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WO2025008993A1 - Procédé amélioré pour la préparation de glycine, n-méthyl-, [2-[[[1-[1-((2r,3r)-3-[4-(4-cyanophényl)-2-thiazolyl]-2-(2,5-difluorophényl)-2-hydroxybutyl]-4h-1,2,4-triazolium-4-yl]éthoxy]carbonyl]méthylamino]-3-pyridinyl]méthylester, sulfate (1 : 1) - Google Patents

Procédé amélioré pour la préparation de glycine, n-méthyl-, [2-[[[1-[1-((2r,3r)-3-[4-(4-cyanophényl)-2-thiazolyl]-2-(2,5-difluorophényl)-2-hydroxybutyl]-4h-1,2,4-triazolium-4-yl]éthoxy]carbonyl]méthylamino]-3-pyridinyl]méthylester, sulfate (1 : 1) Download PDF

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WO2025008993A1
WO2025008993A1 PCT/IN2024/051059 IN2024051059W WO2025008993A1 WO 2025008993 A1 WO2025008993 A1 WO 2025008993A1 IN 2024051059 W IN2024051059 W IN 2024051059W WO 2025008993 A1 WO2025008993 A1 WO 2025008993A1
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isavuconazonium
mixture
sulfate
formula
stirred
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Thirumalai Rajan Srinivasan
Rajeshwar Reddy Sagyam
Navin Kumar Reddy KESHAVAREDDY
Raju KONDENTI
Mounika GUDEPU
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MSN Laboratories Pvt Ltd
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MSN Laboratories Pvt 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
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings

Definitions

  • the present invention relates to an improved process for the preparation of Glycine, N-methyl-, [2-[[[l-[l-((2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2- hydroxybutyl]-4H-l,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1: 1) represented by the following structural formula- 1.
  • Isavuconazonium sulfate is chemically known as Glycine, N-methyl-, [2-[[[l-[l- ((2R,3R)-3-[4-(4-cyanophenyl)-2-thiazolyl]-2-(2,5-difluorophenyl)-2-hydroxybutyl]-4H- l,2,4-triazolium-4-yl]ethoxy]carbonyl]methylamino]-3-pyridinyl]methyl ester, sulfate (1:1), which is a prodrug of Isavuconazole.
  • Isavuconazonium sulfate is a systemic antifungal medication of the triazole class, which is used to treat invasive aspergillosis and mucormycosis and it is approved by USFDA under brand name of CRESEMBA.
  • US6300353 Bl (hereinafter referred as US‘353) discloses Isavuconazole and its process for preparation thereof. 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)-butan-2-ol.
  • Isavuconazonium salts are described in WO2001/32652 Al and a method for preparing Isavuconazonium hydrochloride.
  • Polymorphism is the occurrence of different crystalline forms of a single compound and it is a property of some compounds and complexes. Thus, polymorphs are distinct solids sharing the same molecular formula, yet each polymorph may have distinct physical properties. Therefore, a single compound may give rise to a variety of polymorphic forms where each form has different and distinct physical properties, such as different solubility profiles, different melting point temperatures and/or different X-ray diffraction peaks. Since the solubility of each polymorph may vary, identifying the existence of pharmaceutical polymorphs is essential for providing pharmaceuticals with predicable solubility profiles. It is desirable to investigate all solid-state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form.
  • Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. Additionally, polymorphic forms of the same drug substance or active pharmaceutical ingredient, can be administered by itself or formulated as a drug product (also known as the final or finished dosage form), and are well known in the pharmaceutical art to affect, for example, the solubility, stability, flowability, tractability and compressibility of drug substances.
  • the object of the present invention is to provide simple, cost effective and industrially feasible process for preparation of pure Isavuconazonium sulfate.
  • the present invention also relates to novel crystalline forms of Isavuconazonium sulfate.
  • the present invention relates to an improved process for the preparation of
  • Isavuconazonium sulfate The present invention also relates to crystalline forms of Isavuconazonium sulfate and process for its preparation.
  • Figure 1 Illustrates the PXRD pattern of crystalline form-M of Isavuconazonium sulfate.
  • Figure 2 Illustrates the PXRD pattern of crystalline form-Ml of Isavuconazonium sulfate.
  • Figure 3 Illustrates the PXRD pattern of crystalline form-M2 of Isavuconazonium sulfate.
  • Figure 4 Illustrates the PXRD pattern of crystalline form-M3 of Isavuconazonium sulfate.
  • Figure 5 Illustrates the PXRD pattern of amorphous form of Isavuconazonium hydrobromide.
  • Figure 6 Illustrates the PXRD pattern of amorphous form of Isavuconazonium trifluoroacetate.
  • Figure 7 Illustrates the PXRD pattern of crystalline form-M4 of Isavuconazonium sulfate.
  • Figure 8 Illustrates the PXRD pattern of crystalline form-M5 of Isavuconazonium sulfate.
  • Figure 9 Illustrates the PXRD pattern of crystalline form-M6 of Isavuconazonium sulfate.
  • Figure 10 Illustrates the PXRD pattern of crystalline form-M7 of Isavuconazonium sulfate.
  • solvent used in the present invention refers to "hydrocarbon solvents” such as n-hexane, n-heptane, cyclohexane, petroleum ether, benzene, toluene, xylene and the like; "ether solvents” selected from dimethyl ether, diisopropyl ether, diethyl ether, methyl tertbutyl ether, 1,2-dimethoxy ethane, tetrahydrofuran, trifluoroacetic anhydride, 1,4-dioxane and the like; "ester solvents” selected from methyl acetate, ethyl acetate, isopropyl acetate, n-butyl acetate, isobutyl acetate and the like; "polar-aprotic solvent selected from dimethylacetamide, dimethylformamide, dimethylsulfoxide, N-methylpyrrolidone and the like; "chloro solvents” selected from dichloro solvents
  • base in the present invention is selected from “alkali metal carbonates” selected from sodium carbonate, potassium carbonate, lithium carbonate and the like; “alkali metal bicarbonates” selected from sodium bicarbonate, potassium bicarbonate and the like; “alkali metal hydroxides” selected from sodium hydroxide, potassium hydroxide, lithium hydroxide barium hydroxide, caesium hydroxide, strontium hydroxide, calcium hydroxide, and the like; “alkali metal alkoxides” such as selected from sodium methoxide, sodium ethoxide, potassium methoxide, potassium ethoxide, sodium tert.butoxide, potassium tert.butoxide and the like; “alkali metal hydrides” selected from sodium hydride, potassium hydride and the like; “alkali metal amides” selected from sodium amide, potassium amide, lithium amide, lithium diisopropyl amide (LDA) and the like; “alkali metal phosphates”
  • pure compound of the present invention is meant to cover compound with a purity of at least 95%, or at least 97%, or at least 98%, at least 99%, at least 99.4%, at least 99.5% or at least 99.6% as measured by HPLC.
  • Isavuconazonium hydrobromide is also called Isavuconazonium bromide dihydrobromide.
  • the present invention provides an improved process for the preparation of pure Isavuconazonium sulfate, comprising: a) reacting Isavuconazole of formula-5 with (2-(((l-chloroethoxy)carbonyl)(methyl) amino)pyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl)amino)acetate of formula-4 in presence of a suitable reagent and a suitable solvent to provide compound of general formula-3,
  • the suitable reagent used in step-a) is selected from potassium iodide, sodium iodide, potassium bromide, sodium bromide and the like, preferably potassium iodide;
  • the suitable acid used in step-b) is selected from hydrogen bromide in acetic acid, ethyl acetate in hydrochloric acid, trifluoroacetic acid, and the like, preferably hydrogen bromide in acetic acid.
  • the suitable solvent used in step-a) to step-d) are selected from ketone solvent, nitrile solvent, alcohol solvent, hydrocarbon solvent, ester solvent, chloro solvent, ether solvent, polar solvents and the like.
  • the present invention provides an improved process for the preparation of pure Isavuconazonium sulfate of formula- 1, comprising: a) reacting Isavuconazole of formula-5 with (2-(((l-chloroethoxy)carbonyl)(methyl) amino)pyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl)amino)acetate of formula-4 in the presence of potassium iodide in acetonitrile to provide compound of formula-3a, b) treating the compound of formula-3a with hydrogen bromide in acetic acid and acetonitrile and then adding the obtained mixture to pre-cooled acetone or adding the pre-cooled acetone to the obtained mixture to provide Isavuconazonium hydrobromide of formula-2a, treating the Isavuconazonium hydrobromide of formula-2a with bisulfate resin in water to provide Isavuconazonium sulfate
  • Isavuconazonium sulfate of formula- 1 obtained according to the present invention is having “carbonyl impurity” less than about 0.1%, preferably less than about 0.05% as measured by HPLC.
  • Isavuconazonium sulfate of formula- 1 obtained according to the present invention is having benzamide impurity, alcohol impurity, Isavuconazole impurity, cyano impurity, cyclic impurity and diamine impurity less than about 0.05% as measured by HPLC.
  • the present invention provides crystalline form-M of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M of Isavuconazonium sulfate of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern having 2 theta values at about 5.8 and 9.3 ⁇ 0.2° 2 theta.
  • PXRD X-ray powder diffraction
  • the present invention provides crystalline form-M of Isavuconazonium sulfate of formula- 1, is characterized by its X-ray powder diffraction (PXRD) pattern comprising further 2 theta values at about 6.6, 14.6 and 16.7 ⁇ 0.2° 2.
  • PXRD X-ray powder diffraction
  • the present invention provides crystalline form-M of Isavuconazonium sulfate of formula- 1 is further characterized by its powder X- Ray diffractogram as illustrated in Figure- 1.
  • the present invention provides process for the preparation of crystalline form-M of Isavuconazonium sulfate, comprising: a) contacting Isavuconazonium hydrobromide with a sulfate ion source, b) obtaining crystalline form-M of Isavuconazonium sulfate of formula- 1.
  • the sulfate ion source is MP-sulfate ion exchange resin or bisulfate resin.
  • the step-a) dissolving Isavuconazonium hydrobromide in a mixture of water and dichloromethane, then adding MP- sulfate ion exchange resin and acetonitrile, and further adding pre-cooled ethyl acetate at 0- 5°C.
  • the present invention provides process for the preparation of crystalline form-M of Isavuconazonium sulfate, comprising: a) suspending or dissolving Isavuconazonium sulfate of formula- 1 in water and acetonitrile, b) isolating pure crystalline form-M of Isavuconazonium sulfate of formula- 1.
  • step-a) suspending or dissolving Isavuconazonium sulfate of formula- 1 in water and acetonitrile at a suitable temperature ranging from 25 °C to 50°C.
  • the solution can be filtered to make it particle free.
  • step-a) wherein the mixture obtained in step-a) is cooled to a suitable temperature ranging from -I5°C to -0°C.
  • a suitable temperature ranging from -I5°C to -0°C.
  • the process according to the present invention involves Isavuconazonium sulfate of formula- 1 having a purity of greater than about 99.49% as measured by HPLC.
  • the present invention provides crystalline form-M 1 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-Ml of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure-2.
  • the present invention provides process for the preparation of crystalline form-Ml of Isavuconazonium sulfate, comprising: a) suspending or dissolving Isavuconazonium sulfate of formula- 1 in water and acetonitrile, b) cooling the mixture to 0°C to 5°C and stirring 20 hours, c) isolating crystalline form-Ml of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M2 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M2 of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure-3.
  • the present invention provides process for the preparation of crystalline form M2 of Isavuconazonium sulfate, comprising: a) suspending or dissolving Isavuconazonium sulfate of formula- 1 in water and acetonitrile, b) cooling the mixture to 0°C to 5°C and stirring for 6 hours, c) isolating crystalline form-M2 of Isavuconazonium sulfate of formula- 1.
  • step-b) seed Isavuconazonium sulfate is added to the mixture.
  • the present invention provides crystalline form-M3 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M3 of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure-4.
  • the present invention provides process for the preparation of crystalline form-M3 of Isavuconazonium sulfate, comprising: a) contacting Isavuconazonium trifluoroacetate with GS-300 resin and sulfuric acid in water and acetonitrile, b) optionally seeding the mixture, c) cooling the mixture to - IOC to -15°C, d) isolating crystalline form-M3 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides amorphous form of Isavuconazonium hydrobromide of formula-2a.
  • the present invention provides amorphous form of Isavuconazonium hydrobromide of formula-2a is characterized by its powder X-Ray diffractogram as illustrated in Figure-5.
  • the present invention provides process for the preparation of amorphous form of Isavuconazonium hydrobromide of formula-2a, comprising: a) reacting the Isavuconazole of formula-5 with (2-(((l-chloroethoxy)carbonyl)(methyl) amino)pyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl)amino)acetate of formula- 4 in the presence of potassium iodide in acetonitrile to provide compound formula-3 a, b) treating the compound of formula-3a with hydrogen bromide in acetic acid and acetonitrile and then adding the obtained mixture to pre-cooled acetone or adding the pre-cooled acetone to the obtained mixture to provide amorphous form of Isavuconazonium hydrobromide compound of formula-2a.
  • the present invention provides amorphous form of Isavuconazonium trifluoroacetate.
  • the present invention provides amorphous form of Isavuconazonium trifluoroacetate is characterized by its powder X-Ray diffractogram as illustrated in Figure 6.
  • the present invention provides process for the preparation of amorphous form of Isavuconazonium trifluoroacetate, comprising: a) reacting the Isavuconazole of formula-5 with (2-(((l-chloroethoxy)carbonyl) (methyl) amino)pyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl)amino)acetate of formula- 4 in the presence of sodium bromide in acetonitrile to provide compound of formula- 3b, b) optionally purifying compound of formula-3b using dichloromethane and diisopropyl ether, c) treating the compound of formula-3b with trifluoroacetic acid in dichloromethane to provide Isavuconazonium trifluoroacetate salt, d) optionally purifying Isavuconazonium trifluoroacetate salt using dichloromethane and diisopropyl ether to provide amorph
  • the present invention provides crystalline form-M4 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M4 of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure-7.
  • the present invention provides crystalline form-M5 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M5 of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure-8.
  • the present invention provides crystalline form-M6 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M6 of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure-9.
  • the present invention provides crystalline form-M7 of Isavuconazonium sulfate of formula- 1.
  • the present invention provides crystalline form-M7 of Isavuconazonium sulfate of formula- 1 is characterized by its powder X-Ray diffractogram as illustrated in Figure- 10.
  • Isavuconazonium sulfate obtained according to the present invention has a particle size distribution of D90 less than about 200 pm, preferably less than about 150 pm, more preferably less than about 100 pm.
  • isolating the crystalline forms of Isavuconazonium sulfate can be carrying out by any methods known in the art for e.g. isolated by any of the techniques selected from but not limited to: decantation, filtration by gravity or suction, centrifugation, adding solvent to make slurry followed by filtration, or other techniques specific to the equipment used and the like, and optionally washing with a solvent.
  • the crystalline forms of Isavuconazonium sulfate can be dried in a suitable drying equipment such as tray dryer, vacuum oven, rotatory cone dryer, air oven, fluidized bed dryer, spin flash dryer, flash dryer, or the like.
  • the drying can be carrying out at atmospheric pressure or under reduced pressure at temperature of less than about 40°C, or any other suitable temperature.
  • the drying can be carried out for any time period required for obtaining a desired quality, such as from about 15 minutes to 10 hours or longer.
  • Crystalline forms of Isavuconazonium sulfate prepared according to the present invention can be further micronized or milled in conventional techniques to get the desired particle size to achieve desired solubility profile based on different forms of pharmaceutical composition requirements.
  • Techniques that can be used for particle size reduction include, but not limited to ball milling, roll milling and hammer milling, and jet milling. Milling or micronization can be performed before drying, or after the completion of drying of the product.
  • the present invention provides pharmaceutical composition comprising crystalline forms of Isavuconazonium sulfate and one or more pharmaceutically acceptable excipients.
  • the excipient can be selected from those reported in Excipient Development for Pharmaceutical, Biotechnology, and Drug Delivery Systems 2006.
  • composition comprising crystalline forms of Isavuconazonium sulfate and one or more pharmaceutically acceptable excipients is formulated in a manner suitable for the route of administration to be used.
  • compositions include tablets, pills, powders, liquids, suspensions, emulsions, granules, capsules, suppositories, or injection preparations.
  • P-XRD Method of Analysis PXRD analysis of compounds of the present invention was carried out by using BRUKER/D8 ADVANCE diffractometer using Cu Ka radiation of wavelength 1.5406 A° and continuous scan speed of 0.037min.
  • PSD method of Analysis Particle size distribution (PSD) analysis was performed using Malvern Mastersizer 3000 instrument.
  • HPCL Method of Analysis Isavuconazonium sulfate and its related substances were analyzed by HPLC by using Column: YMC-Triart C18 ExRS, 250 X 4.6mm, S-5 pm,8Dm or Sunniest PhE, 150 X 4.6mm, 3 pm or Chiral ART Cellulose-SZ, 250X 4.6mm, 5pm, Diluent: Chilled (Acetonitrile : 0.1% Sodium chloride (50:50) v/v) (at 2-8°C) or dimethylsulphoxide or 0.2% Diethylamine in Methanol.
  • Example- 1 Preparation of Isavuconazonium hydrobromide of formula-2a.
  • Acetonitrile (1950 ml) and potassium iodide 9.1 gms) was added to Isavuconazole (150 gms) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 45- 50°C and stirred for 30 minutes [Mixture-A].
  • Acetonitrile (900 ml) was added to (2-(((l- chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl) amino)acetate (199.7 gms) at 25-30°C [Mixture-B].
  • Mixture-B was added to Mixture-A at 45-50°C and stirred for 12 hours.
  • Example-2 Preparation of Isavuconazonium sulfate.
  • Example-3 Preparation of crystalline form-M of Isavuconazonium sulfate.
  • Example-4 Preparation of crystalline form-M of Isavuconazonium sulfate.
  • Example-5 Preparation of crystalline form-M of Isavuconazonium sulfate.
  • Example-6 Preparation of crystalline form-Ml of Isavuconazonium sulfate.
  • Example-7 Preparation of crystalline form-M2 of Isavuconazonium sulfate.
  • Example-8 Preparation of Isavuconazonium trifluoroacetate.
  • Acetonitrile (300 ml) and sodium bromide (35.3 gms) was added to Isavuconazole (50 gms) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 45-50°C and stirred for 30 minutes [Mixture- A].
  • Acetonitrile (200 ml) was added to (2-(((l- chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl)methyl 2-((tert-butoxycarbonyl)(methyl) amino)acetate (83.2 gms) at 25-30°C [Mixture-B].
  • Mixture-B was added to the Mixture-A at 45-50°C and stirred for 24 hours.
  • Example-9 Preparation of crystalline form-M3 of Isavuconazonium sulfate.
  • Example-10 Preparation of crystalline form-M of Isavuconazonium sulfate.
  • Bi-sulfate ion resin (270 gms) was loaded in column and washed with water (2700 ml). Column washed with 5% sulfuric acid solution (2700 ml) and water (2700 ml) at 25- 30°C. Water (90 ml) was added to Isavuconazonium hydrobromide (90 gms) and the mixture was passed through the column. Acetonitrile (6300 ml) was added to the obtained column fractions at 25-30°C and stirred for 5 minutes. Cooled the mixture to -15 to -5°C and stirred for 5 minutes. Seed Isavuconazonium sulfate was added to the mixture at -15 to -5°C and stirred for 24 hours.
  • Example- 11 Preparation of crystalline form-M4 of Isavuconazonium sulfate.
  • Bi-sulfate ion resin (3000 gms) was loaded in column and washed with water (5000 ml). Column washed with 5% sulfuric acid solution (5000 ml) and water (10000 ml) at 25- 30°C. Water (700 ml) and Acetonitrile (1750 ml) were added to Isavuconazonium hydrobromide (1000 gms) and mixture passed through above column. Column washed with acetonitrile (8000 ml) at 25-30°C. Fileted the mixture, and acetonitrile (46000 ml) was added to the filtrate at 25-30°C and stirred 5 minutes. Cooled the mixture to -15 to -5°C and stirred for 5 minutes.
  • Seed Isavuconazonium sulfate was added to the mixture and at -15 to -5°C and stirred for 24 hours. Raised temperature of the mixture to 0-5 °C and stirred 2 hours. Ethyl acetate (8000 ml) was added to mixture and stirred for 30 minutes. Filtered the mixture, washed with pre-cooled ethyl acetate and dried to get title compound. Yield: 260 gms.
  • Example-12 Preparation of Isavuconazonium sulfate.
  • Bi-sulfate ion resin 300 gms was loaded in column and washed with water (3000 ml). Column washed with 5% sulfuric acid solution (3000 ml) and water (3000 ml) at 25- 30°C. Water (73 ml) was added Isavuconazonium hydrobromide (100 gms) and mixture passed through column at 25-30°C. Column washed with Acetonitrile (3100 ml) at 25-30°C. Cooled the mixture to -15 to -5°C and stirred for 8 hours. Ethyl acetate (2000 ml) was added to mixture and stirred for 30 minutes. Seed Isavuconazonium sulfate was added to the mixture at -5 to -15°C and stirred for 24 hours. Yield: 5050 ml.
  • Example-13 Preparation of crystalline form-M5 of Isavuconazonium sulfate.
  • Example-14 Preparation of crystalline form-M6 of Isavuconazonium sulfate.
  • Example-15 Preparation of crystalline form-M7 of Isavuconazonium sulfate.
  • Acetonitrile 200 ml was added to the mixture and passed through the column. Acetonitrile (5400 ml) was added to the mixture at 25-30°C and stirred for 5 minutes. Cooled the mixture to -15 to -5°C and stirred for 5 minutes. Seed crystals were added to the mixture at -15 to -5°C and stirred for 20 hours. Raised temperature to 0-5 °C and stirred for 2 hours. Ethyl acetate (800 ml) was added to mixture and stirred for 30 minutes. Filtered the mixture, washed with ethyl acetate and dried to get title compound.
  • Example-16 Preparation of Isavuconazole.
  • Example-17 Preparation of (2-(((l-chloroethoxy)carbonyl)(methyl)amino)pyridin-3-yl) methyl 2-((tert-butoxycarbonyl)(methyl)amino)acetate of formula-4.
  • Pre-cooled aqueous hydrochloride solution was slowly added to the organic layer at 0-5°C and stirred for 15 minutes. Layers were separated. Pre-cooled aqueous sodium carbonate solution was slowly added to the organic layer at 0-5°C and stirred for 15 minutes. Layers were separated. Raised the temperature of the organic layer to 25-30°C. Aqueous sodium chloride solution was added to the organic layer at 25-30°C and stirred for 15 minutes. Layers were separated. Distilled off the solvent completely from the organic layer under vacuum at below 30°C. Dichloromethane (28.0 lit) was added to the obtained compound at 25-30°C and stirred for 10 minutes. Cooled the mixture to 0-5°C.
  • Example-18 Preparation of Isavuconazonium hydrobromide of formula -2a.
  • Acetonitrile (39.0 lit) and potassium iodide (1.59 kg) was added to Isavuconazole (3.0 kg) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 45-50°C and stirred for 30 minutes [Mixture-A].
  • Acetonitrile (18.0 lit) was added to (2-(((l- chloroethoxy)carbonyl)(methyl)aminopyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl) amino)acetate (3.99 kg) at 25-30°C and stirred for 10 minutes. Cooled the mixture to 2-8°C [Mixture-B].
  • Mixture-B was added to Mixture-A at 45-50°C and stirred for 12 hours. Cooled the mixture to 25-30°C. Toluene (9.0 lit) and water (15.0 lit) were added to the mixture at 25- 30°C and stirred for 30 minutes. Layers were separated. Water (45.0 lit) was added to the organic layer at 25-30°C and stirred for 2 hours. Layers were separated and organic layer washed with aqueous sodium chloride solution. Distilled off the solvent completely from the organic layer under vacuum at below 35°C and co-distilled with acetonitrile. Acetonitrile (32.40 lit) was added to the obtained compound at 25-30°C and stirred for 15 minutes. Cooled the mixture to 0-5°C.
  • Example-19 Preparation crystalline form-M of Isavuconazonium sulfate.
  • Acetonitrile (4420 ml) was added to the filtrate at 25-30°C. Cooled the mixture to -15 to - 10°C. Seed Isavuconazonium sulfate (1.3 gm) was added to the mixture at -15 to -10°C and stirred for 24 hours. Raised the temperature of the mixture to 0-5°C and stirred for 2 hours. Pre-cooled ethyl acetate (5200 ml) was added to the mixture at 0-5°C and stirred for 40 minutes. Filtered the solid, washed with ethyl acetate and dried to get the title compound.
  • Acetonitrile (325 ml) and potassium iodide (14.2 g) was added to Isavuconazole (25 gms) at 25-30°C and stirred for 10 minutes. Raised the temperature of the mixture to 45-50°C and stirred for 30 minutes [Mixture-A].
  • Acetonitrile (150 ml) was added to (2-(((l- chloroethoxy)carbonyl)(methyl)aminopyridin-3-yl)methyl2-((tert-butoxycarbonyl)(methyl) amino)acetate (41.58 gms) at 25-30°C [Mixture-B].
  • Mixture-B was added to Mixture-A at 45- 50°C and stirred for 15 hours.

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Abstract

La présente invention concerne un procédé amélioré pour la préparation de glycine, N-méthyl-, [2-[[[1-[1-((2R,3R)-3-[4-(4-cyanophényl)-2-thiazolyl]-2-(2,5-difluorophényl)-2-hydroxybutyl]-4H-1,2,4-triazolium-4-yl]éthoxy]carbonyl]méthylamino]-3-pyridinyl]méthylester, sulfate (1 : 1) représenté par la formule développée 1 suivante.
PCT/IN2024/051059 2023-07-04 2024-07-04 Procédé amélioré pour la préparation de glycine, n-méthyl-, [2-[[[1-[1-((2r,3r)-3-[4-(4-cyanophényl)-2-thiazolyl]-2-(2,5-difluorophényl)-2-hydroxybutyl]-4h-1,2,4-triazolium-4-yl]éthoxy]carbonyl]méthylamino]-3-pyridinyl]méthylester, sulfate (1 : 1) Pending WO2025008993A1 (fr)

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IN202341044910 2023-07-04

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PCT/IN2024/051059 Pending WO2025008993A1 (fr) 2023-07-04 2024-07-04 Procédé amélioré pour la préparation de glycine, n-méthyl-, [2-[[[1-[1-((2r,3r)-3-[4-(4-cyanophényl)-2-thiazolyl]-2-(2,5-difluorophényl)-2-hydroxybutyl]-4h-1,2,4-triazolium-4-yl]éthoxy]carbonyl]méthylamino]-3-pyridinyl]méthylester, sulfate (1 : 1)

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Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2014MN02588A (fr) * 2012-05-25 2015-07-24 Arven Ilac Sanayi Ve Ticaret As
WO2016016766A2 (fr) * 2014-07-26 2016-02-04 Wockhardt Limited Procédé de préparation d'isavuconazonium ou de son sel
WO2020025553A1 (fr) * 2018-08-01 2020-02-06 Basilea Pharmaceutica International AG Procédé de purification de sulfate d'isavuconazonium
IN202121031940A (fr) * 2021-07-15 2023-01-20

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IN2014MN02588A (fr) * 2012-05-25 2015-07-24 Arven Ilac Sanayi Ve Ticaret As
WO2016016766A2 (fr) * 2014-07-26 2016-02-04 Wockhardt Limited Procédé de préparation d'isavuconazonium ou de son sel
WO2020025553A1 (fr) * 2018-08-01 2020-02-06 Basilea Pharmaceutica International AG Procédé de purification de sulfate d'isavuconazonium
IN202121031940A (fr) * 2021-07-15 2023-01-20

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