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WO2011003455A1 - Procédé pour préparer des composés de 4-(alkyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène - Google Patents

Procédé pour préparer des composés de 4-(alkyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène Download PDF

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Publication number
WO2011003455A1
WO2011003455A1 PCT/EP2009/058780 EP2009058780W WO2011003455A1 WO 2011003455 A1 WO2011003455 A1 WO 2011003455A1 EP 2009058780 W EP2009058780 W EP 2009058780W WO 2011003455 A1 WO2011003455 A1 WO 2011003455A1
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WO
WIPO (PCT)
Prior art keywords
acid
salt
propyl
methyl
dimethylmorpholine
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/EP2009/058780
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German (de)
English (en)
Inventor
Uwe Albrecht
Stefanie Ackermann
Marcin Sawicki
Ulrich Weigl
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.)
Cilag AG
Original Assignee
Cilag AG
Priority date (The priority date 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 date listed.)
Filing date
Publication date
Application filed by Cilag AG filed Critical Cilag AG
Priority to PCT/EP2009/058780 priority Critical patent/WO2011003455A1/fr
Publication of WO2011003455A1 publication Critical patent/WO2011003455A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/02—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms containing only hydrogen and carbon atoms in addition to the ring hetero elements

Definitions

  • the present invention relates to a process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, preferably of 4- (1, 1-dimethylpropyl) - 1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene (amorolfine), by selective reduction of the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2, 6-dimethylmorpholine) propyl) benzene with
  • the preferred compound amorolfine is referred to chemically as 4- (1,1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene and has the chemical formula:
  • Amorolfin is a per se known pharmaceutical active substance and is used as an antifungal agent for the treatment of fungal infections, preferably in the form of the hydrochloride salt.
  • amorolfine is prepared by hydrogenating 4- (1,1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene in glacial acetic acid with hydrogen. Laboratory tests showed, however, that with this method, the keto group in the 1-position is hydrogenated only to the hydroxyl group. There is no Amorolfin in technically useful
  • keto group of 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene (hereinafter also referred to as "alpha-Benzylketothetic" ), and preferably the keto group of 4- (1, 1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene, directly reduced to the methylene group, if the hydrogenation presents the alpha-benzyl ketone compound as the salt of a strong acid and hydrogenates this salt with hydrogen in the presence of a suitable catalyst
  • the hydrogenated compound is obtained as a crude product in high yield and high purity.
  • the salt of the hydrogenated compound can be isolated directly from the reaction mixture.
  • the free base which can be converted with acid into a salt.
  • amorolfine can be isolated as free base and with hydrochloric acid in amorolfine. Convert HCl to a purity higher than 99%.
  • the total yield in the range is usually 75-80%.
  • the inventive hydrogenation of the salt of the alpha-benzyl ketone compound can be formulated as follows:
  • Keto compound salt Amorpholfin salt The present invention is defined in the claims.
  • the present invention relates to a process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene by selective reduction of the corresponding alpha-benzyl ketone compound with hydrogen characterized in that the corresponding 4- (alkyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene compound as the salt of a strong acid in a suitable inert
  • the invention also relates to the compounds thus prepared.
  • the invention also relates to the use of Amorolfins, or Amorolfinsalzes prepared according to the invention, as an antifungal agent for the treatment of fungal infections.
  • the invention also relates to the use of Amorolfins, or Amorolfinsalzes prepared according to the invention, for the preparation of a remedy for the treatment of fungal infections.
  • the preparation of 4- (Ci- ⁇ -alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene compounds in particular of corresponding (Ci_ 5 ) alkyl compounds and in particular of (1, 1-dimethylpropyl) compound, that is 4- (1,1-dimethyl-propyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene.
  • the corresponding alpha-benzyl ketone compound as starting compound it is true that this is a (Ci_ 8 ) Alkyl compound, in particular a (Ci_ 5 ) alkyl compound.
  • 4- (1, 1-dimethylpropyl) -1- (2-methyl-1-oxo-3- (2,6-dimethylmorpholine) propyl) benzene is preferred as the starting compound.
  • strong acid salt is understood as meaning the salt of the alpha-benzyl ketone compound with a strong organic or inorganic acid, for example, hydrochloric, hydrobromic, sulfuric, perchloric, trichloroacetic, trifluoroacetic, methylsulfonic, benzenesulfonic or para-hydroxy acids. Particular preference is given to hydrochloric acid and sulfuric acid.
  • a strong acid is an acid having a pKa value in the range of pKs ⁇ 0 to 4.
  • acids are preferred which are dissolved in aqueous solution at a concentration of 0.1 to 1 mol / 1 give an acid value (pH) of less than 2 (pH ⁇ 2) and preferably less than 1 (pH ⁇ 1).
  • the salt of the alpha-benzyl ketone compound is hydrogenated in a suitable inert solvent and in the presence of a strong acid.
  • suitable inert solvents for the hydrogenation are polar protic and aprotic solvents.
  • protic, water-miscible solvents which are inert under the reaction conditions of the hydrogenation according to the invention.
  • Aliphatic alcohols, preferably aliphatic (C 1 -C 8) -alcohols, are preferred
  • Methanol, ethanol, propanol or butanol, or a mixture of these compounds Preference is given to methanol or ethanol or a mixture of these compounds.
  • Aprotic solvents are, for example, dimethylformamide (DMF), dimethylacetamide (DMA) or N-methylpyrrolidone (NMP) and related compounds.
  • DMF dimethylformamide
  • DMA dimethylacetamide
  • NMP N-methylpyrrolidone
  • the inert solvent contains during the
  • Hydrogenation reaction at most 10 wt .-% water, preferably at most 5 wt .-% water, preferably at most 2 wt .-% water, or is substantially anhydrous.
  • the hydrogenation of the salt of the alpha-Benzylketotagen is preferably carried out in acidic medium, d.i. in the presence of a strong acid, as these strong acids are defined in advance.
  • a strong acid to the solvent produces a low acid value (pH).
  • this is in the range of zero to 2, preferably less than 1 (pH ⁇ 1).
  • the acid is added to the reaction mixture until the desired acid value (pH) is reached.
  • the strong acid may be added to the solvent as anhydrous acid, gaseous (e.g., hydrogen chloride or hydrogen bromide) or as a concentrated aqueous solution. If the alpha-benzyl ketone compound is added as the base in the solvent and the strong acid is added to the solvent, the corresponding salt of the alpha-benzyl ketone compound is formed in situ. The same is the case when the solvent already contains the strong acid and then the solvent is added to the alpha-benzyl ketone compound.
  • gaseous e.g., hydrogen chloride or hydrogen bromide
  • a salt of the alpha-benzyl ketone compound for example the hydrochloride or the sulfate. If a strong acid is added in advance or subsequently to the solvent, an equilibrium of the salt of the alpha-benzyl ketone compound is formed in situ if this acid is different from the already present salt-forming acid.
  • the hydrogenation according to the invention is carried out in the presence of at least one catalytically active metal of group VIII of the Periodic system performed.
  • Preferred metals of Group VIII of the Periodic Table are nickel, ruthenium, rhodium, iridium, platinum or palladium, preferably palladium, ruthenium, platinum or rhodium, preferably palladium or platinum, or mixed catalysts which are more than one of these
  • these metals are preferably present in pure form.
  • the catalytically active metal or catalytically active metals used are preferably used together with a support material, preferably applied to activated charcoal as a support material, in known and known amounts for hydrogenation reactions.
  • the hydrogenation reaction is carried out preferably at elevated temperature, preferably in the range of about 40 0 C to 90 0 C, preferably at about 60 0 C to 80 0 C.
  • elevated temperature preferably in the range of about 40 0 C to 90 0 C, preferably at about 60 0 C to 80 0 C.
  • the optimum temperature to use depends on the boiling point of the solvent and the applied pressure and can be readily determined by one skilled in the art.
  • the present invention relates to a process for preparing 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, preferably 4- (1, 1-dimethylpropyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, by selective reduction of the corresponding alpha-benzyl ketone compound with hydrogen, characterized in that
  • Metal of Group VIII of the Periodic Table as a noble metal catalyst.
  • the present invention makes it possible to isolate the hydrogenated compound in salt form or as a free base.
  • the hydrogenated compound is obtained in the form of the hydrochloride, which can be crystallized from the reaction mixture, preferably after removal of the hydrogenation catalyst.
  • amorolfine hydrochloride can be isolated directly from the reaction mixture as a crude product.
  • the present invention further relates to a process for the preparation of 4- (alkyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, preferably 4- (1, 1-dimethyl) propyl) -1- (2-methyl-3- (2,6-dimethylmorpholine) propyl) benzene, in salt form or as the free base, by means of selective reduction of the corresponding alpha-benzyl ketone compound by hydrogen, characterized in that
  • Base preferably isolated by extraction as an oil.
  • the free base can optionally be further purified by distillation and converted into a salt.
  • Acid value are hydroxides, such as alkali metal hydroxides, preferably, in particular sodium hydroxide or potassium hydroxide, preferably sodium hydroxide.
  • a basic acid value pH is preferably generated, preferably a pH in the range of 9 to 14, preferably in the range of 10 to 12, and preferably about 11.5.
  • Amorolfinbase is filtered off after completion of the reaction of the catalyst, the reaction mixture made alkaline by the addition of alkali and the solvent, eg methanol, distilled off profiled.
  • Amorolfin is by means of an organic, immiscible with water, solvent, preferably with a
  • Ester compound such as ethyl acetate extracted from the alkaline aqueous phase.
  • Amorolfin hydrochloride can be crystallized out. Thereafter, amorolfine hydrochloride is recrystallized from a mixture of water and alcohol.
  • Salt form directly from the reaction mixture, optionally after removing a portion of the solvent to crystallize.
  • the methanolic solution is treated with 8 g of aqueous 30% sodium hydroxide solution, whereupon the methanol is distilled off under vacuum.
  • To the residue are added 75 g of an aqueous 10% sodium bicarbonate solution and 105 g of ethyl acetate.
  • the mixture is stirred and the aqueous phase separated.
  • the ethyl acetate phase is dried over 15 g of anhydrous sodium sulfate, the sodium sulfate is filtered off and washed with 60 g of ethyl acetate.
  • the combined phase is added dropwise 3.5 g of aqueous 37% hydrochloric acid, after which the mixture is briefly heated. Upon cooling, the desired product precipitates.
  • 10.5 g of amorolfine hydrochloride are obtained crude, in a purity of more than 99% (> 99%).
  • the crude product is dissolved in a mixture of 40 g of ethanol and 10 g of water at a temperature of about 60 0 C. Upon cooling, the pure product crystallizes out. you receives 9.6g amorolfin hydrochloride with a purity greater than 99.8% (> 99.8%).
  • the methanolic solution is treated with 8 g of aqueous 30% sodium hydroxide solution, whereupon the methanol is distilled off under vacuum.
  • the residue is treated with 75 g of an aqueous 10% sodium bicarbonate solution and 105 g of ethyl acetate.
  • the mixture is stirred and the aqueous phase separated.
  • the ethyl acetate phase is dried over 15 g of anhydrous sodium sulfate, the sodium sulfate is filtered off and washed with 60 g of ethyl acetate.
  • 3.5 g of aqueous 37% strength hydrochloric acid are added dropwise to the combined phase and the mixture is briefly heated. When it cools down that desired product.
  • amorolfine hydrochloride 10.5 g are obtained crude with a purity of more than 99% (> 99%). The crude product is dissolved in a mixture of 40 g of ethanol and 10 g of water in the heat. Upon cooling, the pure product crystallizes out. 9.6 g of amorolfine hydrochloride having a purity of greater than 99.8% (> 99.8%) are obtained.
  • amorpholfin .HCl is directly crystallized, which can be recrystallized from ethanol / water. This gives 10.2 g of amorolfine .HCl crude with a purity greater than 98.8% (> 98.8%).

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention concerne un procédé de préparation de 4-(alkyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène, notamment de préparation de 4-(1,1-diméthylpropyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène (amorolfine) au moyen d’une réduction sélective du composé alpha-benzylcétone correspondant avec de l’hydrogène. Pour ce faire, le composé de 4-(alkyl)-1-(2-méthyl-1-oxo-3-(2,6- diméthylmorpholin)propyl)benzène correspondant sous forme de sel est soumis à un acide dur dans un solvant inerte approprié et ce sel est hydrogéné en présence d’un catalyseur approprié avec de l’hydrogène.
PCT/EP2009/058780 2009-07-09 2009-07-09 Procédé pour préparer des composés de 4-(alkyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène Ceased WO2011003455A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
PCT/EP2009/058780 WO2011003455A1 (fr) 2009-07-09 2009-07-09 Procédé pour préparer des composés de 4-(alkyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène

Applications Claiming Priority (1)

Application Number Priority Date Filing Date Title
PCT/EP2009/058780 WO2011003455A1 (fr) 2009-07-09 2009-07-09 Procédé pour préparer des composés de 4-(alkyl)-1-(2-méthyl-3-(2,6-diméthylmorpholin)propyl)benzène

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WO2011003455A1 true WO2011003455A1 (fr) 2011-01-13

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Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES8604904A1 (es) * 1985-11-25 1986-03-16 Verde Casanova Maria Jose Un procedimiento de preparacion de derivados de (1,1-dimetil-propil)-benceno 4-sustituidos
WO2007012983A2 (fr) * 2005-07-28 2007-02-01 Galderma S.A. Procede de production d'amorolfine
WO2008074887A1 (fr) * 2006-12-21 2008-06-26 Galderma S.A. Procédé de production d'amorolfine

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ES8604904A1 (es) * 1985-11-25 1986-03-16 Verde Casanova Maria Jose Un procedimiento de preparacion de derivados de (1,1-dimetil-propil)-benceno 4-sustituidos
WO2007012983A2 (fr) * 2005-07-28 2007-02-01 Galderma S.A. Procede de production d'amorolfine
WO2008074887A1 (fr) * 2006-12-21 2008-06-26 Galderma S.A. Procédé de production d'amorolfine

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