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WO2018202537A1 - Procédé de préparation d'un dérivé azolique - Google Patents

Procédé de préparation d'un dérivé azolique Download PDF

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Publication number
WO2018202537A1
WO2018202537A1 PCT/EP2018/060713 EP2018060713W WO2018202537A1 WO 2018202537 A1 WO2018202537 A1 WO 2018202537A1 EP 2018060713 W EP2018060713 W EP 2018060713W WO 2018202537 A1 WO2018202537 A1 WO 2018202537A1
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WO
WIPO (PCT)
Prior art keywords
zinc
methylenepiperidine
reaction
formula
process according
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2018/060713
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English (en)
Inventor
Graziano Castaldi
Marco Baratella
Mauro Gaboardi
Alessandro BARUTO
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Seegpharm SA
Original Assignee
Seegpharm SA
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Filing date
Publication date
Application filed by Seegpharm SA filed Critical Seegpharm SA
Publication of WO2018202537A1 publication Critical patent/WO2018202537A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/06—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention refers to a process for the preparation of an azolic derivative and, more in particular, refers to a process for the preparation of efinaconazole or pharmaceutically acceptable salts thereof.
  • Efinaconazole chemical name (2R,3R)-2-(2,4-difluorophenyl)-3-(4-methylene-1- piperidinyl)-1-(1 H-1 ,2,4-triazol-1- -2-butanol, is a triazolic antimycotic of formula (I)
  • Efinaconazole is employed in the treatment of onychomycosis, in particular of distal subungual onychomycosis. It is a selective inhibitor of fungal lanosterol 14a- demethylase which causes lack of conversion of lanosterol to ergosterol, an essential component of fungal cell membrane. The inhibition of ergosterol synthesis leads to an accumulation of C-14 methylated sterols unable to duly interact with membrane phospholipids. Fungal membrane integrity is thereby compromised and the permeability is altered with consequent cellular disorganization and fungus death.
  • efinaconazole (I) is characterized by the presence of a ⁇ - amino alcoholic moiety.
  • Methods known in the art for the synthesis of said ⁇ -amino alcoholic moiety include, among others, the ring-opening reaction of an epoxide by the addition of an amine, usually employed in large excess.
  • WO 94/26734 discloses a process for the preparation of efinaconazole providing for the reaction of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane (hereinafter also referred to as epoxytriazole) with a large excess of 4-methylenepiperidine (hereinafter also referred to as 4-MP) in ethanol and water. After HPLC purification, the product is obtained in 54% yield.
  • (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazol-1- yl)methyl]oxirane hereinafter also referred to as epoxytriazole
  • 4-MP 4-methylenepiperidine
  • EP 2 612 859 discloses a process for the preparation of efinaconazole which provides for the reaction of (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4- triazol-1 -yl)methyl]oxirane with an acid addition salt of 4-methylenepiperidine in the presence of a hydroxide of an alkali metal or an alkaline earth metal selected among lithium and calcium.
  • EP 2 612 859 teaches also that different metallic catalysts affect the course of said reaction (i.e. epoxide ring-opening reaction of the epoxytriazole by addition of 4-MP) with high variability.
  • WO 16/181306 discloses a process for the synthesis of efinaconazole which provides for the reaction of (2R,3S)-2-(2 ! 4-difluorophenyl)-3-methyl-2-[(1 H-1 ! 2,4- triazol-1 -yl)methyl]oxirane with 4-methylenepiperidine or a salt thereof, in the presence of an alkali or an alkaline earth metal halide.
  • EP 2 612 859 and WO 16/181306 do not require the use of a large excess of 4- methylenepiperidine, but provide for the use of very dangerous reaction solvents such as, for example, acetonitrile.
  • Acetonitrile is a highly volatile solvent that, when inhaled, is metabolised by the organism to hydrogen cyanide, extremely toxic.
  • an object of the present invention is a process for the synthesis of efinaconazole (I) or pharmaceutically acceptable salt thereof comprising the reaction between 4-methylenepiperidine of formula (II) or an acid salt thereof
  • said zinc derivative can be a zinc salt.
  • a first aspect of the present invention is a process for the synthesis of efinaconazole (I) or a pharmaceutically acceptable salt thereof comprising the reaction between 4-methylenepiperidine di formula (II)
  • Said zinc salt is selected among zinc bromide, zinc chloride, zinc iodide, zinc acetate, zinc methanesulfonate and zinc trifluoroacetate and is preferably zinc bromide.
  • the molar ratio zinc salt:epoxytriazole (III) is comprised between about 0.5:1 and about 2:1 and is preferably 1 .5:1.
  • the zinc salts of the present invention have shown to be particularly useful and effective in the epoxide ring-opening reaction of the epoxytriazole (III) by addition of 4-MP (II) or a derivative thereof providing the desired ⁇ -amino alcoholic moiety with high yield and excellent chemo, stereo and regioselectivity.
  • a further advantage of the process object of the present invention is the fact that said zinc salt can be generated directly in the reaction environment.
  • said zinc derivative can be a basic zinc derivative.
  • a further aspect of the present invention is a process for the synthesis of efinaconazole (I) or a pharmaceutically acceptable salt thereof comprising the reaction between an acid salt of 4-methylenepiperidine of formula (Ila)
  • HX is an organic or inorganic acid
  • HX means the (organic or inorganic) acid of the acid salt of 4- methylenepiperidine.
  • the acid salt of 4-methylenepiperidine used in the process of the present invention can be any pharmaceutically acceptable acid salt and is preferably selected among 4-methylenepiperidine hydrochloride, 4-methylenepiperidine hydrobromide and 4- methylenepiperidine trifluoroacetate. In a preferred embodiment 4- methylenepiperidine hydrochloride is used.
  • the basic zinc derivative used in the process of the present invention is selected among zinc oxide and basic zinc carbonate and is preferably zinc oxide.
  • the molar ratio basic zinc derivative:acid salt of 4-methylenepiperidine is comprised between about 1 :1 and about 2:1 , and is preferably 1 :1 .
  • the zinc salt can be generated directly in the reaction environment.
  • the acid salt of 4-methylenepiperidine of formula (I la) e.g., 4- methylenepiperidine hydrochloride
  • the acid reacts with the basic zinc derivative (e.g., ZnO) resulting in the corresponding zinc salt (in this case ZnC ).
  • the reaction proceeds according to the process of the present invention, based on which the resultant zinc salt catalyses the reaction between 4-methylenepiperidine of formula (II) and (2R,3S)-2-(2,4-difluorophenyl)-3-methyl-2-[(1 H-1 ,2,4-triazoM -yl)methyl]oxirane of formula (III) to give efinaconazole of formula (I).
  • efinaconazole (I) with very high optical purity, practically without the formation of the enantiomer and/or by-products.
  • the catalyst i.e. the zinc salt
  • the catalyst can be easily removed from the reaction environment, for example, by filtration on coal/celite filter.
  • the process of the present invention does not require any further purification phase such as, for example, column chromatography and/or crystallization.
  • efinaconazole is obtained with optical purity equal to that of the starting epoxytriazole (III) and there are no evidences of the formation of the undesired diastereoisomer (2R,3S)-2-(2,4-difluorophenyl)-3-(4- methylene-1-piperidinyl)-1 -(1 H-1 ,2,4-triazol-1-yl)-2-butanol.
  • the optical purity of the resultant product is equal to 99.0% or higher.
  • the process object of the present invention allows to obtain efinaconazole with an enantiomeric excess yield (e.e.%) equal to 98.0% or higher.
  • the process object of the present invention avoids also the use of a large excess of 4-methylenepiperidine, thus preventing the need to remove large amounts of unreacted amine, the formation of undesired reaction by-products and laborious removal phases thereof.
  • the molar ratio epoxytriazole:4- methylenepiperidine or derivative thereof is preferably comprised between about 1 :1 and about 1 :2. In a preferred embodiment, the molar ratio epoxytriazole:4- methylenepiperidine or derivative thereof is 1 :1.5.
  • the reaction solvent of the present invention is an alcoholic solvent preferably selected among alcohols having a boiling point higher than 80°C. More in particular, said alcoholic solvent is a tertiary alcohol preferably selected among ie f-amyl alcohol, ie f-butanol and 1 -methoxy-2-propanol. In a preferred embodiment, the solvent is ie f-amyl alcohol.
  • Tertiary alcohols of the present invention have the advantage to be stable to oxidation (i.e. they are not metabolized to aldehydes or to carboxylic acid, metabolites that often can be toxic), little reactive and non-volatile.
  • the process object of the present invention is carried out at a temperature between about 80°C and about 130°C, preferably between about 100°C and about 120°C. If desired, the product of formula (I), obtained according to the process disclosed in the present invention, can be converted in a pharmaceutically acceptable salt thereof.
  • the melting point of efinaconazole (I) obtained according to the process of the present invention was experimentally determined by differential scanning calorimeter DSC 3500 S/ ' r/ ' us ® model from NETZSCH to give a range of 86-89°C.
  • the reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.
  • the reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.
  • the reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.
  • the reaction mixture was brought to the reflux temperature of the solvent and maintained under these conditions for twenty-four hours.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Plural Heterocyclic Compounds (AREA)

Abstract

La présente invention concerne un procédé de préparation d'un dérivé azolique utilisé dans le traitement de l'onychomycose. Le procédé de l'invention comprend la réaction entre (2R,3S)-2-(2,4-difluorophényl)-3-méthyl-2-[(1H-1,2,4-triazol-1-yl))méthyl]oxirane et 4-méthylènepipéridine ou un sel correspondant, en présence d'un dérivé de zinc dans un solvant alcoolique.
PCT/EP2018/060713 2017-05-04 2018-04-26 Procédé de préparation d'un dérivé azolique Ceased WO2018202537A1 (fr)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
IT102017000048270A IT201700048270A1 (it) 2017-05-04 2017-05-04 Procedimento per la preparazione di un derivato azolico.
IT102017000048270 2017-05-04

Publications (1)

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WO2018202537A1 true WO2018202537A1 (fr) 2018-11-08

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PCT/EP2018/060713 Ceased WO2018202537A1 (fr) 2017-05-04 2018-04-26 Procédé de préparation d'un dérivé azolique

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IT (1) IT201700048270A1 (fr)
WO (1) WO2018202537A1 (fr)

Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026734A1 (fr) 1993-05-10 1994-11-24 Kaken Pharmaceutical Co., Ltd. Derive d'azolylamine
EP2612859A1 (fr) 2010-08-31 2013-07-10 Kaken Pharmaceutical Co., Ltd. Procédé de production de dérivé de 1-triazole-2-butanol
WO2016181306A1 (fr) 2015-05-12 2016-11-17 Lupin Limited Procédé de préparation d'efinaconazole
WO2016193917A1 (fr) * 2015-06-04 2016-12-08 Glenmark Pharmaceuticals Limited Procédé de préparation d'éfinaconazole

Patent Citations (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1994026734A1 (fr) 1993-05-10 1994-11-24 Kaken Pharmaceutical Co., Ltd. Derive d'azolylamine
EP2612859A1 (fr) 2010-08-31 2013-07-10 Kaken Pharmaceutical Co., Ltd. Procédé de production de dérivé de 1-triazole-2-butanol
WO2016181306A1 (fr) 2015-05-12 2016-11-17 Lupin Limited Procédé de préparation d'efinaconazole
WO2016193917A1 (fr) * 2015-06-04 2016-12-08 Glenmark Pharmaceuticals Limited Procédé de préparation d'éfinaconazole

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
YVES FORT ET AL.: "Activation of reducing agents. Sodiumhydride containing complex reducing agents 21. Regioseletive reduction of alkene oxides", TETRAHEDRON LETTERS., vol. 26, no. 26, 1985, NLELSEVIER SCIENCE PUBLISHERS, AMSTERDAM., pages 3111 - 3114, XP002777041, ISSN: 0040-4039 *

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IT201700048270A1 (it) 2018-11-04

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