Method for preparing high-purity isavuconazole sulfate intermediate
By reacting in ethyl acetate and combining alkalization and purification steps, the problem of residual impurities in isaconazole was solved, and the preparation of high-purity isaconazole was achieved. This method is suitable for the efficient preparation of isaconazole sulfate, and in particular, it removes RS isomer impurities, thereby improving the purity and yield of the product.
Patent Information
- Application Number
- CN202410717647.X
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-06-04
- Publication Date
- 2025-12-05
AI Technical Summary
Existing technologies for preparing isaconazole often result in significant residues of RS isomer and quaternary ammonium salt impurities, leading to excessive impurities in isaconazole sulfate. Furthermore, existing methods are complex to operate and produce products with poor purity.
Using SM1 and SM2 as raw materials, after reaction in ethyl acetate, isoconazole hydrobromide was obtained by filtration. Subsequently, it was purified by sodium bicarbonate and ethyl acetate/methyl tert-butyl ether/n-hexane to remove impurities and obtain high-purity isoconazole.
The preparation of high-purity issaconazole was achieved with low residual impurities, especially RS isomer impurities <0.1%. The operation is simple and suitable for industrial production, and the product purity is greater than 99.0%.
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Figure CN121064183A_ABST
Abstract
Description
Technical Field
[0001] This invention relates to the field of pharmaceutical synthesis technology, specifically to a method for preparing a high-purity intermediate of isaconazole sulfate, a treatment for invasive aspergillosis and mucormycosis. Background Technology
[0002] Isavuconazonium sulfate is an alpha-receptor antagonist developed jointly by Basellia Pharma GmbH (Switzerland) and Astellas Pharma Ltd. (Japan) for the treatment of invasive aspergillosis and mucormycosis. It has been granted orphan drug designation by the US FDA and the European EMA. On March 6, 2015, the US FDA granted priority approval to Astellas Pharma Ltd.'s isavuconazonium sulfate under the brand name Cresemba. On October 15, 2015, the European EMA approved Basellia Pharma Ltd.'s isavuconazonium sulfate (active ingredient: isavuconazonium sulfate) for marketing, available in injection powder (372 mg) and capsules (186 mg).
[0003] In December 2021, the original manufacturer, Basellia (Germany), launched a 100 mg capsule formulation in China. In June 2022, they also launched a 200 mg injection (isaconazole sulfate for injection) in China. Its chemical formula is shown below:
[0004]
[0005] The following is a retrosynthetic analysis diagram of isaconazole sulfate:
[0006]
[0007] As can be seen from the above formula, isaconazole is a key intermediate of isaconazole sulfate and the fragment that ultimately exerts its pharmacological effect; therefore, its quality has a significant impact on the quality of isaconazole sulfate. However, during the preparation of isaconazole, there is a possibility of generating RS isomer impurities and quaternary ammonium salt impurities with the following structure. These two impurities may also remain in isaconazole. Therefore, developing a suitable process to minimize the residue of these two impurities while ensuring the process yield, thereby obtaining high-purity intermediate isaconazole, is crucial for the efficient preparation of the active pharmaceutical ingredient isaconazole sulfate.
[0008]
[0009]
[0010] Regarding the preparation method of isaconazole, Song Chengen mentioned in his master's thesis "Research on the Synthesis Process of Isaconazole Onion Sulfate" that SM1 and SM2 were used as raw materials, ethanol was used as solvent, and isaconazole was obtained by reflux reaction, alkalization, concentration and crystallization. However, it was found in experiments that the crystallization of this method was difficult and the purity of the obtained product was poor.
[0011] In his master's thesis, "Research on the Synthetic Process of Isaconazole Sulfate," Song Haichao mentioned a method using SM1 and SM2 as raw materials and ethyl acetate as solvent. The reaction was refluxed, followed by filtration to obtain isaconazole hydrobromide. This method is simple and yields a product with good purity. However, the alkalization and purification of isaconazole were not mentioned in this preparation step. Instead, it was prepared as a base before use in subsequent steps without purification. Experiments revealed that the isaconazole obtained by this method contained significant residual RS isomer and quaternary ammonium salt impurities, leading to excessive levels of related impurities, especially RS isomers, in the subsequently prepared isaconazole sulfate. Therefore, this invention references this method to prepare isaconazole, but adds alkalization and purification steps to effectively remove RS isomer and quaternary ammonium salt impurities, especially RS isomers, obtaining a high-purity intermediate isaconazole with related substances greater than 99.0% and RS isomer impurities <0.1%.
[0012] To facilitate the efficient preparation of isaconazole sulfate, it is necessary to develop a better method for preparing the intermediate isaconazole, so as to better control the quality of isaconazole sulfate and provide society with safe, effective and quality-controlled drugs. Summary of the Invention
[0013] The purpose of this invention is to provide a method for preparing a high-purity intermediate of isaconazole sulfate.
[0014] This invention provides a method for preparing a high-purity intermediate of isaconazole sulfate, comprising the following steps:
[0015] (I) Starting with SM1 and SM2, after the reaction in ethyl acetate was completed, the intermediate isaconazole hydrobromide was obtained by filtration.
[0016] (II) The above-mentioned isaconazole hydrobromide was dispersed in ethyl acetate, freed in sodium bicarbonate, washed with sodium chloride solution, dried with anhydrous sodium sulfate, filtered and concentrated to obtain the intermediate isaconazole free concentrate.
[0017] (III) The above-mentioned free isaconazole concentrate was purified by ethyl acetate / methyl tert-butyl ether / n-hexane to obtain isaconazole sulfate high-purity intermediate isaconazole;
[0018]
[0019] According to an embodiment of the present invention, in step (I), the reaction feed ratio SM1:SM2 = 1 equivalent: 1 to 1.2 equivalents, for example 1:1, 1:1.1, 1:1.2 (equivalent ratio), and SM1:ethyl acetate = 1:5 to 10, g / mL, for example 1:5, 1:6, 1:7, 1:8, 1:9, 1:10 (g / mL); preferably SM1:SM2 = 1 equivalent: 1 equivalent, and SM1:ethyl acetate = 1:10, g / mL;
[0020] According to an embodiment of the present invention, in step (I), the reaction temperature is 50-80°C, preferably 75-80°C;
[0021] According to an embodiment of the present invention, step (I) further includes washing the filter cake with ethyl acetate after filtration to obtain the intermediate isaconazole hydrobromide;
[0022] According to an embodiment of the present invention, in step (II), the sodium bicarbonate is an aqueous solution with a concentration of 5-10 wt%, for example, 5%, 6%, 7%, 8%, 9%, or 10% (wt);
[0023] According to an embodiment of the present invention, in step (II), the concentration of the sodium chloride aqueous solution is 15-25 wt%, preferably 20 wt%.
[0024] According to an embodiment of the present invention, in step (II), after adding sodium bicarbonate, the mixture is stirred at 15-25°C for 5-20 minutes, preferably for 10 minutes.
[0025] According to an embodiment of the present invention, in step (II), isaconazole hydrobromide is dispersed in ethyl acetate, 8 wt% sodium bicarbonate solution is added, 20 wt% sodium chloride solution is added to the ethyl acetate layer for washing, anhydrous sodium sulfate is added to the ethyl acetate layer for drying, filtered, washed with ethyl acetate, and concentrated under reduced pressure to obtain the intermediate isaconazole free concentrate.
[0026] According to an embodiment of the present invention, in step (III), the ratio of SM1 feed amount to the refining solvent of crude isosorbide dinitrate is, by mass-volume ratio, SM1:ethyl acetate:methyl tert-butyl ether:n-hexane = 1:0.3~1:0.3~1.5:4~7, g / mL, for example 1:0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1:0.3, 0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 1.1, 1.2, 1.3, 1.4, 1.5:4, 5, 6, 7, g / mL, preferably SM1:ethyl acetate:methyl tert-butyl ether:n-hexane = 1:0.5:0.5:5, g / mL;
[0027] According to an embodiment of the present invention, in step (III), ethyl acetate, methyl tert-butyl ether and n-hexane are added to the isaconazole free concentrate, the mixture is heated to dissolve, cooled, and stirred for a period of time to obtain isaconazole sulfate high-purity intermediate isaconazole.
[0028] According to an embodiment of the present invention, in step (III), after adding ethyl acetate, methyl tert-butyl ether and n-hexane to the isaconazole free concentrate, the temperature is raised to 65-70°C, dissolved, and then cooled to 40-45°C. The mixture is stirred for a period of time, then cooled to 20-25°C, and stirred for a period of time to obtain isaconazole sulfate high-purity intermediate isaconazole.
[0029] According to an embodiment of the present invention, in step (III), ethyl acetate, methyl tert-butyl ether and n-hexane are added to the isaconazole free concentrate, and the mixture is stirred and heated to 65-70°C. After dissolving, the mixture is cooled to 40-45°C and stirred for 0.5 hours. The mixture is then cooled to 20-25°C and stirred for another 0.5 hours to obtain isaconazole sulfate high-purity intermediate isaconazole.
[0030] According to an embodiment of the present invention, in step (III), after the isaconazole free concentrate is purified by ethyl acetate / methyl tert-butyl ether / n-hexane, the process further includes filtration, n-hexane washing, and drying.
[0031] The beneficial effects of this invention are:
[0032] This invention uses two commercially available materials, SM1 and SM2, to obtain isaconazole hydrobromide, an intermediate of isaconazole sulfate, through simple filtration in ethyl acetate solvent. This is then further purified by alkalization to obtain high-purity isaconazole, which can be directly added to subsequent steps without prior purification. This allows for more precise feeding and higher quality, especially in terms of the residual RS isomer impurity. The overall process is simple to operate, produces high-purity products with high yields, and is suitable for industrial application. The purity of related substances is greater than 99.0%, and the residual RS isomer impurity is <0.1%. In the purification process of isaconazole, this invention uses a mixed solvent of a good and a bad solvent to directly dissolve the sample and then crystallize it, resulting in a high-purity product. Attached Figure Description
[0033] Figure 1 This is the HPLC chromatogram of isaconazole hydrobromide.
[0034] Figure 2 This is the HPLC spectrum of the free concentrate of isaconazole;
[0035] Figure 3 This is the HPLC chromatogram of the refined isaconazole. Detailed Implementation
[0036] The technical solution of the present invention is further described below through examples. These embodiments are exemplary and do not constitute a limitation on the scope of protection of the present invention. Those skilled in the art, under the guidance of the present invention, can make equivalent substitutions for the technical features based on the prior art, which still fall within the scope of protection of the present invention.
[0037] Example 1
[0038] Add 100.00 g of SM1, 72.00 g of SM2, and 1000 mL of ethyl acetate to a 2000 mL three-necked flask. Heat the mixture to an internal temperature of 75–80 °C with stirring and maintain the temperature for 1 hour. Monitor the reaction by TLC (evolving solvent: dichloromethane / methanol = 15 / 1). The endpoint is defined as ≤1.0% residual SM1. If the endpoint is not reached, monitor the reaction every 0.5 hours until the endpoint is reached.
[0039] After the reaction is complete, cool the system to 65-70°C and keep stirring for 0.5 hours.
[0040] Cool the system to 20–25°C and keep stirring for 0.5 hours;
[0041] Filter, wash the filter cake with 100 mL of ethyl acetate to obtain wet isaconazole hydrobromide (HPLC purity 97.631%, including 0.673% RS isomer impurities and 1.430% quaternary ammonium salt impurities);
[0042] Add 1000 mL of ethyl acetate to the wet product of isaconazole hydrobromide, and then add 200 mL of 8% sodium bicarbonate solution while stirring. After stirring the system at 15-25°C for 10 minutes, separate the ethyl acetate layer.
[0043] The ethyl acetate layer was washed with 200 mL of 20% sodium chloride solution to separate the ethyl acetate layer;
[0044] 100.00 g of anhydrous sodium sulfate was added to the ethyl acetate layer and stirred at 15–25 °C for 0.5 hours. The mixture was filtered, and the filter cake was washed with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure at 50 ± 5 °C until the distillation of the distillate slowed down significantly. The concentration was then maintained for another 0.5 hours to obtain the free isaconazole concentrate (HPLC purity 97.868%, including 0.700% RS isomer impurities and 1.093% quaternary ammonium salt impurities).
[0045] Add 50 mL of ethyl acetate, 50 mL of methyl tert-butyl ether, and 500 mL of n-hexane to the concentrate. Stir the system and heat it to 65–70 °C. After dissolving, cool the system to 40–45 °C and maintain stirring for 0.5 hours. Then cool the system to 20–25 °C and maintain stirring for 0.5 hours.
[0046] The mixture was filtered, washed with 100 mL of n-hexane, and the resulting filter cake was dried under reduced pressure at 50±2 °C to constant weight to obtain isaconazole (off-white solid, 120.15 g, yield 85.8%, HPLC purity 99.086%, including 0.049% RS isomer impurities and 0.801% quaternary ammonium salt impurities).
[0047] 1 H-NMR(600MHz, CDCl3)δ8.041(s,1H),7.844-7.858(m,2H),7.725(s,1H),7.687-7.701(m,2H),7.372(s,1H),6.864-6.8 76(m,2H),6.762(m,1H),5.872(s,1H),4.982-5.006(dd,1H),4.718-4.741(dd,1H),4.133(m,1H),1.670-1.682(m,3H).
[0048] ES-MS M / Z = 437.1(M+).
[0049] Example 2
[0050] Add 100.00 g of SM1, 80.00 g of SM2, and 1000 mL of ethyl acetate to a 2000 mL three-necked flask. Heat the mixture to an internal temperature of 75–80 °C with stirring and maintain the temperature for 1 hour. Monitor the reaction by TLC (evolving solvent: dichloromethane / methanol = 15 / 1). The endpoint is defined as ≤1.0% residual SM1. If the endpoint is not reached, monitor the reaction every 0.5 hours until the endpoint is reached.
[0051] After the reaction is complete, cool the system to 65-70°C and keep stirring for 0.5 hours.
[0052] Cool the system to 20–25°C and keep stirring for 0.5 hours;
[0053] Filter, wash the filter cake with 100 mL of ethyl acetate to obtain wet isaconazole hydrobromide;
[0054] Add 500 mL of ethyl acetate to the wet product of isaconazole hydrobromide, and then add 200 mL of 8% sodium bicarbonate solution while stirring. After stirring the system at 15-25°C for 10 minutes, separate the ethyl acetate layer.
[0055] The ethyl acetate layer was washed with 200 mL of 20% sodium chloride solution to separate the ethyl acetate layer;
[0056] 50.00 g of anhydrous sodium sulfate was added to the ethyl acetate layer and stirred at 15–25 °C for 0.5 hours. The mixture was filtered, and the filter cake was washed with 100 mL of ethyl acetate. The filtrate was concentrated under reduced pressure at 50 ± 5 °C until the distillation of the distillate slowed down significantly. The concentration was then maintained for another 0.5 hours to obtain the free isaconazole concentrate.
[0057] Add 60 mL of ethyl acetate, 100 mL of methyl tert-butyl ether, and 400 mL of n-hexane to the concentrate. Stir the system and heat it to 65–70 °C. After dissolving, cool the system to 40–45 °C and maintain stirring for 0.5 hours. Then cool the system to 20–25 °C and maintain stirring for 0.5 hours.
[0058] The mixture was filtered, washed with 100 mL of n-hexane, and the resulting filter cake was dried under reduced pressure at 50 ± 2 °C to constant weight to give isaconazole (a white solid, 115.35 g, purity 99.2%, yield 82.3%).
[0059] Comparative Example 1
[0060] Add 10.00 g of SM1, 8.00 g of SM2, and 100 mL of ethyl acetate to a 250 mL three-necked flask. Heat the mixture to an internal temperature of 75–80 °C with stirring and maintain the temperature for 1 hour. Monitor the reaction by TLC (evolving solvent: dichloromethane / methanol = 15 / 1). The endpoint is defined as ≤1.0% residual SM1. If the endpoint is not reached, monitor the reaction every 0.5 hours until the endpoint is reached.
[0061] After the reaction is complete, cool the system to 60-70°C and keep stirring for 0.5 hours.
[0062] Cool the system to 15–25°C and keep stirring for 0.5 hours;
[0063] Filter the filter cake and wash it with 10 mL of ethyl acetate to obtain wet isaconazole hydrobromide.
[0064] Add 40 mL of ethyl acetate to wet isaconazole hydrobromide, then add 150 mL of 8% sodium bicarbonate solution while stirring. After stirring the system at 15-25°C for 10 minutes, separate the ethyl acetate layer.
[0065] The ethyl acetate layer was washed with 20 mL of 20% sodium chloride solution to separate the ethyl acetate layer.
[0066] 5.00 g of anhydrous sodium sulfate was added to the ethyl acetate layer and stirred at 15–25 °C for 0.5 hours. The mixture was filtered, and the filter cake was washed with 10 mL of ethyl acetate. The filtrate was concentrated under reduced pressure at 50 ± 5 °C until the distillation of the distillate slowed down significantly. The concentration was then maintained for another 0.5 hours to obtain the free isaconazole concentrate.
[0067] Add 5 mL of ethyl acetate and 5 mL of methyl tert-butyl ether to the concentrate, stir the system and heat it to 65-70°C. After dissolving, add 40 mL of n-hexane, cool the system to 40-45°C and keep stirring for 0.5 hours, then cool it to 20-25°C and keep stirring for 0.5 hours.
[0068] Solids precipitated on the walls of the system and could not be effectively dispersed; no post-treatment was performed.
[0069] Comparative Example 2
[0070] Add 28.00 g of SM1, 21.10 g of SM2, and 280 mL of anhydrous ethanol to a 500 mL three-necked flask. Stir and heat to reflux, and maintain the temperature for 2 hours.
[0071] After the reaction is complete, the system is cooled to 20-30°C and 90% of the solvent is removed by vacuum evaporation.
[0072] Cool the system to 5-10°C, slowly add 30 mL of saturated sodium bicarbonate solution dropwise, and keep stirring for 1 hour;
[0073] The system turned into a white, turbid liquid that stuck to the walls. Extending the stirring time and lowering the crystallization temperature were ineffective, and it could not be filtered, so it was discarded.
[0074] Comparative Example 3
[0075] Add 360 g of ethyl acetate to a 1000 mL three-necked flask, then add 20.00 g of SM1 and 17.92 g of SM2 while stirring. Heat the mixture to 70-80 °C and maintain the temperature for 4 h.
[0076] After the reaction is complete, cool the system to 20-30°C and keep it at that temperature for 2 hours to allow crystals to precipitate.
[0077] Filtration yielded off-white isaconazole hydrobromide, which was dried under reduced pressure at 50±2℃ to obtain the dried product.
[0078] The dried product was transferred to a 1000 mL three-necked flask, 200 mL of ethyl acetate was added, and the mixture was stirred to disperse. 40 mL of 2 mol / L sodium bicarbonate solution was added to the system, and the mixture was stirred at 15-25 °C for 0.5 hours until the solid was completely dissolved. The upper ethyl acetate layer was separated and washed with 40 mL of purified water three times, followed by 40 mL of saturated sodium chloride solution three times. The ethyl acetate layer was then separated, and 40.00 g of anhydrous sodium sulfate was added and dried for 0.5 hours. The desiccant was removed by filtration, and the filtrate was concentrated to dryness under reduced pressure to obtain isaconazole (yellow solid, 21.20 g, yield 75.7%, HPLC purity 97.631%, including 0.673% RS isomer impurities and 1.430% quaternary ammonium salt impurities).
[0079] The embodiments of the present invention have been described above. However, the present invention is not limited to the above embodiments. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.
Claims
1. A process for the preparation of high purity intermediate of eslicarbazepine sulfate characterized in that, Comprising the following steps: (I) using SM1 and SM2 as starting materials, after the reaction is completed, the intermediate esproconazole hydrobromide is obtained by filtration in ethyl acetate; (II) the above esproconazole hydrobromide is dispersed in ethyl acetate, sodium bicarbonate is freed, a sodium chloride solution is washed, anhydrous sodium sulfate is dried, filtered, concentrated to obtain the intermediate esproconazole free concentrate; (III) the above esproconazole free concentrate is refined by ethyl acetate / methyl tert-butyl ether / n-hexane to obtain the high-purity intermediate esproconazole of esproconazole sulfate; 2. The method of claim 1, wherein, In the step (I), the reaction feeding ratio is SM1:SM2=1 equivalent:1-1.2 equivalents, SM1:ethyl acetate=1:5-10, grams / milliliter; preferably SM1:SM2=1 equivalent:1 equivalent, SM1:ethyl acetate=1:10, grams / milliliter.
3. The method according to claim 1 or 2, characterized in that, In the step (I), the reaction temperature is 50-80°C, preferably 75-80°C; and / or, the step (I) further comprises washing the filter cake with ethyl acetate after filtration to obtain the intermediate esproconazole hydrobromide.
4. The method according to any one of claims 1 to 3, characterized in that, In the step (II), the sodium bicarbonate is an aqueous solution with a concentration of 5-10wt%; and / or, the concentration of the sodium chloride aqueous solution is 15-25wt%, preferably 20wt%.
5. The method according to any one of claims 1 to 4, characterized in that, In the step (II), the esproconazole hydrobromide is dispersed in ethyl acetate, 8wt% sodium bicarbonate solution is added, 20wt% sodium chloride solution is added to the ethyl acetate layer for washing, anhydrous sodium sulfate is added to the ethyl acetate layer for drying, filtered, washed with ethyl acetate, and concentrated under reduced pressure to obtain the intermediate esproconazole free concentrate.
6. The method according to any one of claims 1 to 5, characterized in that, In the step (III), the ratio of the amount of SM1 to the refining solvent of the esproconazole crude product is SM1:ethyl acetate:methyl tert-butyl ether:n-hexane=1:0.3-1:0.3-1.5:4-7, grams / milliliter, preferably SM1:ethyl acetate:methyl tert-butyl ether:n-hexane=1:0.5:0.5:5, grams / milliliter.
7. The method according to any one of claims 1 to 6, characterized in that, In the step (III), after the esproconazole free concentrate is added with ethyl acetate, methyl tert-butyl ether and n-hexane, the solution is clarified by heating, then cooled by cooling, and stirred for a period of time to obtain the high-purity intermediate esproconazole of esproconazole sulfate.
8. The method of claim 7, wherein, In the step (III), after the esproconazole free concentrate is added with ethyl acetate, methyl tert-butyl ether and n-hexane, the temperature is raised to 65-70°C, then the solution is clarified by cooling to 40-45°C, stirred for a period of time, cooled to 20-25°C, and continuously stirred for a period of time to obtain the high-purity intermediate esproconazole of esproconazole sulfate.
9. The method of claim 8, wherein, In the step (III), after the esproconazole free concentrate is added with ethyl acetate, methyl tert-butyl ether and n-hexane, the temperature is raised to 65-70°C, then the solution is clarified by cooling to 40-45°C, stirred for 0.5 hours, cooled to 20-25°C, and continuously stirred for 0.5 hours to obtain the high-purity intermediate esproconazole of esproconazole sulfate.
10. The method according to any one of claims 1 to 9, characterized in that, In the step (III), after the esproconazole free concentrate is refined by ethyl acetate / methyl tert-butyl ether / n-hexane, it further comprises the steps of filtration, n-hexane washing, and drying.