Preparation method of isavuconazole sulfate

Abstract

The present invention relates to the field of medical technology, and in particular to a method for preparing isavuconazole sulfate. The method for preparing isavuconazole sulfate comprises the following steps: dissolving a compound having a structure shown in Formula I in a reaction solvent, adding sulfuric acid to remove tert-butyloxycarbonyl, removing the solvent and collecting a precipitate; using a lipid solvent, extracting and removing impurities from the precipitate at least once, and collecting a first aqueous phase; using a styrene-based hydrogen sulfate anion exchange resin, performing at least one ion exchange treatment on the first aqueous phase, and collecting a second aqueous phase; using a chlorinated alkane solvent, extracting and removing impurities from the second aqueous phase at least once, collecting a third aqueous phase, and freeze-drying to prepare isavuconazole sulfate. The present invention can overcome the two technical difficulties of how to convert the iodine salt of isavuconazole into monohydrogen sulfate in large-scale industrial production, and how to remove impurities from the monohydrogen sulfate.

Description

Technical Field

[0001] The invention relates to the technical field of medicines, and in particular to a method for preparing isavuconazole sulfate. Background Art

[0002] Isavuconazonium sulfate is a broad-spectrum antifungal drug developed by Basilea of ​​Switzerland and Astellas of Japan for the treatment of invasive aspergillosis and mucormycosis (combination fungus disease). Its chemical name is N-methyl-[2-[[[1-[1-[(2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridyl]methyl ester, sulfate, and its molecular structure is:

[0003]

[0004] The product was approved for marketing by the U.S. FDA on March 6, 2015 under the trade name Cresemba. Currently, the capsule form has been approved for marketing in China, but the injection has not yet been launched in China.

[0005] In the preparation process of isavuconazole sulfate, the iodine salt of isavuconazole is an important intermediate, and its molecular structure is:

[0006]

[0007] It can be seen that the iodine salt structure of isavuconazonium contains multiple salt-forming sites. How to convert the iodine salt of isavuconazonium into isavuconazonium sulfate is a technical difficulty.

[0008] It has been reported that isavuconazole monosulfate is prepared by redox reaction, and the synthetic route is as follows:

[0009]

[0010] This method requires column chromatography purification, which is costly and difficult to industrialize. In addition, oxidation with metal ions can easily lead to excessive metal ions in the finished product.

[0011] There is a report on a method for converting the hydroxide of isavuconazolium into hydrogen sulfate using a styrene-based hydrogen sulfate anion exchange resin. The synthesis route is as follows:

[0012]

[0013] This method uses the iodine salt of isavuconazonium as a raw material, requires the use of a strong base, has complicated steps, and requires extremely high temperature control. In addition, the stability of the isavuconazonium hydroxide used in the reaction is extremely poor. Therefore, the process is not very operable and is difficult to achieve industrial production.

[0014] In addition, since isavuconazole sulfate has poor thermal stability, it is difficult to achieve the purpose of impurity removal by conventional recrystallization methods of hot-melt crystallization after the iodine salt of isavuconazole sulfate is converted into monohydrogen sulfate. In addition, in the crystallization process of large-scale production, due to the physicochemical properties of isavuconazole sulfate itself, there are disadvantages such as easy formation of oily substances after crystallization and the risk of secondary degradation during high-temperature drying. Therefore, the traditional recrystallization method is not suitable for impurity removal after the iodine salt of isavuconazole sulfate is converted into monohydrogen sulfate. How to remove impurities is another technical difficulty. Summary of the invention

[0015] Based on this, the present invention provides a method for preparing isavuconazole sulfate, which can overcome the two technical difficulties of how to convert isavuconazole iodide salt into monohydrogen sulfate salt in large-scale industrial production and how to remove impurities from the monohydrogen sulfate salt.

[0016] The first aspect of the present invention provides a method for preparing isavuconazole sulfate. The technical scheme is as follows:

[0017] A method for preparing isavuconazole sulfate comprises the following steps:

[0018] (1) dissolving a compound having a structure represented by Formula I in a reaction solvent, adding sulfuric acid to remove the tert-butyloxycarbonyl group, removing the solvent and collecting the precipitate;

[0019] (2) extracting and removing impurities from the precipitate at least once using a lipid solvent, and collecting a first aqueous phase;

[0020] (3) using a styrene-based hydrogen sulfate anion exchange resin to perform at least one ion exchange treatment on the first aqueous phase, and collecting a second aqueous phase;

[0021] (4) extracting and removing impurities from the second aqueous phase at least once using a chlorinated alkane solvent, collecting the third aqueous phase, and freeze-drying to prepare isavuconazole sulfate;

[0022]

[0023] In some embodiments, the precipitate does not contain hydroxide ions.

[0024] In some embodiments, the reaction solvent is selected from one or more of dichloromethane, ethanol, tetrahydrofuran, acetonitrile and ethyl acetate. Preferably, the reaction solvent is ethanol.

[0025] In some embodiments, the lipid solvent is selected from isopropyl acetate or ethyl acetate. Preferably, the lipid solvent is isopropyl acetate.

[0026] In some of the embodiments, during each ion exchange treatment in step (3), 1.5 kg to 3 kg of styrene-based hydrogen sulfate anion exchange resin is added for every 1 kg of the compound having the structure represented by formula I.

[0027] In some embodiments, during each ion exchange treatment in step (3), the temperature is controlled at 10° C. to 30° C. Preferably, during each ion exchange treatment in step (3), the temperature is controlled at 15° C.±5° C.

[0028] In some embodiments, the number of times of ion exchange treatment in step (3) satisfies: the mass percentage of iodide ions in the second aqueous phase is less than 0.1%.

[0029] In some of the embodiments, the precipitate is extracted and impurities are removed twice using the lipid solvent.

[0030] In some embodiments, the chlorinated alkane solvent is dichloromethane.

[0031] In some embodiments, the preparation method does not include a purification step using column chromatography.

[0032] The present invention has the following beneficial effects:

[0033] The invention uses the iodine salt of isavuconazolium as a reactant, first removes the protecting group under the action of sulfuric acid, removes impurities from the obtained precipitate, then uses a styrene-based hydrogen sulfate anion exchange resin for ion exchange to convert the iodine salt of isavuconazolium into monohydrogen sulfate, and finally removes impurities from the obtained monohydrogen sulfate of isavuconazolium to prepare isavuconazol sulfate.

[0034] The present invention not only overcomes the technical difficulty of how to convert the iodine salt of isavuconazole to monohydrogen sulfate, but also can prepare isavuconazole sulfate with high purity, and overcomes the technical difficulty of how to remove impurities from isavuconazole sulfate. 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 step of first converting the iodine salt of isavuconazole to hydroxide and then to monohydrogen sulfate, and directly convert the iodine salt of isavuconazole to monohydrogen sulfate, and strong base can be omitted to avoid the risk of poor stability of intermediate products in large-scale industrial production; for example, the preparation route of the present invention can be applied in large-scale industrial production without column chromatography purification. In addition, there is no risk of excessive metal ions in the final product prepared by the above preparation route. DETAILED DESCRIPTION

[0035] The present invention will be further described in detail below in conjunction with specific embodiments. The present invention can be implemented in many different forms and is not limited to the embodiments described herein. On the contrary, the purpose of providing these embodiments is to make the disclosure of the present invention more thoroughly understood.

[0036] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as those commonly understood by those skilled in the art of the present invention. The terms used in the specification of the present invention herein are only for the purpose of describing specific embodiments and are not intended to limit the present invention.

[0037] the term

[0038] Unless otherwise specified or incompatible herewith, the terms and phrases used herein shall have the following meanings:

[0039] In the present invention, the selection range involving "and / or", "or / and", and "and / or" includes any one of two or more related listed items, and also includes any and all combinations of related listed items, and the arbitrary and all combinations include any combination of two related listed items, any more related listed items, or all related listed items. It should be noted that when at least three items are connected by at least two conjunctions selected from "and / or", "or / and", and "and / or", it should be understood that the technical solution undoubtedly includes technical solutions that are all connected by "logical and", and undoubtedly includes technical solutions that are all connected by "logical or". For example, "A and / or B" includes three parallel solutions of A, B and A+B. For example, 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, the technical solution that is all connected by "logical OR"), and also includes any and all combinations of A, B, C, and D, that is, the combination of any two or any three of A, B, C, and D, and also includes the combination of four of A, B, C, and D (that is, the technical solution that is all connected by "logical AND").

[0040] In the present invention, "plurality", "multiple", "multiple times", "multiple" and the like, unless otherwise specified, refer to a number greater than or equal to 2. For example, "one or more" means one or greater than or equal to two.

[0041] In the present invention, "combinations thereof", "any combinations thereof", "any combination thereof" and the like include all suitable combinations of any two or more of the listed items.

[0042] In the present invention, the “suitable” mentioned in “suitable combination”, “suitable method”, “any suitable method”, etc. shall be based on the ability to implement the technical solution of the present invention, solve the technical problem of the present invention, and achieve the expected technical effect of the present invention.

[0043] In the present invention, “preferred”, “better”, “more preferred” and “suitable” are only used to describe implementation methods or examples with better effects, and it should be understood that they do not constitute limitations on the scope of protection of the present invention.

[0044] In the present invention, the words “further”, “furthermore”, “particularly”, etc. are used for descriptive purposes to indicate differences in content, but should not be construed as limiting the scope of protection of the present invention.

[0045] In the present invention, "optionally", "optional" and "optional" refer to optional, that is, to any one of the two parallel schemes of "yes" or "no". If multiple "options" appear in a technical solution, unless otherwise specified and there is no contradiction or mutual restriction, each "optional" is independent.

[0046] In the present invention, in the "first aspect", "second aspect", "third aspect", "fourth aspect", etc., the terms "first", "second", "third", "fourth", etc. are only used for descriptive purposes and cannot be understood as indicating or implying relative importance or quantity, nor can they be understood as implicitly indicating the importance or quantity of the indicated technical features. Moreover, "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 on quantity.

[0047] In the present invention, the technical features described in an open manner include closed technical solutions composed of the listed features, and also include open technical solutions containing the listed features.

[0048] In the present invention, when it comes to numerical intervals (i.e., numerical ranges), unless otherwise specified, the optional numerical distribution is considered continuous within the above numerical interval, and includes the two numerical endpoints (i.e., the minimum value and the maximum value) of the numerical range, and each numerical value between the two numerical endpoints. Unless otherwise specified, when the numerical interval only refers to the integers within the numerical interval, it includes the two endpoint integers of the numerical range, and each integer between the two endpoints. In this article, it is equivalent to directly listing each integer, such as t is an integer selected from 1 to 10, indicating that t is any integer selected from the group of integers consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9 and 10. In addition, when multiple ranges are provided to describe features or characteristics, these ranges can be combined. In other words, unless otherwise specified, the ranges disclosed herein should be understood to include any and all sub-ranges included therein.

[0049] The temperature parameters in the present invention, if not specifically limited, are allowed to be either constant temperature treatment or to vary within a certain temperature range. It should be understood that the constant temperature treatment allows the temperature to fluctuate within the precision range controlled by the instrument. Fluctuations within the range of ±5°C, ±4°C, ±3°C, ±2°C, and ±1°C are allowed.

[0050] In the present invention, when it comes to percentage content, unless otherwise specified, for solid-liquid mixing and solid-solid mixing, it refers to mass percentage, and for liquid-liquid mixing, it refers to volume percentage.

[0051] In the present invention, when it comes to percentage concentration, unless otherwise specified, it refers to the final concentration. The final concentration refers to the proportion of the added component in the system after the addition of the component.

[0052] In the present invention, % (w / w) and wt% both represent weight percentage, % (v / v) refers to volume percentage, and % (w / v) refers to mass volume percentage.

[0053] In view of the difficulties in preparing isavuconazole sulfate and the defects of the traditional preparation route, the present invention provides a method for preparing isavuconazole sulfate. Specifically:

[0054] A method for preparing isavuconazole sulfate comprises the following steps:

[0055] (1) dissolving a compound having a structure represented by Formula I in a reaction solvent, adding sulfuric acid to remove the tert-butyloxycarbonyl group, removing the solvent and collecting the precipitate;

[0056] (2) extracting and removing impurities from the precipitate at least once using a lipid solvent, and collecting a first aqueous phase;

[0057] (3) using a styrene-based hydrogen sulfate anion exchange resin to perform at least one ion exchange treatment on the first aqueous phase, and collecting a second aqueous phase;

[0058] (4) extracting and removing impurities from the second aqueous phase at least once using a chlorinated alkane solvent, collecting the third aqueous phase, and freeze-drying to prepare isavuconazole sulfate;

[0059]

[0060] The invention uses the iodine salt of isavuconazolium as a reactant, first removes the protecting group under the action of sulfuric acid, removes impurities from the obtained precipitate, then uses a styrene-based hydrogen sulfate anion exchange resin for ion exchange to convert the iodine salt of isavuconazolium into monohydrogen sulfate, and finally removes impurities from the obtained monohydrogen sulfate of isavuconazolium to prepare isavuconazol sulfate.

[0061] The present invention not only overcomes the technical difficulty of how to convert the iodine salt of isavuconazole to monohydrogen sulfate, but also can prepare isavuconazole sulfate with high purity, and overcomes the technical difficulty of how to remove impurities from isavuconazole sulfate. 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 step of first converting the iodine salt of isavuconazole to hydroxide and then to monohydrogen sulfate, and directly convert the iodine salt of isavuconazole to monohydrogen sulfate, and strong base can be omitted to avoid the risk of poor stability of intermediate products in large-scale industrial production; for example, the preparation route of the present invention can be applied in large-scale industrial production without column chromatography purification. In addition, there is no risk of excessive metal ions in the final product prepared by the above preparation route.

[0062] The precipitate of the present invention does not contain hydroxide ions. The preparation route of the present invention does not involve the step of converting the iodine salt of isavuconazolium into hydroxide under the action of a strong base, so the precipitate does not contain hydroxide ions or unstable isavuconazolium hydroxide.

[0063] In the present invention, the styrene-based hydrogen sulfate anion exchange resin can be obtained by the following treatment method:

[0064] Weigh a strong alkaline polystyrene anion exchange resin and load it into an ion exchange column. Rinse the resin with purified water until the effluent is clear and colorless, and soak it for 12 to 16 hours. Then rinse the resin with a sulfuric acid aqueous solution, and then rinse the resin with purified water until the pH of the effluent is ≈ 6; then rinse the resin with a sodium hydroxide aqueous solution, and then rinse the resin with purified water until the pH of the effluent is 7 to 8; finally rinse the resin with a sulfuric acid aqueous solution, and after rinsing, rinse the resin with purified water until the pH of the effluent is 6 to 7, to obtain a styrene hydrogen sulfate anion exchange resin.

[0065] Optionally, during each ion exchange treatment in step (3), 1.5kg to 3kg of styrene-based hydrogen sulfate anion exchange resin is added for every 1kg of the compound having the structure shown in formula I. Preferably, during each ion exchange treatment in step (3), 2kg to 2.5kg of styrene-based hydrogen sulfate anion exchange resin is added for every 1kg of the compound having the structure shown in formula I.

[0066] Optionally, during each ion exchange treatment in step (3), the temperature is controlled at 10° C. to 30° C. Preferably, during each ion exchange treatment in step (3), the temperature is controlled at 15° C.±5° C.

[0067] Optionally, the number of times of the ion exchange treatment in step (3) satisfies: the mass percentage of iodide ions in the second aqueous phase is <0.1%.

[0068] Optionally, the reaction solvent is selected from one or more of dichloromethane, ethanol, tetrahydrofuran, acetonitrile and ethyl acetate.

[0069] Optionally, the lipid solvent is selected from isopropyl acetate or ethyl acetate.

[0070] The inventors of the present invention have found that when ethyl acetate is traditionally selected as a reaction solvent and / or lipid solvent, although the use of ethyl acetate can play a certain positive role in reaction and impurity removal, solvents such as ethyl acetate will introduce other impurities such as glacial acetic acid, and the newly introduced impurities such as glacial acetic acid in previously reported studies have been ignored. Therefore, in a preferred embodiment of the present invention, the reaction solvent is selected from one or more of dichloromethane, anhydrous ethanol, tetrahydrofuran and acetonitrile. In a preferred embodiment of the present invention, the lipid solvent is isopropyl acetate. Newly introduced impurities can be avoided, which is conducive to further improving the purity of subsequent products.

[0071] The inventors of the present invention have also found that when the reaction solvent is dichloromethane, tetrahydrofuran or acetonitrile, although isavuconazole sulfate with qualified purity can be obtained, the yield is relatively low. Therefore, in a preferred embodiment of the present invention, the reaction solvent is ethanol.

[0072] Optionally, the precipitate is extracted and impurity-removed twice using the lipid solvent.

[0073] After the ions are exchanged, the present invention uses a chlorinated alkane solvent to further remove impurities, which is beneficial to further improve the purity of subsequent products.

[0074] Optionally, the chlorinated alkane solvent is dichloromethane.

[0075] Optionally, the second aqueous phase is subjected to an extraction and impurity removal process using a chlorinated alkane solvent.

[0076] Optionally, the preparation method does not include a purification step using column chromatography, and is suitable for industrial large-scale production.

[0077] The following is further described in conjunction with specific examples and comparative examples. The raw materials involved in the following specific examples, unless otherwise specified, can all be sourced from commercial sources. The instruments used, unless otherwise specified, can all be sourced from commercial sources. The processes involved, unless otherwise specified, are all routinely selected by those skilled in the art.

[0078] Example 1

[0079] This embodiment provides a method for preparing isavuconazole sulfate, and the steps are as follows:

[0080] Step 1: Take 8.0 kg of isavuconazolium iodide (compound with the structure shown in Formula I) and dissolve it in 42.26 kg of anhydrous ethanol, add a mixed solution of sulfuric acid (1.24 kg) and ethanol (3.73 kg), stir the reaction for 2.0 h to remove the tert-butyloxycarbonyl group, remove the solvent in vacuo, and collect the precipitate.

[0081]

[0082] Step 2: Use a mixed solution of isopropyl acetate (45 kg) and water (23 kg) to fully dissolve the precipitate obtained in step 1, extract and remove impurities for the first time, collect the aqueous phase, and then use isopropyl acetate to extract and remove impurities for the aqueous phase for the second time, collect the aqueous phase, and record it as the first aqueous phase.

[0083] Step 3: Add the first aqueous phase of step 2 and 20 kg of styrene-based hydrogen sulfate anion exchange resin to the reactor, start stirring, control the temperature at 15°C ± 5°C, stir and react for 0.5 h, filter until no liquid flows out, collect the filtrate, and then add 20 kg / kg styrene-based hydrogen sulfate anion exchange resin to the filtrate, control the temperature at 15°C ± 5°C, stir and react for 0.5 h, take the lower aqueous phase and detect the iodine ion residue <0.1%, then filter to obtain an aqueous solution of isavuconazole sulfate, recorded as the second aqueous phase.

[0084] Step 4: Add DCM (16.5 kg) to the second aqueous phase obtained in step 3 for extraction and impurity removal, collect the aqueous phase by layers, record it as the third aqueous phase, freeze-dry the third aqueous phase, and obtain isavuconazole sulfate (4.91 kg, yield 71.16%). HPLC detection shows that its purity is 98.1%. 1H NMR (400 MHz, 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, 5.2 Hz, 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-MSM / Z=717(M*).

[0085] The isavuconazole sulfate obtained in this example was tested by HPLC external standard method, and the result showed that the residual glacial acetic acid was qualified (the glacial acetic acid content in this example was 0.26%, which was less than 0.5% required by the pharmacopoeia standard).

[0086] Example 2

[0087] Step 1: Take 10.70 kg of isavuconazolium iodide salt (compound of structure shown in Formula I), dissolve it in 42.26 kg of anhydrous ethanol, add a mixed solution of sulfuric acid (1.24 kg) and ethanol (4.73 kg), stir the reaction for 2 h to remove the tert-butyloxycarbonyl group, remove the solvent in vacuo, and collect the precipitate.

[0088]

[0089] Step 2: Use a mixed solution of ethyl acetate (57 kg) and water (31.4 kg) to fully dissolve the precipitate in step 1, extract and remove impurities for the first time, collect the aqueous phase, and then use ethyl acetate to extract and remove impurities for the aqueous phase for the second time, collect the aqueous phase, and record it as the first aqueous phase.

[0090] Step 3: Add the first aqueous phase in step 2 and 21.4 kg of styrene-based hydrogen sulfate anion exchange resin to the reactor, control the temperature at 25°C ± 5°C, stir for 0.5 h, filter until no liquid flows out, collect the filtrate, and then add 21.4 kg / kg styrene-based hydrogen sulfate anion exchange resin to the filtrate, control the temperature at 25°C ± 5°C, stir and react for 0.5 h, take the lower aqueous phase and detect the residual iodine ion <0.1%, then filter to obtain an aqueous solution of isavuconazole sulfate, recorded as the second aqueous phase.

[0091] Step 4: DCM (26.5 kg) was added to the second aqueous phase in step 3 for extraction and impurity removal. After stratification, the aqueous phase was collected and recorded as the third aqueous phase. The third aqueous phase was freeze-dried to obtain isavuconazole sulfate (5.25 kg, yield 75.96%).

[0092] The purity of isavuconazole sulfate was 98.3% as determined by HPLC.

[0093] The isavuconazole sulfate obtained in this example was tested by HPLC external standard method: the residual glacial acetic acid was unqualified (the content of glacial acetic acid in this example was 0.66%, which was greater than the 0.5% required by the pharmacopoeia standard).

[0094] Example 3

[0095] Step 1: Take 10 kg of isavuconazolium iodide salt (compound with the structure shown in Formula I), dissolve it in a mixed solution of 23.6 kg of ethyl acetate and 13.4 kg of anhydrous ethanol, add sulfuric acid (1.24 kg) and ethyl acetate (4.73 kg) solution, stir the reaction for 2.0 h to remove the tert-butyloxycarbonyl group, remove the solvent in vacuo, and collect the precipitate.

[0096]

[0097] Step 2: Use a mixed solution of ethyl acetate (57 kg) and water (31.4 kg) to fully dissolve the precipitate in step 1, extract and remove impurities for the first time, collect the aqueous phase, and then use ethyl acetate to extract and remove impurities for the aqueous phase for the second time, collect the aqueous phase, and record it as the first aqueous phase.

[0098] Step 3: Add the first aqueous phase in step 2 and 20 kg of styrene-based hydrogen sulfate anion exchange resin to the reactor, control the temperature at 25°C ± 5°C, stir for 0.5 h, filter until no liquid flows out, collect the filtrate, add 20 kg of styrene-based hydrogen sulfate anion exchange resin to the filtrate, control the temperature at 25°C ± 5°C, stir and react for 0.5 h, take the lower aqueous phase and detect the residual iodine ion <0.1%, then filter to obtain an aqueous solution of isavuconazole sulfate, recorded as the second aqueous phase.

[0099] Step 4: DCM (26.5 kg) was added to the second aqueous phase obtained in step 3 for extraction, and the impurities were removed by extraction. After separation, the aqueous phase was collected and recorded as the third aqueous phase. The third aqueous phase was freeze-dried to obtain isavuconazole sulfate (5.25 kg, yield 61.06%). The HPLC purity was 98.2%.

[0100] The isavuconazole sulfate obtained in this example was tested by HPLC external standard method, and the result showed that the residual glacial acetic acid was unqualified (the content of glacial acetic acid in this example was 1.22%, which was greater than the 0.5% required by the pharmacopoeia standard).

[0101] It can be seen that isavuconazole sulfate can be prepared on a large scale by adopting the preparation route of the present invention.

[0102] The preparation route of isavuconazole sulfate of the present invention can overcome the following limitations: 1) the technical difficulty of converting isavuconazolium iodide salt into isavuconazole sulfate can be overcome; 2) column chromatography purification can be omitted; 3) there is no risk of excessive metal ions; 4) strong base can be omitted, thereby avoiding the risk of poor stability of intermediate products; and 5) the problem of impurity removal is solved.

[0103] In addition, when the reaction solvent or lipid solvent contains ethyl acetate, glacial acetic acid residue will be caused and can be replaced by isopropyl acetate.

[0104] The technical features of the above-described embodiments may be arbitrarily combined. To make the description concise, not all possible combinations of the technical features in the above-described embodiments are described. However, as long as there is no contradiction in the combination of these technical features, they should be considered to be within the scope of this specification.

[0105] The above-mentioned embodiments only express several implementation methods of the present invention, and the descriptions thereof are relatively specific and detailed, but they cannot be understood as limiting the scope of the invention patent. It should be pointed out that, for ordinary technicians in this field, several variations and improvements can be made without departing from the concept of the present invention, and these all belong to the protection scope of the present invention. Therefore, the protection scope of the patent of the present invention shall be subject to the attached claims.

Claims

1. A method for preparing isavuconazole sulfate, characterized in that: Here are the steps: Step 1: 8.0 kg of the compound of formula I was dissolved in 42.26 kg of anhydrous ethanol, and a mixed solution of 1.24 kg of sulfuric acid and 3.73 kg of ethanol was added, and the mixture was stirred for 2.0 h to remove the tert-butyloxycarbonyl group, and the solvent was removed in vacuo to collect the precipitate; Step 2: Fully dissolve the precipitate obtained in step 1 with a mixed solution of 45 kg isopropyl acetate and 23 kg water, extract and remove impurities for the first time, collect the aqueous phase, and then extract and remove impurities for the aqueous phase with isopropyl acetate for the second time, collect the aqueous phase, and record it as the first aqueous phase; Step 3: Add the first aqueous phase of step 2 and 20 kg of styrene-based hydrogen sulfate anion exchange resin to the reactor, start stirring, control the temperature at 15°C ± 5°C, stir and react for 0.5 h, filter until no liquid flows out, collect the filtrate, add 20 kg / kg of styrene-based hydrogen sulfate anion exchange resin to the filtrate, control the temperature at 15°C ± 5°C, stir and react for 0.5 h, take the lower aqueous phase and test the iodine ion residue to <0.1%, then filter to obtain an aqueous solution of isavuconazole sulfate, recorded as the second aqueous phase; Step 4: Add 16.5 kg of DCM to the second aqueous phase obtained in step 3 for extraction and impurity removal, collect the aqueous phase by layers, record it as the third aqueous phase, and freeze-dry the third aqueous phase to obtain 4.91 kg of isavuconazole sulfate, the yield of isavuconazole sulfate is 71.16%, and the purity is 98.1%;

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