Cefpirome sulfate and preparation method thereof

Abstract

The present invention belongs to the technical field of preparation of cefpirome sulfate, and in particular to a kind of cefpirome sulfate and preparation method thereof. The preparation method of cefpirome sulfate provided by the present invention comprises the following steps: selecting a strongly basic anion exchange resin, first alkali washing and water washing it, then placing the anion exchange resin in the first cefpirome dihydroiodide aqueous solution, the second cefpirome dihydroiodide aqueous solution, and the third cefpirome dihydroiodide aqueous solution in sequence for ultrasonic oscillation to obtain the pretreated anion exchange resin; the pretreated anion exchange resin, cefpirome dihydroiodide and water are mixed and stirred, filtered, decolorized, filtered again, the filtrate is cooled, and then the filtrate pH is adjusted to 1.2-1.4 using sulfuric acid solution, ethanol is added, stirred, filtered, washed, dried, and the cefpirome sulfate is obtained. The preparation method provided by the present invention can effectively reduce the impurity content of cefpirome sulfate while helping to improve its yield.

Description

Technical Field

[0001] The invention belongs to the technical field of cefpirome sulfate preparation, and particularly relates to cefpirome sulfate and a preparation method thereof. Background Art

[0002] The chemical name of cefpirome sulfate is: 1-[[7-[[(2-amino-4-thiazolyl)(methoxyimino)acetyl]-amino]-2-carboxy-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-3-yl]methyl]-6,7-dihydro-5H-cyclopentadienpyridine sulfate. Cefpirome sulfate has a broad-spectrum antibacterial activity and is widely used in the treatment of Gram-positive bacteria.

[0003] At present, there are many synthetic routes for cefpirome sulfate, one of which is to first prepare cefpirome dihydroiodide, and then convert it into the corresponding sulfate using an alkaline anion exchange resin. Since the alkaline anion exchange resin itself may contain certain impurities and have limited exchange activity, which in turn affects the yield and purity of cefpirome sulfate, in order to solve the above problems, the prior art generally performs pretreatment operations such as washing on the alkaline anion exchange resin before using the alkaline anion exchange resin. However, the existing pretreatment method for the alkaline anion exchange resin has limited effect on improving the yield and purity of cefpirome sulfate. Summary of the invention

[0004] Therefore, the technical problem to be solved by the present invention is to overcome the defect that the existing pretreatment method of alkaline anion exchange resin has limited improvement on the yield and purity of cefpirome sulfate, and further provide a preparation method of cefpirome sulfate.

[0005] In order to solve the above problems, the scheme of the present invention is as follows:

[0006] A method for preparing cefpirome sulfate comprises the following steps:

[0007] 1) selecting a strongly basic anion exchange resin, first washing it with alkali and water, then placing the anion exchange resin in a first cefpirome dihydroiodide aqueous solution for ultrasonic vibration, then placing the anion exchange resin in a second cefpirome dihydroiodide aqueous solution for ultrasonic vibration, and finally placing the anion exchange resin in a third cefpirome dihydroiodide aqueous solution for ultrasonic vibration. After the ultrasonic vibration ends, taking it out to obtain a pretreated anion exchange resin;

[0008] The mass concentration of cefpirome dihydroiodide in the first cefpirome dihydroiodide aqueous solution is 0.5-2%, and the mass concentration of sodium iodide is 0.01-0.05%. The mass concentration of cefpirome dihydroiodide in the second cefpirome dihydroiodide aqueous solution is 20-30%. The mass concentration of cefpirome dihydroiodide in the third cefpirome dihydroiodide aqueous solution is 0.5-2%, and the mass concentration of sodium iodide is 0.01-0.05%.

[0009] 2) mixing the pretreated anion exchange resin, cefpirome dihydroiodide and water, stirring, filtering, then adding activated carbon to the filtrate for decolorization, filtering again after the decolorization, cooling the filtrate to 0-5° C., then adjusting the pH of the filtrate to 1.2-1.4 with a sulfuric acid solution, then adding ethanol, stirring again at 0-5° C., filtering after the stirring, washing, and drying to obtain the cefpirome sulfate.

[0010] It can be understood that the first aqueous solution of cefpirome dihydroiodide and the third aqueous solution of cefpirome dihydroiodide contain two substances, namely, cefpirome dihydroiodide and sodium iodide.

[0011] The cefpirome dihydroiodide described in the present invention is an existing conventional substance and can be prepared by an existing method. Its structural formula is as follows:

[0012]

[0013] The present invention does not specifically limit the mass ratio between the strongly basic anion exchange resin and the first cefpirome dihydroiodide aqueous solution, the second cefpirome dihydroiodide aqueous solution or the third cefpirome dihydroiodide aqueous solution, as long as the strongly basic anion exchange resin can be immersed. Optionally, the mass ratio between the strongly basic anion exchange resin, the first cefpirome dihydroiodide aqueous solution, the second cefpirome dihydroiodide aqueous solution and the third cefpirome dihydroiodide aqueous solution is 100:(150-300):(150-300):(150-300).

[0014] Preferably, the alkali washing and water washing steps in step 1) include soaking in a 0.8-1.5 mol / L sodium hydroxide aqueous solution for 10-20 min, and washing with water until the pH of the effluent is 8.0-9.5.

[0015] Preferably, in step 1), ultrasonic oscillation is performed in the first aqueous solution of cefpirome dihydroiodide for 8-15 s, ultrasonic oscillation is performed in the second aqueous solution of cefpirome dihydroiodide for 3-8 s, and ultrasonic oscillation is performed in the third aqueous solution of cefpirome dihydroiodide for 8-15 s; and the ultrasonic oscillation power is 150-300 W.

[0016] Preferably, the strong basic anion exchange resin is selected from 711 strong basic anion exchange resin. The 711 strong basic anion exchange resin used in the present invention is an existing conventional commercial product, and its CAS number is 9036-93-5.

[0017] Preferably, the mass ratio of the pretreated anion exchange resin, cefpirome dihydroiodide and water is (10-18): (4-6): (10-18).

[0018] Preferably, in step 2), the stirring rate is 200-400 rpm, and the stirring time is 10-30 min; the stirring rate is again 200-400 rpm, and the stirring time is again 10-30 min.

[0019] Preferably, the added amount of activated carbon is 2-8% of the mass of cefpirome dihydroiodide.

[0020] Preferably, the decolorization treatment time is 20-40 min; the concentration of the sulfuric acid solution in step 2) is 4-6 mol / L.

[0021] Preferably, the ethanol in step 2) is ethanol cooled to 0-5°C;

[0022] The amount of ethanol added in step 2) is 1.5-3 times the mass of water;

[0023] The washing step in step 2) uses ethanol washing.

[0024] The present invention also provides cefpirome sulfate, which is prepared by the above-mentioned preparation method.

[0025] The technical solution of the present invention has the following advantages:

[0026] The preparation method of cefpirome sulfate provided by the invention comprises the following steps: firstly selecting 711 strongly basic anion exchange resin, washing it with alkali and water, and then sequentially using a 0.5-2% cefpirome dihydroiodide aqueous solution, a 20-30% cefpirome dihydroiodide aqueous solution and a 0.5-2% cefpirome dihydroiodide aqueous solution for ultrasonic oscillation treatment, wherein the 0.5-2% cefpirome dihydroiodide aqueous solution is added with 0.01-0.05% sodium iodide, and the invention ingeniously adds an ultrasonic oscillation step of a specific concentration of cefpirome dihydroiodide aqueous solution in the pretreatment step, and simultaneously introduces sodium iodide into the 0.5-2% cefpirome dihydroiodide aqueous solution, so as to effectively improve the exchange activity of the strongly basic anion exchange resin and reduce its impurities. By using the above method to pretreat the resin, it is experimentally verified that the impurity content of the cefpirome sulfate obtained after ion exchange can be effectively reduced and the yield thereof can be improved. DETAILED DESCRIPTION

[0027] The following examples are provided for further understanding of the present invention, but are not intended to limit the best mode of implementation and do not limit the scope of protection of the present invention.

[0028] The experimental steps or conditions not specified in the following embodiments of the present invention can be implemented according to the conventional experimental steps and conditions used in the existing literature in the field. The reagents or instruments used without specifying the manufacturer are all conventional reagents or instruments that can be purchased commercially.

[0029] Example 1

[0030] This embodiment provides a method for preparing cefpirome sulfate, comprising the following steps:

[0031] 1) Choose 100g 711 strong alkaline anion exchange resin, first soaked in 1 mol / L sodium hydroxide aqueous solution for 15 min, washed with water until the pH value of the water outlet is 8.9, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%, and the mass concentration of sodium iodide is 0.01%) for ultrasonic oscillation for 10s, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 25%) for ultrasonic oscillation for 5s, finally the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%, and the mass concentration of sodium iodide is 0.01%) for ultrasonic oscillation for 10s, the ultrasonic oscillation power is 200W, after the ultrasonic oscillation ends, the anion exchange resin is taken out to obtain the pretreated anion exchange resin;

[0032] 2) 15 g of the pretreated anion exchange resin, 5 g of cefpirome dihydroiodide and 15 g of water were mixed and stirred at a stirring rate of 300 rpm for 20 min, at which time the cefpirome dihydroiodide was completely dissolved, filtered, and then 0.2 g of activated carbon was added to the filtrate for decolorization for 20 min, filtered again, the filtrate was cooled to 4° C., and then the pH of the filtrate was adjusted to 1.4 with a 5 mol / L sulfuric acid solution, and then 30 g of ethanol cooled at 0° C. was added, and stirred at 4° C. for 3 h at a stirring speed of 300 rpm. After the stirring was completed, the mixture was filtered, washed with ethanol, and vacuum dried to obtain the cefpirome sulfate with a yield of 72.5% and a total impurity of 0.10%.

[0033] Example 2

[0034] This embodiment provides a method for preparing cefpirome sulfate, comprising the following steps:

[0035] 1) Choose 100g 711 strong alkaline anion exchange resin, first soaked in 1 mol / L sodium hydroxide aqueous solution for 15 min, washed with water until the pH value of the water outlet is 9.0, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%, and the mass concentration of sodium iodide is 0.02%) for ultrasonic oscillation for 10s, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 25%) for ultrasonic oscillation for 5s, finally the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%, and the mass concentration of sodium iodide is 0.02%) for ultrasonic oscillation for 10s, the ultrasonic oscillation power is 200W, after the ultrasonic oscillation ends, the anion exchange resin is taken out to obtain the pretreated anion exchange resin;

[0036] 2) 16 g of the pretreated anion exchange resin, 5 g of cefpirome dihydroiodide and 15 g of water were mixed and stirred at a stirring rate of 300 rpm for 30 min, at which time the cefpirome dihydroiodide was completely dissolved, filtered, and then 0.4 g of activated carbon was added to the filtrate for decolorization for 20 min, filtered again, the filtrate was cooled to 4° C., and then the pH of the filtrate was adjusted to 1.4 with a 5 mol / L sulfuric acid solution, and then 30 g of ethanol cooled at 0° C. was added, and stirred at 4° C. for 3 h at a stirring speed of 300 rpm. After the stirring was completed, the mixture was filtered, washed with ethanol, and vacuum dried to obtain the cefpirome sulfate with a yield of 72.1% and a total impurity of 0.08%.

[0037] Example 3

[0038] This embodiment provides a method for preparing cefpirome sulfate, comprising the following steps:

[0039] 1) Choose 100g 711 strong alkaline anion exchange resin, first soaked in 1 mol / L sodium hydroxide aqueous solution for 15 min, washed with water until the pH value of the water outlet is 9.2, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%, and the mass concentration of sodium iodide is 0.01%) for ultrasonic oscillation for 10s, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 25%) for ultrasonic oscillation for 8s, finally the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%, and the mass concentration of sodium iodide is 0.01%) for ultrasonic oscillation for 10s, the ultrasonic oscillation power is 200W, after the ultrasonic oscillation ends, the anion exchange resin is taken out to obtain the pretreated anion exchange resin;

[0040] 2) 12 g of the pretreated anion exchange resin, 5 g of cefpirome dihydroiodide and 20 g of water were mixed and stirred at a stirring rate of 300 rpm for 40 min, at which time the cefpirome dihydroiodide was completely dissolved, filtered, and then 0.4 g of activated carbon was added to the filtrate for decolorization for 20 min, filtered again, the filtrate was cooled to 5° C., and then the pH of the filtrate was adjusted to 1.4 with a 5 mol / L sulfuric acid solution, and then 50 g of ethanol cooled at 0° C. was added, and stirred at 5° C. for 3 h at a stirring speed of 300 rpm. After the stirring was completed, the mixture was filtered, washed with ethanol, and vacuum dried to obtain the cefpirome sulfate with a yield of 73.8% and a total impurity content of 0.13%.

[0041] Example 4

[0042] This embodiment provides a method for preparing cefpirome sulfate, comprising the following steps:

[0043] 1) Choose 100g 711 strong alkaline anion exchange resin, first soaked in 1 mol / L sodium hydroxide aqueous solution for 15 min, washed with water until the pH value of the outlet water is 9.0, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 2%, and the mass concentration of sodium iodide is 0.01%) for ultrasonic oscillation for 10s, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 25%) for ultrasonic oscillation for 8s, finally the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 2%, and the mass concentration of sodium iodide is 0.01%) for ultrasonic oscillation for 10s, the ultrasonic oscillation power is 200W, after the ultrasonic oscillation ends, the anion exchange resin is taken out to obtain the pretreated anion exchange resin;

[0044] 2) 14 g of the pretreated anion exchange resin, 5 g of cefpirome dihydroiodide and 20 g of water were mixed and stirred at a stirring rate of 300 rpm for 40 min, at which time the cefpirome dihydroiodide was completely dissolved, filtered, and then 0.5 g of activated carbon was added to the filtrate for decolorization for 30 min, filtered again, the filtrate was cooled to 5° C., and then the pH of the filtrate was adjusted to 1.4 with a 5 mol / L sulfuric acid solution, and then 40 g of ethanol cooled at 0° C. was added, and stirred at 5° C. for 3 h at a stirring speed of 300 rpm. After the stirring was completed, the mixture was filtered, washed with ethanol, and vacuum dried to obtain the cefpirome sulfate with a yield of 73.2% and a total impurity content of 0.12%.

[0045] Comparative Example 1

[0046] This comparative example provides a method for preparing cefpirome sulfate, which is different from Example 1 in that 100g of 711 strong alkaline anion exchange resin is selected in step 1), first soaked in 1mol / L sodium hydroxide aqueous solution for 15min, washed with water until the pH of the effluent is 8.9, and the pretreated anion exchange resin is obtained. The yield of the obtained cefpirome sulfate is 68.1%, and the total impurity content is 0.21%.

[0047] Comparative Example 2

[0048] This comparative example provides a method for preparing cefpirome sulfate, which is different from Example 1 in that 100 g of 711 strong alkaline anion exchange resin, first soaked in 1mol / L sodium hydroxide aqueous solution for 15min, washed with water until the pH value of the water outlet is 8.9, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%) for ultrasonic oscillation for 10s, then the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 25%) for ultrasonic oscillation for 5s, finally the anion exchange resin is placed in 200g cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 1%) for ultrasonic oscillation for 10s, the ultrasonic oscillation power is 200W, after the ultrasonic oscillation ends, the anion exchange resin is taken out to obtain the pretreated anion exchange resin. The yield of the obtained cefpirome sulfate is 70.9%, and the total impurity is 0.15%.

[0049] Comparative Example 3

[0050] This comparative example provides a preparation method of cefpirome sulfate, which is different from Example 1 in that 100g of 711 strong alkaline anion exchange resin is selected in step 1), first soaked in 1mol / L sodium hydroxide aqueous solution for 15min, washed with water until the pH value of the effluent is 8.9, and then the anion exchange resin is placed in 200g of cefpirome dihydroiodide aqueous solution (the mass concentration of cefpirome dihydroiodide in the cefpirome dihydroiodide aqueous solution is 25%) for ultrasonic oscillation for 25s, the ultrasonic oscillation power is 200W, and after the ultrasonic oscillation ends, the anion exchange resin is taken out to obtain the pretreated anion exchange resin. The yield of the obtained cefpirome sulfate is 69.4%, and the total impurity content is 0.17%.

[0051] Obviously, for ordinary technicians in the field, other modifications can be made based on the above embodiments, and the obvious modifications brought about by these modifications are still within the protection scope of the present invention.

Claims

1. A method for preparing cefpirome sulfate, characterized in that: The steps include: 1) Select a strongly alkaline anion exchange resin, wash it with alkali and water, then place the anion exchange resin in a first cefpirome dihydroiodide aqueous solution for ultrasonic vibration, then place the anion exchange resin in a second cefpirome dihydroiodide aqueous solution for ultrasonic vibration, and finally place the anion exchange resin in a third cefpirome dihydroiodide aqueous solution for ultrasonic vibration. After the ultrasonic vibration is completed, take it out to obtain a pretreated anion exchange resin; The mass concentration of cefpirome dihydroiodide in the first cefpirome dihydroiodide aqueous solution is 0.5-2%, and the mass concentration of sodium iodide is 0.01-0.05%. The mass concentration of cefpirome dihydroiodide in the second cefpirome dihydroiodide aqueous solution is 20-30%. The mass concentration of cefpirome dihydroiodide in the third cefpirome dihydroiodide aqueous solution is 0.5-2%, and the mass concentration of sodium iodide is 0.01-0.05%. 2) mixing the pretreated anion exchange resin, cefpirome dihydroiodide and water, stirring and filtering, then adding activated carbon to the filtrate for decolorization, filtering again after the decolorization, cooling the filtrate to 0-5° C., adjusting the pH of the filtrate to 1.2-1.4 with sulfuric acid solution, then adding ethanol, stirring again at 0-5° C., filtering after the stirring, washing, and drying to obtain the cefpirome sulfate; The strong basic anion exchange resin is selected from 711 strong basic anion exchange resin; In step 1), ultrasonic oscillation is performed in the first aqueous solution of cefpirome dihydroiodide for 8-15 seconds, ultrasonic oscillation is performed in the second aqueous solution of cefpirome dihydroiodide for 3-8 seconds, and ultrasonic oscillation is performed in the third aqueous solution of cefpirome dihydroiodide for 8-15 seconds; the ultrasonic oscillation power is 150-300W.

2. The preparation method according to claim 1, characterized in that In step 1), the alkali washing and water washing steps include soaking in a 0.8-1.5 mol / L sodium hydroxide aqueous solution for 10-20 minutes, and washing with water until the pH of the effluent is 8.0-9.

5.

3. The preparation method according to claim 1, characterized in that: The mass ratio of the pretreated anion exchange resin, cefpirome dihydroiodide and water is (10-18): (4-6): (10-18).

4. The preparation method according to claim 1, characterized in that: In step 2), the stirring rate is 200-400 rpm, and the stirring time is 10-30 min; the stirring rate is again 200-400 rpm, and the stirring time is again 10-30 min.

5. The preparation method according to claim 1, characterized in that: The amount of activated carbon added is 2-8% of the mass of cefpirome dihydroiodide.

6. The preparation method according to claim 1, characterized in that: The decolorization treatment time is 20-40 minutes; the concentration of the sulfuric acid solution in step 2) is 4-6 mol / L.

7. The preparation method according to claim 1, characterized in that: The ethanol in step 2) is ethanol cooled to 0-5°C; The amount of ethanol added in step 2) is 1.5-3 times the mass of water; The washing step in step 2) uses ethanol washing.

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