WO2024037212A1 - 硫酸艾沙康唑的制备方法 - Google Patents

硫酸艾沙康唑的制备方法 Download PDF

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WO2024037212A1
WO2024037212A1 PCT/CN2023/103764 CN2023103764W WO2024037212A1 WO 2024037212 A1 WO2024037212 A1 WO 2024037212A1 CN 2023103764 W CN2023103764 W CN 2023103764W WO 2024037212 A1 WO2024037212 A1 WO 2024037212A1
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isavuconazole
sulfate
aqueous phase
preparation
solvent
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French (fr)
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牛键
李彦磊
彭春睿
杨敬泽
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扬子江药业集团上海海尼药业有限公司
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Publication of WO2024037212A1 publication Critical patent/WO2024037212A1/zh

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

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  • the present invention relates to the field of medical technology, and in particular to a preparation method of isavuconazole sulfate.
  • Isavuconazonium sulfate is a product jointly developed by Switzerland's Basilea and Japan's Astellas for the treatment of invasive aspergillosis and mucormycosis (conjugated mycosis)
  • a broad-spectrum antifungal drug with the chemical name N-methyl-[2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazole base]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]- 3-Pyridyl]methyl ester sulfate, its molecular structure is:
  • This method uses the iodized salt of isavuconazole as raw material, requires the use of a strong alkali, has cumbersome steps, extremely high temperature control requirements, and the stability of isavuconazolium hydroxide used in the reaction is extremely poor, so this process The operability is not strong and it is difficult to achieve industrial production.
  • the object of the present invention is to provide a preparation method of isavuconazole sulfate, which can convert the iodide salt of isavuconazole into monohydrogen sulfate in large-scale industrial production, and realize the processing of monohydrogen sulfate. After removing impurities, high-yield and high-purity isavuconazole sulfate is obtained.
  • a first aspect of the invention provides a preparation method of isavuconazole sulfate.
  • the technical solution is as follows:
  • a preparation method of isavuconazole sulfate comprising the following steps:
  • the precipitate does not contain hydroxide ions.
  • the reaction solvent is selected from one or more of dichloromethane, ethanol, tetrahydrofuran, acetonitrile and ethyl acetate.
  • the reaction solvent is ethanol.
  • the lipid solvent is selected from isopropyl acetate or ethyl acetate.
  • the lipid solvent is isopropyl acetate.
  • the temperature is controlled to be 10°C to 30°C.
  • the temperature is controlled to be 15°C ⁇ 5°C.
  • the number of exchange ion treatments in step (3) satisfies the following requirement: the mass percentage of iodide ions in the second aqueous phase is ⁇ 0.1%.
  • the lipid solvent is used to extract and remove impurities from the precipitate twice.
  • the chlorinated alkane solvent is methylene chloride.
  • the preparation method does not include a step of purification using column chromatography.
  • the present invention uses the iodide salt of isavuconazolium as a reactant, first deprotects it under the action of sulfuric acid, and then performs ion exchange with a styrene-based hydrogen sulfate anion exchange resin after the resulting precipitate is subjected to impurity removal treatment.
  • the iodized salt of isavuconazole is converted into a bisulfate monosulfate, and finally the obtained monobisulfate salt of isavuconazole is impurized to prepare isavuconazole sulfate.
  • the present invention not only overcomes the technical difficulty of how to convert isavuconazole iodide salt into monobisulfate salt, but also can prepare isavuconazole sulfate with high purity, and overcomes the problem of how to remove impurities from isavuconazole sulfate.
  • Technical Difficulties The preparation route of isavuconazole sulfate can also be applied in large-scale industrial production. For example, the preparation route of the present invention can omit the conversion of the iodide salt of isavuconazole into hydroxide first and then into hydrogen sulfate monosulfate.
  • the iodized salt of isavuconazole is directly converted into a monobisulfate salt without the use of a strong base, thereby avoiding the risk of poor stability of the intermediate product in large-scale industrial production; for example: the preparation route of the present invention does not need to be used Column chromatography purification is used in large-scale industrial production. In addition, there is no risk of excessive metal ions in the final product prepared by the above preparation route.
  • the selection range involving “and/or”, “or/and”, “and/or” includes two or more related listed Any item in the project also includes any and all combinations of related listed items, and any and all combinations include any two related listed items, any more related listed items, or all of them. A combination of related listed items. It should be noted that when at least three items are connected with at least two conjunctions selected from “and/or”, “or/and”, “and/or”, it should be understood that the technical solution undoubtedly includes The technical solutions that are all connected by "logical AND” also undoubtedly include the technical solutions that are all connected by "logical OR”. For example, "A and/or B” includes three parallel solutions: A, B and A+B.
  • the technical solution of "A, and/or, B, and/or, C, and/or, D” includes any one of A, B, C, and D (that is, they are all connected with "logical OR” technical solution), also includes any and all combinations of A, B, C, and D, that is, including combinations of any two or any three of A, B, C, and D, and also includes A, B, C , four combinations of D (that is, technical solutions that are all connected by "logical AND").
  • references to "plurality”, “multiple types”, “multiple times”, “multiple”, etc. mean that the number is greater than 2 or equal to 2 unless otherwise specified.
  • “one or more” means one or more than two.
  • references to “preferred”, “better”, “better” and “suitable” are only used to describe implementations or examples with better effects. It should be understood that they do not limit the scope of protection of the present invention.
  • references to “optional”, “optional” and “optional” refer to being optional or not, that is to say, any one selected from the two parallel solutions of "with” or “without”. If there are multiple “optionals” in a technical solution, each “optional” will be independent unless otherwise specified and there is no contradiction or mutual restriction.
  • first aspect when referring to the "first aspect”, “second aspect”, “third aspect”, “fourth aspect”, etc., the terms “first”, “second”, “third” and “fourth” “, etc. are only for descriptive purposes and cannot be understood as indicating or implying the relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Furthermore, “first”, “second”, “third”, “fourth”, etc. only serve the purpose of non-exhaustive enumeration and description, and it should be understood that they do not constitute a closed limitation of quantity.
  • the technical features described in open terms include closed technical solutions composed of the listed features, and also include open technical solutions including the listed features.
  • the optional numerical distribution is considered to be continuous within the above-mentioned numerical intervals, and includes the two numerical endpoints of the numerical range (i.e., the minimum value and the maximum value). value), and every value between the two numeric endpoints.
  • a numerical interval only points to integers within the numerical interval, including the two endpoint integers of the numerical range, and every integer between the two endpoints, in this article, it is equivalent to directly enumerating each Integer, for example, t is an integer selected from 1 to 10, indicating that t is any integer selected from the integer group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10.
  • the temperature parameter in the present invention is allowed to be treated at a constant temperature, and is also allowed to vary within a certain temperature range. It should be understood that the thermostatic treatment described allows the temperature to fluctuate within the accuracy of the instrument control. It is allowed to fluctuate within the range of ⁇ 5°C, ⁇ 4°C, ⁇ 3°C, ⁇ 2°C and ⁇ 1°C.
  • solid-liquid mixing and solid-solid phase mixing refer to mass percentage
  • liquid-liquid phase mixing refers to volume percentage
  • percentage concentration refers to the final concentration unless otherwise specified.
  • the final concentration refers to the proportion of the added component in the system after adding the component.
  • % (w/w) and wt% both represent weight percentage, % (v/v) refers to volume percentage, and % (w/v) refers to mass volume percentage.
  • the present invention provides a preparation method of isavuconazole sulfate. Specifically:
  • a preparation method of isavuconazole sulfate comprising the following steps:
  • the present invention uses the iodide salt of isavuconazolium as a reactant, first deprotects it under the action of sulfuric acid, and then performs ion exchange with a styrene-based hydrogen sulfate anion exchange resin after the resulting precipitate is subjected to impurity removal treatment.
  • the iodized salt of isavuconazole is converted into a bisulfate monosulfate, and finally the obtained monobisulfate salt of isavuconazole is impurized to prepare isavuconazole sulfate.
  • the present invention not only overcomes the technical difficulty of how to convert isavuconazole iodide salt into monobisulfate salt, but also can prepare isavuconazole sulfate with high purity, and overcomes the problem of how to remove impurities from isavuconazole sulfate.
  • Technical Difficulties The preparation route of isavuconazole sulfate can also be applied in large-scale industrial production. For example, the preparation route of the present invention can omit the conversion of the iodide salt of isavuconazole into hydroxide first and then into hydrogen sulfate monosulfate.
  • the iodized salt of isavuconazole is directly converted into a monobisulfate salt without the use of a strong base, thereby avoiding the risk of poor stability of the intermediate product in large-scale industrial production; for example: the preparation route of the present invention does not need to be used Column chromatography purification is used in large-scale industrial production. In addition, there is no risk of excessive metal ions in the final product prepared by the above preparation route.
  • the precipitate of the present invention does not contain hydroxide ions.
  • the preparation route of the present invention does not go through the step of first converting the iodide salt of isavuconazolium into hydroxide under the action of a strong alkali, so the precipitate does not contain hydroxide ions, nor does it contain unstable hydroxide isavuconazole. Conazolium.
  • the styrene-based hydrogen sulfate anion exchange resin can be obtained by the following method:
  • styrene-based hydrogen sulfate anion exchange resin is added for every 1kg of the compound having the structure shown in Formula I.
  • 2kg to 2.5kg of styrene-based hydrogen sulfate is added for every 1kg of the compound having the structure shown in formula I.
  • the temperature is controlled to be 10°C to 30°C.
  • the temperature is controlled to be 15°C ⁇ 5°C.
  • the number of exchange ion treatments in step (3) satisfies: the mass percentage of iodide ions in the second aqueous phase is ⁇ 0.1%.
  • the reaction solvent in step (1) is selected from one or more of dichloromethane, ethanol, tetrahydrofuran, acetonitrile and ethyl acetate.
  • the lipid solvent in step (2) is selected from isopropyl acetate or ethyl acetate.
  • the reaction solvent is selected from one or more of dichloromethane, absolute ethanol, tetrahydrofuran and acetonitrile.
  • the lipid solvent is isopropyl acetate. The inventor found in the research that newly introduced impurities can be avoided by selecting one or more of methylene chloride, absolute ethanol, tetrahydrofuran and acetonitrile as the reaction solvent, and/or selecting isopropyl acetate as the lipid solvent. , which is conducive to further improving the purity of subsequent products.
  • the reaction solvent is ethanol.
  • the inventor found in the research that selecting ethanol as the reaction solvent can obtain higher yield of isavuconazole sulfate.
  • the lipid solvent is used to perform two extractions on the precipitate to remove impurities.
  • the present invention uses chlorinated alkane solvents to further remove impurities, which is beneficial to further improving the purity of subsequent products.
  • the chlorinated alkane solvent is methylene chloride.
  • a chlorinated alkane solvent is used to perform an extraction and impurity removal on the second aqueous phase.
  • the preparation method does not include the step of purifying by column chromatography, and is suitable for industrial large-scale production.
  • This embodiment provides a preparation method of isavuconazole sulfate, the steps are as follows:
  • Step 1 Dissolve 8.0kg of isavuconazolium iodide salt (compound with the structure shown in formula I) in 42.26kg of absolute ethanol, add a mixed solution of sulfuric acid (1.24kg) and ethanol (3.73kg), and stir the reaction De-tert-butoxycarbonyl was carried out for 2 hours, the solvent was removed in vacuo, and the precipitate was collected.
  • Step 2 Use a mixed solution of isopropyl acetate (45kg) and water (23kg) to fully dissolve the precipitate obtained in step 1. Extract and remove impurities for the first time, collect the water phase, and then use isopropyl acetate to separate the water phase. Carry out the second extraction to remove impurities, collect the aqueous phase, and record it as the first aqueous phase.
  • Step 3 Add the first aqueous phase of Step 2 and 20kg of styrene hydrogen sulfate anion exchange resin to the reaction kettle, start stirring, control the temperature to 15°C ⁇ 5°C, stir and react for 0.5h, filter until no liquid flows out, and then collect.
  • Step 4 Add dichloromethane (DCM, 16.5kg) to the second aqueous phase obtained in step 3 for extraction and impurity removal, collect the aqueous phase in layers, record it as the third aqueous phase, and freeze-dry the third aqueous phase to obtain Isavuconazole sulfate (4.91kg, yield 71.16%). Its purity was 98.1% as measured by HPLC.
  • DCM dichloromethane
  • the isavuconazole sulfate obtained in this example was tested by the HPLC external standard method, and the results showed that the glacial acetic acid content was 0.26%.
  • Step 1 Dissolve 10.70kg of isavuconazolium iodide salt (compound with the structure shown in formula I) in 42.26kg of absolute ethanol, add a mixed solution of sulfuric acid (1.24kg) and ethanol (4.73kg), and stir the reaction De-tert-butoxycarbonyl was carried out for 2 hours, the solvent was removed in vacuo, and the precipitate was collected.
  • Step 2 Use a mixed solution of ethyl acetate (57kg) and water (31.4kg) to fully dissolve the precipitate in step 1, extract and remove impurities for the first time, collect the water phase, and then use ethyl acetate to perform the third step on the water phase. After secondary extraction to remove impurities, collect the aqueous phase and record it as the first aqueous phase.
  • Step 3 Add the first aqueous phase in Step 2 and 21.4kg of styrene hydrogen sulfate anion exchange resin to the reaction kettle, start stirring, control the temperature to 25°C ⁇ 5°C, stir and react for 0.5h, and filter until no liquid flows out. , collect the filtrate, then add 21.4kg styrene hydrogen sulfate anion exchange resin to the filtrate, control the temperature to 25°C ⁇ 5°C, stir and react for 0.5h, remove the lower water phase and detect the iodide ion residue ⁇ 0.1wt%, and then pump out Filter to obtain isavuconazole sulfate aqueous solution, which is recorded as the second aqueous phase.
  • Step 4 Add DCM (26.5kg) to the second aqueous phase in step 3 for extraction and removal of impurities. After layering, collect the aqueous phase and record it as the third aqueous phase. Lyophilize the third aqueous phase to obtain Edison Sulfate. Conazole (5.25kg, yield 75.96%).
  • the purity of isavuconazole sulfate was determined by HPLC to be 98.3%.
  • the isavuconazole sulfate obtained in this example was detected by HPLC external standard method: the glacial acetic acid content was 0.66%.
  • Step 1 Take 10kg of isavuconazolium iodide salt (compound with the structure shown in formula I), dissolve it in a mixed solution of 23.6kg of ethyl acetate and 13.4kg of absolute ethanol, add sulfuric acid (1.24kg) and ethyl acetate. The mixed solution of ester (4.73kg) was stirred for 2 hours to remove tert-butoxycarbonyl, the solvent was removed in vacuo, and the precipitate was collected.
  • isavuconazolium iodide salt compound with the structure shown in formula I
  • Step 2 Use a mixed solution of ethyl acetate (57kg) and water (31.4kg) to fully dissolve the precipitate in step 1, extract and remove impurities for the first time, collect the water phase, and then use ethyl acetate to perform the third step on the water phase. After secondary extraction to remove impurities, collect the aqueous phase and record it as the first aqueous phase.
  • Step 3 Add the first aqueous phase in Step 2 and 20kg of styrene hydrogen sulfate anion exchange resin to the reaction kettle, start stirring, control the temperature to 25°C ⁇ 5°C, stir for 0.5h, and filter until no liquid flows out. Collect the filtrate, then add 20kg of styrene hydrogen sulfate anion exchange resin to the filtrate, control the temperature to 25°C ⁇ 5°C, stir the reaction for 0.5h, remove the lower aqueous phase and detect the residual iodide ion ⁇ 0.1wt%, and then filter it with suction. An aqueous solution of isavuconazole sulfate was obtained, which was recorded as the second aqueous phase.
  • Step 4 Add DCM (26.5kg) to the second aqueous phase obtained in step 3 for extraction, perform extraction and remove impurities, collect the aqueous phase after layering, record it as the third aqueous phase, and freeze-dry the third aqueous phase to obtain Isavuconazole sulfate (5.25kg, yield 61.06%). HPLC purity was 98.2%.
  • the isavuconazole sulfate obtained in this example was tested by the HPLC external standard method, and the results showed that the glacial acetic acid content was 1.22%.
  • isavuconazole sulfate can be prepared on a large scale using the preparation route of the present invention.
  • the preparation route of isavuconazole sulfate of the present invention 1) can overcome the technical difficulty of converting the iodized salt of isavuconazole into isavuconazole sulfate; 2) can not use column chromatography for purification; 3) is metal-free Risk of excessive ions; 4) No need to use strong alkali to avoid the risk of poor stability of intermediate products; 5) Solve the problem of impurity removal.

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Abstract

一种硫酸艾沙康唑的制备方法，包括以下步骤：于反应溶剂中溶解艾沙康唑鎓的碘盐，加硫酸进行脱叔丁氧羰基，去除溶剂而收集沉淀物；利用脂类溶剂，对沉淀物进行至少一次萃取除杂，收集第一水相；利用苯乙烯系硫酸氢阴离子交换树脂，对第一水相进行至少一次交换离子处理，收集第二水相；利用氯代烷烃类溶剂，对第二水相进行至少一次萃取除杂，收集第三水相，冻干制备硫酸艾沙康唑。

Description

硫酸艾沙康唑的制备方法
本申请要求于2022年08月17日提交中国专利局、申请号为202210988155.5发明名称为“硫酸艾沙康唑的制备方法”的中国专利申请的优先权，其全部内容通过引用结合在本申请中。
技术领域
本发明涉及医药技术领域，特别是涉及硫酸艾沙康唑的制备方法。
背景技术
硫酸艾沙康唑(Isavuconazonium sulfate)是由瑞士巴塞利亚(Basilea)和日本的安斯泰来(Astellas)公司共同研发的一款用于侵袭性曲霉病和毛霉菌病(结合菌病)治疗的广谱抗真菌药，化学名为N-甲基-[2-[[[1-[1-[(2R,3R)-3-[4-(4-氰基苯基)-2-噻唑基]-2-(2,5-二氟苯基)-2-羟基丁基]-4H-1,2,4-三唑鎓-4-基]乙氧基]羰基]甲基氨基]-3-吡啶基]甲酯硫酸盐，其分子结构为：
该产品于2015年3月6日经美国食品药品监督管理局(FDA)优先审批批准上市，商品名Cresemba，目前胶囊剂已经在国内获批上市，注射液国内尚未上市。
在硫酸艾沙康唑制备过程中，艾沙康唑鎓的碘盐是一个重要的中间体，其分子结构式为：
可见，艾沙康唑鎓的碘盐结构中含有多个成盐位点，如何从艾沙康唑鎓的碘盐转变为硫 酸艾沙康唑是一个技术难点。
有报道通过氧化还原反应制备艾沙康唑单硫酸盐，合成路线如下所示：
但是该方法需使用柱层析纯化，成本高，难以进行工业化生产。此外，用金属离子氧化，极易导致成品中金属离子超标。
还有报道用苯乙烯系硫酸氢阴离子交换树脂实现艾沙康唑鎓的氢氧化物转化为硫酸氢盐的方法，合成路线如下所示：
该方法以艾沙康唑鎓的碘盐为原料，需要使用强碱，步骤繁琐，温度控制要求极高，且反应中使用到的氢氧化艾沙康唑鎓的稳定性极差，因此该工艺可操作性不强，很难实现工业化生产。
此外，由于硫酸艾沙康唑热稳定性也较差，由艾沙康唑鎓的碘盐转变为单硫酸氢盐后，通过常规的热溶解析晶的重结晶方法难以达到除杂的目的，且在大规模生产的析晶过程中， 由于硫酸艾沙康唑本身物化性质，存在析晶后易形成油状物、在高温烘干过程存在二次降解风险等缺点，因此，传统的重结晶方法不适用于在艾沙康唑鎓的碘盐转变为单硫酸氢盐后进行除杂，如何除杂是另一个技术难点。
发明内容
本发明的目的在于提供一种硫酸艾沙康唑的制备方法，能够实现在大规模工业化生产中，将艾沙康唑鎓的碘盐转变为单硫酸氢盐，以及实现对单硫酸氢盐进行除杂，得到高收率、高纯度的硫酸艾沙康唑。
本发明的第一方面提供了一种硫酸艾沙康唑的制备方法。其技术方案如下：
一种硫酸艾沙康唑的制备方法，包括以下步骤：
(1)于反应溶剂中溶解具有式I所示结构的化合物，加硫酸进行脱叔丁氧羰基，去除溶剂而收集沉淀物；
(2)利用脂类溶剂，对所述沉淀物进行至少一次萃取除杂，收集第一水相；
(3)利用苯乙烯系硫酸氢阴离子交换树脂，对所述第一水相进行至少一次交换离子处理，收集第二水相；
(4)利用氯代烷烃类溶剂，对所述第二水相进行至少一次萃取除杂，收集第三水相，冻干制备硫酸艾沙康唑；
在其中一些实施例中，所述沉淀物中不含有氢氧根离子。
在其中一些实施例中，所述反应溶剂选自二氯甲烷、乙醇、四氢呋喃、乙腈和乙酸乙酯中的一种或几种。优选地，所述反应溶剂为乙醇。
在其中一些实施例中，所述脂类溶剂选自乙酸异丙酯或乙酸乙酯。优选地，所述脂类溶剂为乙酸异丙酯。
在其中一些实施例中，所述步骤(3)中的各次交换离子处理时，每1kg所述具有式I所 示结构的化合物对应加入1.5kg～3kg苯乙烯系硫酸氢阴离子交换树脂。
在其中一些实施例中，所述步骤(3)中的各次交换离子处理时，控制温度为10℃～30℃。优选地，所述步骤(3)中的各次交换离子处理时，控制温度为15℃±5℃。
在其中一些实施例中，所述步骤(3)中交换离子处理的次数满足：所述第二水相中，碘离子的质量百分比<0.1％。
在其中一些实施例中，利用所述脂类溶剂，对所述沉淀物进行两次萃取除杂。
在其中一些实施例中，所述氯代烷烃类溶剂为二氯甲烷。
在其中一些实施例中，所述制备方法不包括利用柱层析进行纯化的步骤。
本发明具有以下有益效果：
本发明以艾沙康唑鎓的碘盐作为反应物，先将其在硫酸作用下脱保护基，对所得沉淀物进行除杂处理后，再用苯乙烯系硫酸氢阴离子交换树脂进行离子交换，将艾沙康唑鎓的碘盐转变为单硫酸氢盐，最后再对所得艾沙康唑鎓的单硫酸氢盐进行除杂，制备硫酸艾沙康唑。
本发明不仅克服了如何从艾沙康唑鎓的碘盐转变为单硫酸氢盐的技术难点，还能够制备纯度高的硫酸艾沙康唑，克服了如何对硫酸艾沙康唑进行除杂的技术难点。还能够使硫酸艾沙康唑的制备路线在大规模工业生产中得以应用，例如：本发明的制备路线可以省略艾沙康唑鎓的碘盐先转变为氢氧化物，再转变为单硫酸氢盐的步骤，直接从艾沙康唑鎓的碘盐转变为单硫酸氢盐，可以不使用强碱，避免大规模工业生产的中间产物稳定性差的风险；例如：本发明的制备路线可以不使用柱层析纯化，应用在大规模工业化生产中。另外，上述制备路线制备的最终产品中无金属离子超标风险。
具体实施方式
为使本发明的目的、技术方案、及优点更加清楚明白，以下对本发明进一步详细说明。显然，所描述的实施例仅仅是本发明一部分实施例，而不是全部的实施例。本领域技术人员基于本发明所获得的所有其他实施例，都属于本发明保护的范围。
除非另有定义，本文所使用的所有的技术和科学术语与属于本发明的技术领域的技术人员通常理解的含义相同。本文中在本发明的说明书中所使用的术语只是为了描述具体的实施例的目的，不是旨在于限制本发明。
术语
除非另外说明或存在矛盾之处，本文中使用的术语或短语具有以下含义：
本发明中，涉及“和/或”、“或/和”、“及/或”的选择范围包括两个或两个以上相关所列 项目中任一个项目，也包括相关所列项目的任意的和所有的组合，所述任意的和所有的组合包括任意的两个相关所列项目、任意的更多个相关所列项目、或者全部相关所列项目的组合。需要说明的是，当用至少两个选自“和/或”、“或/和”、“及/或”的连词组合连接至少三个项目时，应当理解，该技术方案毫无疑问地包括均用“逻辑与”连接的技术方案，还毫无疑问地包括均用“逻辑或”连接的技术方案。比如，“A及/或B”包括A、B和A+B三种并列方案。又比如，“A，及/或，B，及/或，C，及/或，D”的技术方案，包括A、B、C、D中任一项(也即均用“逻辑或”连接的技术方案)，也包括A、B、C、D的任意的和所有的组合，也即包括A、B、C、D中任两项或任三项的组合，还包括A、B、C、D的四项组合(也即均用“逻辑与”连接的技术方案)。
本发明中，涉及“多个”、“多种”、“多次”、“多元”等，如无特别限定，指在数量上大于2或等于2。例如，“一种或多种”表示一种或大于等于两种。
本发明中，涉及“其组合”、“其任意组合”、“其任意组合方式”等中包括所列项目中任两个或任两个以上项目的所有合适的组合方式。
本发明中，涉及“合适的组合方式”、“合适的方式”、“任意合适的方式”等中所述“合适”，以能够实施本发明的技术方案、解决本发明的技术问题、实现本发明预期的技术效果为准。
本发明中，涉及“优选”、“更好”、“更佳”、“为宜”仅为描述效果更好的实施方式或实施例，应当理解，并不构成对本发明保护范围的限制。
本发明中，涉及“进一步”、“更进一步”、“特别”等用于描述目的，表示内容上的差异，但并不应理解为对本发明保护范围的限制。
本发明中，涉及“可选地”、“可选的”、“可选”，指可有可无，也即指选自“有”或“无”两种并列方案中的任一种。如果一个技术方案中出现多处“可选”，如无特别说明，且无矛盾之处或相互制约关系，则每项“可选”各自独立。
本发明中，涉及“第一方面”、“第二方面”、“第三方面”、“第四方面”等中，术语“第一”、“第二”、“第三”、“第四”等仅用于描述目的，不能理解为指示或暗示相对重要性或数量，也不能理解为隐含指明所指示的技术特征的重要性或数量。而且“第一”、“第二”、“第三”、“第四”等仅起到非穷举式的列举描述目的，应当理解并不构成对数量的封闭式限定。
本发明中，以开放式描述的技术特征中，包括所列举特征组成的封闭式技术方案，也包括包含所列举特征的开放式技术方案。
本发明中，涉及到数值区间(也即数值范围)，如无特别说明，可选的数值分布在上述数值区间内视为连续，且包括该数值范围的两个数值端点(即最小值及最大值)，以及这两个数值端点之间的每一个数值。如无特别说明，当数值区间仅仅指向该数值区间内的整数时，包括该数值范围的两个端点整数，以及两个端点之间的每一个整数，在本文中，相当于直接列举了每一个整数，比如t为选自1～10的整数，表示t为选自由1、2、3、4、5、6、7、8、9和10构成的整数组的任一个整数。此外，当提供多个范围描述特征或特性时，可以合并这些范围。换言之，除非另有指明，否则本文中所公开之范围应理解为包括其中所归入的任何及所有的子范围。
本发明中的温度参数，如无特别限定，既允许为恒温处理，也允许在一定温度区间内存在变动。应当理解的是，所述的恒温处理允许温度在仪器控制的精度范围内进行波动。允许在如±5℃、±4℃、±3℃、±2℃、±1℃的范围内波动。
本发明中，涉及到百分比含量，如无特别说明，对于固液混合和固相-固相混合均指质量百分比，对于液相-液相混合指体积百分比。
本发明中，涉及到百分比浓度，如无特别说明，均指终浓度。所述终浓度，指添加成分在添加该成分后的体系中的占比。
本发明中，％(w/w)与wt％均表示重量百分比，％(v/v)指体积百分比，％(w/v)指质量体积百分数。
针对硫酸艾沙康唑的制备难点和传统制备路线的缺陷，本发明提供一种硫酸艾沙康唑的制备方法。具体为：
一种硫酸艾沙康唑的制备方法，包括以下步骤：
(1)于反应溶剂中溶解具有式I所示结构的化合物，加硫酸进行脱叔丁氧羰基，去除溶剂而收集沉淀物；
(2)利用脂类溶剂，对所述沉淀物进行至少一次萃取除杂，收集第一水相；
(3)利用苯乙烯系硫酸氢阴离子交换树脂，对所述第一水相进行至少一次交换离子处理，收集第二水相；
(4)利用氯代烷烃类溶剂，对所述第二水相进行至少一次萃取除杂，收集第三水相，冻干制备硫酸艾沙康唑；
本发明以艾沙康唑鎓的碘盐作为反应物，先将其在硫酸作用下脱保护基，对所得沉淀物进行除杂处理后，再用苯乙烯系硫酸氢阴离子交换树脂进行离子交换，将艾沙康唑鎓的碘盐转变为单硫酸氢盐，最后再对所得艾沙康唑鎓的单硫酸氢盐进行除杂，制备硫酸艾沙康唑。
本发明不仅克服了如何从艾沙康唑鎓的碘盐转变为单硫酸氢盐的技术难点，还能够制备纯度高的硫酸艾沙康唑，克服了如何对硫酸艾沙康唑进行除杂的技术难点。还能够使硫酸艾沙康唑的制备路线在大规模工业生产中得以应用，例如：本发明的制备路线可以省略艾沙康唑鎓的碘盐先转变为氢氧化物，再转变为单硫酸氢盐的步骤，直接从艾沙康唑鎓的碘盐转变为单硫酸氢盐，可以不使用强碱，避免大规模工业生产的中间产物稳定性差的风险；例如：本发明的制备路线可以不使用柱层析纯化，应用在大规模工业化生产中。另外，上述制备路线制备的最终产品中无金属离子超标风险。
本发明的所述沉淀物中不含有氢氧根离子。本发明的制备路线不经过艾沙康唑鎓的碘盐在强碱作用下先转变为氢氧化物的步骤，因此沉淀物中不含有氢氧根离子，也不含有不稳定的氢氧化艾沙康唑鎓。
本发明中，苯乙烯系硫酸氢阴离子交换树脂可通过以下方法处理而得：
称取强碱性聚苯乙烯系阴离子交换树脂装入离子交换柱中，用纯化水冲洗树脂至流出液澄清无色，并充分浸泡12～16h。然后用硫酸水溶液冲洗树脂，再用纯化水冲洗树脂直至流出液pH≈6；然后用氢氧化钠水溶液冲洗树脂，用纯化水冲洗树脂直至流出液pH＝7～8；最后用硫酸水溶液冲洗树脂，冲洗完毕后，用纯化水冲洗树脂直至流出液pH＝6～7，得苯乙烯系硫酸氢阴离子交换树脂。
可选地，所述步骤(3)中的各次交换离子处理时，每1kg所述具有式I所示结构的化合物对应加入1.5kg～3kg苯乙烯系硫酸氢阴离子交换树脂。优选地，所述步骤(3)中的各次交换离子处理时，每1kg所述具有式I所示结构的化合物对应加入2kg～2.5kg苯乙烯系硫酸氢阴 离子交换树脂。
可选地，所述步骤(3)中的各次交换离子处理时，控制温度为10℃～30℃。优选地，所述步骤(3)中的各次交换离子处理时，控制温度为15℃±5℃。
可选地，所述步骤(3)中的所述交换离子处理的次数满足：所述第二水相中，碘离子的质量百分比<0.1％。
可选地，所述步骤(1)中的反应溶剂选自二氯甲烷、乙醇、四氢呋喃、乙腈和乙酸乙酯中的一种或几种。
可选地，所述步骤(2)中的脂类溶剂选自乙酸异丙酯或乙酸乙酯。
在本发明一个优选的实施例中，所述反应溶剂选自二氯甲烷、无水乙醇、四氢呋喃和乙腈中的一种或几种。在本发明一个优选的实施例中，所述脂类溶剂为乙酸异丙酯。发明人在研究中发现，选择二氯甲烷、无水乙醇、四氢呋喃和乙腈中的一种或几种作为反应溶剂，和/或，选择乙酸异丙酯作为脂类溶剂，可以避免新引入的杂质，有利于进一步提高后续产物的纯度。
在本发明一个优选的实施例中，所述反应溶剂为乙醇。发明人在研究中发现，选择乙醇作为反应溶剂可以得到更高收率的硫酸艾沙康唑。
可选地，利用所述脂类溶剂，对所述沉淀物进行两次萃取除杂。
本发明在交换离子后，使用氯代烷烃类溶剂进一步进行除杂，有利于进一步提高后续产物的纯度。
可选地，所述氯代烷烃类溶剂为二氯甲烷。
可选地，利用氯代烷烃类溶剂，对所述第二水相进行一次萃取除杂。
可选地，所述制备方法不包括利用柱层析进行纯化的步骤，适用于工业化大规模生产。
以下结合具体实施例和对比例进行进一步说明，以下具体实施例中所涉及的原料，若无特殊说明，均可来源于市售，所使用的仪器，若无特殊说明，均可来源于市售，所涉及到的工艺，如无特殊说明，均为本领域技术人员常规选择。
实施例1
本实施例提供一种硫酸艾沙康唑的制备方法，步骤如下：
步骤1：取8.0kg艾沙康唑鎓的碘盐(式I所示结构的化合物)溶于42.26kg无水乙醇中，加硫酸(1.24kg)和乙醇(3.73kg)的混合溶液，搅拌反应2h进行脱叔丁氧羰基，真空除去溶剂，收集沉淀物。
步骤2：用乙酸异丙酯(45kg)和水(23kg)的混合溶液将所得步骤1中的沉淀物充分溶解，第一次萃取除杂，收集水相，再用乙酸异丙酯对水相进行第二次萃取除杂，收集水相，记为第一水相。
步骤3：向反应釜加入步骤2的第一水相和20kg苯乙烯系硫酸氢阴离子交换树脂，开启搅拌，控制温度15℃±5℃，搅拌反应0.5h，抽滤至无液体流出后，收集滤液，再向滤液中加入20kg苯乙烯系硫酸氢阴离子交换树脂，控制温度15℃±5℃，搅拌反应0.5h，取下层水相中控检测碘离子残留<0.1wt％，随后抽滤，得到硫酸艾沙康唑水溶液，记为第二水相。
步骤4：向步骤3得到的第二水相中加入二氯甲烷(DCM，16.5kg)进行萃取除杂，分层收集水相，记为第三水相，将第三水相冻干，得硫酸艾沙康唑(4.91kg，产率为71.16％)。HPLC检测其纯度为98.1％。
1H NMR(400MHz,DMSO)10.54-11.33(m,1H),9.13-9.34(m,1H),8.49(s,1H),8.35-8.41(m,1H),8.14,8.01(s,3H),7.90(s,2H),7.44-7.47(dd,J＝7.2,5.2Hz,1H),7.32,7.20,7.04(s,3H),6.78-6.86(s,1H),4.93-5.21(m,4H),4.13-4.17(m,1H),3.76-3.86(m,2H),3.12-3.23(m,3H),2.53(s,3H),1.59-1.93(m,3H),1.24-1.29(m,3H)，ES-MS M/Z＝717(M*)。
对本实施例所得硫酸艾沙康唑进行HPLC外标法检测，结果显示：冰乙酸含量为0.26％。
实施例2
步骤1：取10.70kg艾沙康唑鎓的碘盐(式I所示结构的化合物)溶于42.26kg无水乙醇中，加硫酸(1.24kg)和乙醇(4.73kg)的混合溶液，搅拌反应2h进行脱叔丁氧羰基，真空除去溶剂，收集沉淀物。
步骤2：用乙酸乙酯(57kg)和水(31.4kg)的混合溶液将步骤1中的沉淀物充分溶解，第一次萃取除杂，收集水相，再用乙酸乙酯对水相进行第二次萃取除杂，收集水相，记为第一水相。
步骤3：向反应釜加入步骤2中的第一水相与21.4kg苯乙烯系硫酸氢阴离子交换树脂，开启搅拌，控制温度25℃±5℃，搅拌反应0.5h，抽滤至无液体流出后，收集滤液，再向滤液中加入21.4kg苯乙烯系硫酸氢阴离子交换树脂，控制温度25℃±5℃，搅拌反应0.5h，取下层水相中控检测碘离子残留<0.1wt％，随后抽滤，得到硫酸艾沙康唑水溶液，记为第二水相。
步骤4：向步骤3中的第二水相中加入DCM(26.5kg)进行萃取除杂，分层后收集水相，记为第三水相，将第三水相冻干，获得硫酸艾沙康唑(5.25kg，产率为75.96％)。
用HPLC检测硫酸艾沙康唑纯度为98.3％。
对本实施例所得硫酸艾沙康唑进行HPLC外标法检测：冰乙酸含量为0.66％。
实施例3
步骤1：取10kg艾沙康唑鎓的碘盐(式I所示结构的化合物)，溶于23.6kg乙酸乙酯和13.4kg无水乙醇的混合溶液中，加硫酸(1.24kg)和乙酸乙酯(4.73kg)的混合溶液，搅拌反应2h进行脱叔丁氧羰基，真空除去溶剂，收集沉淀物。
步骤2：用乙酸乙酯(57kg)和水(31.4kg)的混合溶液将步骤1中的沉淀物充分溶解，第一次萃取除杂，收集水相，再用乙酸乙酯对水相进行第二次萃取除杂，收集水相，记为第一水相。
步骤3：向反应釜加入步骤2中的第一水相与20kg苯乙烯系硫酸氢阴离子交换树脂，开启搅拌，控制温度25℃±5℃，搅拌反应0.5h，抽滤至无液体流出后，收集滤液，再向滤液中加入20kg苯乙烯系硫酸氢阴离子交换树脂，控制温度25℃±5℃，搅拌反应0.5h，取下层水相中控检测碘离子残留<0.1wt％，随后抽滤，得到硫酸艾沙康唑水溶液，记为第二水相。
步骤4：向步骤3得到的第二水相中加入DCM(26.5kg)进行萃取，进行萃取除杂，分层后收集水相，记为第三水相，将第三水相冻干，得硫酸艾沙康唑(5.25kg，产率为61.06％)。HPLC纯度为98.2％。
对本实施例所得硫酸艾沙康唑进行HPLC外标法检测，结果显示：冰乙酸含量为1.22％。
可知，采用本发明的制备路线可以大规模制备硫酸艾沙康唑。
本发明的硫酸艾沙康唑的制备路线：1)可以克服从艾沙康唑鎓的碘盐转变为硫酸艾沙康唑的技术难点；2)可以不使用柱层析纯化；3)无金属离子超标风险；4)可以不使用强碱，避免中间产物稳定性差的风险；5)解决除杂的问题。
以上所述实施例的各技术特征可以进行任意的组合，为使描述简洁，未对上述实施例中的各个技术特征所有可能的组合都进行描述，然而，只要这些技术特征的组合不存在矛盾，都应当认为是本说明书记载的范围。
以上所述实施例仅表达了本发明的几种实施方式，其描述较为具体和详细，但并不能因此而理解为对发明专利范围的限制。应当指出的是，对于本领域的普通技术人员来说，在不脱离本发明构思的前提下，还可以做出若干变形和改进，这些都属于本发明的保护范围。因此，本发明专利的保护范围应以所附权利要求为准。

Claims (10)

  1. 一种硫酸艾沙康唑的制备方法，其特征在于，包括以下步骤：
    (1)于反应溶剂中溶解具有式I所示结构的化合物，加硫酸进行脱叔丁氧羰基，去除溶剂而收集沉淀物；
    (2)利用脂类溶剂，对所述沉淀物进行至少一次萃取除杂，收集第一水相；
    (3)利用苯乙烯系硫酸氢阴离子交换树脂，对所述第一水相进行至少一次交换离子处理，收集第二水相；
    (4)利用氯代烷烃类溶剂，对所述第二水相进行至少一次萃取除杂，收集第三水相，冻干制备硫酸艾沙康唑；
  2. 根据权利要求1所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(1)中的反应溶剂选自二氯甲烷、乙醇、四氢呋喃、乙腈和乙酸乙酯中的一种或几种。
  3. 根据权利要求2所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(1)中的反应溶剂为乙醇。
  4. 根据权利要求1所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(2)中的脂类溶剂选自乙酸异丙酯或乙酸乙酯。
  5. 根据权利要求4所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(2)中的脂类溶剂为乙酸异丙酯。
  6. 根据权利要求1～5任一项所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(3)中的各次交换离子处理时，每1kg所述具有式I所示结构的化合物对应加入1.5kg～3kg苯乙烯系硫酸氢阴离子交换树脂。
  7. 根据权利要求1～5任一项所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(3) 中的各次交换离子处理时，控制温度为10℃～30℃。
  8. 根据权利要求7所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(3)中的各次交换离子处理时，控制温度为15℃±5℃。
  9. 根据权利要求1～5任一项所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(3)中交换离子处理的次数满足：所述第二水相中，碘离子的质量百分比<0.1％。
  10. 根据权利要求1～5任一项所述的硫酸艾沙康唑的制备方法，其特征在于，所述步骤(4)中的氯代烷烃类溶剂为二氯甲烷。
PCT/CN2023/103764 2022-08-17 2023-06-29 硫酸艾沙康唑的制备方法 WO2024037212A1 (zh)

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