WO2018036416A1 - Procédé de préparation d'éfinaconazole et forme cristalline m d'éfinaconazole - Google Patents

Procédé de préparation d'éfinaconazole et forme cristalline m d'éfinaconazole Download PDF

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WO2018036416A1
WO2018036416A1 PCT/CN2017/097803 CN2017097803W WO2018036416A1 WO 2018036416 A1 WO2018036416 A1 WO 2018036416A1 CN 2017097803 W CN2017097803 W CN 2017097803W WO 2018036416 A1 WO2018036416 A1 WO 2018036416A1
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acid
magnesium
methyl
fluconazole
ethanol
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PCT/CN2017/097803
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English (en)
Chinese (zh)
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张健
覃鸿健
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山东特珐曼药业有限公司
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Priority claimed from CN201710004560.8A external-priority patent/CN107778283A/zh
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Priority to CN201780051243.XA priority Critical patent/CN109843865B/zh
Publication of WO2018036416A1 publication Critical patent/WO2018036416A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

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  • the invention relates to the technical field of pharmacy, in particular to a preparation method of fluconazole, a novel crystal form M thereof, and a preparation method of the crystal form M.
  • fluconazole chemical name: (2R, 3R)-2-(2,4-difluorophenyl)-3-(4-methylene pipe Patent for compounds of pyridin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.
  • the patent also discloses a free 50% KOH solution of 4-methylene piperidine hydrochloride, followed by (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H- 1,2,4-triazol-1-yl)methyl]oxirane is obtained as a solvent in ethanol/water at 85 ° C, and purified by column chromatography to obtain effluentazole product.
  • the route is as follows:
  • CN103080100A discloses a process for preparing fluconazole which is in the presence of a hydroxide of an alkali metal or alkaline earth metal selected from lithium, sodium, calcium and barium or a hydrate thereof in a reaction solvent.
  • a hydroxide of an alkali metal or alkaline earth metal selected from lithium, sodium, calcium and barium or a hydrate thereof in a reaction solvent.
  • the alkane is reacted with a 4-methylene piperidic acid addition salt, wherein the reaction solvent may be acetonitrile, 1,2-dimethoxyethane, cyclopentyl methyl ether, isopropanol, 1-butanol or 4 -methyl-2-pentanone.
  • the method reported in the WO1994026734 patent has the disadvantages of low yield, high impurities, and purification by column chromatography.
  • the method reported by CN103080100A although the raw materials used are Higher yields were obtained with 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodide, but when the starting material was 4-methylene piperidine hydrochloride, the yield It can only reach about 70%, and it is only the yield that can be obtained when the scale is very small.
  • the purity of the obtained product can only reach about 95%, and in order to ensure the purity of the product, it is necessary to carry out column purification, which is not conducive to industrial amplification.
  • Efluconazole molecules may also produce different crystal forms with different crystal structures and physical properties. Different crystal forms of the same molecule can be analyzed by X-ray powder diffraction spectrum and differential scanning calorimetry. Spectrum and so on. The discovery of polymorphic forms of pharmaceutically useful compounds provides new opportunities to improve the performance characteristics of pharmaceutical products.
  • Another object of the invention is to provide a new crystalline form of effluentazole.
  • Another object of the present invention is to provide a process for the preparation of a new crystalline form of effluentazole.
  • the invention provides a preparation method of efconazole, which has the advantages of easy raw materials, simple process, mild reaction conditions and suitable for industrial production.
  • the method comprises the steps of 4-methylene piperidine or an acid addition salt thereof and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H) -1,2,4-triazol-1-yl)methyl]oxirane in any one selected from the group consisting of metal alkoxides M(OR 1 ) n , metal halides MY n or metal oxides M n O
  • metal alkoxides M(OR 1 ) n
  • metal halides MY n or metal oxides M n O metal halides
  • HX is absent or is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid, and Sulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid; the HX is preferably hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid; the HX is most preferably hydrochloric acid;
  • Y is selected from halogen
  • M is selected from any one of an alkali metal or an alkaline earth metal, R 1 is selected from an alkyl group having 1 to 5 carbon atoms, and n is 1 or 2;
  • the metal alkoxide M(OR 1 ) n is selected from the group consisting of sodium methoxide, potassium methoxide, lithium ethoxide, sodium ethoxide, magnesium methoxide, magnesium ethoxide, magnesium n-propoxide, calcium methoxide, calcium ethoxide, sodium t-butoxide, and tert-butyl Lithium alkoxide, magnesium t-butoxide, magnesium isobutoxide or magnesium t-pentoxide, preferably magnesium ethoxide, magnesium n-propoxide, magnesium t-butoxide or magnesium isobutoxide, particularly preferably magnesium ethoxide or magnesium t-butoxide ;
  • the metal halide MY n is selected from the group consisting of lithium iodide, lithium bromide, lithium chloride, magnesium iodide, magnesium bromide, magnesium chloride, calcium chloride, calcium bromide, barium chloride, barium bromide, preferably lithium bromide. , lithium chloride, magnesium bromide or magnesium chloride, particularly preferred is magnesium chloride;
  • the metal oxide M n O is preferably selected from lithium oxide, magnesium oxide, calcium oxide, strontium oxide or barium oxide; more preferred is lithium oxide or magnesium oxide.
  • the effect is achieved independent of the particular 4-methylene piperidonic acid addition salt.
  • the 4-methylene piperidine acid addition salt can be selected from 4-methylene piperidine hydrochloride, 4-methylene piperidine hydrobromide or 4-methylene A combination of one or more of a piperidine hydroiodide, but is not limited thereto.
  • the 4-methylene piperidine acid addition salt is preferably 4-methylene piperidine hydrochloride, 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodic acid. More preferably, the salt may be 4-methylene piperidine hydrochloride.
  • the solvent is selected from the group consisting of acetonitrile, 1,2-dimethoxyethane, cyclopentyl methyl ether, isopropanol, 1-butanol, 4-methyl-2-pentanone or N,N-dimethyl A combination of one or more of the carbachamides; preferably, the solvent is acetonitrile or cyclopentyl methyl ether.
  • the molar ratio of 2,4-triazol-1-yl)methyl]oxirane is from about 1:1 to 5:1; preferably, the 4-methylene piperidine or acid addition salt thereof And the (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl] ring
  • the molar ratio of oxyethane to be charged is about 1:1 to 3:1, more preferably about 1:1 to 1.5:1.
  • the 4-methylene piperidine or an acid addition salt thereof is selected from the group consisting of metal alkoxides M(OR 1 ) n , metal halides MY n or metal oxides molar feed ratio of either reagent M n O is about 1: 1 to 3: 1; more preferably, said 4-methylene piperidine or an acid addition salt selected from metal alkoxide M (
  • the charge ratio of any one of OR 1 ) n , metal halide MY n or metal oxide M n O is about 1:1 to 1.5:1.
  • the reaction is carried out at a temperature of from 0 ° C to 150 ° C. Preferably, the reaction is carried out at from 20 to 120 ° C.
  • the reaction time is usually from 1 h to 48 h.
  • the reaction can be carried out under any pressure, but it is usually carried out under normal pressure.
  • the product system is simply post-treated, and the column is separated without column chromatography to obtain an effluent product having a purity of 99.9% or more.
  • the post-treatment is to concentrate the reaction solution to dryness, dissolve in an organic solvent, wash with water, separate the liquid, and then dry and concentrate to obtain an oily substance, and then crystallize the oil with an alcohol-water mixed solvent to obtain
  • the crude form of effluentazole in solid form can be obtained by repeating the crystallization operation to obtain effluent with a purity of 99.9% or higher.
  • the organic solvent is selected from one or more of dichloromethane, ethyl acetate or diethyl ether.
  • the alcohol in the alcohol-water mixed solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol.
  • the method reported in CN103080100A obtains a higher yield when the raw material used is 4-methylene piperidine hydrobromide or 4-methylene piperidine hydroiodide, but when the raw material is 4-methylene When the piperidine hydrochloride is used, the yield can only reach about 70%.
  • the yield can reach 80 to 90%. Since the cost of 4-methylene piperidine hydrochloride is significantly lower than that of 4-methylene piperidine hydrobromide and 4-methylene piperidine hydroiodide, the stability is better, the use is convenient, and more Conducive to industrial amplification.
  • the present invention provides a crystal form M of fluconazole having an X-ray powder diffraction pattern of about 7.7° ⁇ 0.2° and 15.4° ⁇ 0.2° at a diffraction angle 2 ⁇ . , characteristic peaks at 16.7 ° ⁇ 0.2 ° and 18.9 ° ⁇ 0.2 °;
  • the X-ray powder diffraction pattern of the crystalline form M of the fluconazole is also about 10.0° ⁇ 0.2°, 12.5° ⁇ 0.2°, 20.2° ⁇ 0.2°, 23.2° ⁇ 0.2° at the diffraction angle 2 ⁇ . a characteristic peak at 24.5 ° ⁇ 0.2 °, and 25.3 ° ⁇ 0.2 °; preferably, the crystal form M of the fluconazole has the X-ray powder diffraction pattern shown in Figure 1;
  • the 2 ⁇ angle and relative intensity of each peak on the XRPD diffraction pattern may vary. Generally, the 2 ⁇ angle change is within ⁇ 0.2°, but the range may be slightly exceeded. Those skilled in the art should understand that the relative of diffraction The strength may depend, for example, on the sample preparation or the equipment used.
  • the differential scanning calorimetry pattern of the crystal form M of the fluconazole has a maximum peak at about 87.83 ⁇ 1 ° C. More preferably, the crystal form M of the fluconazole has a difference as shown in FIG. 2 . A scanning calorimetry map is shown.
  • the invention also provides a preparation method of the crystal form M of efconazole, the preparation method comprises: dissolving the crude product of efconazole in an alcohol solvent, cooling to -10 to 10 ° C, adding water, and mixing The suspension, the crystal form M of efconazole was isolated from the suspension.
  • the alcohol solvent is one or more selected from the group consisting of methanol, ethanol, isopropanol, n-butanol, tert-butanol, and tert-amyl alcohol; preferably, the alcohol solvent is one of methanol and ethanol. Or a variety.
  • the weight ratio of the crude product of the fluconazole to the alcohol solvent is about 1 Kg: (0.5 to 5) L, and the weight-to-volume ratio of the crude product of the fluconazole to water is about 1 Kg: (0.5 to 5) L.
  • the method of separating the crystalline form M of effluentazole from the suspension is a conventional separation method such as filtration or centrifugation of the suspension, preferably filtration.
  • the filter cake obtained after the filtration may also be washed with a washing solvent selected from one or more of water, methanol, ethanol, isopropanol, n-butanol, tert-butanol and tert-amyl alcohol.
  • the washing solvent is a mixed solvent having a water to ethanol volume ratio of about 1:1.
  • the inventors have found that during the preparation of Form M of efconazole, the temperature at which water is added is critical. When the temperature is higher than 10 ° C, the precipitated solid is powdery, which is not conducive to filtration and baking; the temperature is lower than -10 ° C When the solid precipitates too quickly, it is easy to form agglomerated impurities, which is not conducive to purification.
  • the crystal form M prepared by the method of the invention has the advantages of good crystallinity, uniform particles, easy filtration, easy drying and the like.
  • the present invention has the following advantages compared with the prior art:
  • the present invention enables 4-methylene piperidine or its acid addition salt and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2) , 4-triazol-1-yl)methyl]oxirane is carried out in the presence of magnesium tert-butoxide or magnesium chloride, the reaction is complete, the reaction conditions are mild, the selectivity is good, the by-products are small, the yield is high, and the simple After the treatment, an effluconazole product having a purity greater than 99.9% can be obtained; furthermore, according to the method of the invention, the yield of the method of the invention is higher regardless of the form of the 4-methylene piperidic acid addition salt of the raw material. .
  • Example 1 is an X-ray powder diffraction pattern of Form M of efconazole in Example 1;
  • Example 2 is a differential scanning calorimetry diagram of Form M of effluconazole in Example 1;
  • FIG. 3 is a polarizing microscope photograph of a crystal form M of effluconazole in Example 1.
  • the inventors of the present invention have intensively studied 4-methylene piperidine or its acid addition salt and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[( The reaction mechanism of 1H-1,2,4-triazol-1-yl)methyl]oxirane found that the specific magnesium salt has a very prominent catalytic effect on the reaction, and when the magnesium salt is magnesium tert-butoxide When introduced in the form of magnesium chloride, the reaction rate is fast, the reaction is complete, the stereoselectivity is good, and the by-products formed are small. Without column chromatography, a product with a purity higher than 99.9% can be obtained by simple post-treatment.
  • the synthetic route of the present invention can be expressed as follows:
  • HX is absent or is selected from the group consisting of hydrochloric acid, hydrobromic acid, hydroiodic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, boric acid, chloric acid, carbonic acid, formic acid, acetic acid, trifluoroacetic acid, propionic acid, oxalic acid , methanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid.
  • H NMR (1 H NMR) and C NMR (13 C NMR) was measured with Bruker Avance III 300 NMR spectrometer, using TMS as the internal standard, the unit is chemical shift ppm; Mass spectra Finnigan LCQ/DECA and Micromass Ultra Q-TOF (ESI) mass spectrometry; purity analysis using a liquid phase model of Waters 2489; color development using a Precision WFH-203B three-use UV analyzer with wavelengths of 254 nm and 365 nm. All temperatures are expressed in ° C (degrees Celsius), and room temperature or ambient temperature means 20 to 25 ° C.
  • Test instrument model DSC Q2000, heating rate: 10 ° C / min, heated from 45 ° C to 200 ° C.
  • Test instrument model Bruker D8 advance
  • Test conditions voltage is 40kV, current is 40mA, scanning type: two-axis linkage; scanning range: 3° to 40°; scanning step: 0.02°; scanning speed: 0.1 second/step.
  • the TLC silica gel plate is a HSGF-254 thin-layer chromatography silica gel plate produced by Yantai Chemical Plant.
  • the thickness of the chromatography plate used for thin layer chromatography is 0.2 ⁇ 0.03 mm, dichloromethane, ethyl acetate, methanol, and magnesium tert-butoxide.
  • the reagents such as magnesium ethoxide and anhydrous magnesium chloride are of analytical grade and are provided by Sinopharm Chemical Reagent Co., Ltd.
  • the reagents and solvents used are not specially treated unless otherwise specified.
  • Injection volume 20 ⁇ L, flow rate: 1.0 mL/min, column temperature: room temperature, detection wavelength: 210 nm.
  • the reaction mixture was concentrated to dryness.
  • the oil was stirred and dissolved in 25 mL of ethanol, cooled to 0 to 10 ° C with an ice bath, and 25 mL of purified water was gradually added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the crude product was stirred and dissolved again with 25 mL of ethanol, and cooled to 0 to 10 ° C with an ice bath, and 25 mL of purified water was gradually added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the crude product was stirred and dissolved with 20 mL of ethanol, and cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the crude product was stirred and dissolved with 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the oil was stirred and dissolved in 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes.
  • the crude product was stirred and dissolved with 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the crude product was stirred and dissolved with 20 mL of ethanol, cooled to 5 to 10 ° C with an ice bath, and 20 mL of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the crude product was dissolved in dichloromethane (10L), washed with The oil was concentrated to dryness to obtain 1.5 Kg of an oil.
  • the oil was dissolved in 2 L of ethanol, and cooled to 5 to 10 ° C in an ice bath, and 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 30 minutes, and filtered.
  • the crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was slowly added dropwise to precipitate a solid, and then kept warm and stirred.
  • the reaction mixture was concentrated to dryness crystals crystals eluted eluted eluted eluted eluted eluted
  • the crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was slowly added dropwise to precipitate a solid, which was stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was slowly added dropwise to precipitate a solid, which was stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 1 hour.
  • the oil was stirred and dissolved in 2.5 L of ethanol, and cooled to 0 to 10 ° C in an ice bath.
  • 2.5 L of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the crude product was stirred and dissolved again with 2.5 L of ethanol, and cooled to 0 to 10 ° C with an ice bath, and 2.5 L of purified water was slowly added dropwise to precipitate a solid, which was then stirred for 1 hour.
  • the reaction mixture was concentrated to dryness crystals crystals crystals crystals crystals crystals crystals.
  • the crude product was stirred and dissolved with 2 L of ethanol, cooled to 5 to 10 ° C with an ice bath, and 2 L of purified water was gradually added dropwise to precipitate a solid, which was stirred for 1 hour.
  • Example 1 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl] in Example 1
  • the molar ratio of ethylene oxide, magnesium t-butoxide, and 4-methylene piperidine was adjusted to 1:1.4:1.4, and the amounts were 10 g, 9.50 g, and 5.41 g, respectively, and the reaction was carried out in the same manner as in Example 1. Pure fluconazole crystals were obtained, white to off-white solid: 11.8 g, molar yield: 85%, HPLC purity: 99.9%.
  • Example 1 The solvent acetonitrile in Example 1 was replaced with 1,2-dimethoxyethane, and the reaction was carried out in the same manner as in Example 1 to obtain pure fluconazole crystals, white to off-white solid: 11.2 g, mol. Yield: 80.5%, HPLC purity: 99.9%.
  • Example 1 The solvent acetonitrile in Example 1 was replaced with cyclopentyl methyl ether, and the reaction was carried out in the same manner as in Example 1 to obtain pure fluconazole crystals, white to off-white solid: 11.1 g, molar yield: 80% , HPLC purity: 99.9%.
  • Example 11 (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-[(1H-1,2,4-triazol-1-yl)methyl] in Example 11
  • the molar ratio of ethylene oxide, magnesium ethoxide, and 4-methylene piperidine hydrochloride was adjusted to 1:1.5:1.5, and the amounts were 1 kg, 681 g, and 795 g, respectively, and the reaction was carried out in the same manner as in Example 11. Pure fluconazole crystals were obtained, white to off-white solid: 1.12 Kg, molar yield: 80.6%, HPLC purity: 99.9%.
  • Example 11 The magnesium ethoxide in Example 11 was replaced with magnesium methoxide, and the reaction was carried out in the same manner as in Example 11 to obtain pure fluconazole crystals, white to off-white solid: 1.11 Kg, molar yield: 80%, HPLC purity : 99.9%.
  • the reaction mixture was concentrated to dryness.
  • the oil was dissolved by stirring with 25 mL of ethanol, and cooled to X ° C with an ice bath. Then, 25 mL of purified water was gradually added dropwise to precipitate a solid, and the mixture was stirred for 1 hour.
  • the crude product was stirred and dissolved again with 25 mL of ethanol, and cooled to X ° C with an ice bath, and 25 mL of purified water was gradually added dropwise to precipitate a solid, which was stirred for 1 hour.
  • the inventors of the present invention conducted repeated experiments in which, when magnesium hydroxide or magnesium carbonate was used, most of the raw materials in the reaction system were unreacted. In the presence of a magnesium alkoxide or a magnesium halide, the reaction is complete, the reaction conditions are mild, the selectivity is good, the by-products are small, and the yield is high. Moreover, when a magnesium alkoxide is used as a catalyst, the reaction effect is superior to that of the corresponding lithium alcohol salt.
  • the yield can reach about 90%.
  • 4-methylene piperidine hydrochloride is significantly lower in cost than 4-methylene piperidine hydrobromide and 4-methylene piperidine hydroiodide, it is stable and better, and is convenient to use. More Conducive to industrial amplification.

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Abstract

L'invention concerne un procédé de préparation d'Éfinaconazole, une forme cristalline M d'Éfinaconazole, et un procédé de préparation de forme cristalline M. Le procédé de préparation d'Éfinaconazole comprend : l'activation du chlorhydrate de 4-méthylènepiperidine ou d'un sel d'addition d'acide de celui-ci et de l'oxyde d'éthylène (2R,3S)-2-(2,4-difluorophényl)-3-méthyl-2-[(1H -1,2,4-triazole-1-groupe) méthyl] pour subir une réaction dans une solution en présence d'au moins l'un des réactifs choisis parmi l'alcoxyde métallique M (OR 1 ) n , l'halogénure métallique MY n ou l'oxyde métallique M n O, de manière à générer l'Éfinaconazole. La formule de réaction est comme suit : Dans le procédé de préparation, la réaction est complète, la condition de réaction est modérée, le taux de rendement est élevé, la sélectivité est bonne, et l'Éfinaconazole ayant une pureté supérieure à 99 % peut être obtenu au moyen d'un traitement simple.
PCT/CN2017/097803 2016-08-26 2017-08-17 Procédé de préparation d'éfinaconazole et forme cristalline m d'éfinaconazole WO2018036416A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113795484A (zh) * 2019-09-26 2021-12-14 大峰Ls株式会社 共晶型艾氟康唑及其制备方法
CN115028557A (zh) * 2022-06-30 2022-09-09 中船(邯郸)派瑞特种气体股份有限公司 一种节约成本的n-苯基双三氟甲磺酰亚胺的制备方法

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CN103080100A (zh) * 2010-08-31 2013-05-01 科研制药株式会社 1-三唑-2-丁醇衍生物的制造方法
WO2016181306A1 (fr) * 2015-05-12 2016-11-17 Lupin Limited Procédé de préparation d'efinaconazole
WO2016193917A1 (fr) * 2015-06-04 2016-12-08 Glenmark Pharmaceuticals Limited Procédé de préparation d'éfinaconazole
US20170129874A1 (en) * 2015-11-10 2017-05-11 Virupaksha Organics Limited Novel improved process for preparing a triazole antifungal agent

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Publication number Priority date Publication date Assignee Title
CN103080100A (zh) * 2010-08-31 2013-05-01 科研制药株式会社 1-三唑-2-丁醇衍生物的制造方法
WO2016181306A1 (fr) * 2015-05-12 2016-11-17 Lupin Limited Procédé de préparation d'efinaconazole
WO2016193917A1 (fr) * 2015-06-04 2016-12-08 Glenmark Pharmaceuticals Limited Procédé de préparation d'éfinaconazole
US20170129874A1 (en) * 2015-11-10 2017-05-11 Virupaksha Organics Limited Novel improved process for preparing a triazole antifungal agent

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN113795484A (zh) * 2019-09-26 2021-12-14 大峰Ls株式会社 共晶型艾氟康唑及其制备方法
EP3928769A4 (fr) * 2019-09-26 2022-08-24 Daebong LS Co., Ltd. Éfinaconazole co-cristallin, et son procédé de production
CN113795484B (zh) * 2019-09-26 2024-07-09 大峰Ls株式会社 共晶型艾氟康唑及其制备方法
CN115028557A (zh) * 2022-06-30 2022-09-09 中船(邯郸)派瑞特种气体股份有限公司 一种节约成本的n-苯基双三氟甲磺酰亚胺的制备方法
CN115028557B (zh) * 2022-06-30 2023-08-01 中船(邯郸)派瑞特种气体股份有限公司 一种节约成本的n-苯基双三氟甲磺酰亚胺的制备方法

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