Method for reducing moisture of butyl acetate extract and improving quality of tilmicosin phosphate
By adding anhydrous sodium sulfate to the butyl acetate extract and optimizing reflux conditions, the method effectively reduces water content and improves tilmicosin phosphate quality, addressing inefficiencies in existing production methods.
Patent Information
- Application Number
- CN202411372102.6
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-29
- Publication Date
- 2025-01-03
AI Technical Summary
Existing methods for reducing the water content of butyl acetate extract in the production of tilmicosin phosphate are inefficient, leading to incomplete reflux reactions and reduced quality of the final product, with prolonged production times and high labor intensity.
The method involves adding anhydrous sodium sulfate to the butyl acetate extract, stirring, filtering, and conducting a reflux reaction at controlled temperatures and times to achieve a water content below 2%, thereby ensuring a sufficient reflux reaction and improving the quality of tilmicosin phosphate.
This approach enhances the tylosin conversion rate to 99.5% and reduces total impurities by 3.0 percentage points, while shortening production hours and maintaining process compatibility.
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Abstract
Description
Technical Field
[0001] The invention relates to the technical field of biological veterinary drug preparation, in particular to a method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate. Background Art
[0002] Tilmicosin phosphate is a chemical substance, off-white or light yellow powder, with a molecular formula of C46H80N2013.H3PO4 and a molecular weight of 967.14. It is a semi-synthetic macrolide drug of tylosin, with antibacterial activity similar to that of macrolide drugs, effective against Gram-positive bacteria and some Gram-negative bacteria and mycoplasma, and is an antibiotic for animals. The chemical name of Tilmicosin phosphate is 4A-O-de(2,6-dideoxy-3-C-methyl-L-ribose-pyranohexyl)-20-deoxy-20-(3,5-dimethyl-1-piperidinyl)-tylosin phosphate.
[0003] Tilmicosin phosphate is prepared by extracting tylosin concentrate with butyl acetate, separating the extracted wastewater, and then performing reflux reaction, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray drying to obtain Tilmicosin phosphate.
[0004] In the production process of Tilmicosin phosphate, the reflux reaction is the most important step in the production of Tilmicosin phosphate. The reflux reaction needs to be carried out under anhydrous conditions to complete the reflux reaction, reduce impurities, and improve the quality of Tilmicosin phosphate. If the water content of the butyl acetate extract during the reflux reaction is high, the reflux reaction will be incomplete, increase impurities, and reduce the quality of Tilmicosin phosphate.
[0005] At present, in order to improve the quality of tilmicosin phosphate, it is necessary to reduce the water content of butyl acetate extract before reflux reaction. In production, the water content of butyl acetate extract is mainly controlled by extending the standing time of butyl acetate extraction and increasing the frequency of water separation. However, this method of reducing the water content of butyl acetate extract will lead to problems such as long production hours and high labor operation intensity. At the same time, the effect of removing the water content of butyl acetate extract cannot always reach the ideal state, and thus the quality of tilmicosin phosphate cannot be guaranteed.
[0006] Therefore, effectively reducing the water content of butyl acetate extract and improving the quality of thiamethoxam phosphate extraction is an urgent problem to be solved. Summary of the invention
[0007] The object of the present invention is to provide a method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate, which can effectively remove the water content of butyl acetate extract, reduce impurities, and increase the tylosin conversion rate of the reflux reaction to 99.5%, thereby effectively reducing the total impurities of the tilmicosin phosphate product by 3.0 percentage points, and can solve the problems raised in the above-mentioned background technology.
[0008] To achieve the above object, the present invention provides the following technical solutions:
[0009] The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate comprises the following steps:
[0010] Step 1: adding butyl acetate to the tylosin tartrate concentrate for extraction, allowing the mixture to stand, and discarding the aqueous phase to obtain a butyl acetate extract;
[0011] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, stirring, filtering out the anhydrous sodium sulfate, and performing a reflux reaction;
[0012] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0013] Furthermore, the resting time of step 1 is 35 minutes.
[0014] Furthermore, the anhydrous sodium sulfate added to remove water is 5-15% of the mass of butyl acetate.
[0015] Furthermore, the stirring time after adding butyl acetate to anhydrous sodium sulfate is 30-60 minutes.
[0016] Furthermore, the reflux reaction in step 2 is: the butyl acetate extract from which the anhydrous sodium sulfate has been filtered out is reacted in a reflux kettle.
[0017] Furthermore, in step 2, the temperature of the reflux reaction is 65-75° C., and the time is 3-3.5 hours.
[0018] Furthermore, after the butyl acetate extract is dehydrated in step 2, the water content of the butyl acetate extract is less than 2%.
[0019] Working principle: The present invention adds anhydrous sodium sulfate to the butyl acetate extract to completely remove the water inside as much as possible, so that the water content is less than 2.0%. The greater the water content, the less sufficient the reflux reaction is, and the more impurities there are, which affects the quality of tilmicosin phosphate. The introduction of anhydrous sodium sulfate can greatly reduce the water content in butyl acetate, the conversion rate of tylosin in the reflux reaction can reach 99.5%, and the total impurities of the obtained tilmicosin phosphate powder can be reduced by 3.0 percentage points.
[0020] Compared with the prior art, the present invention has the following beneficial effects:
[0021] The invention ensures sufficient reflux reaction by adding anhydrous sodium sulfate, improves the quality of the finished product of Tilmicosin phosphate, and reduces the total impurities by 3.0%. The original process requires 5-6 hours for static water separation, and the water separation time after adding anhydrous sodium sulfate is 30-60 minutes, which reduces the production working hours. The invention does not cause conflicts with the existing production process and equipment, is simple to operate and easy to execute, and only needs to add anhydrous sodium sulfate. DETAILED DESCRIPTION
[0022] The following will be combined with the embodiments of the present invention to clearly and completely describe the technical solutions in the embodiments of the present invention. Obviously, the described embodiments are only part of the embodiments of the present invention, not all of the embodiments. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0023] The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate comprises the following steps:
[0024] Step 1: Add butyl acetate to the tylosin tartrate concentrate for extraction, let stand for 35 minutes, discard the aqueous phase, and obtain a butyl acetate extract;
[0025] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, stirring for 30-60 minutes, filtering out the anhydrous sodium sulfate, and performing a reflux reaction. The butyl acetate extract from which the anhydrous sodium sulfate has been filtered out is reacted in a reflux kettle. The reflux reaction temperature is between 65° C. and 75° C., and the reaction time is 3-3.5 hours.
[0026] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0027] Example 1: A method for reducing the water content of butyl acetate extract to improve the quality of tilmicosin phosphate, comprising the following steps:
[0028] Step 1: Add butyl acetate to the tylosin tartrate concentrate for extraction, let stand for 35 minutes, discard the aqueous phase, and obtain a butyl acetate extract;
[0029] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, the anhydrous sodium sulfate is 3% of the mass of butyl acetate, stirring time is 50min, filtering out the anhydrous sodium sulfate, and performing reflux reaction, the butyl acetate extract after filtering out the anhydrous sodium sulfate is reacted in a reflux kettle, the reflux reaction temperature is 70°C, and the time is 3 hours;
[0030] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0031] Example 2: A method for reducing the water content of butyl acetate extract to improve the quality of tilmicosin phosphate, comprising the following steps:
[0032] Step 1: Add butyl acetate to the tylosin tartrate concentrate for extraction, let stand for 35 minutes, discard the aqueous phase, and obtain a butyl acetate extract;
[0033] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, the anhydrous sodium sulfate is 5% of the mass of butyl acetate, stirring time is 50min, filtering out the anhydrous sodium sulfate, and performing reflux reaction, the butyl acetate extract after filtering out the anhydrous sodium sulfate is reacted in a reflux kettle, the reflux reaction temperature is 75°C, and the time is 3 hours;
[0034] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0035] Example 3: A method for reducing the water content of butyl acetate extract to improve the quality of tilmicosin phosphate, comprising the following steps:
[0036] Step 1: Add butyl acetate to the tylosin tartrate concentrate for extraction, let stand for 35 minutes, discard the aqueous phase, and obtain a butyl acetate extract;
[0037] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, the anhydrous sodium sulfate is 8% of the mass of butyl acetate, stirring time is 60min, filtering out the anhydrous sodium sulfate, and performing reflux reaction, the butyl acetate extract after filtering out the anhydrous sodium sulfate is reacted in a reflux kettle, the reflux reaction temperature is 75°C, and the time is 3.5 hours;
[0038] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0039] Example 4: A method for reducing the water content of butyl acetate extract to improve the quality of tilmicosin phosphate, comprising the following steps:
[0040] Step 1: Add butyl acetate to the tylosin tartrate concentrate for extraction, let stand for 35 minutes, discard the aqueous phase, and obtain a butyl acetate extract;
[0041] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, the anhydrous sodium sulfate being 12% of the mass of butyl acetate, stirring for 50 min, filtering out the anhydrous sodium sulfate, and conducting a reflux reaction. The butyl acetate extract from which the anhydrous sodium sulfate has been filtered out is reacted in a reflux kettle, the reflux reaction temperature is 65° C., and the time is 3 hours;
[0042] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0043] Example 5: A method for reducing the water content of butyl acetate extract to improve the quality of tilmicosin phosphate, comprising the following steps:
[0044] Step 1: Add butyl acetate to the tylosin tartrate concentrate for extraction, let stand for 35 minutes, discard the aqueous phase, and obtain a butyl acetate extract;
[0045] Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, the anhydrous sodium sulfate being 15% of the mass of butyl acetate, stirring for 60 minutes, filtering out the anhydrous sodium sulfate, and conducting a reflux reaction. The butyl acetate extract from which the anhydrous sodium sulfate has been filtered out is reacted in a reflux kettle, the reflux reaction temperature is 70° C., and the time is 3 hours;
[0046] Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0047] Comparative Example 1
[0048] After adding butyl acetate to the tylosin tartrate concentrate for extraction, the static time is 35 minutes, and the aqueous phase is discarded to obtain a butyl acetate extract;
[0049] Add anhydrous sodium sulfate to the butyl acetate extract in proportion, the anhydrous sodium sulfate is 0% of the mass of butyl acetate, the stirring time is 50 minutes, filter out the anhydrous sodium sulfate, and perform a reflux reaction. The butyl acetate extract from which the anhydrous sodium sulfate has been filtered out is reacted in a reflux kettle. The reflux reaction temperature is 70° C. and the time is 3 hours.
[0050] After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
[0051] The amount of anhydrous sodium sulfate added is the core of the present invention. When the amount of anhydrous sodium sulfate added is too much, it will cause a waste of anhydrous sodium sulfate, increase production costs, block equipment, affect production progress and other adverse consequences. When the amount of anhydrous sodium sulfate added is too little, it is impossible to fully remove the water in butyl acetate, affect the reflux reaction, and fail to achieve the purpose of reducing impurities and improving the quality of tilmicosin phosphate. Different proportions of anhydrous sodium sulfate were added to the butyl acetate extract, and the quality of the produced tilmicosin phosphate is as shown in Table 1:
[0052] Table 1
[0053]
[0054] By comparing the quality data of the finished product of Tilmicosin phosphate with different amounts of anhydrous sodium sulfate added to the butyl acetate extract, it can be seen that when the butyl acetate extract does not add anhydrous sodium sulfate (0% addition) or the amount added is insufficient (3%), the single impurities and total impurities of the corresponding finished product of Tilmicosin phosphate are both high and the content is low. When the amount of anhydrous sodium sulfate added reaches 5%-12%, the single impurities and total impurities of the corresponding Tilmicosin phosphate are significantly reduced, and the content is significantly increased. When the amount of anhydrous sodium sulfate added to the butyl acetate extract exceeds 12%, the single impurities and total impurities of the Tilmicosin phosphate product are no longer significantly reduced, and the content is no longer significantly increased.
[0055] In production, the ratio of anhydrous sodium sulfate added to the butyl acetate extract is generally controlled between 5% and 12%. If the butyl acetate extract does not contain excessive water after water separation, the ratio of anhydrous sodium sulfate added can be controlled to 8%, and the stirring time is 30-60 minutes.
[0056] Comparative Example 2: A method for preparing tilmicosin phosphate is carried out according to the traditional method, that is, butyl acetate is added to the tylosin tartrate concentrate for extraction, the aqueous phase is discarded to obtain a butyl acetate extract, reflux reaction, acid extraction hydrolysis, decolorization, crystallization centrifugation, phosphoric acid extraction, and the phosphoric acid extract is dried using a spray centrifugal drying tower to obtain tilmicosin phosphate powder.
[0057] Experiment: The methods of Example 4 and Comparative Example 2 were used to carry out three comparative productions using different tylosin tartrate concentrates, and the products after each batch of production were tested.
[0058] The test results are shown in Tables 1, 2 and 3 below.
[0059] Table 1
[0060] Single impurity % Total impurities% Moisture% content% Example 4 2.1 5.5 3.1 83.98 Comparative Example 2 2.3 8.6 3.2 78.90
[0061] Table 2
[0062] Single impurity % Total impurities% Moisture% content% Example 4 1.6 4.9 3.1 84.23 Comparative Example 2 1.8 8.0 3.0 79.90
[0063] Table 3
[0064] Single impurity % Total impurities% Moisture% content% Example 4 2.4 5.4 3.0 83.45 Comparative Example 2 2.6 8.7 3.2 78.33
[0065] It can be seen from the comparison of the above three batches of production that, compared with Comparative Example 2, the total impurities in Example 4 of the present invention are reduced by an average of 3.20%; the content is increased by 4.84%, and the effect is obvious.
[0066] The above description is only a preferred specific implementation manner of the present invention, but the protection scope of the present invention is not limited thereto. Any technician familiar with the technical field can make equivalent replacements or changes according to the technical scheme and inventive concept of the present invention within the technical scope disclosed by the present invention, which should be covered by the protection scope of the present invention.
Claims
1. A method for reducing the water content of butyl acetate extract to improve the quality of tilmicosin phosphate, characterized in that: The steps include: Step 1: adding butyl acetate to the tylosin tartrate concentrate for extraction, allowing the mixture to stand, and discarding the aqueous phase to obtain a butyl acetate extract; Step 2: adding anhydrous sodium sulfate to the butyl acetate extract in proportion, stirring, filtering out the anhydrous sodium sulfate, and performing a reflux reaction; Step 3: After the reflux reaction is completed, acid extraction, hydrolysis, decolorization, crystallization, centrifugation, phosphoric acid extraction, and spray centrifugal drying are performed to obtain tilmicosin phosphate powder.
2. The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate according to claim 1, characterized in that: The resting time of step 1 is 35 minutes.
3. The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate according to claim 1, characterized in that: The amount of anhydrous sodium sulfate added to remove water is 3-15% of the mass of butyl acetate.
4. The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate according to claim 1, characterized in that: After butyl acetate is added to anhydrous sodium sulfate, the stirring time is 30-60 minutes.
5. The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate according to claim 4, characterized in that: The reflux reaction in step 2 is: the butyl acetate extract from which the anhydrous sodium sulfate has been filtered out is reacted in a reflux kettle.
6. The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate according to claim 1, characterized in that: The temperature of the reflux reaction in step 2 is 65-75°C and the time is 3-3.5 hours.
7. The method for reducing the water content of butyl acetate extract and improving the quality of tilmicosin phosphate according to claim 1, characterized in that: After the butyl acetate extract is dehydrated in step 2, the water content of the butyl acetate extract is less than 2%.