164650-44-6

Basic information

• Product Name: KP 103
• Synonyms: KP 103;Efinaconazole;(alphaR,betaR)-alpha-(2,4-Difluorophenyl)-beta-methyl-4-methylene-alpha-(1H-1,2,4-triazol-1-ylmethyl)-1-piperidineethanol;KP 103 (pharmaceutical);Jublia;Efinaconazole(KP 103);(2R,3R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)-2-butanol;(R,R)-2-(2,4-Difluorophenyl)-3-(4-methylenepiperidin-1-yl)-1-(1,2,4-triazol-1-yl)-2-butanol
• CAS NO: 164650-44-6
• Molecular Formula: C18H22F2N4O
• Molecular Weight: 348.3902864
• EINECS: 1592732-453-0
• Product Categories: Inhibitors
• Mol File: 164650-44-6.mol

Chemical Properties

• Boiling Point: 512.2±60.0 °C(Predicted)
• Appearance: /
• Density: 1.26±0.1 g/cm3(Predicted)
• Storage Temp.: -20°C
• Solubility: Chloroform (Slightly), Methanol (Slightly)
• PKA: 12.11±0.29(Predicted)
• CAS DataBase Reference: KP 103(CAS DataBase Reference)
• NIST Chemistry Reference: KP 103(164650-44-6)
• EPA Substance Registry System: KP 103(164650-44-6)

Safety Data

• Hazardous Substances Data: 164650-44-6(Hazardous Substances Data)

Usage

Originator

Kaken Pharmaceuticals (Japan)

Biochem/physiol Actions

Efinaconazole is a triazole antifungal drug approved clinically for the treatment of nail fungus (Onychomycosis). It inhibits sterol biosynthesis by inhibition of cytochrome P450 14α-demethylase, an enzyme in the sterol biosynthesis pathway that leads from lanosterol to ergosterol. Efinaconazole has better nail penetration, so is more effective than other topical agents and as effective as oral medication for nail fungus.

Synthesis

Commercially available (R)-methyl lactate (55) was first converted to THP protected alcohol 57 in 4 steps and 78% yield via morpholino amide 56. Grignard displacement of the morpholine afforded ketone 58 in 81% yield. Next, ketone 58 was epoxidized by means of the Corey ylide followed by ring-opening of the epoxide by triazole which had been activated by exposure to sodium tbutoxide. Finally, subjection to methanesulfonic acid furnished diol 59 in 51% yield as the corresponding mesylate salt. Diol 59 was then converted to epoxide 60 through the use of mesyl chloride and triethylamine in 78% yield and >99% ee. Finally, treatment of epoxide 60 with 4-methylene piperidine–HBr in the presence of lithium hydroxide afforded efinaconazole (VIII) in 87% yield.

Upstream product

• 148133-82-8 4-methylene piperidine 
• 135270-07-4 (2S,3R)-2-(2,4-difluorophenyl)-3-methyl-2-<(1H-1,2,4-triazol-1-yl)methyl>oxirane 
• 63608-15-1 (4-(chloromethyl)piperidin-1-yl)(phenyl)methanone 
• 188904-84-9 N-benzoyl-4-methylenepiperidine 
• 124627-86-7 1-(((2R,3S)-2-(2,4-difluorophenyl)-3-methyloxiran-2-yl)-methyl)-1H-1,2,4-triazole 
• 144230-50-2 4-methylenepiperidine monohydrochloride 
• 144230-50-2 4-methylenepiperidine hydrochloride 
• 132507-89-2 (2R,3R)-2-(2,4-Difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2,3-butanediol 
• 51336-94-8 2-chloro-1-(2,4-dichlorophenyl)ethanone 
• 861718-83-4 (S)-3-chloro-2-(2,4-difluorophenyl)-2-((trimethylsilyl)oxy)propanenitrile 
• 861718-85-6 3-chloro-2-(2,4-difluorophenyl)-2-(trimethylsilanyloxy)propionaldehyde 
• 127000-91-3 (2R,3R)-3-Amino-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)-2-butanol 
• 86404-63-9 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazolyl)ethanone 
• 102429-07-2 2-bromo-2',4'-difluoroacetophenone 

Relevant articles and documents

Identification, synthesis, and control of efinaconazole impurities

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.

A Facile Epoxide Aminolysis Promoted by (t-BuO)2Mg and Its Application to the Synthesis of Efinaconazole

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.

PREPARATION METHOD FOR EFINACONAZOLE

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

NOVEL METHOD FOR PREPARATION OF EPOXYTRIAZOLE DERIVATIVES

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.

Asymmetric Catalytic Epoxidation of Terminal Enones for the Synthesis of Triazole Antifungal Agents

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.

METHOD FOR PREPARATION OF EFINACONAZOLE IN IONIC LIQUID MEDIUM

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.

Efinaconazole preparation method

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.

Preparing method of 1-triazole-2-butanol derivative

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

METHOD OF PRODUCING 1-TRIAZOLE-2-BUTANOL DERIVATIVES

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

PROCESS FOR THE PREPARATION OF AN AZOLIC DERIVATIVE

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.