WO2015058272A1 - Procédé de préparation sélective de (1h-1,2,4-triazol-1-yl)alcanols, composé hydrazinyl-alcanol obtenu au moyen de ce procédé et son utilisation - Google Patents

Procédé de préparation sélective de (1h-1,2,4-triazol-1-yl)alcanols, composé hydrazinyl-alcanol obtenu au moyen de ce procédé et son utilisation Download PDF

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WO2015058272A1
WO2015058272A1 PCT/BR2014/000383 BR2014000383W WO2015058272A1 WO 2015058272 A1 WO2015058272 A1 WO 2015058272A1 BR 2014000383 W BR2014000383 W BR 2014000383W WO 2015058272 A1 WO2015058272 A1 WO 2015058272A1
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triazol
alkanols
selective preparation
preparation
hydrazinylalkanol
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PCT/BR2014/000383
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English (en)
Portuguese (pt)
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Anderson Silva De SOUZA
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Iharabras S.A. Indústrias Químicas
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    • 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
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C243/00—Compounds containing chains of nitrogen atoms singly-bound to each other, e.g. hydrazines, triazanes
    • C07C243/10—Hydrazines
    • C07C243/12—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms
    • C07C243/16—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton
    • C07C243/18—Hydrazines having nitrogen atoms of hydrazine groups bound to acyclic carbon atoms of an unsaturated carbon skeleton containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D239/00—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings
    • C07D239/02—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings
    • C07D239/24—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members
    • C07D239/28—Heterocyclic compounds containing 1,3-diazine or hydrogenated 1,3-diazine rings not condensed with other rings having three or more double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to ring carbon atoms
    • C07D239/30—Halogen atoms or nitro radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/22—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C07D277/28—Radicals substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D403/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00
    • C07D403/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings
    • C07D403/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, not provided for by group C07D401/00 containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
    • 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
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/02—Systems containing only non-condensed rings with a three-membered ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C2601/00—Systems containing only non-condensed rings
    • C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
    • C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated

Definitions

  • the present invention describes a process for the selective preparation of 2,4-triazol-1-yl) alkanols useful as synthesis intermediates and as pharmaceutical, veterinary and agrochemical active ingredients, as well as the use of their intermediates, processing conditions. .
  • Fluconazole, Voriconazole and, more recently, Ravuconazole are just a few examples of antifungal medicines for human use.
  • Triticonazole has already been prescribed for veterinary treatments.
  • a number of other (1H-1,2,4-triazol-1-yl) alkanols are of high importance in the treatment of plant fungal diseases such as Cyproconazole, Diclobutrazol, Flutriafol, Hexacohazole, Ipconazole, Metconazole and Tebuconazole.
  • R 2 (1H-1,2,4-triazol-1-yl) methyl) was first described in the patent family containing US4404216 by the reaction of 1- [2- (2,4-difluorophenyl) - 2,3-epoxypropyl] -1H-1,2,4-triazole with 100% molar excess of 1H-1,2,4-triazole in dimethylformamide at 90 ° C and with anhydrous potassium carbonate as proton acceptor . After 4.5h of reaction and a laborious isolation process, the product was obtained in 44% yield.
  • BR8807554 proposes the isomerization of the 4-substituted triazoles to their 1-substituted equivalents.
  • it requires drastic temperature conditions and the presence of a catalyst, although it has not been proven effective for all compounds.
  • this technique represents an additional step in the overall process of preparing (1H-1,2,4-triazol-1-yl) alkanols.
  • the present innovative process is inspired by the conventional process of preparing unsubstituted 1W-1,2,4-triazole based on the reaction of hydrazine with formic acid, formamide and / or ammonia as exemplified by US4490539.
  • the innovation is not an obvious derivation, as, so far, no publications have been found describing the process of preparing (1H-1,2,4-triazol-1-yl) alkanols by reacting hydrazinylalkanols with forming reagents.
  • 1 H-1,2,4-triazophyll as object of the present invention, much less foreseeing the use of its products and intermediates in the preparation of pharmaceutical, veterinary and agrochemical active ingredients.
  • This invention introduces a novel process for obtaining (1H-1,2,4-triazol-1-yl) alkanols to meet the following objectives:
  • oxiranes and halphydrias react with hydrazine (in any presentation form, hydrates or salts) to yield hydrazinylalkanol type intermediates which are converted to (1H-1,2,4-triazol-1-yl ) alkanols by reaction with some 1,2,4-triazolyl forming reagent.
  • the present invention describes a process for the preparation of (1H-1,2,4-triazol-1-yl) alkanols comprising the steps of: a) reaction of halohydrin of formula (II) or oxirane compound of formula (III) , below:
  • R1, R2, R3 and R4 are independently hydrogen, heteroatoms or carbon chains substituted or not substituted by heteroatoms, especially aliphatic, cyclic, heterocyclic, aromatic and heteroaromatic substituent groups, even halogenated, oxygenated, sulfonated and nitrated; with hydrazine or its salts, hydrates and derivatives to obtain a hydrazinylalkanole intermediate of formula (IV), given below:
  • the present invention describes a method for preparing (1H-1,2,4-triazol-1-yl) alkanols via alkylation of hydrazine (in any presentation, hydrate or salt) with oxiranes or halohydrins, followed by cyclization. with some 1H-1,2,4-triazolyl forming reagent according to the following steps:
  • R1, R2, R3 and R4 are independently hydrogen, heteroatoms or heteroatom-substituted carbon chains, especially aliphatic, cyclic, heterocyclic, aromatic substituent groups and heteroaromatic, even halogenated, oxygenated, sulfonated and nitrated
  • R 1 and R 2 are preferably alkyl or aryl groups, whether or not independently substituted by heteroatoms; R3 and R4 may be aryl or alkyl groups, whether or not independently substituted by heteroatom, or preferably H).
  • 1,2,4-triazolyl forming reagent is any reagent containing a carbon atom bonded to a hydrogen by single covalent bonding, also to a single covalent bonding heteroatom and to an additional double covalent bonding heteroatom reaction with ammonia and / or already combined with an unsubstituted nitrogen atom.
  • Unlimited examples of the 1,2,4-triazoiyl forming reagent are 1,3,5-triazine, formamidine, formamidinium salts or derivatives, formamide, and combinations of formic acid and / or ammonium derivatives thereof. Combinations of these reagents are still possible.
  • the formation reactions of the hydrazinylalkanol intermediate are preferably conducted in the absence of solvent, or in solution with short chain alcohols, up to 4 carbon atoms, or in the presence of glycols, or in the presence of a phase transfer catalyst. Temperatures may range from room temperature to reflux temperature, atmospheric pressure or positive pressure.
  • the triazole ring formation step is preferably conducted in the absence of solvent, or in solution with a solvent compatible with the 1,2,4-triazolyl forming reagent or in excess of the 1,2,4-triazolyl forming reagent.
  • solvent paper at temperatures preferably above 100 ° C, the upper limit being the decomposition temperature of the reaction medium components.
  • the reaction may be conducted at atmospheric pressure, positive pressure or vacuum, may be catalyzed by mineral acids, organic acids or bases, or may occur in the absence of catalysts.
  • the discovery technique represents an advance over the state of the art by not allowing the formation of 4-position substituted isomers of the triazole ring, the (1H-1,2,4-triazol-4-yl) alkanols.
  • the present invention proposes a novel process for the selective preparation of (1 H -1,2,4-triazol-1-yl) alkanols (known sterol biosynthesis inhibitors) which differs from the state of the art mainly by preventing the formation of (1 H-1, 2,4-triazol-4-yl) alkanis isomers, which have no biological activity or economic value, and whose formation (unavoidable by conventional synthesis routes) compromises process yields and creates the need for laborious and complex purification processes.
  • (1 H -1,2,4-triazol-1-yl) alkanols known sterol biosynthesis inhibitors
  • the new process also allows process conditions where solvents and excess unreacted materials can be easily recovered and recycled for use in successive batches,
  • Step 1 Synthesis of a hidrazinilalcanol (comprising two alternative synthesis routes)
  • X is preferably chlorine, bromine or iodine, more preferably chlorine or bromine, even more preferably chlorine;
  • R 1 and R 2 are preferably alkyl or aryl, whether or not independently substituted by heteroatoms.
  • R3 and R4 are preferably hydrogen.
  • Hydrazine is preferably employed in hydrate or salt form, more preferably in hydrate form.
  • the hydrazine content of the hydrate may range from 1 to 80%, preferably from 20 to 70%, more preferably from 60 to 70%.
  • the reaction may proceed in stoichiometric proportion.
  • molar excess of hydrazine is preferable to accelerate the reaction, consume the formed hydrogen halide and prevent formation of disubstituted hydrazines.
  • the molar ratio of hydrazine to halohydrin may range from 1 to 50, preferably from 2 to 20, more preferably from 5 to 15.
  • solvent can be selected from the group of short chain alcohols, from 1 to 4 carbons, preferably from 2 to 3 carbons, more preferably isopropanol.
  • glycols and alkylglycols may be employed, preferably alkyl (di) glycols, more preferably ethyl and butyl (di) glycols, even more preferably ethylglycol.
  • Catalysts are not essential for the progress of the reaction, but alkalines may be employed as non-limited examples: alkali metal hydrides, hydroxides, carbonates and borates, tertiary amines, pyridines and pyrimidines, diazabicycloundecene (DBU), or still base transfer catalyst, among others.
  • the molar ratio of catalyst to limiting reagent may range from 0.0001 to 1, preferably from 0.005 to 0.5, more preferably from 0.01 to 0.20.
  • the reaction occurs from room temperature, but may be accelerated by increasing the temperature. Temperatures of 25 to 200 ° C are acceptable, preferably 40 to 150 ° C, more preferably from 60 to 120 ° C, depending on the vapor pressures of the selected components.
  • the process allows and contemplates the accomplishment of this synthesis step in batch, continuous or semi-batch mode, in any equipment design available in the art: agitated tank, tubular reactor, microreactor, among others. In all cases, especially for semi-battered processes, the present process contemplates any order of addition of reagents and auxiliaries.
  • reaction times depend on the physicochemical properties of the selected halohydrin, its reactivity, steric effects, temperature and pressure conditions, stoichiometric ratios, dilution ratio, stirring efficiency, among other factors, but according to The present invention for complete consumption of the limiting reagent may range from 10 min to 50 h. Under conditions closer to ideal for safe operation and better yields, reaction times preferably range from 1 to 20h, more preferably from 2 to 10h.
  • Oxiranes prepared by any means described in the art, are reacted with hydrazine, its hydrate or salts thereof, to form a hydrazinylalkanol by opening the oxirane ring via attack of one of the least-carbon hydrazine nitrogen atoms.
  • R1, R2, R3 and R4 are as defined above.
  • the same considerations made for the alternative (a) of the first stage are valid for the alternative (b) with regard to:
  • a compound of the type (1/1M, 2,4-triazol-1-yl) alkanol is hidrazinilalcanol prepared by the reaction produced in the first forming step with a reagent 1, 2,4-triazolyl.
  • Possible reagents include, but are not limited to: 1,2,5-triazine, formamidine, formamidine salts or derivatives, formamide, and combinations of formic acid and / or ammonium derivatives thereof, preferably formamide and combination of formic acid with ammonia, more preferably formamide only. This process further permits and contemplates possible combinations of these reagents with each other.
  • the elevated temperature significantly increases the reaction rate, being the preferred range according to the invention 100-220 * 0, more preferably 130-200 ° C, most preferably 150-180 ° C. Higher temperatures are possible, but subject the reagents to decomposition, especially formamide.
  • Formamide is a preferred reagent as it also acts as a reaction solvent.
  • reaction solvent reactive solvent
  • This process recommends and contemplates formamide to hydrazinylalkane molar ratios of between 2 and 500, preferably between 3 and 50, more preferably between 5 and 20.
  • Catalysts are not essential to the progress of the reaction, but alkalines can be employed as non-limited examples: alkali metal hydrides, hydroxides, carbonates and borates, ammonia, tertiary amines, pyridines and pyrimidines, diazabicycloundecene (DBU). ), or base transfer catalyst, among others.
  • the molar ratio of catalyst to limiting reagent may range from 0.0001 to 1, preferably from 0.005 to 0.5, more preferably from 0.01 to 0.20.
  • Ammonia generated as a reaction by-product may be removed at atmospheric pressure or by vacuum, or may be contained in the reaction medium by generating positive pressure.
  • the reaction medium may be pressurized with inert gas or ammonia gas.
  • the second step may be carried out after isolation of the intermediate generated in the first step by distillation / evaporation of excess and auxiliary materials, or by solvent extraction followed by evaporation, or followed by washing crystallization, or by any another means of isolation. Nevertheless, the process allows the step 2 may occur subsequently to the first, since the materials employed are compatible with each other and with the provisos that provided that the molar ratios are balanced to correct for possible losses with parallel reactions (as might occur with traces of hydrazine consuming formamide to generate 1 H-1, 2,4-triazole and / or 4-aminp-4H-1, 2,4-triazole).
  • Preferred, non-limiting examples of the scope of this invention are the processes for preparing (1 H -1,2,4-triazoM-yl) alkanols of formula (I) comprised of the group containing: Fiuconazole, Voriconazole, Ravuconazole, Triticonazole , Cyproconazole, Diclobutrazol, Flutriafol, Hexaconazole, Ipconazole, Etconazole and Tebuconazole.
  • Preferred, non-limiting examples of the scope of this invention are those processes which use as main intermediates halohydrins and oxiranes which give rise to the products mentioned above.
  • Preferred, non-limiting examples of the scope of this invention are the processes that generate and use the hydrazinylanitic intermediates for the purpose of preparing the products mentioned above.
  • preferred, non-limiting examples of the scope of this invention are the processes which employ in their respective steps (depending on the class of compound) the molecules shown in Table 1, as well as their
  • oxiranes (III) 2- (2-fluorophenyl) -2- (4-fluorophenyl) oxirane and 2- (4-chlorophenyl) -2- (1-cyclopropylethyl) oxirane; the preparation and use of the respective (IV) 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2-hydrazinylethanol and 2- (4-chlorophenyl) -3-cyclopropyl-1-hydrazinylbutanecarboxylicides.
  • Products with melting temperature below 150 ° C may be obtained in liquid form at the end of this process.
  • those which are normally solid at room temperature may further be purified and crystallized according to techniques described in the art.
  • Example 1b - 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2- (1H-1,2,4-triazol-1-yl) ethanoyl
  • the intermediate was transferred to a reactor containing 40g formamide and 10g ammonium acetate, and the temperature was set to 150 ° C. The reaction continued for 12h.
  • the product was treated at 75-80 ° C by dilution with 200g of water, 30g of toluene and 60g of cyclohexane. After crystallization, filtration and drying, 14.8g of 1- (2-fluorophenyl) -1- (4-fluorophenyl) -2- (1 / - / - 1,2,4-triazoyl-1-yl) product remained.
  • the isomer containing structure 1 H-1,2,4-triazol-4-H was not detected.
  • Example 3 b 2- (4-chlorophenyl) -3-cyclopropyl-1- (1 H -1,4,4-triazol-1-yl) butan-2-one;

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Heterocyclic Carbon Compounds Containing A Hetero Ring Having Nitrogen And Oxygen As The Only Ring Hetero Atoms (AREA)

Abstract

La présente invention concerne un procédé de préparation sélective de (1H-1,2,4-triazol-1-yl)alcanols utiles comme intermédiaires de synthèse et comme ingrédients actifs pharmaceutiques, vétérinaires et agrochimiques, ainsi que l'utilisation de leurs intermédiaires, et les conditions de traitement. Selon la présente invention, les oxiranes et les halohydrines réagissent avec l'hydrazine (sous n'importe quelle forme de présentation, hydrates ou sels) pour donner lieu à des intermédiaires du type hydrazinylalcanol, lesquels sont convertis en (1H-1,2,4-triazol-1-yl)alcanols par réaction avec un quelconque réactif de formation de 1,2,4-triazolyl. La technique découverte représente une avancée par rapport à l'état de la technique étant donné qu'elle ne empêche la formation d'isomères substitués en position 4 de l'anneau triazol, les 1H-1,2,4-triazoI-4-yl)alcanols. Les procédés décrits dans la présente invention sont particulièrement avantageux par rapport à l'état de la technique étant donné qu'ils offrent de meilleurs rendements, des temps de traitement réduits, une simplification des opérations unitaires, une plus grande facilité de récupération des matières auxiliaires n'ayant pas réagi, et une sélectivité totale pour la formation de régioisomères.
PCT/BR2014/000383 2013-10-23 2014-10-22 Procédé de préparation sélective de (1h-1,2,4-triazol-1-yl)alcanols, composé hydrazinyl-alcanol obtenu au moyen de ce procédé et son utilisation WO2015058272A1 (fr)

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BR102013027313-9A BR102013027313B1 (pt) 2013-10-23 2013-10-23 Processo para a preparação seletiva de (1h-1,2,4-triazol-1-il) alcanóis, composto hidrazinil alcanol obtido por tal processo e seu uso

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN109020905A (zh) * 2017-06-09 2018-12-18 华东理工大学 两种环丙唑醇的多晶型及其制备方法
CN110291078A (zh) * 2016-11-18 2019-09-27 美国陶氏益农公司 4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1h-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈及制备方法
CN113666840A (zh) * 2021-10-22 2021-11-19 江苏七洲绿色科技研究院有限公司 一种丙硫菌唑中间体的制备方法

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GB2099818A (en) * 1981-06-06 1982-12-15 Pfizer Ltd Triazoles
US4404216A (en) * 1981-06-06 1983-09-13 Pfizer Inc. Antifungal 1,3-bis-triazolyl-2-propanol derivative
US4490539A (en) * 1982-06-22 1984-12-25 Nehezvegyipari Kutato Intezet Process for the preparation of 1,2,4-triazole
US4664696A (en) * 1983-03-04 1987-05-12 Sandoz Ltd. α-phenyl- or benzyl-α-cyclopropylalkylene-1H-imidazole- and 1,2,4-triazole-1-ethanols and use against fungus
US5484936A (en) * 1993-03-29 1996-01-16 Teva Pharmaceutical Industries Ltd. Processes for the preparation of 1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol derivatives
WO1997044330A1 (fr) * 1996-05-21 1997-11-27 Krka, Tovarna Zdravil D.D. Novo Mesto Procede de preparation de derives biologiquement actifs de 1,2,4-triazole et intermediaires utilises dans ce procede
US5710280A (en) * 1996-07-09 1998-01-20 Development Center For Biotechnology Preparation of fluconazole and pharmaceutically acceptable salts thereof
WO1998032744A1 (fr) * 1997-01-29 1998-07-30 Dae Woong Pharmaceutical Co., Ltd. Procede de fabrication de fluconazole

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Publication number Priority date Publication date Assignee Title
GB2099818A (en) * 1981-06-06 1982-12-15 Pfizer Ltd Triazoles
US4404216A (en) * 1981-06-06 1983-09-13 Pfizer Inc. Antifungal 1,3-bis-triazolyl-2-propanol derivative
US4490539A (en) * 1982-06-22 1984-12-25 Nehezvegyipari Kutato Intezet Process for the preparation of 1,2,4-triazole
US4664696A (en) * 1983-03-04 1987-05-12 Sandoz Ltd. α-phenyl- or benzyl-α-cyclopropylalkylene-1H-imidazole- and 1,2,4-triazole-1-ethanols and use against fungus
US5484936A (en) * 1993-03-29 1996-01-16 Teva Pharmaceutical Industries Ltd. Processes for the preparation of 1,3-bis(1,2,4-triazol-1-yl)-propan-2-ol derivatives
WO1997044330A1 (fr) * 1996-05-21 1997-11-27 Krka, Tovarna Zdravil D.D. Novo Mesto Procede de preparation de derives biologiquement actifs de 1,2,4-triazole et intermediaires utilises dans ce procede
US5710280A (en) * 1996-07-09 1998-01-20 Development Center For Biotechnology Preparation of fluconazole and pharmaceutically acceptable salts thereof
WO1998032744A1 (fr) * 1997-01-29 1998-07-30 Dae Woong Pharmaceutical Co., Ltd. Procede de fabrication de fluconazole

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN110291078A (zh) * 2016-11-18 2019-09-27 美国陶氏益农公司 4-((6-(2-(2,4-二氟苯基)-1,1-二氟-2-羟基-3-(5-巯基-1h-1,2,4-三唑-1-基)丙基)吡啶-3-基)氧基)苄腈及制备方法
CN109020905A (zh) * 2017-06-09 2018-12-18 华东理工大学 两种环丙唑醇的多晶型及其制备方法
CN109020905B (zh) * 2017-06-09 2022-12-23 华东理工大学 两种环丙唑醇的多晶型及其制备方法
CN113666840A (zh) * 2021-10-22 2021-11-19 江苏七洲绿色科技研究院有限公司 一种丙硫菌唑中间体的制备方法

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