WO2016055918A1 - Nouveaux polymorphes stables d'isavuconazole ou de son sel - Google Patents

Nouveaux polymorphes stables d'isavuconazole ou de son sel Download PDF

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Publication number
WO2016055918A1
WO2016055918A1 PCT/IB2015/057599 IB2015057599W WO2016055918A1 WO 2016055918 A1 WO2016055918 A1 WO 2016055918A1 IB 2015057599 W IB2015057599 W IB 2015057599W WO 2016055918 A1 WO2016055918 A1 WO 2016055918A1
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Prior art keywords
isavuconazole
solvent
base
formula
diol
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PCT/IB2015/057599
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English (en)
Inventor
Rupesh Chhaganbhai KHUNT
Mohammad Rafeeq
Arvind Yekanathsa Merwade
Keshav Deo
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Wockhardt Limited
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Publication of WO2016055918A1 publication Critical patent/WO2016055918A1/fr

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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
    • C07D417/02—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 two hetero rings
    • C07D417/06—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 two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles

Definitions

  • the present invention relates to novel stable novel stable polymorphs of Isavuconazole or its salt thereof, having purity more than 90 % when measured by HPLC.
  • the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base.
  • present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5- difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol.
  • Isavuconazole, Isavuconazonium, Voriconazole, and Ravuconazole are azole derivatives and known as antifungal drugs for treatment of systemic mycoses as reported in US 5,648,372, US 5,792,781, US 6,300,353 and US 6,812,238.
  • the '353 described the process for the preparation Isavuconazole involve the use of 2-(2,5-difluoro-phenyl)-l- [l ,2,4]triazol-l-yl-butane-2,3-diol (referred herein after "diol base”) in an oil form, which is difficult to isolate and purify.
  • diol base 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base, without purification, reflects the purity of Isavuconazole and Isavuconazonium sulfate. However, the reported process not feasible industrially.
  • an object of the present invention is to provide simple, cost effective and industrially feasible processes for preparation of Isavuconazole or its salt thereof in enhanced yield as well as purity.
  • a particular present invention directs to novel stable polymorphs of Isavuconazole or its salt thereof.
  • the present invention also provides a solid amorphous form of Isavuconazole base, compound of Formula I,
  • the present invention also provides a process for the preparation of solid amorphous form of Isavuconazole base, having purity more than 90 %, when measured by HPLC.
  • the present invention also provides the conversion of solid amorphous form of Isavuconazole base to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.
  • the present invention provides a novel stable crystalline form of Isavuconazole base, compound of Formula I,
  • the present invention also provides a process for the preparation of stable crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC.
  • the present invention also provides a stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formula II,
  • Formula II having purity more than 95 %, when measured by HPLC.
  • the present invention also provides a process for the preparation of stable crystalline form of Isavuconazole Hydrobromide salt, having purity more than 95 %, when measured by HPLC.
  • the present invention also relates to the conversion of stable crystalline form of Isavuconazole Hydrobromide to Isavuconazole base and subsequently converted into Isavuconazonium iodide hydrochloride, which is further converted into Isavuconazonium sulfate.
  • the present invention provides a oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol, compound of formula IV
  • the present invention provides a crystalline form of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl- butane-2,3-diol, compound of formula IV
  • the present invention provides a process for preparation of crystalline form of oxalate salt of 2-(2,5-difluoro- phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-d
  • Formula IV in particular aspect of the present invention also relates to the conversion of diol base to diol oxalate salt and its conversion to diol base of enhanced purity.
  • the diol base is also converted to Isavuconazole, subsequently converted into Isavuconazonium iodide hydrochloride and to Isavuconazonium sulfate.
  • Figure 1 shows an illustrative example of X-ray powder diffraction pattern of solid stable amorphous form of Isavuconazole base
  • Figure 2 shows an illustrative example of differential scanning calorimetry thermogram of solid stable amorphous form of Isavuconazole base.
  • Figure 3 shows an illustrative example of thermogravimetric analysis curve of solid stable amorphous form of Isavuconazole base
  • Figure 4 shows an illustrative example of X-ray powder diffraction pattern of a stable crystalline form of Isavuconazole base
  • Figure 5 shows an illustrative example of differential scanning calorimetry thermogram of stable crystalline form of Isavuconazole base
  • Figure 6 shows an illustrative example of thermogravimetric analysis curve of stable crystalline form of Isavuconazole base
  • Figure 7 shows an illustrative example of X-ray powder diffraction pattern of stable crystalline form of Isavuconazole hydrobromide
  • Figure 8 shows an illustrative example of differential scanning calorimetry thermogram of stable crystalline form of Isavuconazole hydrobromide
  • Figure 9 shows an illustrative example of thermogravimetric analysis curve of stable crystalline form of Isavuconazole hydrobromide
  • Figure 10 shows an illustrative example of X-ray powder diffraction pattern of crystalline solid form of oxalate salt of 2-(2,5-difluoro-phenyl)-l -[l ,2,4]triazol-l-yl-butane-2,3-diol.
  • Figure 11 shows an illustrative example of differential scanning calorimetry thermogram of crystalline solid form of oxalate salt of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol
  • Figure 12 shows an illustrative example of thermogravimetric analysis curve of crystalline solid form of oxalate salt of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol
  • the X-ray diffraction powder patterns of the present invention were obtained using a Bruker or PANalytical export Pro Powder X-ray Diffractometer at Cu Ka radiation, having the wavelength 1.54 A.
  • aspect of the present invention provides a stable amorphous form of Isavuconazole base, compound of Formula I,
  • the present invention provides a stable amorphous form of Isavuconazole base, having an X- ray diffraction pattern as depicted in Figure 1 , which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K a-radiation source; differential scanning calorimetry thermogram as shown in Figure 2 and thermogravimetric analysis curve as shown in Figure 3.
  • the stable amorphous form of Isavuconazole base obtained according to the present invention was stored at 25 °C for a period of 3 months and no conversion in the polymorphic form was observed.
  • aspect of the present invention provides the process for the preparation of stable amorphous form of Isavuconazole base, the process includes the steps of
  • step b) removal of alcohol solvent, c) treating residue of step b) with water and acetate solvent followed by adjusting the pH of step c) at 7 to 7.5,
  • the process involves reaction of thioamide compound with and 4-cyano phenacyl bromide in alcohol solvent.
  • the reaction mixture is heated to temperature of 50°C to 100°C under stirring for l-5hours. After completion of the reaction, solvent is removed under vacuum and the reaction mass is treated with water and acetate solvent.
  • reaction mixture is adjusted to 7 to 7.5 by using 10% sodium bicarbonate solution. After pH adjustment, organic layer is separated and washed with saturated solution of sodium chloride. Further organic layer is concentrated under vacuum and thus residue obtained treated with methyl tert-butyl ether.
  • the reaction mass stir for an hour at about 40°C to 50°C and then cooled to temperature below 35°C and product is filtered, isolated and dried to get off white to pale yellow amorphous Isavuconazole.
  • the alcohol solvent is selected from the group comprising one or more of methanol, ethanol, isopropyl alcohol, butanol and the like, preferably ethanol.
  • the acetate solvent is selected from the group comprising one or more of ethyl acetate, methyl acetate, t-butyl acetate and the like.
  • the ether solvent is selected from the group comprising one or more of methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether and the like.
  • the reaction may be conducted at a temperature of about 40°C to about 50 °C.
  • the reaction may be performed for a period of about lhour to about 5 hours.
  • the isolation step may be performed by removal of solvent, addition of anti-solvent, cooling the reaction mixture and filtration and drying to obtain the product.
  • the anti-solvent is selected from the group comprising one or more of tertiary butyl methyl ether, hexane, pentane and the solvent having lower polarity index.
  • the present invention provides Isavuconazole base produced by the process of preparation of the present invention is characterized by purity greater than 90 % when measured by HPLC.
  • the present invention provides a stable crystalline form of Isavuconazole base, having an X- ray diffraction pattern according to Figure 4, differential scanning calorimetry thermogram as shown in Figure 5 and thermogravimetric analysis curve as shown in Figure 6.
  • X-ray diffraction pattern which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K a-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 13.32, 13.96, 14.35, 14.75, 19.02, 21.32, 25.27 and 25.59 ⁇ 0.2°.
  • the stable crystalline form of Isavuconazole base obtained according to the present invention was stored at 25 °C for a period of 3 months and no conversion in the polymorphic form was observed.
  • aspect of the present invention provides the process for the preparation of stable crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC,
  • the process includes the steps of
  • step b) treating step a) mass with aqueous sodium bicarbonate solution to get clear reaction mixture, c) separating organic layer and treated it hydrochloric acid solution,
  • step b) of the present invention involves treating step a) mass with aqueous solution of about 10 % sodium bicarbonate to get clear reaction mixture.
  • the step c) of the present invention involves treatment of organic layer with hydrochloric acid solution of about 1 % to about 2 %, followed by treatment with saturated solution of sodium chloride.
  • the halogenated solvent is selected from the group comprising one or more of dichloromethane, dichloroethane chloroform carbon tetrachloride and the like;
  • isolation step may be performed by removal of solvent, addition of anti-solvent, cooling the reaction mixture and filtration and drying to obtain the product.
  • the anti-solvent is selected from the group comprising one or more of tertiary butyl methyl ether, hexane, pentane and the solvent, having lower polarity index.
  • the present invention provides Isavuconazole base produced by the process of purification of the present invention is characterized by purity greater than 95 % when measured by HPLC.
  • aspect of the present invention provides the conversion of Isavuconazole Hydrobromide to Isavuconazole base and subsequently converted into Isavuconazonium iodide hydrochloride, which is further converted into Isavuconazonium sulfate.
  • the present invention provides a stable crystalline form of Isavuconazole Hydrobromide salt, having an X-ray diffraction pattern according to Figure 7, differential scanning calorimetry thermogram as shown in Figure 8 and thermogravimetric analysis curve as shown in Figure 9.
  • X-ray diffraction pattern which is expressed in terms of 2 theta angles and obtained with a diffractometer equipped with a copper K a-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta angles of 6.96, 7.28, 20.70, 22.09, 23.28 and 25.56 + 0.2°.
  • the stable crystalline form of Isavuconazole Hydrobromide salt obtained according to the present invention was stored at 25 °C for a period of 3 months and no conversion in the polymorphic form was observed.
  • aspect of the present invention provides the process for the preparation of stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formula II,
  • the process includes steps of
  • the alcohol solvent is selected from the group comprising one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert43utanol, or in combination thereof.
  • the step b) of the present invention involves heating the reaction mixture of about 30 to about 60 °C for a period of about lhour to about 5 hours.
  • the term isolating includes of removal of solvent, addition of anti-solvent, cooling the reaction mixture and filtration and drying to obtain the product.
  • the anti-solvent is selected from the group comprising one or more of tertiary butyl methyl ether, hexane, pentane and the solvent having lower polarity index.
  • aspect of the present invention provides the conversion of Isavuconazole Hydrobromide salt to Isavuconazole base having HPLC purity more than 95 %.
  • the present invention provides Isavuconazole Hydrobromide salt produced by the process of preparation of the present invention is characterized by purity greater than 90 %, particularly greater than 95 % when measured by
  • aspect of the present invention provides the conversion Isavuconazole and its Hydrobromide salt prepared according to the present invention to Isavuconazole base, Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.
  • the present invention provides a oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol, compound of formula IV
  • the present invention provides a crystalline solid form of oxalate salt of 2-(2,5-difluoro- phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol, having an X-ray diffraction pattern according to Figure 10, differential scanning calorimetry thermogram as shown in Figure 11 and thermogravimetric analysis curve as shown in Figure 12.
  • X-ray diffraction pattern which is expressed in terms of 2 theta values and obtained with a diffractometer equipped with a copper K a-radiation source, wherein said X-ray powder diffraction pattern includes two or more peaks selected from the group comprising of peaks with 2 theta values of 16.10, 23.21, 21.11, 15.77, 11.56, 25.36, 5.16 and 22.75 ⁇ 0.2°.
  • the crystalline solid form of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol obtained according to the present invention was stored at 25 °C for a period of 3 months and no conversion into other polymorphic form was observed.
  • the process includes the steps of
  • step c) Isavuconazole base to Isavuconazonium sulfate.
  • the step a) of the present invention involves treatment of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane- 2,3-diol base, with oxalic acid, in suitable solvent, followed by heating the reaction mixture for 1 hour at about 40 °C to about 55 °C.
  • the suitable solvent are ester and ethers.
  • the ester is selected from the group comprising one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, hexyl acetate and the like;
  • ethers is selected from the group comprising one or more of diethyl ether and methyl tert-butyl ether, tetrahydrofuran and the like.
  • the step b) of the present invention involves isolation of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol- 1-yl-butane -2,3-diol.
  • the isolation process involves the cooling the reaction mixture at about 25°C to about 35 °C, followed by addition of suitable antisolvent to obtain solid precipitate or partial removal of the solvent under vacuum or stirring of reaction mixture at temperature about 10° C to about 15° C, for a period of time as required for a more complete isolation of the product e.g. 3-5 hours.
  • the exact cooling temperature and time required for complete isolation can be readily determined by a person skilled in the art and will also depend on parameters such as concentration and temperature of the solution or slurry.
  • the step c) of the present invention involves the treatment of oxalate salt with base.
  • the bases used are organic or inorganic bases.
  • the organic base is selected from ⁇ , ⁇ -diisopropylethylamine (DIPEA), dimethylamine, diethylamine, triefhylamine, N-methylpyrrolidone, n-methylmorpholine.
  • the inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably sodium carbonate is used.
  • the step d) of the present invention involves the conversion of oxalate salt of 2-(2,5-difluoro-phenyl)-l- [l ,2,4]triazol-l-yl-butane-2,3-diol to Isavuconazole and subsequently Isavuconazonium sulfate.
  • the conversion of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol to Isavuconazole and subsequently to Isavuconazonium sulfate can be carried out know method, e.g. US 6,300,353; US 6,812,238; IN 2424 MUM/2014; IN 2588/MUM/2014 and IN 3189/MUM/2014, IN 253/MUM/2015, IN 254/MUM/2015.
  • isolation step may be performed by removal of solvent, addition of anti-solvent, cooling the reaction mixture and filtration and drying to obtain the product.
  • the anti-solvent includes the solvent in which oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl- butane-2,3-diol, is not soluble or has low solubility, get precipitate out after adding suitable anti-solvent such as petroleum ether, o-xylene, m-xylene, p-xylene, diisopropyl ether, tertiary butyl methyl ether, hexane, heptane, pentane, toluene and the like.
  • suitable anti-solvent such as petroleum ether, o-xylene, m-xylene, p-xylene, diisopropyl ether, tertiary butyl methyl ether, hexane, heptane, pentane, toluene and the like.
  • the present invention provides oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol produced by the process of preparation of the present invention is characterized by purity greater than 55% when measured by HPLC.
  • aspect of the present invention provides the purification of 2-(2,5-difluoro-phenyl)-l- [l ,2,4]triazol-l-yl-butane-2,3-diol.
  • the 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol base to enhance the purity to 60 % or more by converting it to oxalate salt and further converting to purified diol as free base.
  • the said conversion of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol to 2-(2,5- difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base involves the treatment of suitable base to oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol to obtain base of 2-(2,5-difluoro-phenyl)-l- [l ,2,4]triazol-l-yl-butane-2,3-diol.
  • the bases used are organic or inorganic bases.
  • the organic base is selected from N,N-diisopropylethylamine (DIPEA), dimethylamine, diethylamine, triethylamine, N-methylpyrrolidone, n-methylmo ⁇ holine.
  • the inorganic base is selected from ammonia, sodium carbonate, potassium carbonate, sodium bicarbonate, potassium bicarbonate, sodium hydroxide or potassium hydroxide, preferably sodium carbonate is used.
  • Exaniple-7 Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate

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  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

La présente invention concerne de nouveaux polymorphes stables d'isavuconazole ou de son sel, présentant une pureté supérieure à 90 % comme mesurée par HPLC. La présente invention concerne, en particulier, un procédé de préparation de formes solides amorphes et cristallines d'isavuconazole base. Dans un autre mode de réalisation, la présente invention concerne une forme cristalline de sel de bromhydrate et de sel d'oxalate d'isavuconazole de 2-(2,5-difluoro-phényl)-1-[1,2,4] triazol-1-yl-butane-2,3-diol.
PCT/IB2015/057599 2014-10-08 2015-10-05 Nouveaux polymorphes stables d'isavuconazole ou de son sel WO2016055918A1 (fr)

Applications Claiming Priority (6)

Application Number Priority Date Filing Date Title
IN3189MU2014 2014-10-08
IN3189/MUM/2014 2014-10-08
IN3369/MUM/2014 2014-10-15
IN3369MU2014 2014-10-15
IN3753MU2014 2014-11-26
IN3753/MUM/2014 2014-11-26

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Cited By (10)

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CN106619541A (zh) * 2016-10-27 2017-05-10 南京师范大学 艾沙康唑鎓硫酸盐冻干粉针剂及制备方法
CN106749222A (zh) * 2016-12-15 2017-05-31 重庆东得医药科技有限公司 艾沙康唑的晶型a及其制备方法、药物组合物和用途
CN106883226A (zh) * 2017-03-30 2017-06-23 成都绿林科技有限公司 艾莎康唑硫酸酯的制备方法
CN107778306A (zh) * 2016-08-30 2018-03-09 江苏奥赛康药业股份有限公司 一种艾沙康唑化合物及其制备方法
CN107982221A (zh) * 2016-10-27 2018-05-04 江苏正大丰海制药有限公司 注射用硫酸艾沙康唑鎓冻干粉针剂及制备方法
CN109206421A (zh) * 2017-07-03 2019-01-15 上海医药集团股份有限公司 一种艾沙康唑晶型及其制备方法
CN111978302A (zh) * 2019-05-24 2020-11-24 帕潘纳(北京)科技有限公司 一种三唑氰类化合物及其制备方法
CN115215857A (zh) * 2022-08-17 2022-10-21 扬子江药业集团上海海尼药业有限公司 硫酸艾沙康唑的制备方法
CN115536643A (zh) * 2022-12-05 2022-12-30 南京桦冠生物技术有限公司 一种艾沙康唑类药物关键中间体的制备方法
EP4289840A1 (fr) * 2022-06-07 2023-12-13 Zaklady Farmaceutyczne Polpharma S.A. Procede de preparation de sulfate d'isavuconazonium

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CN107778306B (zh) * 2016-08-30 2020-10-16 江苏奥赛康药业有限公司 一种艾沙康唑化合物及其制备方法
CN107778306A (zh) * 2016-08-30 2018-03-09 江苏奥赛康药业股份有限公司 一种艾沙康唑化合物及其制备方法
CN107982221A (zh) * 2016-10-27 2018-05-04 江苏正大丰海制药有限公司 注射用硫酸艾沙康唑鎓冻干粉针剂及制备方法
CN106619541A (zh) * 2016-10-27 2017-05-10 南京师范大学 艾沙康唑鎓硫酸盐冻干粉针剂及制备方法
CN106749222B (zh) * 2016-12-15 2019-06-11 重庆东得医药科技有限公司 艾沙康唑的晶型a及其制备方法、药物组合物和用途
CN106749222A (zh) * 2016-12-15 2017-05-31 重庆东得医药科技有限公司 艾沙康唑的晶型a及其制备方法、药物组合物和用途
CN106883226A (zh) * 2017-03-30 2017-06-23 成都绿林科技有限公司 艾莎康唑硫酸酯的制备方法
CN109206421A (zh) * 2017-07-03 2019-01-15 上海医药集团股份有限公司 一种艾沙康唑晶型及其制备方法
CN111978302A (zh) * 2019-05-24 2020-11-24 帕潘纳(北京)科技有限公司 一种三唑氰类化合物及其制备方法
EP4289840A1 (fr) * 2022-06-07 2023-12-13 Zaklady Farmaceutyczne Polpharma S.A. Procede de preparation de sulfate d'isavuconazonium
WO2023237534A1 (fr) * 2022-06-07 2023-12-14 Zaklady Farmaceutyczne Polpharma S.A. Procédé de préparation de sulfate d'isavuconazonium
CN115215857A (zh) * 2022-08-17 2022-10-21 扬子江药业集团上海海尼药业有限公司 硫酸艾沙康唑的制备方法
CN115536643A (zh) * 2022-12-05 2022-12-30 南京桦冠生物技术有限公司 一种艾沙康唑类药物关键中间体的制备方法

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