A process for the preparation of low moisture ampicillin acid

Abstract

The application discloses a preparation method of low-moisture ampicillin acid, and belongs to the field of ampicillin acid, and comprises the following steps: step one, stirring and heating after mixing ampicillin trihydrate and isopropyl alcohol in a reaction kettle; step two, starting vacuumizing after heating; step three, carrying out reflux operation after vacuumizing; step four, after refluxing for a certain period of time, leading out distillate, and synchronously supplementing isopropyl alcohol; step five, stopping distillation after leading out distillate, cooling and breaking vacuum; and step six, filtering out solid after cooling, washing, drying and obtaining low-moisture ampicillin acid. The water and isopropyl alcohol of ampicillin trihydrate are slowly distilled out of the system by azeotropic distillation, so that low-moisture ampicillin acid is obtained. The low-moisture ampicillin acid can slow down the degradation of ampicillin by water, effectively reduce the impurity content, and improve the yield of ampicillin sodium produced by ampicillin acid.

Description

Technical Field

[0001] This invention belongs to the field of ampicillin, specifically a method for preparing low-moisture ampicillin. Background Technology

[0002] Ampicillin, also known as ampicillin, is a β-lactam antibiotic used to treat a variety of bacterial infections. Indications include respiratory tract infections, urinary tract infections, meningitis, salmonellosis, and endocarditis. It can also be used to prevent group B streptococcal infections in newborns and can be administered orally, intramuscularly, or intravenously.

[0003] Anhydrous ampicillin is an important precursor for the preparation of ampicillin sodium for injection, so its quality directly affects the quality and safety of the injected drug. Currently, most commercially available anhydrous ampicillin products use inorganic salt drying processes, resulting in incomplete dehydration and moisture content as high as 1%, severely impacting the quality and safety of the pharmaceutical intermediate. While some processes use solvation dehydration, the reported minimum moisture content control is below 0.3%, failing to meet the standard requirement of below 0.1%. Long-term storage still carries a risk of stability degradation and negatively impacts product yield and quality during ampicillin sodium production. Summary of the Invention

[0004] This invention provides a method for preparing low-moisture ampicillin to overcome the deficiencies in the prior art.

[0005] This invention is achieved through the following technical solution: A method for preparing low-moisture ampicillin includes the following steps: Step 1: Add ampicillin trihydrate and isopropanol to the reaction vessel, mix, stir, and heat. Step 2: After heating is complete, begin vacuuming; Step 3: After vacuuming is complete, perform a reflux operation; Step 4: After refluxing for a certain period of time, collect the distillate. Step 5: After the distillate has been drawn out, stop distillation, cool down and break the vacuum; Step 6: After cooling, filter out the solid, wash, and dry to obtain low-moisture ampicillin.

[0006] In the preparation method of low-moisture ampicillin acid described above, the mass-to-volume ratio of benzylpenicillin trihydrate and isopropanol in step one is 1:5.

[0007] In the preparation method of low-moisture ampicillin as described above, the stirring speed in step one is 80-120 r / min and the temperature range is 50-60℃.

[0008] In the preparation method of low-moisture ampicillin as described above, the vacuum level in step two is maintained at -0.07 to -0.1 MPa.

[0009] In the preparation method of low-moisture ampicillin as described above, in step three, after reflux for 5 minutes, the azeotrope of isopropanol and water is drawn out.

[0010] In the preparation method of low-moisture ampicillin as described above, in step four, the outflow of the azeotrope of isopropanol and water is counted in real time and an equal volume of isopropanol is added to the reaction vessel, and the flow rate of adding isopropanol to the reaction vessel is controlled to be the same as the flow rate of the azeotrope of isopropanol and water.

[0011] In the preparation method of low-moisture ampicillin as described above, the distillate extraction operation is stopped in step five when the amount of distillate extracted reaches half of the initial isopropanol addition volume.

[0012] In the preparation method of low-moisture ampicillin as described above, filtration begins when the temperature is lowered to 20-30°C in step six.

[0013] In the preparation method of low-moisture ampicillin as described above, the washing in step six is ​​performed with isopropanol, and the number of washings is 2 to 4. The volume-to-mass ratio of the amount of isopropanol used in each washing to the volume of the solid obtained after filtration is 1 to 4:1.

[0014] In the preparation method of low-moisture ampicillin as described above, the drying temperature in step six is ​​30-40°C, the drying vacuum degree is -0.08--0.1 MPa, and the drying time is 1-2 hours.

[0015] The advantages of this invention are: This invention achieves low-moisture ampicillin acid by slowly azeotropically distilling the water and isopropanol removed from the ampicillin trihydrate system. Low-moisture ampicillin acid can slow down the degradation of ampicillin by water, effectively reduce impurity content, and simultaneously improve the yield of ampicillin sodium production from ampicillin acid. Attached Figure Description

[0016] To more clearly illustrate the technical solutions in the embodiments of the present invention or the prior art, the drawings used in the description of the embodiments or the prior art will be briefly introduced below. Obviously, the drawings described below are some embodiments of the present invention. For those skilled in the art, other drawings can be obtained based on these drawings without creative effort.

[0017] Figure 1 This is a schematic diagram of dehydrated ampicillin acid according to Example 1 of the present invention; Figure 2 This is a schematic diagram showing the moisture content of dehydrated ampicillin acid in Example 1 of the present invention. Figure 3 This is a chromatogram of the purity test results of ampicillin acid after dehydration in Example 1 of the present invention; Figure 4 This is a schematic diagram of dehydrated ampicillin acid according to Example 2 of the present invention; Figure 5 This is a schematic diagram showing the moisture content of dehydrated ampicillin acid in Example 2 of the present invention. Figure 6 This is a chromatogram of the purity test results of dehydrated ampicillin acid in Example 2 of the present invention; Figure 7 This is a schematic diagram of dehydrated ampicillin acid in Example 3 of the present invention; Figure 8 This is a schematic diagram of the moisture content detection results of dehydrated ampicillin acid in Example 3 of the present invention; Figure 9 This is a chromatogram of the purity test results of ampicillin acid after dehydration in Example 3 of the present invention; Figure 10 This is a schematic diagram of the dehydrated ampicillin acid as a comparative example of the present invention; Figure 11 This is a schematic diagram showing the moisture content of dehydrated ampicillin acid in a comparative example according to the present invention. Figure 12 This is a chromatogram of the purity test results of dehydrated ampicillin acid in the comparative example of the present invention. Detailed Implementation

[0018] To make the objectives, technical solutions, and advantages of the embodiments of the present invention clearer, the technical solutions of the embodiments of the present invention will be clearly and completely described below with reference to the accompanying drawings. Obviously, the described embodiments are only some embodiments of the present invention, not all embodiments. Based on the embodiments of the present invention, all other embodiments obtained by those skilled in the art without creative effort are within the scope of protection of the present invention.

[0019] Example 1

[0020] Step 1: Add 400 kg of ampicillin trihydrate and 2000 L of isopropanol to the reaction vessel, and heat to 50 °C while stirring at 120 r / min. Step 2: After heating is complete, begin vacuuming to a vacuum level of -0.095 MPa; Step 3: After vacuuming is complete, perform a reflux operation; Step 4: After 5 minutes of reflux, start to draw out the azeotrope of isopropanol and water. Count the outflow of the azeotrope of isopropanol and water in real time and add the same volume of isopropanol to the reactor. Control the flow rate of adding isopropanol to the reactor to be the same as the flow rate of drawing out the azeotrope of isopropanol and water. Step 5: When the amount of isopropanol and water azeotrope drawn up reaches 1000L, stop distillation, cool down and break the vacuum. Step Six: Cool to 20℃ and filter out the solid. Wash with isopropanol twice, with the volume-to-mass ratio of isopropanol to the filtered solid being 4:1 each time. After washing, dry the solid at 30℃ under a vacuum of -0.095 MPa for 2 hours. The result is low-moisture ampicillin acid (e.g., ...). Figure 1 As shown), its moisture content is 0.0743% (as indicated). Figure 2 As shown), its purity is 99.708% (as shown). Figure 3 (As shown).

[0021] Example 2

[0022] Step 1: Add 400 kg of ampicillin trihydrate and 2000 L of isopropanol to the reaction vessel, and heat to 60 °C while stirring at 80 r / min. Step 2: After heating is complete, begin vacuuming to a vacuum level of -0.07 MPa; Step 3: After vacuuming is complete, perform a reflux operation; Step 4: After 5 minutes of reflux, start to draw out the azeotrope of isopropanol and water. Count the outflow of the azeotrope of isopropanol and water in real time and add the same volume of isopropanol to the reactor. Control the flow rate of adding isopropanol to the reactor to be the same as the flow rate of drawing out the azeotrope of isopropanol and water. Step 5: When the amount of isopropanol and water azeotrope drawn up reaches 1000L, stop distillation, cool down and break the vacuum. Step Six: Cool to 30℃ and filter out the solid. Wash with isopropanol three times, with the volume-to-mass ratio of isopropanol to the filtered solid being 3:1 each time. After washing, dry the solid at 35℃ under a vacuum of -0.085 MPa for 1.5 hours. The result is low-moisture ampicillin acid (e.g., ...). Figure 4 As shown), its moisture content is 0.0622% (as indicated). Figure 5 As shown), its purity is 99.805% (as shown). Figure 6 (As shown).

[0023] Example 3

[0024] Step 1: Add 400 kg of ampicillin trihydrate and 2000 L of isopropanol to the reactor, and heat to 55 °C while stirring at 100 r / min. Step 2: After heating is complete, begin vacuuming to a vacuum level of -0.08 MPa; Step 3: After vacuuming is complete, perform a reflux operation; Step 4: After 5 minutes of reflux, start to draw out the azeotrope of isopropanol and water. Count the outflow of the azeotrope of isopropanol and water in real time and add the same volume of isopropanol to the reactor. Control the flow rate of adding isopropanol to the reactor to be the same as the flow rate of drawing out the azeotrope of isopropanol and water. Step 5: When the amount of isopropanol and water azeotrope drawn up reaches 1000L, stop distillation, cool down and break the vacuum. Step Six: Cool to 25℃ and filter out the solid. Wash with isopropanol four times, with the volume-to-mass ratio of isopropanol to the filtered solid being 1:1 each time. After washing, dry the solid at 40℃ under a vacuum of -0.08 MPa for 1 hour. The result is low-moisture ampicillin (e.g., ...). Figure 7 As shown), its moisture content is 0.0738% (as indicated). Figure 8 As shown), its purity is 99.814% (as shown). Figure 9 (As shown).

[0025] Comparative Example 400 kg of ampicillin trihydrate and 2000 L of isopropanol were added to a reaction vessel. The mixture was heated to 55 °C and maintained at 100 rpm for 60 minutes. The mixture was then cooled, filtered, and dried. After drying, low-moisture ampicillin acid (e.g., ...) was obtained. Figure 10 As shown), its moisture content is 0.5927% (as shown). Figure 11 As shown), its purity is 99.431% (as shown). Figure 12 (As shown).

[0026] In summary, the method of this invention can effectively dehydrate ampicillin trihydrate, achieving excellent dehydration results. The moisture content of the dehydrated ampicillin acid can be controlled below 0.1%, and the purity is significantly superior to other methods, reaching over 99.7%. This demonstrates that heating the isopropanol solvent system effectively removes the water of crystallization from ampicillin into the solvent, and then effectively removes the water from the solvent through vacuum distillation. This ensures that the entire dehydration process is conducted in a low-moisture state, solving the problem of ampicillin decomposition during dehydration and also addressing the issue of low yield in the production of ampicillin sodium.

[0027] Finally, it should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention, and not to limit them; although the present invention has been described in detail with reference to the foregoing embodiments, those skilled in the art should understand that modifications can still be made to the technical solutions described in the foregoing embodiments, or equivalent substitutions can be made to some of the technical features; and these modifications or substitutions do not cause the essence of the corresponding technical solutions to deviate from the spirit and scope of the technical solutions of the embodiments of the present invention.

Claims

1. A method for preparing low-moisture ampicillin, characterized in that: Includes the following steps: Step 1: Add ampicillin trihydrate and isopropanol to the reaction vessel, mix, stir, and heat. Step 2: After heating is complete, begin vacuuming; Step 3: After vacuuming is complete, perform a reflux operation; Step 4: After refluxing for a certain period of time, collect the distillate. Step 5: After the distillate has been drawn out, stop distillation, cool down and break the vacuum; Step 6: After cooling, filter out the solid, wash, and dry to obtain low-moisture ampicillin.

2. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step one, the mass-to-volume ratio of benzylpenicillin trihydrate to isopropanol is 1:

5.

3. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: The stirring speed in step one is 80-120 r / min, and the temperature range is 50-60℃.

4. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step two, the vacuum level is maintained at -0.07 to -0.1 MPa.

5. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step three, after 5 minutes of reflux, the azeotrope of isopropanol and water is drawn out.

6. The method for preparing low-moisture ampicillin according to claim 5, characterized in that: In step four, the outflow of the azeotrope of isopropanol and water is counted in real time, and an equal volume of isopropanol is added to the reactor. The flow rate of isopropanol added to the reactor is controlled to be the same as the flow rate of the azeotrope of isopropanol and water.

7. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step five, the distillate extraction operation is stopped when the amount of distillate extracted reaches half of the initial isopropanol addition volume.

8. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step six, filtration begins when the temperature drops to 20-30°C.

9. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step six, isopropanol is used for washing, and the washing is performed 2 to 4 times. The volume-to-mass ratio of isopropanol used in each washing to the solid obtained after filtration is 1 to 4:

1.

10. The method for preparing low-moisture ampicillin according to claim 1, characterized in that: In step six, the drying temperature is 30–40°C, the drying vacuum is -0.08–-0.09 MPa, and the drying time is 1–2 hours.

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