- 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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- Triazole alcohol derivative as well as preparation method and application thereof
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The invention relates to a triazole alcohol derivative as well as a preparation method and application thereof. The chemical structure of the triazole alcohol derivative is shown as a formula I, R1 represents a benzene ring or a substituted benzene ring, and substituent groups of the substituted benzene ring can be located at all positions of the benzene ring, can be mono-substituted or multi-substituted, and can be selected from a) halogen which is F and Cl; b) an electron withdrawing group which is cyano or trifluoromethyl; c ) a lower alkyl of 1-4 carbon atoms or a halogen substituted loweralkyl; and d) lower alkoxy of 1-4 carbon atoms or halogen substituted lower alkoxy. The compound of the invention has strong antifungal activity, has the advantages of low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal drugs.
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Paragraph 0101; 0110; 0123-0124
(2020/03/11)
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- Triazole alcohol derivative, and preparation method and application thereof
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The invention relates to a triazole alcohol derivative, and a preparation method and an application thereof. The chemical structure of the triazole alcohol derivative is represented by formula I, A inthe formula I represents a benzene ring or a substituted benzene ring, and the substituent group of the substituted benzene ring can be located at each position of the benzene ring, is monosubstituted or polysubstituted, and is selected from: a) halogen which is F, Cl, Br or I; b) an electron-withdrawing group, wherein the electron withdrawing group is a cyano group, a nitro group or a trifluoromethyl group; c) a C1-4 low alkyl group or a halogen-substituted low alkyl group; and d) a C1-4 low alkoxy group or a halogen-substituted low alkoxy group. The compound has the advantages of high antifungal activity, low toxicity, wide antibacterial spectrum and the like, and can be used for preparing antifungal medicines.
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Paragraph 0109; 0122-0123
(2020/05/01)
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- PROCESS FOR PRODUCING EPOXY ALCOHOL COMPOUND
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A compound represented by formula (II): (where Ar represents a phenyl group optionally substituted by 1 to 3 substituents selected from the group consisting of a halogen atom and a trifluoromethyl group, and R represents a hydrogen atom or an alkyl group having 1 to 12 carbon atoms) is produced by step A: reacting trimethyl oxosulfonium salt or trimethyl sulfonium salt with a base in a solvent, and removing the resulting solid to obtain a trimethyl oxosulfonium ylide solution or a trimethyl sulfonium ylide solution; and step B: reacting a compound represented by formula (I): and the solution obtained in step A, and the compound represented by formula (II) can be derived to a compound represented by formula (V): that is useful for production of an antifungal agent.
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- Synthesis method of efinaconazole intermediate
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Belonging to the field of biomedical industry, the invention discloses a synthesis method of an efinaconazole intermediate VI. The method includes: taking benzyl as a hydroxyl protecting group to generate a new compound II, then carrying out Grignard reaction, epoxidation reaction and epoxy ring-opening reaction on the compound II, and finally carrying out deprotection reaction to obtain the efinaconazole intermediate VI. The preparation method provided by the invention adopts benzyl as the hydroxyl protecting group, improves the problem of easy ring opening of tetrahydropyrane protecting group under an acidic condition in an original method, and at the same time has the advantages of good product purity and high yield.
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- METHOD FOR PRODUCING ALCOHOL COMPOUND
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A high-purity alcohol compound can be obtained by a method comprising passing a solution containing an ester compound and methanol and/or ethanol through a column packed with an anion exchange resin having methoxide and/or ethoxide as a counter anion to g
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Paragraph 0104-0142; 0147
(2019/10/23)
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- METHOD FOR PRODUCING TRIAZOLE COMPOUND
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PROBLEM TO BE SOLVED: To provide a novel method for producing a triazole compound useful as a pharmaceutical intermediate. SOLUTION: A production method includes reacting a lactic acid derivative with thionyl chloride, then reacting it with 1,3-difluoro benzene in the presence of Al chloride to obtain a ketone derivative, which is turned into an olefin with a Wittig reagent to be derived into compound (2), and it is then turned into an epoxy and a triazole to be derived into compound (1). SELECTED DRAWING: None COPYRIGHT: (C)2018,JPOandINPIT
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Paragraph 0078
(2018/09/21)
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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 0129; 0138; 0139; 0140; 0141
(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 0129; 0138; 0139; 0140; 0141
(2017/05/19)
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- Synthetic method for antifungal drug intermediate (2R,3S)-1-(1,2,4-triazol)-2-difluorophenyl-2,3-epoxybutane
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The invention discloses a synthetic method for an antifungal drug intermediate (2R,3S)-1-(1,2,4-triazol)-2-difluorophenyl-2,3-epoxybutane. The synthetic method comprises the following steps: (1) reacting a compound IV with a Grignard reagent to obtain a compound III; (2) employing a one-pot reaction to react the compound III with trimethylsulfoxonium iodide and 1,2,4-triazole and then react with p-toluenesulfonic acid, so as to obtain a compound II; and (3) reacting the compound II with methanesulfonyl chloride under an alkali condition to generate the target compound I, wherein the Grignard reagent is 2,4-difluorophenylmagnesium bromide or 2,5-difluorophenylmagnesium bromide, and the structural formula of the compound IV is shown in the specification. According to the synthetic route, the reaction conditions are mild and easy to control, the reaction route is simple, the related solvents in the reaction process all are common solvents, the reaction conversion rate is high, and the method possesses extremely high feasibility, is beneficial for industrialized batch production, and possesses extremely large exploitation potential and extremely good application prospect.
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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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- The process development of ravuconazole: An efficient multikilogram scale preparation of an antifungal agent
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The development of a safe, robust process for the preparation of ravuconazole (1), an antifungal agent, is described. The discovery and development of procedures enabling the efficient synthesis of multikilogram quantities of 1 and the process demonstration through plant scale preparations are presented. A controlled means to prepare a Grignard reagent and utilization of Fourier Transform Infrared spectroscopy (FTIR) monitoring to safely conduct the reaction is featured.
- Pesti, Jaan,Chen, Chien-Kuang,Spangler, Lori,DelMonte, Albert J.,Benoit, Serge,Berglund, Derek,Xbien, Derek,Brodfuehrer, Paul,Chan, Yeung,Corbett, Elisabeth,Costello, Carrie,DeMena, Paul,Discordia, Robert P.,Doubleday, Wendel,Gao, Zhinong,Gingras, Stephane,Grosso, John,Haas, Oscar,Kacsur, David,Lai, Chiajen,Leung, Simon,Miller, Melanie,Muslehiddinoglu, Jale,Nguyen, Nina,Qiu, Jun,Olzog, Martina,Reiff, Emily,Thoraval, Dominique,Totleben, Michael,Vanyo, Dale,Vemishetti, Purushotham,Wasylak, John,Wei, Chenkou
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body text
p. 716 - 728
(2010/04/22)
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- Discovery of novel indazole-linked triazoles as antifungal agents
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The in vitro and in vivo activities of a series of (2R, 3R)-2-(2,4-difluorophenyl)-3-(substituted indazol-1-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol as potential antifungal agents are described. In particular, the analog 12j having 5-bromo substitution on the indazole ring exhibited significant antifungal activity against a variety of fungal cultures (Candida spp. and Aspergillus spp.). In addition, oral administration of 12j showed its excellent efficacy against Candida albicans in a murine infection model and the significantly improved survival rates of the infected mice.
- Park, Joon Seok,Yu, Kyung A,Kang, Tae Hee,Kim, Sunghoon,Suh, Young-Ger
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p. 3486 - 3490
(2008/02/11)
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- PROCESS FOR PRODUCING EPOXYTRIAZOLE DERIVATIVE
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This invention provides a process for producing an epoxytriazole derivative represented by formula (2): (wherein R and Ar are defined below), which comprises a step including a reaction of an epoxy derivative represented by formula (1'): (wherein R represents a hydrogen atom or C1-12 alkyl group and Ar represents an aromatic group optionally substituted by a halogen atom(s) or trifluoromethyl group(s), and X' represents a hydroxy group or leaving group), with 1,2,4-triazole in the presence of a base and water.
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Page/Page column 11
(2008/06/13)
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- PROCESS FOR PRODUCING EPOXYTRIAZOLE COMPOUND AND INTERMEDIATE THEREFOR
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The present invention provides a compound of the formula (I); wherein Ar represents difluorophenyl group, which is useful as an intermediate in a process for producing an epoxytriazole compound of the formula (VII); wherein Ar represents difluorophenyl group, which is a synthetic intermediate of antifungal agents. The present invention also provides a process for producing a compound of the formula (VII) which comprises epoxydation step, deprotection step, reaction step with a compound represented by RSO2X, and reaction step with 1,2,4-triazole; or comprises epoxydation step, reaction step with 1,2,4-triazole, deprotection step, reaction step with a compound represented by RSO2X and treatment step by a base.
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Page/Page column 26
(2010/11/23)
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- ANTIFUNGAL AZOLE DERIVATIVES HAVING A FLUOROVINYL MOIETY AND PROCESS FOR THE PREPARATION THEREOF
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An azole derivative of formula (I) having a fluorovinyl moiety or a pharmaceutically acceptable salt thereof is superior to the conventional antifungal drugs in antifungal activity against a wide spectrum of pathogenic fungi, and has advantageously low toxicity.
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Page/Page column 14
(2010/02/10)
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- OPTICALLY ACTIVE AZOLE DERIVATIVE AND PROCESS FOR PRODUCING THE SAME
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The present invention provides a method for producing an optically active 2-phenyl-2,3,-dihydroxypropyl azole derivative, which is a useful compound in the field of medicines and agricultural chemicals, and is, in particular, a significantly important int
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- Preparations of antifungal Sch 42427/SM 9164: Preparative chromatographic resolution, and total asymmetric synthesis via enzymatic preparation of chiral α-hydroxy arylketones
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Efficient approaches towards the preparation of chiral azole antifungals Sch 42427/SM 9164 (1) via large scale chromatographic separation of its enantiomers, or via enzymatic syntheses of key chiral intermediates α-hydroxy arylketones 5 in excellent enantiomeric excesses (ees) are described.
- Gala, Dinesh,DiBenedetto, Donald J.,Clark, Jon E.,Murphy, Bruce L.,Schumacher, Doris P.,Steinman, Martin
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p. 611 - 614
(2007/10/02)
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- Optically active azole derivatives, their production and use
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A process for preparing a compound of the formula (IV) or a salt thereof, , wherein R1 is an optionally substituted aliphatic or aromatic hydrocarbon residue or an optionally substituted aromatic heterocyclic group, one of Y and Z is a nitrogen atom and t
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- Stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl )-2-butanol (SM-8668)
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The stereoselective synthesis of antifungal agent threo-2-(2,4-difluorophenyl)-3-methylsulfonyl-1-(1H-1,2,4-triazol-1-yl )-2-butanol (SM-8668) is described. The key step is the selective synthesis of intermediate threo-2-(2,4-difluorophenyl)-2-(1-substituted ethyl)oxirane. threo-2-(2,4-difluorophenyl)-2-(1-methylthioethyl)oxirane was synthesized threo-selectively by the reaction of 1-(2,4-difluorophenyl)-2-methylthio-1-propanone with dimethyloxosulfonium methylide in a heterogeneous media consisting of a hydrophobic solvent and aqueous alkaline solution.
- Saji,Tamoto,Tanaka,Miyauchi,Fujimoto,Ohashi
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p. 1427 - 1433
(2007/10/02)
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- Optically active antifungal azoles. I. Synthesis and antifungal activity of (2R,3R)-2-(2,4-difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2- butanol and its stereoisomers
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(2R,3R)-2-(2,4-Difluorophenyl)-3-mercapto-1-(1H-1,2,4-triazol-1-yl)-2- butanol [(2R,3R)-7] and its stereoisomers [(2S,3R)-, (2S,3S)- and (2R,3S)-7] were prepared from the optically active oxiranes 6 by a newly developed ring- opening reaction and evaluated for antifungal activity. The thiol (2R,3R)-7 showed extremely potent antifungal activity in vitro and in vivo. The optically active oxirane (2R,3S)-6, a useful intermediate for the synthesis of sulfur-containing antifungal azoles 5, was synthesized from methyl (R)- lactate [(R)-8] via eight steps in a stereocontrolled manner. The key step in the synthesis is the Grignard reaction of an amide derivative [(R)-12a] of (R)-lactic acid with 2,4-difluorophenyl-magnesium bromide (13).
- Tasaka,Tamura,Matsushita,Teranishi,Hayashi,Okonogi,Itoh
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p. 1035 - 1042
(2007/10/02)
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- Payne rearrangement route to the optically active oxirane precursor for the preparation of triazole antifungals
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Optically active epoxide 1, an important intermediate for the preparation of antifungal triazole-amides 2, was synthesized starting from the (S)-lactic acid-derived ketone 9 and taking advantage of the Payne rearrangement of the epoxyalcohol 8.
- Konosu,Miyaoka,Tajima,Oida
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p. 562 - 564
(2007/10/02)
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