- Identification, synthesis, and control of efinaconazole impurities
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Impurities A-F were observed, identified, and confirmed during the efinaconazole production process. The possible formation pathways of the mentioned impurities were understood, and thereafter, a controlling strategy was established by locating the proper process parameters with the consideration of efficient cost and less waste as well. This impurity investigation is also essential for quality control of consistently delivering of qualified efinaconazole API.
- Zhu, Fuqiang,Zhang, Jian,Xiamuxi, Hainimu,Chen, Weiming,Hu, Tianwen,Yang, Xiaojun,Tian, Guanghui,Ni, Runyan,Li, Jian,Suo, Jin,Xie, Yuanchao,Shen, Jingshan,Aisa, Haji A.,He, Yang
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Read Online
- A Facile Epoxide Aminolysis Promoted by (t-BuO)2Mg and Its Application to the Synthesis of Efinaconazole
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A novel and efficient method for the aminolysis of trizole epoxides is described. This method consists of a facile ring opening of the epoxides mediated by t-BuOMgCl generated in situ from amine hydrochlorides and (t-BuO)2Mg. The desired β-amino alcohols were obtained in good yields without employing other heavy metals or precious catalysts. The optimized conditions were successfully applied to the synthesis of a number of potential triazole antifungal compounds as well as efinaconazole on up to a 700 g scale.
- Zhu, Fuqiang,Xie, Yuanchao,Zhang, Jian,Tian, Guanghui,Qin, Hongjian,Yang, Xiaojun,Hu, Tianwen,He, Yang,Aisa, Haji A.,Shen, Jingshan
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Read Online
- NOVEL METHOD FOR PREPARATION OF EPOXYTRIAZOLE DERIVATIVES
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The present invention relates to novel processes for preparing epoxytriazole derivatives. The method of claim 1, further comprising the step of adding a base to the intermediate compound. The present invention relates to an epoxytriazole derivative and a manufacturing method thereof. Chemical Formula 1. Here, Ar denotes C. 6 -C10 Aryl group or C aryl group2 -C9 The aryl group 1 -4 is substituted or unsubstituted, and when 2 or more halogen is substituted, the heteroaryl group may be the same as or different from each other, and the heteroaryl group is represented by 1 -4 fluorine, chlorine, or C. 1 -C3 Substituted or unsubstituted alkyl groups, and fluorine, chlorine, or C. 1 -C3 When more than 2 substituents are substituted, each of these substituents may be the same or different and may be different from each other. The A is C. 1 -C3 Represents an alkyl group, and the R represents an alkyl group. 1 And R2 Is a methyl group or an ethyl group.
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- Asymmetric Catalytic Epoxidation of Terminal Enones for the Synthesis of Triazole Antifungal Agents
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An enantioselective epoxidation of α-substituted vinyl ketones was realized to construct the key epoxide intermediates for the synthesis of various triazole antifungal agents. The reaction proceeded efficiently in high yields with good enantioselectivities by employing a chiral N,N′-dioxide/ScIII complex as the chiral catalyst and 35% aq. H2O2 as the oxidant. It enabled the facile transformation for optically active isavuconazole, efinaconazole, and other potential antifungal agents.
- Feng, Xiaoming,He, Qianwen,Liu, Xiaohua,Zhang, Dong,Zhang, Fengcai
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p. 6961 - 6966
(2021/09/11)
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- PREPARATION METHOD FOR EFINACONAZOLE
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The present invention provides a preparation method for Efinaconazole, comprising the following steps: in the presence of a bromide and a base, subjecting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazole-1-yl)methyl]oxirane and an inorganic a
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Paragraph 0031-0048
(2021/11/26)
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- METHOD FOR PREPARATION OF EFINACONAZOLE IN IONIC LIQUID MEDIUM
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The present invention relates to a novel method for preparation of efinaconazole in an ionic liquid medium, the method comprising: reacting 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole, and 4-methylenepiperidine or an organic chemically acceptable salt thereof, wherein the 4-methylenepiperidine or the organic chemically acceptable salt thereof is anionized on a base; and performing a coupling reaction with the 1-[[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole in the presence of an ionic liquid compound. The present invention uses an ionic liquid instead of an organic solvent when preparing efinaconazole, thereby reducing related substances compared to the conventional method, shortens the reaction time, thereby making it possible to easily obtain the final compound, efinaconazole, with high purity and high yield, and may be very suitably used for mass production.
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- PROCESS FOR THE PREPARATION OF AN AZOLIC DERIVATIVE
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The present invention refers to a process for the preparation of an azolic derivative used in the treatment of onychomycosis. Said process comprises the reaction between (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane and 4-methylenepiperidine or a salt thereof, in the presence of a zinc derivative in an alcoholic solvent.
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Page/Page column 8
(2018/11/26)
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- Anti-Selective Catalytic Asymmetric Nitroaldol Reaction of α-Keto Esters: Intriguing Solvent Effect, Flow Reaction, and Synthesis of Active Pharmaceutical Ingredients
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A rare-earth metal/alkali metal bimetallic catalyst proved particularly effective for enantioselectively coupling nitroalkanes and α-keto esters in an anti-selective manner to afford synthetically versatile, densely functionalized, and optically active α-nitro tertiary alcohols. A chiral diamide ligand captured two distinct metal cations, giving rise to a catalytically competent solid-phase heterobimetallic catalyst by simple mixing via self-assembly. The advantage of the solid-phase asymmetric catalyst was realized by successful application to the enantio- and diastereoselective reaction in a continuous-flow platform. The use of closely related solvents in terms of structures and polarity parameters, THF and its methylated congener 2-Me-THF, had an unexpectedly large solvent effect both on the reaction rate and the stereoselectivity. The nitroaldol products share a privileged unit for active pharmaceutical ingredients, as demonstrated by the streamlined enantioselective synthesis of the marketed antifungal agents efinaconazole and albaconazole.
- Karasawa, Tomoya,Oriez, Rapha?l,Kumagai, Naoya,Shibasaki, Masakatsu
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p. 12290 - 12295
(2018/09/27)
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- Efinaconazole preparation method
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The invention discloses an efinaconazole preparation method, wherein the chemical name of the efinaconazole is (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazole-1-yl) butane-2-ol, and the chemical formula is C18H22F2N4O. According to the present invention, the preparation process has characteristics of simple process, easily available raw materials and simple designand development, can effectively avoid the disadvantages of difficult obtaining of the raw material and the catalyst and not high yield, is suitable for industrialization, can promote the economic and technological development of efinaconazole bulk drugs, is economical and environmental protection, can reduce the production cost, and is suitable for mass production.
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Paragraph 0008; 0011-0013
(2018/09/08)
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- Preparing method of 1-triazole-2-butanol derivative
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The invention relates to a preparing method of a 1-triazole-2-butanol derivative. The preparing method comprises the steps of making 4-methylpiperidine addition salt react with (2R,3S)-2-(2,4-di-fluorophenyl)-3-methyl-2-[(1H-1,2,4-traizole-1-radical)methy
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Paragraph 0023; 0026; 0028; 0029; 0031-0074
(2018/03/24)
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- METHOD OF PRODUCING 1-TRIAZOLE-2-BUTANOL DERIVATIVES
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PROBLEM TO BE SOLVED: To provide a novel method of producing 1-triazole-2-butanol derivatives useful as pharmaceuticals. SOLUTION: A method of producing a 1-triazole 2-butanol derivative represented by formula (1) comprises reacting a compound represented by formula (2) with 4-methylenepiperidine (3) in the presence of a metal salt (excluding lithium salts). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0039-0066
(2018/05/15)
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- PROCESS FOR PREPARING INTERMEDIATES USEFUL IN THE SYNTHESIS OF ANTIFUNGAL DRUGS
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Subject-matter of the invention is a process for preparing intermediates useful in the synthesis of drugs, for example antifungal drugs, such as efinaconazole. Subject-matter of the invention are also such novel synthesis intermediates and the use thereof.
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- fukang zuo and its intermediate synthesis method
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The invention provides a synthesis method of efinaconazole. The method comprises the following steps: carrying out substitution reaction on a compound (8) and a compound (9) to obtain a compound (7), carrying out amidation reaction to obtain a compound (6), carrying out Grignard addition reaction on the compound (6) to obtain a compound (5), carrying out addition reaction on the compound (5) and nitroethane to obtain a racemic mixture (4), carrying out chiral resolution to obtain a compound (3), carrying out reduction reaction on the compound (3) to obtain a compound (2), and finally, carrying out substitution reaction on the compound (2) and a compound (10) to obtain the efinaconazole. The method provided by the invention is simple to operate, has the advantages of low production cost and favorable product quality, and is suitable for industrial production.
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Paragraph 0021; 0080-0082
(2017/07/07)
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- NOVEL IMPROVED PROCESS FOR PREPARING A TRIAZOLE ANTIFUNGAL AGENT
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An improved process for the preparation of Efinaconazole of Formula (I) or its salts may include reacting triazole compound of Formula (III) or its salts with compound of Formula (IV) or its salts wherein X represents CH2, O or S, in the presence of an al
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Paragraph 0101; 0102
(2017/05/28)
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- Method for preparing efinaconazole intermediate
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The invention discloses a method for preparing an efinaconazole intermediate. The method comprises the following step: in a solvent, performing Sharpless asymmetric dihydroxylation on a compound as shown in the formula 2 under the actions of a chiral catalyst, an oxidant and a co-oxidant to prepare a compound as shown in the formula 3, wherein R is halogen or 1,2,4-triazolyl, and R is hydrogen or methyl. The method is green and environment-friendly, high in security, mild in condition, low in cost, simple in step, high in yield and suitable for industrial application. The formula 2 and the formula 3 are as shown in the description.
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Paragraph 0115; 0124; 0125; 0126; 0127
(2017/05/19)
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- Efinaconazole, preparation method of efinaconazole intermediate and efinaconazole intermediate
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The invention discloses efinaconazole, a preparation method of an efinaconazole intermediate and the efinaconazole intermediate. A preparation method of efinaconazole comprises the following step: in a solvent, under the action of a reducing agent, performing reductive amination reaction on a compound shown in the formula 4 and a compound shown in the formula B. The invention also provides the efinaconazole intermediate shown in the formula 4 and the preparation method thereof, and the preparation method comprises the following step: performing oxidizing reaction on a compound shown in the formula 3 to obtain the compound shown in the formula 4. A preparation method of the compound shown in the formula 3 comprises the following step: in a solvent, performing Sharpless asymmetric dihydroxylation on a compound shown in the formula 2 under the actions of a chiral catalyst, an oxidant and a co-oxidant. The efinaconazole and the preparation method of the efinaconazole intermediate are green and environment-friendly, high in security, mild in condition, low in cost, simple in step, high in yield and suitable for industrial application. The formulas 2, 3, 4 and B are as shown in the description.
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Paragraph 0115; 0124; 0125; 0126; 0127
(2017/05/19)
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- PROCESS FOR THE SYNTHESIS OF EFINACONAZOL
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PROCESS FOR THE SYNTHESIS OF EFINACONAZOL Disclosed is a process for the synthesis of efinaconazole (I), starting from 1- [[(2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiranyl]methyl]-1H-1,2,4-triazole and 4-methylenepiperidine, as free base or hydrochloride,
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Page/Page column 10
(2017/07/31)
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- Method for preparation of Efinaconazole
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The invention provides a method for preparation of Efinaconazole. The method comprises the following step: in the presence of iodide or its hydrate, in a reaction solvent and alkali, a compound as shown in the formula 2 is contacted with a compound as sho
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Paragraph 0042-0070
(2017/08/28)
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- Efinaconazole crystal form and preparation method thereof
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The invention discloses an Efinaconazole crystal form I and a preparation method thereof. Diffraction peaks are formed at the parts which are about 7.68+/-0.2 degrees, 15.38+/-0.2 degrees and 16.70+/-0.2 degrees in a powder X-ray diffraction pattern represented by a 2theta angle of the Efinaconazole crystal form I. The prepared Efinaconazole crystal form I has not been reported and has high purity and few individual impurities; and furthermore, the preparation process is simple, reaction conditions are mild, the product yield is high, and the preparation process is safe, environment-friendly and beneficial to the large-scale industrial production of Efinaconazole crystal form products. The preparation method has the beneficial effects that high-purity crystals can be separated from a system, impurities in the reaction process can be effectively removed, the production efficiency is improved, and the production cost is lowered.
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Paragraph 0054; 0055; 0056
(2017/08/29)
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- PROCESS FOR THE PREPARATION OF EFINACONAZOLE
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The present invention relates to a process for the preparation of Efinaconazole and salts thereof.
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Paragraph 00123
(2016/12/22)
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- PROCESS FOR THE PREPARATION OF PIPERIDINE COMPOUNDS
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The present invention relates to a process for the preparation of efinaconazole.
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Paragraph 0049
(2017/01/23)
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- Method for preparing philippines Kang Zuo
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The invention discloses a preparation method of efinaconazole (I). The preparation method comprises the following steps: performing asymmetric addition reaction on 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazole-1-yl)aceton (II) and nitroethane in the presence of a catalyst cupreine and a promoter benzoic acid to generate (2R,3R)-3-nitro-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (III); performing nitro reduction reaction on the intermediate (III) to generate (2R,3R)-3-amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazole-1-yl)-2-butanol (IV); and performing cyclization reaction on the intermediate (IV) and 1,5-di-halogen-3-methylene pentane (V) to prepare efinaconazole (I). The preparation method is easily available in raw materials and concise in process, is economical and environment-friendly and is suitable for industrial production.
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- INTERMEDIATE COMPOUNDS AND PROCESS FOR THE PREPARATION OF EFINACONAZOLE
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The present invention relates to a process for the preparation of (2R,3R)-2-(2,4- difluorophenyl)-3-(4-methylene-1-piperidinyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol (Efinaconazole) and intermediates used in such process.
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Page/Page column 19; 20
(2016/06/15)
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- PROCESS FOR THE PREPARATION OF EFINACONAZOLE
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The present invention provides an improved process for the preparation of Efinaconazole in higher yield by the ring-opening addition reaction of epoxytriazole with 4- methylenepiperidine or its acid addition salt under mild conditions without using a large 5 excess of 4-methylenepiperidine in the presence of an alkali or an alkaline earth metal halide.
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Page/Page column 8
(2016/11/28)
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- Efinaconazole intermediate and preparation method thereof
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The invention provides an efinaconazole intermediate compound (VI) and a preparation method thereof and relates to the field of pharmaceutical technology. The preparation method comprises the following steps: a compound (V) reacts with trimethylsulfoxonium iodide to obtain a compound (VV); and the compound (VV) experiences a ring-opening reaction with 1,2,4-triazole to obtain the compound (VI). The method has the advantages of easiness in operation, low production cost and good product quality and is suitable for industrial production.
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Paragraph 0061; 0062; 0063
(2016/10/10)
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- An enantioselective synthesis of the key intermediate for triazole antifungal agents; Application to the catalytic asymmetric synthesis of efinaconazole (jublia)
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A new synthetic route, the shortest reported to date, to access a key intermediate for the synthesis of various triazole antifungal agents was developed. The elusive tetrasubstituted stereogenic center that is essential in advanced triazole antifungal agents was constructed via the catalytic asymmetric cyanosilylation of a ketone. The subsequent transformations were performed in two one-pot operations, enhancing the overall synthetic efficiency toward the intermediate. This streamlined synthetic approach was successfully applied to efficient enantioselective syntheses of efinaconazole (Jublia) and ravuconazole.
- Tamura, Keiji,Kumagai, Naoya,Shibasaki, Masakatsu
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p. 3272 - 3278
(2014/05/06)
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- PROCESS FOR PRODUCING 1-TRIAZOLE-2-BUTANOL DERIVATIVES
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An object is to provide a process for producing the compound of formula 1 in higher yield by the ring-opening addition reaction of epoxytriazole with amine under mild conditions without using a large excess of 4-methylenepiperidine. The process for producing (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol or an acid addition salt thereof comprises reacting (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1H-1,2,4-triazol-1-yl)methyl]oxirane with an acid addition salt of 4-methylenepiperidine in a reaction solvent in the presence of a hydroxide of an alkali metal or an alkaline earth metal selected from the group consisting of lithium, sodium, calcium, and strontium, or a hydrate thereof.
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Paragraph 0053; 0054; 0055; 0056; 0057
(2013/06/27)
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- Synthesis and antifungal activities of (2R,3R)-2-aryl-1-azolyl-3- (substituted amino)-2-butanol derivatives as topical antifungal agents
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2-Aryl-1-azolyl-3-(substituted amino)-2-butanol derivatives I were prepared by ring-opening reaction of epoxides II with excess amine, and their antifungal activities were evaluated as topical agents. Azolyl-cyclic amine derivatives with a methylene group showed extremely strong activity with a broad spectrum in vitro. In general, anti-Trichophyton mentagrophytes activities of most of the topical antifungal agents are substantially reduced by addition of keratin (a major constituent of the keratinized tissue). However, the triazole derivative (2R,3R)-2-(2,4-difluorophenyl)-3-(4- methylenepiperidino)-1-(1H-1,2,4-triazol-1-yl)-2-butanol ((-)-40, KP-103) showed very little deactivation by addition of keratin. This biological characteristic of triazole derivative (-)-40 resulted in excellent therapeutic efficacy on dermatophytosis superior to that of the corresponding imidazole derivative ((-)-41).
- Ogura, Hironobu,Kobayashi, Haruhito,Nagai, Kiyoshi,Nishida, Tokiko,Naito, Takanobu,Tatsumi, Yoshiyuki,Yokoo, Mamoru,Arika, Tadashi
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p. 1417 - 1425
(2007/10/03)
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- Azolylamine derivative
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There is disclosed a fungicide containing, effective ingredient, a compound having the general formula (I): STR1 or an acid addition salt thereof, particularly the compound wherein an absolute configuration of the asymmetric carbon atoms is R,R-configurat
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