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WO2016055918A1 - Novel stable polymorphs of isavuconazole or its salt thereof - Google Patents

Novel stable polymorphs of isavuconazole or its salt thereof 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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French (fr)
Inventor
Rupesh Chhaganbhai KHUNT
Mohammad Rafeeq
Arvind Yekanathsa Merwade
Keshav Deo
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Wockhardt Ltd
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Wockhardt Ltd
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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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Abstract

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. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment present invention directs to crystalline form Isavuconazole Hydrobromide salt and oxalate salt of 2-(2,5-difluoro- phenyl)-1-[1,2,4]triazol-1-yl-butane-2,3-diol.

Description

NOVEL STABLE POLYMORPHS OF ISAVUCONAZOLE OR ITS SALT THEREOF
Field of Invention
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. In particular the present invention directs process for the preparation of solid amorphous and crystalline form of Isavuconazole base. In a further embodiment of 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.
Background of the invention
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 US patent No. 6,300,353 discloses Isavuconazole and its process. It has chemical name [(2R,3R)-3-[4-(4- cyanophenyl)thiazol-2-yl)]-l -(lH-l,2,4-triazol-l-yl)-2-(2,5-difluorophenyl)43utan-2-ol; and has the structural formula I:
Figure imgf000002_0001
Formula I
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. The use of 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.
Thus, 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. In a particular present invention directs to novel stable polymorphs of Isavuconazole or its salt thereof. Summary of the Invention
The present invention also provides a solid amorphous form of Isavuconazole base, compound of Formula I,
Figure imgf000003_0001
Formula I
having purity more than 90 %, when measured by HPLC.
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,
Figure imgf000003_0002
Formula I
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 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,
Figure imgf000003_0003
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
Figure imgf000004_0001
.(COOH)2
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
Figure imgf000004_0002
.(COOH)2
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
Figure imgf000004_0003
.(COOH)2
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.
Brief Description of the Drawings
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
Description of the Invention For purposes of the present invention, the following terms are defined below.
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.
In one another, aspect of the present invention provides a stable amorphous form of Isavuconazole base, compound of Formula I,
Figure imgf000006_0001
Formula I
having purity more than 90 % when measured by HPLC.
In another aspect, 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.
In one another, aspect of the present invention provides the process for the preparation of stable amorphous form of Isavuconazole base, the process includes the steps of
a) reacting thioamide (2R,3R)-3-(2,5-difluorophenyl)-3-hydroxy-2-methyl-4-(lH-l ,2,4-triazol-l- yl)butanethioamide, comp d herein after "thioamide compound")
Figure imgf000006_0002
Formula-Ill
with 4-cyano phenacyl bromide in alcohol solvent
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,
d) separating and concentrating acetate solvent layer,
e) isolating Isavuconazole by adding ether solvent.
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.
The pH of the 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.
In one aspect of the present invention provides a stable crystalline form of Isavuconazole base, compound of Formula I,
Figure imgf000008_0001
Formula I
having purity more than 95 % when measured by HPLC.
In another aspect, 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 XRPD characteristic peaks of the stable crystalline form of Isavuconazole base, having purity more than 95 %, further defined from the Table 1 :
Crystalline XRD Isavuconazole Base
2 Theta peaks d-spacing [A°] Relative Intensity [% ]
7.87 1 1.22 23.22
13.32 6.64 65.36
13.96 6.34 75.27
14.35 6.16 55.81
14.75 6.00 75.06
16.55 5.35 23.98
19.02 4.66 60.03
19.72 4.50 15.62
20.42 4.34 47.22
20.90 4.24 35.32
21.32 4.16 100.00
23.82 3.73 29.98 24.58 3.62 21.71
25.27 3.52 93.43
25.59 3.48 79.90
26.82 3.32 19.98
27.35 3.26 19.46
27.81 3.20 17.27
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.
In one another, 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
a) adding Isavuconazole hydrobromide in the halogenated solvent,
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,
d) isolating Isavuconazole base.
The 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;
The process where 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. In one another, 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.
In one another aspect of the present invention provides a stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formu
Figure imgf000010_0001
Formula II
having purity more than 95 % , when measured by HPLC.
In another aspect, 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 XRPD characteristic peaks of the stable crystalline form of Isavuconazole Hydrobromide salt further defined from the Table 1
2 Theta peaks d-spacing [A°] Relative Intensity [% ]
6.96 12.68 100
7.28 12.13 35.43
11.58 7.63 32.97
12.37 7.15 31.57
16.43 5.39 30.14
17.94 4.94 34.62
19.41 4.57 17.48
20.70 4.29 42.48
22.09 4.02 52.72 22.70 3.91 18.41
23.28 3.81 42.41
24.90 3.57 33.87
25.20 3.53 28.76
25.56 3.48 96.21
26.11 3.41 17.20
28.42 3.14 16.31
31.67 2.82 24.34
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.
In one another, aspect of the present invention provides the process for the preparation of stable crystalline form of Isavuconazole Hydrobromide salt, compound of Formula II,
Figure imgf000011_0001
Formula II
having purity more than 95%, the process includes steps of
a) treating the compound of
Figure imgf000011_0002
Formula-Ill
with 4-cyano phenacyl bromide in alcohol solvent,
b) heat of the reaction mixture,
c) isolating isavuconazole hydrobromide.
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.
In one another, 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
HPLC.
In one another, 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
Figure imgf000012_0001
Formula IV
In one aspect of 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, IV
Figure imgf000012_0002
.(COOH);
Formula IV In another aspect, 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 XRPD characteristic peaks of the crystalline solid form of oxalate salt of 2-(2,5-difluoro-phenyl)-l- [l ,2,4]triazol-l-yl-butane-2,3-diol, further defined in Table 1.
TABLE-1
Figure imgf000013_0001
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.
In one aspect of the present invention provides an improved process for the preparation of Isavuconazole, compound of formula I,
Figure imgf000014_0001
Formula I
the process includes the steps of
a) reacting of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base, with the oxalic acid in suitable solvent,
b) isolating oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol from the reaction mixture of step (a),
c) treating oxalate salt with base,
d) converting 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 Ν,Ν-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.
The process where 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.
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.
In one another, 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-methylmoφholine. 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 present invention is further illustrated by the following example, which does not limit the scope of the invention. Certain modifications and equivalents will be apparent to those skilled in the art and are intended to be included within the scope of the present application.
Examples
Example-1: Preparation of Amorphous Isavuconazole
In a round bottomed flask charged ethanol (250 ml), thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) under stirring. The reaction mixture were heated to 70 °C. After completion of reaction the solvent was removed under vacuum distillation and water (250 ml) and Ethyl acetate (350 ml) were added to reaction mass. The reaction mixture was stirred and its pH was adjusted between 7 to 7.5 by 10 % solution of sodium bicarbonate. The layer aqueous layer was discarded and organic layer was washed with saturated sodium chloride solution (100 ml) and concentrated under vacuum to get residue. The residue was suspended in methyl tert-butyl ether (250 ml) and the reaction mixture was heated to at 40°C to make crystals uniform and finally reaction mass is cooled to room temperature filtered and washed with the methyl tert-butyl ether. The product was isolated dried to get pale yellowish solid product.
Yield: 26.5 gm
HPLC purity: 92.7%
Example-2: Preparation of crystalline Isavuconazole Base
Charged methylene dichloride (250 ml) and 25.0 gm Isavuconazole Hydrobromide compound of formula-II into 1.0 L flask and stirred. Added aqueous solution of sodium bi carbonate in to the reaction mass to obtained clear solution. The layers were separated and organic layer was washed with dilute hydrochloric acid solution followed by saturated solution of sodium chloride. Finally, Organic layer was concentrated under vacuum to get titled product.
Yield: 18.5 gm
HPLC Purity: 97% Example-3: Preparation of crystalline Isavuconazole Hydrobromide
Charged isopropanol alcohol (250 ml) followed by thioamide compound (25.0 gm) and 4-cyano phenacyl bromide (18.4 gm) into 1.0 L flask. The reaction mixture was stirred and heated to 50 C, after completion of reaction the precipitated material was filtered and washed with isopropanol alcohol (25 ml). The wet cake is dried under vacuum for 4-5 hrs at 40 C to obtain off-white solid product.
Yield: 26.5 gm
HPLC Purity: 97.3%
Exaniple-4: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Dissolved crude 50 gm 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol base compound in 150 ml of ethyl acetate. Oxalic acid dihydrate 25 gm was added into the reaction mixture and stirred. Heat the reaction mixture for 1 hour at 50-55 °C. The reaction mixture was cooled to 25°C to 35°C. Toluene 300 ml was added into the reaction mixture to precipitate the solid. The precipitate was washed with toluene and dried under vacuum to obtain the solid crystalline form of titled compound.
Yield: 58 g
HPLC Purity: 76%
Exaniple-5: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate salt
Exemplified procedure in example 1 with the replacement ethyl acetate solvent with tetrahydrofuran and antisolvent toluene with petroleum ether were used to get the title compound.
Exaniple-6: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 with the replacement ethyl acetate solvent with isopropyl acetate and antisolvent toluene with diisopropyl ether were used to get the title compound.
Exaniple-7: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and toluene or heptane was used as antisolvent to get the title compound. Example-8: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 wherein diethyl ether is used in place of ethyl acetate and isolation of the product were done by means of partial removal of the solvent under vacuum.
Example-9: Synthesis of 2-(2,5-difluoro-phenyl)-l -[l,2,4]triazol-l-yl-butane-2,3-diol oxalate
Exemplified procedure in example 1 wherein ethyl acetate is replaced with isopropyl acetate and further, the reaction mass was stirred at lower temperatures to about 10°C to about 15°C for 3-5 hours and subsequently precipitated product was isolated and dried.
Example-10: Synthesis of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol base
Stirring the suspension of 260 ml water and 65 gm 2-(2,5-difluoro-phenyl)-l-[l,2,4] triazol-l-yl-butane-2,3-diol oxalate salt were added. The reaction mixture pH was adjusted by addition of 10 % aqueous sodium carbonate solution. The pH was maintained to about pH 7 to about 8, 300 ml dichloro methane was added into the reaction mixture with stirring. The layers were separated and dichloromethane layer was collected. Aqueous layer was extracted with 150 ml dichloromethane. Dichloromethane layer was combined and washed with water. Dichloromethane was distilled out to get titled compound.
Yield: 35 gm
Purity: 87%

Claims

We Claim:
1. A stable amorphous form of Isavuco la I,
Figure imgf000019_0001
Formula I
having purity more than 90 % when measured by HPLC
2. The stable amorphous form of Isavuconazole base of claim 1, characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 1 ;
ii. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 2, iii. a Thermogavimetric Analysis (TGA) substantially in accordance with Figure 3;
3. Use of the Isavuconazole base according to claim 1 in the preparation of Isavuconazonium iodide hydrochloride or Isavuconazonium sulfate in subsequent steps.
4. A process for the preparation of stable amorphous form of Isavuconazole base, the process comprising steps of,
a) reacting thioamide compound of formula- III
Figure imgf000019_0002
Formula-Ill
with 4-cyano phenacyl bromide in alcohol solvent,
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,
d) separating and concentrating acetate solvent layer, and
e) isolating Isavuconazole by adding ether solvent.
5. The process of claim 4, wherein the alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or a mixture thereof.
6. The process of claim 5, wherein the alcohol solvent is ethanol.
7. The process of claim 4, wherein the acetate solvent is one or more of ethyl acetate, methyl acetate, t-butyl acetate, or a mixture thereof.
8. The process of claim 7, wherein the acetate solvent is ethyl acetate.
9. The process of claim 4, wherein the ether solvent is one or more of methyl tert-butyl ether, ethyl tert-butyl ether, diethyl ether, di-tert-butyl ether, water or a mixture thereof .
10. The process of claim 9, wherein the ether solvent is methyl tert-butyl ether.
11. A stable crystalline form of Isavuconazole base, compound of Formula I,
Figure imgf000020_0001
Formula I
having purity more than 95 % when measured by HPLC
12. The stable crystalline form of Isavuconazole base of claim 1 , characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 4;
ii. a powder X-ray diffraction pattern having peaks at about 13.32, 13.96, 14.35, 14.75, 19.02, 21.32, 25.27 and 25.59 ± 0.2°,
iii. a powder X-ray diffraction pattern having additional peaks at about 7.87, 16.55, 19.72, 20.42, 20.90, 23.82, 24.58, 26.82, 27.35, 27.81,
iv. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 5, v. a Thermogavimetric Analysis (TGA) substantially in accordance with Figure 6,
13. A process for the preparation of stable crystalline form of Isavuconazole base, having purity more than 95 % when measured by HPLC, the process comprises the steps of
a) adding Isavuconazole hydrobromide in the halogenated solvent,
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,
d) isolating Isavuconazole base, having the purity more than 95%.
14. The process of claim 13, wherein the halogenated solvent is one or more of dichloromethane, chloroform carbon tetrachloride or a mixture thereof.
15. A stable crystalline form of Isavucon mpound of Formula II,
Figure imgf000021_0001
Formula II
having purity more than 95 %
16. The stable crystalline form of Isavuconazole Hydrobromide salt of claim 15, characterized by at least one of the following properties
a) a powder X-ray diffraction pattern substantially in accordance with Figure 7;
b) a powder X-ray diffraction pattern having peaks at about 6.96, 7.28, 20.70, 22.09, 23.28 and 25.56 c) a powder X-ray diffraction pattern having additional peaks at about 11.58, 12.37, 16.43, 17.94, 19.41, 22.70, 24.90, 25.20, 26.11 , 28.42 and 31.67
d) a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 8, e) a Thermogavimetric Analysis (TGA) substantially in accordance with Figure 9
17. Use of the Isavuconazole or a hydrobromide salt thereof according to claim 11 and 16 in the preparation of Isavuconazole base, Isavuconazonium iodide hydrochloride or Isavuconazonium sulfate.
18. A process for preparation of stable crystalline form of Isavuconazole Hydrobromide salt, the process comprises the step of
a) treating the compound of Formula III
Figure imgf000022_0001
Formula-Ill
with 4-cyano phenacyl bromide in alcohol solvent,
b) heating the reaction mixture, and
c) isolating isavuconazole hydrobromide.
19. The process of claim 18, wherein the alcohol solvent is one or more of methanol, ethanol, n-propanol, isopropanol, n-butanol, isobutanol, tert-butanol or a mixture thereof.
20. The process of claim 19, wherein alcohol solvent is Isopropanol.
21. Crystalline solid 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
Figure imgf000022_0002
.(COOH)2
Formula IV
22. The crystalline solid form of oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol of claim 21 , characterized by at least one of the following properties
i. a powder X-ray diffraction pattern substantially in accordance with Figure 10;
ii. a powder X-ray diffraction pattern having 2 theta values at about 16.10, 23.21, 21.11, 15.77, 11.56, 25.36, 5.16 and 22.75 + 0.2°,
iii. a powder X-ray diffraction pattern having additional peaks at 2 theta values about 22.25, 19.07, 14.85,
18.58, 26.68, 11.22, and 14.07 ± 0.2°,
iv. a differential scanning calorimetric (DSC) thermogram substantially in accordance with Figure 11 , v. Thermogavimetric Analysis (TGA) substantially in accordance with Figure 12
23. The 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol prepared according to claim 21 , converted to Isavuconazole or its salt to Isavuconazonium iodide hydrochloride and Isavuconazonium sulfate in subsequent steps.
24. An improved process for the preparation of Isavuconazole, compound of formula I,
Figure imgf000023_0001
Formula I
the process comprises steps of,
a) reacting of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol base, with the oxalic acid in a suitable solvent,
b) isolating oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol from the reaction mixture of step (a),
c) treating the oxalate salt a base,
d) converting step c) Isavuconazole base to Isavuconazonium sulfate.
25. The process of claim 24, wherein the suitable solvent is an ester or an ether solvent.
26. The process of claim 25, wherein the ester solvent is one or more of methyl acetate, ethyl acetate, propyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, or hexyl acetate.
27. The process of claim 25, wherein the ether solvent is one or more of diethyl ether, methyl tert-butyl ether, or tetrahydrofuran .
28. The process of claim 24, wherein isolation is carried out by addition of a suitable antisolvent.
29. The process of claim 28, wherein the antisolvent is one or more of petroleum ether, o-xylene, m-xylene, p- xylene, diisopropyl ether, tertiary butyl methyl ether, hexane, heptane, pentane, or toluene. A purification process of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l-yl-butane-2,3-diol, the process comprises step
(a) converting diol base to oxalate salt of 2-(2,5-difluoro-phenyl)-l-[l ,2,4]triazol-l -yl-butane-2,3-diol
(b) treatment with base and
(c) isolation of purified 2-(2,5-difluoro-phenyl)-l-[l,2,4]triazol-l-yl-butane-2,3-diol base, has purity more than 60%, when measured by HPLC.
PCT/IB2015/057599 2014-10-08 2015-10-05 Novel stable polymorphs of isavuconazole or its salt thereof Ceased WO2016055918A1 (en)

Applications Claiming Priority (6)

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CN106749222A (en) * 2016-12-15 2017-05-31 重庆东得医药科技有限公司 Crystal formation A of Chinese mugwort Saperconazole and preparation method thereof, pharmaceutical composition and purposes
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CN107778306B (en) * 2016-08-30 2020-10-16 江苏奥赛康药业有限公司 A kind of isavuconazole compound and preparation method thereof
CN107778306A (en) * 2016-08-30 2018-03-09 江苏奥赛康药业股份有限公司 One kind Chinese mugwort Saperconazole compound and preparation method thereof
CN107982221A (en) * 2016-10-27 2018-05-04 江苏正大丰海制药有限公司 Injection sulfuric acid Chinese mugwort Saperconazole freeze drying powder injection and preparation method
CN106619541A (en) * 2016-10-27 2017-05-10 南京师范大学 Isavuconazonium sulfate freeze-dried powder injection and preparation method
CN106749222B (en) * 2016-12-15 2019-06-11 重庆东得医药科技有限公司 Crystal form A of Chinese mugwort Saperconazole and preparation method thereof, pharmaceutical composition and purposes
CN106749222A (en) * 2016-12-15 2017-05-31 重庆东得医药科技有限公司 Crystal formation A of Chinese mugwort Saperconazole and preparation method thereof, pharmaceutical composition and purposes
CN106883226A (en) * 2017-03-30 2017-06-23 成都绿林科技有限公司 The preparation method of Ai Shakang azoles sulfuric esters
CN109206421A (en) * 2017-07-03 2019-01-15 上海医药集团股份有限公司 A kind of Chinese mugwort Saperconazole crystal form and preparation method thereof
US12428414B2 (en) 2018-08-01 2025-09-30 Basilea Pharmaceutica International AG Methods for purifying isavuconazonium sulfate
CN111978302A (en) * 2019-05-24 2020-11-24 帕潘纳(北京)科技有限公司 Triazole cyanide compound and preparation method thereof
EP4289840A1 (en) * 2022-06-07 2023-12-13 Zaklady Farmaceutyczne Polpharma S.A. A process for preparing isavuconazonium sulfate
WO2023237534A1 (en) * 2022-06-07 2023-12-14 Zaklady Farmaceutyczne Polpharma S.A. A process for preparing isavuconazonium sulfate
CN115215857A (en) * 2022-08-17 2022-10-21 扬子江药业集团上海海尼药业有限公司 The preparation method of isavuconazole sulfate
CN115536643A (en) * 2022-12-05 2022-12-30 南京桦冠生物技术有限公司 Preparation method of key intermediate of isavuconazole medicine

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