A method for reducing sulbactam impurities

Abstract

The present invention discloses a method for reducing impurities of sulbactam, which belongs to the technical field of drug synthesis. The steps are as follows: Using 6,6-dibromo penicillanic acid sulfone as the raw material, zinc powder and sulfuric acid are used for de-bromination reduction reaction to obtain sulbactam. After the reaction is completed, filtration, extraction and washing are carried out to obtain the organic phase. The organic phase is treated with peracetic acid, and then quenched with sodium bisulfite. After phase separation, the organic phase is treated with hydrogen peroxide, and after phase separation, a product solution with low impurities is obtained. Through distillation, filtration and drying, the product is obtained. This method reduces the impurities in the product, improves the product quality, and the obtained product has good stability, low color grade and does not turn yellow when placed at room temperature.

Description

Technical Field

[0001] The present invention belongs to the technical field of pharmaceutical synthesis, and particularly relates to a method for reducing sulbactam impurities. Background Art

[0002] Sulbactam is a semi-synthetic broad-spectrum β-lactamase inhibitor, which has the characteristics of good stability, low toxicity, and strong enzyme inhibitory activity. Due to the excellent performance of sulbactam, many domestic and foreign enterprises and research institutions are conducting research on the synthesis process of sulbactam. However, there are still many problems in the current synthesis process of sulbactam, especially the poor product stability, and the appearance is prone to yellowing after being stored for a long time (the current regulatory requirements for storage conditions are low-temperature refrigeration (2-8°C)). Therefore, it is urgent to develop a sulbactam synthesis method with less environmental pollution and high product stability to improve the product quality and stability.

[0003]

[0004] In CN111848645A, CN111620892, and CN106699774, a sulbactam synthesis method is disclosed, in which 6-aminopenicillanic acid, hypophosphorous acid, and sodium nitrite are subjected to a diazotization reaction for hydrogenation, and then oxidation is carried out.

[0005] The disadvantage is that the content of product impurities is high, and it is difficult to obtain a product with high quality.

[0006]

[0007] In CN111808122, CN102532164, CN103848850, CN104262359, CN109705142, CN109438475, and CN106279206, a method is disclosed in which 6-APA is used as a raw material, 6-APA is dibrominated, oxidized, and reduced to obtain sulbactam, but it uses bromine with relatively high danger; and the by-product salt content is high in the recycling of bromine, and no effective treatment plan for product quality and stability is given.

[0008]

[0009] In CN101967155A, a method is disclosed in which the organic phase reduction product is washed with 4%-10% potassium permanganate, and then washed with saturated brine to obtain sulbactam. The disadvantage is that the treatment with potassium permanganate will produce manganese salts, which is not conducive to environmental protection and recycling.

[0010] Summary of the Invention

[0011] In order to solve the above problems, the present invention proposes a method for reducing sulbactam impurities. The specific steps are as follows:

[0012] 1) Using 6,6-dibromo penicillin sulfonic acid as the raw material, ethyl acetate and water as solvents, add sodium bicarbonate solution to the reaction system, adjust the pH of the system to 5-7, so that 6,6-dibromo penicillin sulfonic acid forms a salt and transfers to the aqueous phase, and control the system temperature at -5°C to 5°C; the addition ratio of 6,6-dibromo penicillin sulfonic acid to ethyl acetate is: 1:7;

[0013]

[0014] 2) When the reaction system in step 1) cools down to -5°C, add zinc powder at one time. The molar ratio of zinc powder to 6,6-dibromo penicillin sulfonic acid is 2-3:1. Slowly add sulfuric acid solution, control the pH at 4-6 during the process, react for 0.5-0.7 h, and adjust the pH to 1.5-2.0 after the reaction to obtain a mixed phase;

[0015]

[0016] 3) Perform solid-liquid separation on the mixed phase to remove zinc powder to obtain a reaction solution. Phase-separate the reaction solution. Wash the aqueous phase with ethyl acetate, collect and combine the washed ethyl acetate, add peracetic acid to it for decolorization, then wash with an aqueous solution of sodium bisulfite, and collect the organic phase; add peracetic acid as an oxidant to oxidize the reducing impurities in the organic phase solution system, and then use sodium bisulfite as a reducing agent for reduction to remove the excess peracetic acid.

[0017] 4) Wash the organic phase with hydrogen peroxide and dehydrate it with anhydrous magnesium sulfate, filter and separate. Distill the filtrate. When the remaining filtrate is 10-20% of the original volume of the solution, stop evaporation, cool to -5°C to 0°C for crystal cultivation for 0.5 h, filter, spray-wash with ice ethyl acetate, and dry to obtain sulbactam.

[0018] In step 3) above, the addition amount of peracetic acid is 1-5% of the solution volume; the concentration of peracetic acid is 15-25 wt%.

[0019] In step 3) above, the concentration of peracetic acid is 20-24 wt%.

[0020] In step 3) above, the concentration of the aqueous solution of sodium bisulfite is 20 wt%; the addition amount of the aqueous solution of sodium bisulfite is 1.2-2 times the volume of peracetic acid.

[0021] In step 3) above, the number of washing times is 2-3 times.

[0022] In step 4) above, crystal cultivation is carried out in a cold well, the crystal cultivation temperature is -5°C to 5°C, the crystal cultivation time is 1 h; the temperature of ice ethyl acetate is -10°C; drying is carried out using a vacuum drying oven, the drying temperature is 20°C, and the drying time is 30 min.

[0023] In step 4), the concentration of hydrogen peroxide is 15-30 wt%. Using hydrogen peroxide to remove impurities from the product results in a product with low impurity content, improved product stability. When placed under the accelerated test conditions for refrigerated bulk drugs, the product quality is qualified.

[0024] In step 2), the acid solution is a sulfuric acid solution with a concentration of 6 mol / L; in step 1), the concentration of the sodium bicarbonate solution is 10-12 wt%.

[0025] The beneficial effects of the present invention are as follows:

[0026] 1. The purpose of the present invention is to avoid the deficiencies in the above-mentioned prior art, improve the product quality and stability, improve the product appearance, and provide a good product quality basis for downstream products.

[0027] 2. This method reduces the impurity content in the sulbactam product, improves the product quality, and the obtained product has good stability, low color grade. When placed at room temperature, the product no longer turns yellow, and the color grade can be maintained at 1 / 2#.

[0028] 3. The sulbactam obtained by the method of the present invention can be placed for at least 6 months under the conditions of 25±2°C / 60%RH±5%RH; the product content still remains above 99.2%, the product color remains unchanged, maintaining a near-white color, and the color grade is 1 / 2#.

[0029] 4. The treatment method of the present invention improves the yield of sulbactam, and its single-step molar yield can reach more than 90%.

[0030] 5. The present invention does not use activated carbon for decolorization, avoiding the generation of solid waste during the production process. Specific Embodiments

[0031] The following further elaborates on the present invention in conjunction with specific embodiments:

[0032] Example 1

[0033] Add 50 g of 6,6-dibromopenicillanic acid and 300 mL of ethyl acetate into a reaction flask. Add 150.0 mL of purified water, stir and cool down to 5 °C, and adjust the pH to 6.0 with saturated sodium bicarbonate solution; cool the reaction system to below -4 °C, add 25 g of zinc powder at one time, and slowly adjust the pH to 4.0 with 6 mol / L sulfuric acid while maintaining below -5 °C. After the reaction is completed, adjust the pH to 1.5 - 2.0 with 6 mol / L sulfuric acid to obtain a mixed phase; filter the mixed phase by suction and wash with water to remove zinc slag, and collect the filtrate; separate the phases of the filtrate, extract the aqueous phase with ethyl acetate 3 times, 30 mL each time, and combine the organic phases; add 5 mL of 24% peracetic acid to the organic phase and stir, then add 10 mL of 20% sodium bisulfite for washing, separate the phases, and collect the organic phase; add 10 mL of 20% hydrogen peroxide to the organic phase for washing and stirring, then after separating the phases, add 7.0 g of anhydrous magnesium sulfate, stir for dehydration for 45 min, and filter by suction; carry out vacuum distillation on the filtrate, with the pressure at -0.086 Mpa and the temperature at 20 °C; control the amount of mother liquor at 40 mL, stop distillation, transfer the material liquid to a cold well at -5 to 5 °C for crystal cultivation for 1 h; filter the product by suction, and spray and wash the wet powder with 20 mL of ethyl acetate cooled to -10 °C; after the washing is completed, transfer the wet material to a vacuum drying oven and dry at 20 °C for 30 min to obtain 19.37 g of sulbactam product;

[0034] The single-step molar yield of sulbactam by the described method is 90.0%; the total impurities of the product are ≤0.3%, and impurity A is ≤0.1%; the maximum single impurity is ≤0.05%, and the color grade is 1 / 2#.

[0035] Comparative Example 2

[0036] Add 50 g of 6,6-dibromopenicillanic acid and 300 mL of ethyl acetate into a reaction flask. Add 150.0 mL of purified water, stir and cool down to 5 °C, and adjust the pH to about 6.0 with saturated sodium bicarbonate solution. Cool the reaction solution to below -4 °C, add 25 g of zinc powder at one time, and slowly adjust the pH to about 4.0 while maintaining below -5 °C. After the reaction is completed, adjust the pH to 1.50 - 2.0 with 6 mol / L sulfuric acid. Filter the product by suction to remove zinc slag, wash with water, collect the filtrate, extract the aqueous phase with ethyl acetate 3 times, 30 mL each time, combine the organic phases, add 7.0 g of anhydrous magnesium sulfate, stir for dehydration for 45 min, and filter by suction. Carry out vacuum distillation on the filtrate.

[0037] Control the amount of mother liquor at about 40 mL. Stop distillation, transfer the material liquid to a cold well at -5 - 5 °C for crystal cultivation for 1 h. Filter the product by suction, and spray and wash the wet powder with 20 mL of ethyl acetate (-10 °C). After the washing is completed, transfer the wet material to a vacuum drying oven and dry at 20 °C for 30 min to obtain 19.54 g of the product. The single-step molar yield is 90.6%. Using the USP method for sulbactam sodium for detection, the total impurities of the product are ≤1.0%, and impurity A is ≤0.5%; the maximum single impurity is ≤0.1%, and the color grade is 1#.

[0038] Comparative Example 3

[0039] Add 50 g of 6,6-dibromo penicillin sulfonic acid and 300 mL of ethyl acetate into a reaction flask, add 150.0 mL of purified water, stir and cool down to 5 °C, adjust the pH to about 6.0 with saturated sodium bicarbonate solution, cool the reaction solution to below -4 °C, add 25 g of zinc powder at one time, slowly adjust the pH to about 4.0 with 6 mol / L sulfuric acid while maintaining below -5 °C. After the reaction ends, adjust the pH to 1.50 - 2.0 with 6 mol / L sulfuric acid. Filter the product by suction to remove zinc slag, wash with water, collect the filtrate, extract the aqueous phase with ethyl acetate 3 times, 30 mL each time, combine the organic phases, add 5 mL of 20% peracetic acid to the organic phase and stir, then add 10 mL of 20% sodium bisulfite for washing, separate the phases, and collect the organic phase. Add 7.0 g of anhydrous magnesium sulfate, stir for dehydration for 45 min, and filter by suction. Distill the filtrate under reduced pressure.

[0040] Control the mother liquor volume to about 40 mL. Stop distillation, transfer the material liquid to a cold well at -5 - 5 °C for crystal cultivation for 1 h. Filter the product by suction, and spray-wash the wet powder with 20 mL of ice-cold ethyl acetate (-10 °C). After the washing is completed, transfer the wet material to a vacuum drying oven and dry at 20 °C for 30 min to obtain 19.45 g of the product. The single-step molar yield is 90.3%. Use the USP method for sulbactam sodium for detection, the total impurities of the product ≤ 0.5%, impurity A ≤ 0.2%; the maximum single impurity ≤ 0.05%, and the color grade is 1 / 2#.

[0041] Comparative Example 4

[0042] Add 50 g of 6,6-dibromo penicillin sulfonic acid and 300 mL of ethyl acetate into a reaction flask, add 150.0 mL of purified water, stir and cool down to 5 °C, adjust the pH to about 6.0 with saturated sodium bicarbonate solution, cool the reaction solution to below -4 °C, add 25 g of zinc powder at one time, slowly adjust the pH to about 4.0 with 6 mol / L sulfuric acid while maintaining below -5 °C. After the reaction ends, adjust the pH to 1.50 - 2.0 with 6 mol / L sulfuric acid. Filter the product by suction to remove zinc slag, wash with water, collect the filtrate, extract the aqueous phase with ethyl acetate 3 times, 30 mL each time, combine the organic phases, add 10 mL of 20% hydrogen peroxide to the organic phase for washing, separate the phases, and collect the organic phase. Add 7.0 g of anhydrous magnesium sulfate, stir for dehydration for 45 min, and filter by suction. Distill the filtrate under reduced pressure.

[0043] The mother liquor volume was controlled at about 40 mL. The distillation was stopped, and the feed liquid was transferred to a cold well at -5 to 5 °C for crystal cultivation for 1 h. The product was suction filtered, and the wet powder was spray washed with 20 mL of ice ethyl acetate (-10 °C). After the washing was completed, the wet material was transferred to a vacuum drying oven and dried at 20 °C for 30 min to obtain 19.42 g of the product. The single-step molar yield was 90.2%. The USP method for sulbactam sodium was used for detection, and the total impurities of the product were ≤0.5%, and the impurity A was ≤0.5%; the maximum single impurity was ≤0.1%, and the color grade was 1 / 2#.

[0044] Example 5

[0045] 50 g of 6,6-dibromo penicillin sulfonic acid and 300 mL of ethyl acetate were added to a reaction flask, 150.0 mL of purified water was added, and the mixture was stirred and cooled to 5 °C. The pH was adjusted to 6.0 with saturated sodium bicarbonate solution; the reaction system was cooled to below -4 °C, 25 g of zinc powder was added at one time, and the pH was slowly adjusted to 4.0 with 6 mol / L sulfuric acid while maintaining below -5 °C. After the reaction was completed, the pH was adjusted to 1.5 - 2.0 with 6 mol / L sulfuric acid to obtain a mixed phase; the mixed phase was suction filtered and washed with water to remove zinc slag, and the filtrate was collected; the filtrate was phase-separated, the aqueous phase was extracted with ethyl acetate 3 times, 30 mL each time, the organic phases were combined, 5 mL of 15% peracetic acid was added to the organic phase and stirred, then 10 mL of 20% sodium bisulfite was added for washing, phase-separated, and the organic phase was collected; 10 mL of 20% hydrogen peroxide was added to the organic phase for washing and stirring, then after phase-separation, 7.0 g of anhydrous magnesium sulfate was added, stirred for dehydration for 45 min, and suction filtered; the filtrate was subjected to vacuum distillation; the mother liquor volume was controlled at 40 mL, the distillation was stopped, and the feed liquid was transferred to a cold well at -5 to 5 °C for crystal cultivation for 1 h; the product was suction filtered, and the wet powder was spray washed with 20 mL of ice ethyl acetate at -10 °C; after the washing was completed, the wet material was transferred to a vacuum drying oven and dried at 20 °C for 30 min to obtain 19.44 g of sulbactam product;

[0046] The single-step molar yield of sulbactam by the said method was 90.21%, the total impurities of the product were ≤0.3%, and the impurity A was ≤0.1%; the maximum single impurity was ≤0.05%, and the color grade was 1 / 2#.

[0047] Comparative Example 6

[0048] Add 50 g of 6,6-dibromo penicillanic acid sulfone and 300 mL of ethyl acetate into a reaction flask. Add 150.0 mL of purified water, stir and cool down to 5 °C. Adjust the pH to about 6.0 with saturated sodium bicarbonate solution. Cool the reaction solution to below -4 °C, add 25 g of zinc powder at one time, and slowly adjust the pH to about 4.0 with 6 mol / L sulfuric acid while maintaining below -5 °C. After the reaction ends, adjust the pH to 1.50 - 2.0 with 6 mol / L sulfuric acid. Filter the product by suction to remove zinc slag, wash it with water, collect the filtrate. Extract the aqueous phase with ethyl acetate three times, 30 mL each time. Combine the organic phases, wash the organic phase with 100 mL of saturated brine, separate the phases, collect the organic phase, add 3 g of activated carbon and 7.0 g of anhydrous magnesium sulfate, stir for 45 min for dehydration and decolorization, and then filter by suction. Distill the filtrate under reduced pressure.

[0049] Control the mother liquor volume at about 40 mL. Stop distillation, transfer the feed liquid to a cold well at -5 - 5 °C for crystal cultivation for 1 h. Filter the product by suction, and spray-wash the wet powder with 20 mL of ice-cold ethyl acetate (-10 °C). After washing, transfer the wet material to a vacuum drying oven and dry at 20 °C for 30 min to obtain 19.44 g of the product. The single-step molar yield is 90.21%. Use the USP method for sulbactam sodium for detection. The total impurities of the product ≤ 0.5%, impurity A ≤ 0.3%; the maximum single impurity ≤ 0.1%, and the color grade is 1 / 2#. Refer to the post-treatment of Patent 106279206.

[0050] Respectively take the samples produced by the methods of Example 1 and Example 5, and Comparative Examples 2, 3, 4, and 6, and place them according to the accelerated test conditions for cold storage drugs of bulk drugs, at a temperature of 25 ± 2 °C / 60% RH ± 5% RH, and detect the quality changes of the products at 0, 3, and 6 months, as shown in Table 1 below.

[0051] Table 1 Performance parameters of sulbactam

[0052]

[0053]

Claims

1. A method for reducing sulbactam impurities, characterized in that, The following steps are involved: 1) Using 6,6-dibromopenicillin sulfone acid as a raw material, ethyl acetate and water as solvents, adding a sodium bicarbonate solution to the reaction system, adjusting the pH of the system to 5-7, so that the 6,6-dibromopenicillin sulfone acid salt is transferred to the water phase, and controlling the system temperature to -5°C to 5°C; wherein the addition ratio of 6,6-dibromopenicillin sulfone acid to ethyl acetate is 1:7; 2) After the reaction system of step 1) is cooled to -5°C, zinc powder is added at once, and the molar ratio of zinc powder to 6,6-dibromopenicillin sulfonic acid is 2-3:1, and sulfuric acid solution is slowly added dropwise, and the pH is controlled at 4-6 during the process, and the reaction is carried out for 0.5-0.7h. After the reaction is completed, the pH is adjusted to 1.5-2.0 to obtain a mixed phase; 3) separating the mixed phase into solid and liquid, removing zinc powder, obtaining a reaction solution, separating the reaction solution into phases, washing the aqueous phase with ethyl acetate, collecting and merging the washed ethyl acetate, adding peracetic acid thereto for decolorization, then washing with a sodium bisulfite aqueous solution, and collecting the organic phase; the amount of peracetic acid added in step 3) is 1 to 5% of the volume of the solution; the concentration of peracetic acid is 15 to 25 wt%; 4) The organic phase is washed with hydrogen peroxide, dehydrated with anhydrous magnesium sulfate, filtered and separated, and the filtrate is distilled. When the remaining filtrate is 10-20% of the volume of the original solution, the evaporation is stopped, the temperature is lowered to -5-0°C for crystal growth for 0.5h, filtered, sprayed with glacial ethyl acetate, and dried to obtain sulbactam; the concentration of hydrogen peroxide in step 4) is 15-30wt%.

2. The method for reducing sulbactam impurities according to claim 1, wherein In the step 3), the concentration of peracetic acid is 20-24 wt %.

3. The method for reducing sulbactam impurities according to claim 1, wherein The concentration of the sodium bisulfite aqueous solution in step 3) is 20 wt %; the amount of the sodium bisulfite aqueous solution added is 1.2 to 2 times the volume of the peracetic acid.

4. The method for reducing sulbactam impurities according to claim 1, wherein The washing times in step 3) are 2-3 times.

5. The method for reducing sulbactam impurities according to claim 1, characterized in that, In the step 4), the crystal growing is carried out in a cold well, the crystal growing temperature is -5°C to 5°C, and the crystal growing time is 1 hour; the temperature of the glacial ethyl acetate is -10°C; and the drying is carried out in a vacuum drying oven, the drying temperature is 20°C, and the drying time is 30 minutes.

6. The method for reducing sulbactam impurities according to claim 1, wherein, The acid solution in step 2) is a sulfuric acid solution with a concentration of 6 mol / L; the concentration of the sodium bicarbonate solution in step 1) is 10-12 wt%.

Images