A method for purifying tedizolid

Abstract

The application discloses a purification method of tediroxine, and belongs to the technical field of drug purification, and comprises the following steps: dissolving, filtering and separating: under the condition of a first preset temperature, a V1 amount of water is added dropwise, a small amount of solid is precipitated from the system, and after filtering, the system is separated into two layers, and the lower layer is taken; crystallization: under the condition of a second preset temperature, a V2 amount of water is added dropwise, and solid tediroxine is precipitated, and after crystal growing, filtering and drying, the tediroxine is obtained, and the mass ratio of the crude tediroxine to the V1 amount and the V2 amount of water is 1:6.0-10.0:30-50. The application has the beneficial effects that the use of other second-class solvents is reduced, no harmful gas is generated, the reaction temperature is easy to control, the probability of danger generation is reduced, the method is low in cost and environmental protection, the yield of the product is high, and the product is high in purity.

Description

TECHNICAL FIELD

[0001] The present application belongs to the technical field of drug purification, and more particularly relates to a tildipirosin purification method. BACKGROUND

[0002] Tildipirosin is a new animal-specific semisynthetic macrolide antibiotic developed by Intervet, which is a derivative of tylosin. It has a very obvious therapeutic effect on respiratory diseases of cattle and pigs, and is stronger than tylosin and tilmicosin in terms of drug efficacy. Moreover, it has the advantages of animal specificity, small dosage, one-time administration for whole-course treatment, super-long elimination half-life, high bioavailability, low residue, etc. The chemical name of tildipirosin is 20, 23-dipiperidyl-5-oxo-mycaminosyl-tylonide.

[0003] The structural formula is as follows

[0004]

[0005] For the synthesis of the compound, the methods reported so far mainly include the following:

[0006] Patent CN110981926A discloses a tildipirosin purification method. The tildipirosin crude product is dissolved in acetonitrile, filtered, and then water is added for crystallization. After crystallization, centrifugation and drying, tildipirosin pure product is obtained. This method uses acetonitrile, a Class II solvent specified by ICH, as a refining solvent, and the residual limit is not more than 0.041%. After drying, the acetonitrile limit cannot reach the specified level.

[0007] Patent CN108033988A: Tylosin is converted into piperidyl at position 20 of tylosin by amination reaction, and the sugar groups at positions 4 and 15 are removed by hydrolysis reaction, and then the hydroxyl group at position 23 is converted into piperidyl by oxidation reaction and amination reaction in turn, and finally tildipirosin is obtained. This method is complicated in operation and has many steps, resulting in low product yield, and the purity of tildipirosin is only 97%, and the product purity is low.

[0008] Patent CN104672287A discloses a tildipirosin purification method. The tildipirosin crude product is acidified with sulfuric acid, impurities are removed using silica gel or alumina, and then the product is basified and crystallized at 75℃. This method is prone to generate base-damaged impurities at high temperature, and generates solid waste such as silica gel and alumina, increasing the production cost.

[0009] Patent CN113201033A discloses a new purification method, which mixes the crude tediroxine with ethanol, water solution, decolorizes with activated carbon, filters, crystallizes to obtain tediroxine solid. The method not only obtains high content of tediroxine isomer, but also the activated carbon decolorization at high temperature is easy to cause part of the material to be adsorbed and cause low yield.

[0010] In summary: the above methods all have more or less problems: some products have low yield; some residual solvent limits do not meet the standard, which cannot meet the industrial production; some products have high impurities and by-products, which cause low product purity. Therefore, it is of great significance to develop an environmentally friendly and economically feasible purification method of tediroxine. SUMMARY

[0011] To solve the above problems and overcome the shortcomings of the prior art, the present application provides a purification method of tediroxine, which can effectively solve the problems of residual solvent limit not meeting the standard, which cannot meet the industrial production; high product impurities and by-products.

[0012] The specific technical scheme for solving the above technical problems is: a purification method of tediroxine, characterized in that the method comprises the following process steps:

[0013] (1) Dissolution: add the crude tediroxine to the mixed solvent, heat to 71-81℃ to dissolve,

[0014] (2) Filtration and layering:

[0015] Under the first preset temperature condition, V1 amount of water is added to step (1), a small amount of solid is precipitated, after filtration, the lower layer is taken;

[0016] (3) Crystallization:

[0017] Under the second preset temperature condition, V2 amount of water is added to step (2), tediroxine solid is precipitated, after crystallization, filtration and drying, tediroxine is obtained.

[0018] Further, the mixed solvent is a mixture of isopropyl alcohol and n-heptane.

[0019] Further, the mass volume ratio of crude tediroxine, isopropyl alcohol and n-heptane is 1g:(5-8)mL:(15-25)mL.

[0020] Further, the first preset temperature is 71-81℃.

[0021] Further, the second preset temperature is 75-85℃.

[0022] Furthermore, in step (3), the crystal growth time is 10-20 hours; the drying temperature is controlled at 35-55°C; and the drying time is 10-20 hours.

[0023] Furthermore, the mass ratio of the crude tidal product to water (V1 and V2) is 1:6.0-10.0:30-50.

[0024] The beneficial effects of this invention are:

[0025] (1) This invention provides a new purification method for tidalin, which reduces the use of other second-class solvents, produces no harmful gases, and makes the reaction temperature easy to control, reducing the probability of danger. At the same time, the method is low-cost, environmentally friendly, and produces products with high yield and high purity.

[0026] (2) This invention creatively uses a stepwise water addition method to separate the impurities from teldrolidine first, and then crystallizes the teldrolidine after the impurities are separated to obtain teldrolidine with high purity, which solves the problems of residual solvent limit not meeting the standard and not being able to meet industrial production requirements; and high product impurities and by-products.

[0027] (3) The present invention creatively discovered that when isopropanol and n-heptane are used as solvents, there is a range within which the amount added in the embodiments of the present invention is within 60-100 ml, so that impurities and teldrone with similar physicochemical properties can be preferentially precipitated. The preferentially precipitated impurities can be separated from teldrone, thus avoiding the waste of teldrone and improving the overall yield. Attached image description:

[0028] Appendix Figure 1 This is a schematic diagram comparing the content of tidalin and impurities in the first filtration solids in Embodiment 1 of the present invention;

[0029] Appendix Figure 2 This is a schematic diagram comparing the content of tidalin and impurities in the first filtration solids in Embodiment 2 of the present invention;

[0030] Appendix Figure 3 This is a schematic diagram comparing the content of tidalin and impurities in the first filtration solids in Example 3 of the present invention;

[0031] Appendix Figure 4 This is a schematic diagram comparing the content of tidalin and impurities in the first filtration solids of Comparative Example 9 of the present invention.

[0032] Appendix Figure 5 This is a schematic diagram comparing the content of tidalin and impurities in the first filtration solids of Comparative Example 15 of the present invention.

[0033] Appendix Figure 6This is a schematic diagram comparing the content of tidalin and impurities in the first filtration solids of Comparative Example 17 of the present invention.

[0034] Appendix Figure 7 This is a schematic diagram comparing the content of tidalin and impurities in the solids from the first filtration in Comparative Example 18 of this invention; (See attached diagram:) Detailed implementation method:

[0035] Specific details in the description of this invention are merely to provide a thorough understanding of the embodiments thereof; however, those skilled in the art should understand that the implementation of this invention is not limited to these details. Furthermore, well-known structures and functions have not been described or shown in detail to avoid obscuring the key points of the embodiments of this invention. Those skilled in the art can understand the specific meaning of the above terms in this invention based on the specific circumstances.

[0036] Specific embodiments of the present invention:

[0037] To better understand the present invention, specific embodiments are described. It is worth emphasizing that the effects of these embodiments are not substantially different from those of various embodiments within the scope of protection of the present invention, including their respective reagents and reagent content ratios. All of them can achieve the effects described in the present invention and solve the above-mentioned problems. Other combinations are not described here.

[0038] (1) The crude product of terdiroxin, isopropanol and n-heptane are mixed and then heated to dissolve; the dissolving temperature is 71-81℃; the mass-volume ratio of crude terdiroxin to isopropanol and n-heptane is 1:5-8:15-25.

[0039] (2) At 71-81℃, water is added dropwise to the system for the first time in step (1). A small amount of solid is precipitated in the system. After filtration, the layers are separated and the lower layer is taken out. The mass-volume ratio of the crude tadalafil to water is 1:6.0-10.0.

[0040] (3) At 75-85℃, water is added dropwise a second time in step (2), thereby precipitating teldrone solid. After crystal growth, filtration and drying, teldrone with high purity is obtained. The mass ratio of crude teldrone to water is 1:30-50;

[0041] In step (3), the crystal growth time is 10-20 hours; the drying temperature is controlled at 35-55°C; and the drying time is 10-20 hours.

[0042] As a specific embodiment of the present invention:

[0043] Example 1:

[0044] 10.0 g of crude tebuconazole (95.8% purity), 70 ml of isopropanol, and 180 ml of n-heptane were sequentially placed in a 500 ml three-necked flask and heated to 71–81 °C with stirring until dissolved. At 73 °C, 100 ml of water was added dropwise, resulting in the precipitation of a small amount of solid. After stirring for approximately 0.5 h, the mixture was filtered. The filtrate was separated into two layers; the upper n-heptane phase was discarded, and the lower layer was collected and placed in a 1000 ml three-necked flask. At 75 °C, 300 ml of water was added dropwise, causing tebuconazole solid to precipitate. The addition was completed after approximately 1.0 h. The mixture was slowly cooled to 0–5 °C for crystal growth for 12 h, then filtered. The filter cake was washed with water and dried at 45 °C for approximately 15 h to obtain tebuconazole. The product yield was 94.4%, and the purity was 99.68%.

[0045] Example 2:

[0046] 10.0 g of crude tebuconazole (95.1% purity), 50 ml of isopropanol, and 150 ml of n-heptane were sequentially placed in a 500 ml three-necked flask and heated to 71–81 °C with stirring until dissolved. At 78 °C, 60 ml of water was added dropwise, resulting in the precipitation of a small amount of solid. After stirring for approximately 0.5 h, the mixture was filtered. The filtrate was separated into two layers; the upper n-heptane phase was discarded, and the lower layer was collected and placed in a 500 ml three-necked flask. At 80 °C, 500 ml of water was added dropwise, causing tebuconazole solid to precipitate. The addition was completed after approximately 1.0 h. The mixture was slowly cooled to 0–5 °C for crystal growth for 15 h, then filtered. The filter cake was washed with water and dried at 45 °C for approximately 12 h to obtain tebuconazole. The product yield was 93.6%, and the purity was 99.64%.

[0047] Example 3:

[0048] 10.0 g of crude tebuconazole (94.2% purity), 80 ml of isopropanol, and 200 ml of n-heptane were sequentially placed in a 500 ml three-necked flask and heated to 71–81 °C with stirring until dissolved. At 81 °C, 80 ml of water was added dropwise, resulting in the precipitation of a small amount of solid. After stirring for approximately 0.5 h, the mixture was filtered. The mother liquor was separated into two layers; the upper n-heptane phase was discarded, and the lower layer was collected and placed in a 1000 ml three-necked flask. At 85 °C, 400 ml of water was added dropwise, causing tebuconazole solid to precipitate. The addition was completed after approximately 1.0 h. The mixture was slowly cooled to 0–5 °C for crystal growth for 17 h, then filtered. The filter cake was washed with water and dried at 45 °C for approximately 18 h to obtain tebuconazole. The product yield was 92.8%, and the purity was 99.73%.

[0049] To more intuitively demonstrate the technological advantages of this invention, a comparison is made between the novel purification method for tyrosine described in this invention and a method using equivalent substitutions in the same process.

[0050] Comparative Example 1:

[0051] The preparation method is the same as in Example 3, except that water is added all at once during the preparation process of this comparative example, and the amount of water added is V = V1 + V2.

[0052] Comparative Example 2:

[0053] The preparation method is the same as in Example 3, except that the water is added rapidly instead of dropwise during the preparation process of this comparative example.

[0054] Comparative Example 3:

[0055] The preparation method is the same as in Example 3, except that a single solvent, isopropanol, is added during the preparation of this comparative example.

[0056] Comparative Example 4:

[0057] The preparation method is the same as in Example 3, except that the mixed solvent in this comparative example is a mixture of n-propanol and n-heptane.

[0058] Comparative Example 5:

[0059] The preparation method is the same as in Example 3, except that the mixed solvent in this comparative example is a mixture of ethanol and n-heptane.

[0060] Table 1: Comparison of Tedrosin and Impurity Content in Solids from Different Processes and Filtration Methods

[0061]

[0062] Analysis of the data in Table 1 shows that:

[0063] (1) Compared with Examples 1-3 and Comparative Examples 1-2:

[0064] In the embodiments of the present invention, the content of impurities in the first filtered solids was relatively high while the content of teldrone was extremely low. In contrast, in Comparative Examples 1-2, the content of impurities in the first filtered solids was relatively low, at 2.0% and 2.6%, while the content of teldrone was as high as 97.4% and 98%.

[0065] It can be seen that the present invention creatively introduces a two-stage water addition method. The first water addition is of a smaller amount, which allows impurities and teldrolidine with similar physicochemical properties to precipitate preferentially. After separation, a large amount of water solvent is added to crystallize teldrolidine, thereby achieving the purpose of impurity removal.

[0066] As can be seen from the comparative example, adding water at once will cause impurities to precipitate out, but it will also cause a large amount of tadalafil to precipitate out. This results in all the impurities entering the tadalafil, ultimately leading to a high level of impurities in the product. Without purification, this does not meet the requirements of the National Pharmacopoeia for tadalafil.

[0067] (2) Compared with Examples 1-3 and Comparative Example 3:

[0068] In Comparative Example 3, the content of impurities in the first filtration solids was high while the content of teldrolidine was extremely low. However, the content of impurities in the second filtration solids was as high as 2.64%, resulting in a high level of impurities in the product. Without purification, this does not meet the requirements of the National Pharmacopoeia for teldrolidine.

[0069] This may be because the single solvent, isopropanol, cannot separate the impurities from teldrolidine by adding water in steps. In the case of adding a small amount of water to isopropanol in the first step, the impurities cannot preferentially precipitate out with teldrolidine, which has similar physicochemical properties, resulting in a large amount of impurities entering the system. Ultimately, this leads to a high level of impurities in the product, which does not meet the requirements of the National Pharmacopoeia for teldrolidine without purification.

[0070] (3) Compared with Examples 1-3 and Comparative Example 4:

[0071] In Comparative Example 4, no solids were produced during the first filtration, which prevented the preferential precipitation of impurities and tepidiloxine, which have similar physicochemical properties. This resulted in a high level of impurities in the product, which, without purification, does not meet the requirements of the National Pharmacopoeia for tepidiloxine.

[0072] This may be because the mixed solvents—n-propanol and n-heptane—cannot separate the impurities from teldrolidine by adding water in steps.

[0073] (4) Compared with Examples 1-3 and Comparative Example 5:

[0074] Comparative Example 5 was able to produce a first filtration solid, but a large amount of tadalafil was precipitated from the filtration solid, resulting in most of the impurities entering the tadalafil and ultimately leading to a high level of impurities in the product. Without purification, it does not meet the requirements of the National Pharmacopoeia for tadalafil.

[0075] To further demonstrate the technological advantages of this invention, a comparison is made between the novel purification method for thiamethoxam described in this invention and a method using equivalent substitutions in the same process.

[0076] Based on Comparative Example 4, the amount of water V1 added in step (1) is adjusted by gradient: see the table below for details.

[0077] Table 2: Comparison of the effects of different V1 addition rates of isopropanol and n-heptane solvents on the content of teldrone and impurities in the solids from the first filtration.

[0078]

[0079] Analysis of the data in Table 2 shows that:

[0080] Using isopropanol and n-heptane as solvents, different gradient addition amounts of V1 resulted in varying contents of teldrone and impurities in the solids from the first filtration.

[0081] Specifically:

[0082] (1) In the embodiment of the present invention, within the amount added, i.e. V1 amount = 60-100ml, there is a range in which a large amount of impurities are precipitated, while the amount of teldroxine is not too much. The solids in the first filtration are already small, and the loss of teldroxine of 0.2% is not large. The final overall yield can reach more than 93%.

[0083] (2) When the gradient addition amount of V1 is less than the protection scope of the present invention, it was found that the solids were not precipitated during the first filtration. This indicates that the addition amount does not affect the polarity of the system, so that the impurities cannot be preferentially precipitated with tylosin, which has similar physicochemical properties. In this way, all the impurities enter the final product.

[0084] (3) When the gradient addition of V1 is greater than the protection scope of the present invention, a lot of solids will be precipitated during the first filtration. The test found that the content of tediloxine was as high as 5.21%, which resulted in a low final yield. The recovery of this part of tediloxine is difficult.

[0085] Table 3: Comparison of the effects of different V1 addition rates of n-propanol and n-heptane solvents on the content of teldrone and impurities in the solids from the first filtration.

[0086]

[0087] Analysis of the data in Table 3 shows that:

[0088] Using n-propanol and n-heptane as solvents, different gradient addition amounts of V1 resulted in varying contents of teldrone and impurities in the solids from the first filtration.

[0089] Specifically:

[0090] (1) In the embodiment of the present invention, the amount added is V1 = 60-100ml. Unlike the present invention, no solids were precipitated during the first filtration. This indicates that the amount added will not affect the polarity of the system, so that impurities cannot be preferentially precipitated with tylosin, which has similar physicochemical properties. In this way, all impurities enter the final product.

[0091] (2) When the gradient addition amount of V1 is less than the protection scope of the present invention, it was found that no solids were precipitated during the first filtration.

[0092] (3) When the gradient addition amount of V1 is greater than the protection scope of the present invention, a large amount of solids will be precipitated in the first filtration. The test results showed that the content of teldrolidine was as high as 93.2%, while the content of impurities was only 6.8%. This indicates that when the amount is greater than that of V1 in the present invention, teldrolidine will be precipitated in large quantities along with impurities, resulting in a low final yield. The recovery of this part of teldrolidine is difficult. More importantly, when using n-propanol and n-heptane as solvents, there is no range in which impurities can preferentially precipitate with teldrolidine, which has similar physicochemical properties, thereby satisfying the effect of separation from teldrolidine.

[0093] Table 4: Comparison of the effects of different V1 addition rates of ethanol and n-heptane solvents on the content of teldrone and impurities in the solids from the first filtration.

[0094]

[0095] Analysis of the data in Table 4 shows that:

[0096] Using ethanol and n-heptane as solvents, different gradient addition amounts of V1 resulted in varying levels of teldrone and impurities in the solids from the first filtration.

[0097] Specifically:

[0098] (1) In the embodiment of the present invention, the amount added is V1 = 60-100ml. Unlike the present invention, in this range, there will be more solids precipitated during the first filtration. The test found that the content of teldeluxin is as high as 93.2%, while the impurity content is only 6.8%. Teldeluxin will precipitate out in large quantities along with the impurities, resulting in a low final yield. The recovery of this part of teldeluxin is difficult.

[0099] (2) When the gradient addition amount of V1 is less than the protection scope of the present invention, it is found that the first filtration of solids does not precipitate, and there is no interval as in the present invention. In this interval, impurities can preferentially precipitate with tediloxine, which has similar physicochemical properties, thereby satisfying the effect of separation from tediloxine.

[0100] (3) When the gradient addition of V1 exceeds the protection scope of this invention, a large amount of solids will precipitate during the first filtration. Testing revealed that the content of tylosin was as high as 98.4%, while the impurity content was only 1.60%.

[0101] This indicates that when the amount exceeds that in Embodiment V1 of the present invention, a large amount of teldrone will precipitate out along with impurities, resulting in a low final yield, and the recovery of this portion of teldrone is quite difficult.

[0102] Therefore, there is no specific range between using ethanol and n-heptane as solvents and using n-propanol and n-heptane as solvents, within which impurities can preferentially precipitate out with teldrone, which has similar physicochemical properties, thus achieving the desired separation from teldrone. Only when isopropanol and n-heptane are used as solvents does a specific range exist, namely within the addition amounts in the embodiments of this invention, V1 = 60-100 ml, where impurities with similar physicochemical properties can preferentially precipitate out with teldrone. The preferentially precipitated impurities can be separated from teldrone, avoiding waste of teldrone and improving the overall yield.

[0103] In summary: (1) This invention provides a new purification method for tidalin, which reduces the use of other second-class solvents, produces no harmful gases, and makes the reaction temperature easy to control, reducing the probability of danger. At the same time, this method is low-cost, environmentally friendly, and produces products with high yield and high purity.

[0104] (2) This invention creatively uses a stepwise water addition method to separate the impurities from teldrolidine first, and then crystallizes the teldrolidine after the impurities are separated to obtain teldrolidine with high purity, which solves the problems of residual solvent limit not meeting the standard and not being able to meet industrial production requirements; and high product impurities and by-products.

[0105] (3) The present invention creatively discovered that when isopropanol and n-heptane are used as solvents, there is a range within which the amount added in the embodiments of the present invention is within 60-100 ml, so that impurities and teldrone with similar physicochemical properties can be preferentially precipitated. The preferentially precipitated impurities can be separated from teldrone, thus avoiding the waste of teldrone and improving the overall yield.

Claims

1. A novel purification method for thiamethoxam, characterized in that... This method includes the following process steps: (1) Dissolution: Add crude terbinafine to a mixed solvent and heat to 71~81℃ to dissolve. The mixed solvent is a mixture of isopropanol and n-heptane. The mass-volume ratio of crude terbinafine to isopropanol and n-heptane is 1g:(5~8)mL:(15~25)mL. (2) Filtration and stratification: Under the first preset temperature condition, V1 amount of water is added dropwise to step (1), a small amount of solid is precipitated in the system, and after filtration, the layers are separated and the lower layer is taken off; (3) Crystallization: Under the second preset temperature condition, V2 amount of water is added dropwise to step (2) to precipitate teldrone solid. After crystal growth, filtration and drying, teldrone is obtained. The mass ratio of crude tylosin to water (V1 and V2) is 1:6.0~10.0:30~50.

2. The new purification method for thiamethoxam according to claim 1, characterized in that... The first preset temperature is 71~81℃.

3. The new purification method for thiamethoxam according to claim 1, characterized in that... The second preset temperature is 75~85℃.

4. The new purification method for thiamethoxam according to claim 1, characterized in that... In step (3), the crystal growth time is 10-20 hours; the drying temperature is controlled at 35-55°C; and the drying time is 10-20 hours.

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