35℃, heptazobatan crystal seeds are added, the temperature is lowered to 0-5℃, and the crystal is maintained for 20-40 minutes; S5, suction filtration and drying: the material after the crystal is maintained is suction filtered to obtain wet powder, and the wet powder is dried at 30-35℃ and under a pressure lower than-0.080 MPa to a constant weight to obtain the heptazobatan product.

2. The method of claim 1, wherein, In the step S1, dilute hydrochloric acid or dilute sulfuric acid is used for pH adjustment.

3. The method of claim 1, wherein, In the step S2, the pretreated crude mother liquor is adsorbed by the ion exchange resin column at a flow rate of 1-3 BV / h at a temperature of 5-20℃.

4. The method of claim 1, wherein, In the step S3, the ion exchange resin column after adsorption is eluted at a flow rate of 0.3-0.7 BV / h at a temperature of 50-60℃.

5. The method of claim 1, wherein, In the step S4, after the eluate is concentrated at a temperature not exceeding 35℃, heptazobatan crystal seeds are added, the temperature is lowered to 0-5℃ at a rate of 0.2-0.8℃ / min, and the crystal is maintained at a rotation speed of 70-100 rpm for 20-40 minutes.

6. The method of claim 1, wherein, The ion exchange resin is a 001X7 resin column.

7. The method of claim 1, wherein, In the step S4, the addition amount of the heptazobatan crystal seeds is 1%-3% of the theoretical mass of heptazobatan in the eluate.

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