- PROCESS FOR THE PREPARATION OF LULICONAZOLE
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The present invention provides a process for the preparation E-isomer of Luliconazole (I) with substantially free of Z-isomer and unwanted salts.
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Page/Page column 8-11
(2021/02/05)
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- Production methods of luliconazole and hydrochloride thereof
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The invention discloses production methods of luliconazole and hydrochloride thereof. The production method of the luliconazole hydrochloride comprises the following step of: i, with or without inert gas protection, reacting a luliconazole product with hydrogen chloride in a mixed solvent of an ether solvent and an ester solvent to obtain the luliconazole hydrochloride. The production method of the luliconazole comprises the following step of: a, with or without inert gas protection, reacting the luliconazole hydrochloride with an alkaline substance in a mixed solvent of water and an ester solvent to obtain luliconazole. According to the methods disclosed by the invention, the luliconazole hydrochloride and the alkaline substance react to produce luliconazole, the target product is convenient to separate and purify, a luliconazole product with high purity and high e.e. value can be conveniently obtained, and a brand new process route is provided for the production of luliconazole.
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Paragraph 0118-0119; 0124-0160
(2021/10/27)
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- Preparation method of azole antifungal drug
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The invention discloses a preparation method of an azole antifungal drug, which comprises the following steps: (a) reacting (S)-2-chloro-1-(2,4-dichlorophenyl)ethanol with methanesulfonyl chloride, and crystallizing the reaction product to obtain a compound crystal as shown in a formula (III); (b) reacting imidazole with chloroacetonitrile, and crystallizing the reaction product to obtain 1-(cyanomethyl)imidazole crystals; (c) reacting the 1-(cyanomethyl)imidazole with carbon disulfide under an alkaline condition to obtain a compound as shown in a formula (VIII); (d) reacting the compound as shown in the formula (III) with a compound as shown in a formula (VIII) under an alkaline condition to obtain luliconazole oil; and (e) dissolving the luliconazole oil into acetonitrile, dropwise adding water into the solution, separating out crystals, and filtering the mixture while hot to obtain a luliconazole pure product. According to the method, industrially common and cheap raw materials areselected, the luliconazole pure product conforming to the medicine is efficiently prepared, so that the invention solves the technical problems that the luliconazole purification yield is low, 1- (cyanomethyl) imidazole is prone to water absorption and deliquescence, and (S)-2-chloro-1-(2,4-dichlorophenyl) ethyl methanesulfonate is unstable and easy to decompose at the normal temperature.
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- Development of an Enzymatic Process for the Synthesis of (S)-2-Chloro-1-(2,4-dichlorophenyl) Ethanol
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(S)-2-Chloro-1-(2,4-dichlorophenyl) ethanol (3) is a chiral intermediate in the synthesis of luliconazole ((R)-E-1). Here, we report a novel biopreparation of 3 by bioreduction of 2-chloro-1-(2,4-dichlorophenyl) ethanone (2) using recombinant Escherichia
- Wei, Teng-Yun,Tang, Jia-Wei,Ni, Guo-Wei,Wang, Hong-Yi,Yi, Dong,Zhang, Fu-Li,Chen, Shao-Xin
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p. 1822 - 1828
(2019/09/30)
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- A PROCESS FOR PREPARATION OF LULICONAZOLE
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The present invention discloses an improved process for preparation of Luliconazole in high yield and purity involving a novel intermediate i.e., (S)- 2,4-Dichloro-alpha-(chloro methyl)benzene methanol 4-chlorosulfonyl chloride.
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Page/Page column 15-18
(2019/08/26)
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- Chemoenzymatic Synthesis of Luliconazole Mediated by Lipases
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A straightforward chemoenzymatic synthesis of luliconazole has been developed. The key step involved the preparation of the enantiomerically pure β-halohydrin (1S)-2-chloro-1-(2,4-dichlorophenyl)-1-ethanol through kinetic resolution of the corresponding racemic acetate. This was achieved by a hydrolytic approach, mediated by the lipase from Thermomyces lanuginosus or Novozym 435. The latter enzyme proved to be a robust biocatalyst for the kinetic resolution, and the (S)-β-halohydrin was obtained with high selectivity (ee > 99 %, E > 200) after just 15 min, at 45 °C. It could be reused five times with maintenance of high values of both conversion and enantioselectivity. Subsequently, the (S)-β-halohydrin was subjected to a mesylation reaction; the mesylated derivative reacted with 1-cyanomethylimidazole in the presence of CS2 to give luliconazole in 43 % yield with >99 % ee.
- Fonseca, Thiago de S.,Lima, Lara D.,de Oliveira, Maria da C. F.,de Lemos, Telma L. G.,Zampieri, Davila,Molinari, Francesco,de Mattos, Marcos C.
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p. 2110 - 2116
(2018/05/31)
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- COMPOUNDS OF R-(-)-(E)-[4-(2,4-DICHLOROPHENYL)-1,3-DITHIOLAN-2-YLIDENE]-1 -IMIDAZOLYLACETONITRILE-HA (LULICONAZOLE-HA) AS ANTIFUNGALS
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The present invention refers to compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile HA, wherein HA is an acid; and to a process for their preparation. The present invention also refers to the use of compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile HA for the manufacturing of luliconazole and pharmaceutically acceptable salts or co-crystals thereof in high yield and purity. The present invention further is directed to this compound R-(-)-(E)-[4-(2,4-dichlorophenyl)-1,3-dithiolan-2-ylidene]-1-imidazolylacetonitrile HA in the treatment of fungal infections.
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- Imidazole acetonitrile derivative acid salt as well as preparation method and application thereof
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The invention relates to an imidazole acetonitrile derivative acid salt as well as a preparation method and an application thereof, belongs to the technical field of drug synthesis, and aims to solve the problem about how to improve stability and increase the yield. The method comprises steps as follows: an imidazole acetonitrile derivative is dissolved in a water-insoluble polar organic solvent, then corresponding acid is added for a salt forming reaction, and the acid salt of the product imidazole acetonitrile derivative is gradually separated out, and applied to preparation of Luliconazole. The acid salt itself has better stability and used as an intermediate for preparing Luliconazole at the same time, the problem of mutual inversion of Z-E configuration in the Luliconazole preparation process can be solved, the Z configuration can be inverted into the E configuration, the configuration inversion stability is guaranteed, and the yield is higher. The effects of simple technology and easiness in operation are also realized.
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Paragraph 0100; 0101
(2016/10/10)
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- Method for synthesizing Luliconazole
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The invention relates to a method for synthesizing Luliconazole. The method comprises the steps of subjecting m-dichlorobenzene to Friedel-Crafts acylation with chloroacetyl chloride, catalytic chiral reduction with (S)-2-methyl-CBS-oxazaborolidine and esterification with methylsulfonyl chloride so as to obtain (S)-2,2',4'-ethyl trichlorobenzene methanesulfonate, and finally, subjecting (S)-2,2',4'-ethyl trichlorobenzene methanesulfonate to a reaction with carbon disulfide and imidazolyl acetonitrile, thereby obtaining Luliconazole. According to the method, the total yield is about 30%.
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- A Novel Method for Separation of Luliconazole Isomers
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Provided are a salt compound which is useful for producing luliconazole and an isolation method thereof. According to the present invention, the method includes: a steps of isolating a salt compound of chemical formula 1 by carrying out a reaction between acid and a geometrical isomeric mixture composed of a compound represented by chemical formula 1 (E-isomer) and a compound represented by chemical formula 2 (Z-isomer), in the presence of an organic solvent, water, or a solvent mixed with the organic solvent and water; and obtaining a compound of chemical formula 1 from the salt compound of chemical formula 1 by using base in the presence of the organic solvent, water, or the solvent mixed with the organic solvent and water.
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Paragraph 0042; 0043
(2017/04/04)
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- EXTERNAL PHARMACEUTICAL COMPOSITION
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A pharmaceutical composition for external use, including: i) luliconazole represented by the following structural formula (1) and/or a salt thereof; and ii) one or two or more selected from N-methyl-2-pyrrolidone, propylene carbonate, and crotamiton.
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Page/Page column 7-8
(2009/01/24)
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- A ketene S,S-acetal derivative, a process for manufacturing thereof and a method for curing mycosis by administering it
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A novel ketene S,S-acetal derivative which is useful as an antimycotic agent and an agricultural chemical of fungicidal, plant growth regulating or insecticidal properties represented by the general formula (I): (in which R1 represents a hydrogen atom, a wherein R represents a hydrogen atom; an alkyl group having 1 to 8 carbon atoms; a cycloalkyl group having 3 to 6 carbon atoms; a methylene group; a lower alkenyl group; a lower alkyl group substituted by a halogen atom, a cyano group, a lower alkoxyl group, a lower alkylthio group; a carbamoyl group, an acyl group, or an alkenoyloxy group; a phenyl group represented by halogen atom, a straight or branched chain lower alkyl group, a lower alkoxyl group which may be substituted by one or more halogen atoms, a phenoxy group or a methylenedioxy group, and m represents an integer of 1 to 3); a benzyl group; a methylenedioxybenzyl group; a phenoxyalkyl group; a phenoxyalkyl group substituted by a halogen atom; a naphthyl group; or a substituted or unsubstituted pyridyl group.
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