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WO2024200617A1 - Procédé et intermédiaires pour la préparation d'un médicament pour le traitement de troubles du cycle de l'urée - Google Patents

Procédé et intermédiaires pour la préparation d'un médicament pour le traitement de troubles du cycle de l'urée Download PDF

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Publication number
WO2024200617A1
WO2024200617A1 PCT/EP2024/058427 EP2024058427W WO2024200617A1 WO 2024200617 A1 WO2024200617 A1 WO 2024200617A1 EP 2024058427 W EP2024058427 W EP 2024058427W WO 2024200617 A1 WO2024200617 A1 WO 2024200617A1
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Prior art keywords
formula
phenylethyl
propanedioic acid
sodium
phenylbutyrate
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English (en)
Inventor
Francesco LANZA
Giuseppina TRUGLIO
Davide Rossi
Alessandro Restelli
Matteo PANZA
Chiara Vladiskovic
Gabriele Razzetti
Anna SIMONETTO
Giovanni Battista Giovenzana
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Dipharma Francis SRL
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Dipharma Francis SRL
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Priority claimed from IT102023000005922A external-priority patent/IT202300005922A1/it
Priority claimed from IT102023000019125A external-priority patent/IT202300019125A1/it
Application filed by Dipharma Francis SRL filed Critical Dipharma Francis SRL
Publication of WO2024200617A1 publication Critical patent/WO2024200617A1/fr
Anticipated expiration legal-status Critical
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/347—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups
    • C07C51/377—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups
    • C07C51/38—Preparation of carboxylic acids or their salts, halides or anhydrides by reactions not involving formation of carboxyl groups by splitting-off hydrogen or functional groups; by hydrogenolysis of functional groups by decarboxylation
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/09—Preparation of carboxylic acids or their salts, halides or anhydrides from carboxylic acid esters or lactones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C51/00—Preparation of carboxylic acids or their salts, halides or anhydrides
    • C07C51/41—Preparation of salts of carboxylic acids
    • C07C51/412—Preparation of salts of carboxylic acids by conversion of the acids, their salts, esters or anhydrides with the same carboxylic acid part
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C57/00—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms
    • C07C57/30—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings
    • C07C57/34—Unsaturated compounds having carboxyl groups bound to acyclic carbon atoms containing six-membered aromatic rings containing more than one carboxyl group
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C67/00—Preparation of carboxylic acid esters
    • C07C67/30—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group
    • C07C67/333—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton
    • C07C67/343—Preparation of carboxylic acid esters by modifying the acid moiety of the ester, such modification not being an introduction of an ester group by isomerisation; by change of size of the carbon skeleton by increase in the number of carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the present invention relates to a process for the preparation and the purification of sodium 4-phenylbutyrate.
  • Sodium 4-phenylbutyrate formula (I) is used in the treatment of urea cycle disorders resulting from defects of the liver enzymes ornithine transcarbamylase (OTC), carbamyl phosphate synthetase (CPS) and arginosuccinic acid synthetase (AS), which are involved in the removal of ammonia from the bloodstream.
  • OTC liver enzymes ornithine transcarbamylase
  • CPS carbamyl phosphate synthetase
  • AS arginosuccinic acid synthetase
  • urea cycle diseases comprise dietary protein restrictions, supplementing arginine or citrulline, treatment with sodium phenylbutyrate of formula (I) or even liver transplantation.
  • Indian patent application IN 1279/MUM/2012 describes a one-pot process comprising the condensation of 2-bromo-ethylbenzene with diethylmalonate in the presence of a base and a catalyst, such as tetrabutylammonium bromide, and subsequent hydrolysis of the ester obtained with sodium hydroxide. After addition of hydrochloric acid, the diacid is extracted in monochlorobenzene and finally decarboxylated to obtain phenylbutyric acid.
  • a catalyst such as tetrabutylammonium bromide
  • EP 0 361 365 describes a process for preparing 2-(2-phenylethyl)propanedioic acid of formula (II): by reacting 2-bromo-ethylbenzene with diethylmalonate in the presence of a metallic sodium solution. Diethylphenylethylmalonate is then hydrolyzed with sodium hydroxide, and the clear solution acidified with hydrochloric acid providing 2-(2-phenylethyl)propanedioic acid of formula (II).
  • Sodium phenylbutyrate of formula (I) both for the treatment of urea cycle disorders as well as for the treatment of ALS, is administered in doses up to 6 g per day, thus in an amount of more than 2 g per day, which is the threshold above which greater purity of a pharmaceutical active ingredient is needed.
  • the active pharmaceutical ingredient must be particularly pure and even known impurities must be lower than 0.05%.
  • the present application relates to a new and safe method for making sodium phenylbutyrate of formula (I) based on the purification of key intermediates and of the final product, which thanks to high yields and a lower presence of impurities, is suitable for industrial productions.
  • This new process thanks to the specific conditions, provides a pure product, which is suitable to meet the regulatory requirements required for active pharmaceutical ingredients (APIs).
  • the present application is directed to a process for preparing sodium 4- phenylbutyrate of formula (I): comprising: forming a dispersion of 2-(2-phenylethyl)propanedioic acid of formula (II): in an apolar aprotic solvent; or forming a dispersion of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III): in a polar solvent; dissolving it; cooling or concentrating the solution to obtain a precipitation of 2-(2- phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III); isolating the solid; and subsequently decarboxylating 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedi
  • the present application is directed to a process for preparing sodium 4-phenylbutyrate of formula (I) as defined above, wherein 2-(2-phenylethyl)propanedioic acid of formula (II) obtained after cooling or concentration is in crystalline form 1 as defined below.
  • the present application is directed to a process for preparing sodium 4-phenylbutyrate of formula (I): comprising: forming a solution of 4-phenylbutyric acid of formula (IV): salifying 4-phenylbutyric acid of formula (IV) to obtain sodium 4-phenylbutyrate of formula (I), recovering sodium 4-phenylbutyrate of formula (I) as a solid by freeze-drying.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 was characterized by X-ray powder diffraction (XRPD) and differential scanning calorimetry (DSC).
  • DSC Differential Scanning Calorimetry
  • Figure 1 shows the XRPD spectrum of 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1.
  • Figure 2 shows the DSC trace of 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1.
  • the present application is directed to a process for preparing sodium 4- phenylbutyrate of formula (I): comprising: forming a dispersion of 2-(2-phenylethyl)propanedioic acid of formula (II): in an apolar aprotic solvent; or forming a dispersion of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III): in a polar solvent; dissolving it; cooling or concentrating the solution to obtain a precipitation of 2-(2- phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III); isolating the solid; and subsequently decarboxylating 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedi
  • 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III), used as the starting material can be in any form, for instance in non-crystalline form or in anhydrous, hydrated or solvated crystalline form.
  • An apolar aprotic solvent according to the invention may be chosen for example from a group comprising hexane, heptane, cyclohexane, toluene, o-xylene, m-xylene or p-xylene, or a mixture of two or three of these solvents.
  • the apolar aprotic solvent is toluene.
  • a polar solvent may be an aprotic dipolar solvent or a protic polar solvent.
  • An aprotic dipolar solvent according to the invention may be selected for example from a group comprising dimethylformamide (DMF), dimethylacetamide (DMA/ N- methylpyrrolidone (NMP), acetonitrile or dimethyl sulfoxide (DMSO); an acyclic or cyclic ether, for example tetrahydrofuran (THF), methyl-THF, diethyl ether, methyl tert-butyl ether, or dioxane; a ketone, for example methyl ethyl ketone, methyl isobutyl ketone or acetone.
  • DMF dimethylformamide
  • DMSO dimethyl sulfoxide
  • an acyclic or cyclic ether for example tetrahydrofuran (THF), methyl-THF, diethyl ether, methyl tert-butyl ether, or dioxane
  • a protic polar solvent according to the present invention may be selected from the group comprising a linear or branched Ci-Ce alcohol, for example a C1-C4 alcohol, typically methanol, ethanol, n-propanol, isopropanol or n-butanol; or water.
  • a linear or branched Ci-Ce alcohol for example a C1-C4 alcohol, typically methanol, ethanol, n-propanol, isopropanol or n-butanol; or water.
  • the polar solvent may be a mixture of two or more polar solvents, preferably two or three of the polar solvents listed above.
  • the polar solvent is a mixture of a linear or branched Ci-Ce alcohol and water, for example isopropanol and water.
  • the concentration of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) may be between about 2% (moles/moles of solvent or mixture of solvents) and about 50%, for example between about 10% and about 40%.
  • the dissolution of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) in the solvent may be carried out by heating the dispersion up to the solvent reflux temperature, for example at about 120°C, at about 110°C, at about 100°C, at about 90°C, at about 80°C, at about 70°C, at about 60°C or at about 50°C.
  • the dissolution of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) may be advantageously carried within 15 minutes or more than 15 minutes, for example within 30 minutes, within 45 minutes, within 1 hour, within 2 hours, within 3 hours, within 4 hours, within 5 hours, within 6 hours, within 7 hours, within 8 hours, within 9 hours, within 10 hours, within 11 hours, within 12 hours or within 18 hours.
  • the apolar aprotic solvent is toluene and the dissolution in 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out by heating to about 110°C, to about 100°C, to about 90°C, to about 85°C, to about 83°C, to about 80°C, or to about 70°C, for example between 80°C and 90°C.
  • the dissolution of 2-(2-phenylethyl)propanedioic acid of formula (II) in toluene may be advantageously carried out in a reaction time of 15 minutes or in a reaction time greater than 15 minutes, for example 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours.
  • the dissolution of 2-(2-phenylethyl)propanedioic acid of formula (II) in toluene may be advantageously carried out between about 80°C and 100°C for a time between 15 minutes and 5 hours.
  • the authors of the present invention have surprisingly found that the dissolution of 2- (2-phenylethyl)propanedioic acid of formula (II) in toluene between about 80°C and 100°C, for example within a time between 15 minutes and 5 hours, allows to obtain the 2-(2- phenylethyl)propanedioic acid of formula (II) with a high purity. For example, heating to 83°C for 2 hours allows to obtain the product with a purity of 100.00% (measured at 220 nm in HPLC). Much higher temperatures and much longer times can lead to a partial decarboxylation of 2-(2-phenylethyl)propanedioic acid of formula (II). For example, the authors have seen that heating 2-(2-phenylethyl)propanedioic acid of formula (II) in toluene to about 110°C for over 24 hours leads to a decarboxylation of 55%.
  • the cooling of the solution to obtain the precipitation of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) may be carried out by decreasing the temperature of the solution down to between about 0°C and about 30°C, or between about 17°C and about 25°C, for example at about 20°C.
  • the cooling of the solution to obtain the precipitation of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) may be carried out within a time frame between about one hour and 10 hours, preferably between about 2 and about 7 hours.
  • the solution comprising 2-(2-phenylethyl)propanedioic acid of formula (II) in toluene can be cooled down to a temperature of between about 0°C and about 30°C, for example to 20°C and for example at a rate of about 0.1 to 0.5°C per minute.
  • the concentration of the solution comprising 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) to obtain the precipitation of 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) may be carried out by distillation. The distillation may be performed at ambient pressure or at reduced pressure.
  • the solution comprising 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) may be concentrated and cooled, for instance to a temperature of about 0°C to about 30°C or of about 17 to about 25°C, or to about at 20°C.
  • the solution comprising 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) may be concentrated and cooled down between about one hour to about 10 hours, for instance between about 2 and about 7 hours.
  • the solution comprising 2-(2-phenylethyl)propanedioic acid of formula (II) in toluene may be concentrated and cooled down, for instance to a temperature of about 0°C to about 30°C, for example to 20°C, and for example at a rate of about 0.1 to 0.5°C per minute.
  • the isolation of the solid consisting of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) can be carried out by known techniques, for example by filtration or centrifugation, preferably by filtration.
  • the so obtained solid can be dried according to known manner, for instance under reduced pressure.
  • the precipitate obtained after cooling or concentration is 2-(2- phenylethyl)propanedioic acid of formula (II) in crystalline form.
  • the precipitate obtained after cooling or concentration is 2-(2- phenylethyl)propanedioic acid of formula (II) in crystalline form 1 as defined below.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is an anhydrous crystalline form.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by one or more peaks in its XRPD pattern, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about 20.77 and about 21.18° ⁇ 0.20° in 29.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by two or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by three or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about 20.77 and about 21.18° ⁇ 0.20° in 29.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by four or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about 20.77 and about 21.18° ⁇ 0.20° in 29.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by five or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by six or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by seven or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about 20.77 and about 21.18° ⁇ 0.20° in 29.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by eight or more peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about 20.77 and about 21.18° ⁇ 0.20° in 29.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by nine peaks, obtained using CuKa radiation, selected from those at about 8.29; about 12.21; about 14.43; about 15.74; about 16.67; about 18.16; about 19.19; about 20.77 and about 21.18° ⁇ 0.20° in 29.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by nine or more peaks obtained using CuKa radiation:
  • 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by one or more of the following characteristics:
  • the size of the crystals of 2-(2-phenylethyl)propanedioic acid of formula (II) in form 1, as obtainable according to the procedures described herein, is characterized by a value of D50 between about 25 and 250 pm. If desired, this value can be reduced by micronization or end milling.
  • a further aspect concerns 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 as defined above with a high purity, typically > 99.95% measured at 220 nm in HPLC, for example at 100.00%.
  • a further aspect concerns 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1, for example as obtainable according to the procedures described herein, with a high purity, typically > 99.95% measured at 220 nm in HPLC, for example at 100.00%, so that impurities are present in an amount less than or equal to 0.03%, preferably less than or equal to 0.01% measured at 220 nm in HPLC.
  • a further aspect concerns 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III).
  • 2-(2-Phenylethyl)propanedioic acid monosodium salt of formula (III), as obtainable according to the procedures described herein, has a high purity, typically > 98.00% or > 99.95% measured at 245 nm in HPLC(HPLC-UV, Area%), for example 100.00%, so that impurities are present in amounts less than or equal to 0.03%, preferably less than or equal to 0.01% measured at 220 nm in HPLC.
  • a further aspect of the application concerns the use of 2-(2-phenylethyl)propanedioic acid of formula (II), for example in crystalline form 1 as defined above, or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) to prepare sodium 4- phenylbutyrate of formula (I).
  • a further aspect of the application concerns the use of 2-(2-phenylethyl)propanedioic acid of formula (II), for example in crystalline form 1 as defined above, or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) to prepare particularly pure 4- phenylbutyrate sodium of formula (I), typically > 99.95%, measured at 220 nm or at 245 nm in HPLC (HPLC-UV, Area% - A%).
  • 2-(2-Phenylethyl)propanedioic acid monosodium salt of formula (III) obtained by the above disclosed crystallization process can be optionally converted into 2-(2- phenylethyl)propanedioic acid of formula (II) before performing the decarboxylation step.
  • the conversion of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) to 2-(2-phenylethyl)propanedioic acid of formula (II) can be carried out according to known methods by adding acid, for example by adding a mineral acid.
  • a mineral acid may be selected, for example, from the group comprising sulphuric acid, phosphoric acid, and hydrochloric acid, for example hydrochloric acid.
  • the mineral acid is an aqueous solution of hydrochloric acid, for example at concentrations of about 2 molars, 6 molars or 12 molars.
  • (IV) can be carried out in a solvent.
  • the solvent is typically an aprotic apolar solvent, as defined above, an acyclic or cyclic ether, as defined above, an aprotic dipolar solvent, as defined above; or a mixture of two or more, for example two or three, of the solvents mentioned above.
  • the solvent is selected from hexane, heptane, cyclohexane, toluene, o-xylene, m-xylene, p-xylene, dimethylacetamide, acetonitrile, l-methyl-2 -pyrrolidone (or N- methyl-2 -pyrrolidone or NMP) or a mixture of two or more, for example two or three, of the solvents mentioned above.
  • the solvent is toluene.
  • the decarboxylation of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) may be carried out without the use of a solvent, for example by melting 2-(2- phenylethyl)propanedioic acid of formula (II).
  • the decarboxylation of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) may be performed by heating to about 150°C, to about 140°C, to about 130°C, to about 120°C, to about 110°C, to about 100°C, to about 90°C, to about 80°C or to about 70°C.
  • the decarboxylation of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) may be advantageously carried out in a reaction time of 5 hours or in a reaction time greater than 5 hours , for example 6 hours, 12 hours, 24 hours, 36 hours, 48 hours, 72 hours, 96 hours, 144 hours, 240 hours or 480 hours.
  • the organic base may be an aliphatic tertiary amine or a heteroaromatic amine.
  • the aliphatic tertiary amine may be triethylamine, diisopropylethylamine, tri-n-butylamine, diazabicycloundecene, TV-Ci-Ce alkyl pyrrolidine, TV-Ci-Ce alkyl morpholine, TV-Ci-Ce alkyl piperidine, TV-Ci-Ce alkyl piperazine or TV.TV’-diCi-Ce alkyl piperazine.
  • the organic base may be pyridine or Ci-Ce alkyl pyridine.
  • the organic base is triethylamine.
  • Ci-Ce alkyl refers to a linear or branched hydrocarbon chain, consisting only of carbon and hydrogen atoms and having from one to six carbon atoms.
  • the "Ci-Ce alkyl” group is a linear or branched "C1-C4 alkyl” group.
  • Examples of a "Ci-Ce alkyl” are methyl, ethyl, n-propyl, isopropyl, n-butyl, ec-butyl, or tert-butyl.
  • the decarboxylation may be advantageously carried out using about 5.0 to about 0.001 moles of organic base per mole of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2- (2-phenylethyl)propanedioic acid monosodium salt of formula (III), for example 4 moles, 3 moles, 2 moles, 1.5 moles, 1.1 moles, 1.0 moles, 0.9 moles, 0.8 moles, 0.7 moles, 0.6 moles, 0.5 moles, 0.4 moles, 0.3 moles, 0.2 moles, 0.1 moles, 0.07 moles, 0.05 moles or 0.03 moles organic base per mole of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III).
  • the decarboxylation of 2-(2-phenylethyl)propanedioic acid of formula (II) or of 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III) in the presence of an organic base can be advantageously carried out in a reaction time of 0.5 hours or in a reaction time greater than 0.5 hours , for example 1 hour, 2 hours, 3 hours, 6 hours, 9 hours, 12 hours, 24 hours or 48 hours.
  • Salification of phenylbutyric acid of formula (TV) to sodium 4-phenylbutyrate of formula (I) can be performed according to known methods.
  • phenylbutyric acid of formula (IV) can be treated with a solution of NaOH, NaHCCh, Na2COs, sodium methoxide, sodium ethoxide or sodium 2-ethylhexanoate.
  • Salification of phenylbutyric acid of formula (IV) into sodium 4-phenylbutyrate of formula (I) may be carried out in a solvent selected from an aprotic dipolar solvent, as defined above; a cyclic or acyclic ether, as defined above; a ketone, for example methyl ethyl ketone, methyl isobutyl ketone or acetone; a linear or branched Ci-Cs alcohol, for example methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1-pentanol, 2-pentanol, 3-pentanol, or 1 -heptanol; an apolar aprotic solvent, typically toluene; an ester, for example ethyl acetate; or a mixture of two or more, preferably two or three, of these solvents; or in water or in an aqueous solution comprising one
  • the salification of phenylbutyric acid of formula (IV) into sodium 4-phenylbutyrate of formula (I) is carried out in isopropanol, in acetonitrile, in water or in a mixture of two or three of these solvents.
  • the salification of phenylbutyric acid of formula (IV) in sodium 4-phenylbutyrate of formula (I) is carried out in water or in a mixture of water and acetonitrile.
  • sodium 4-phenylbutyrate of formula (I) can be converted into phenylbutyric acid of formula (IV) or into a pharmaceutically acceptable salt thereof, or vice versa.
  • the conversion of the free acid into its pharmaceutically acceptable salt, or vice versa the conversion of the pharmaceutically acceptable salt into the free acid can be carried out according to known methodologies.
  • 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2- phenylethyl)propanedioic acid monosodium salt of formula (III), used as starting material can be prepared by a process comprising reacting a compound of formula (V): wherein X is a halogen, with a compound of formula (VI): wherein R 1 and R 2 are independently selected from Ci-Ce alkyl or C3-C8 cycloalkyl, and wherein the Ci-Ce alkyl or C3-C8 cycloalkyl may be optionally substituted by one or more substituents, preferably by one to three equal or different substituents, such as halogen or aryl; in the presence of a base; to obtain a compound of formula (VII): wherein R 1 and R 2 are defined as above; and subsequently hydrolysing the compound of formula (VII) to form 2-(2-phenylethyl)prop
  • the halogen may be fluorine, chlorine, bromine, or iodine.
  • the halogen is chlorine or bromine, more preferably bromine.
  • the "Ci-Ce alkyl” group is as defined above.
  • C3-C8 cycloalkyl refers to a cyclic hydrocarbon chain, consisting only of carbon and hydrogen atoms and having three to eight carbon atoms.
  • C3-C8 cycloalkyl examples include cyclopropyl, cyclobutyl, or cyclohexyl.
  • aryl refers to a monocyclic or bicyclic aromatic ring comprising 6, 9 or 10 carbon atoms.
  • Aryl may be, for example, a phenyl or naphthyl group.
  • the aryl is typically phenyl.
  • the aryl group may optionally be substituted by one to three substituents selected independently from a linear or branched Ci-Ce alkyl group, which in turn may be optionally substituted by one to three halogen atoms, typically fluorine; a hydroxyl group; a Ci-Ce alkoxy group, for example methoxy; a halogen atom, such as bromine or chlorine; a cyano group; or a nitro group.
  • substituents selected independently from a linear or branched Ci-Ce alkyl group, which in turn may be optionally substituted by one to three halogen atoms, typically fluorine; a hydroxyl group; a Ci-Ce alkoxy group, for example methoxy; a halogen atom, such as bromine or chlorine; a cyano group; or a nitro group.
  • the base may be an organic base or an inorganic base.
  • the organic base is as defined above.
  • An inorganic base is typically a hydroxide, carbonate, hydrogen carbonate, or phosphate of an alkali or alkaline earth metal.
  • inorganic bases are sodium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate, lithium hydrogen carbonate, sodium hydrogen carbonate, potassium hydrogen carbonate, magnesium hydrogen carbonate or calcium hydrogen carbonate, sodium phosphate, potassium phosphate, magnesium phosphate or calcium phosphate.
  • the base is potassium carbonate.
  • reaction of the compound of formula (V) with the compound of formula (VI) may be carried out in a solvent, for example in a dipolar aprotic solvent, as defined above; in a cyclic or acyclic ether, as defined above; in an apolar aprotic solvent, as defined above; or in a mixture of two or more, preferably two or three, of the solvents listed above.
  • a solvent for example in a dipolar aprotic solvent, as defined above; in a cyclic or acyclic ether, as defined above; in an apolar aprotic solvent, as defined above; or in a mixture of two or more, preferably two or three, of the solvents listed above.
  • the solvent is toluene or a dipolar aprotic solvent, typically dimethylformamide, dimethylacetamide, acetonitrile or DMSO, or a mixture of two or more, preferably two or three, of the solvents listed above.
  • the solvent is dimethylacetamide.
  • the reaction of the compound of formula (V) with the compound of formula (VI) may be carried out at a temperature between -10°C and the reflux temperature of the solvent, preferably between about 0°C and about 150°C, for example at about 20°C, at about 40°C, at about 60°C, at about 70°C, at about 80°C, at about 85°C, at about 90°C or at about 100°C.
  • reaction of the compound of formula (V) with the compound of formula (VI) may be advantageously carried out using about 1.2 to about 0.4 moles of the compound of formula (V) per mole of the compound of formula (VI), for example 1.0 mole, 0.9 moles, 0.8 moles, 0.7 moles, 0.6 moles, 0.5 moles of the compound of formula (V) per mole of the compound of formula (VI).
  • reaction of the compound of formula (V) with the compound of formula (VI) can be advantageously carried out using about 1.0 to about 0.6 moles of the compound of formula (V) per mole of the compound of formula (VI).
  • reaction of the compound of formula (V) with the compound of formula (VI) can be advantageously carried out using about 0.95 to about 0.70 moles of the compound of formula (V) per mole of the compound of formula (VI).
  • the subsequent hydrolysis of the compound of formula (VII) to form 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out with an inorganic base.
  • the inorganic base used for the hydrolysis of the compound of formula (VII) to form 2-(2-phenylethyl)propanedioic acid of formula (II) is typically a hydroxide or a carbonate of an alkali or alkaline earth metal.
  • Examples of inorganic bases used for the hydrolysis of the compound of formula (VII) to form 2-(2-phenylethyl)propanedioic acid of formula (II) are sodium hydroxide, potassium hydroxide, magnesium hydroxide or calcium hydroxide, lithium carbonate, sodium carbonate, potassium carbonate, magnesium carbonate or calcium carbonate.
  • the hydrolysis of the compound of formula (VII) to form 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out in a solvent, for example in a dipolar aprotic solvent, as defined above; in a cyclic or acyclic ether, as defined above; in an apolar aprotic solvent, as defined above; in a chlorinated solvent, for example dichloromethane, di chloroethane, chloroform or chlorobenzene; in a protic polar solvent, typically a linear or branched Ci-Ce alcohol as defined above; in water or in a mixture of two or more, preferably two or three, of the above listed solvents.
  • a solvent for example in a dipolar aprotic solvent, as defined above; in a cyclic or acyclic ether, as defined above; in an apolar aprotic solvent, as defined above; in a chlorinated solvent, for example dichloromethane, di
  • the hydrolysis of the compound of formula (VII) to form 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out in a mixture of water and a dipolar aprotic solvent, as defined above; or a cyclic or acyclic ether as defined above; or an apolar aprotic solvent, as defined above; or a chlorinated solvent, as defined above; or a protic polar solvent.
  • the hydrolysis of the compound of formula (VII) to form 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out in a mixture comprising water and an apolar aprotic solvent, as defined above, for example water and toluene.
  • the hydrolysis of the compound of formula (VII) to form 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out between about 10 minutes and about 96 hours, for example in about 1 hour, in about 2 hours, in about 3 hours, in about 4 hours, in about 5 hours, in about 6 hours, in about 12 hours, in about 24 hours, in about 36 hours or in about 48 hours.
  • the hydrolysis of the compound of formula (VII) to form 2-(2- phenylethyl)propanedioic acid of formula (II) may be carried out at a temperature between about 0°C and the reflux temperature of the reaction mixture, for example at temperatures about at 100°C or less, for example at about 80°C, at about 60°C, at about 50°C, at about 40°C, at about 30°C, at about 25°C, at about 20°C, at about 15°C, at about 10°C or at about 0°C.
  • an acid for example hydrochloric acid
  • an acid for example hydrochloric acid
  • a pH value equal to or less than 3, or equal to or less than 2
  • 2-(2-phenylethyl)propanedioic acid of formula (II) is added to decrease the pH of less than about 4, for example to a pH value equal to or less than 3, or equal to or less than 2, to obtain 2-(2-phenylethyl)propanedioic acid of formula (II) to be used as starting material.
  • the process may also comprise an azeotropic distillation step with an apolar aprotic solvent prior to the formation of a dispersion of 2-(2- phenylethyl)propanedioic acid of formula (II) in an apolar aprotic solvent, its dissolution, precipitation and isolation of 2-(2-phenylethyl)propanedioic acid of formula (II) as defined above.
  • an acid for example hydrochloric acid
  • a pH value around 6 may be added up to a pH value around 6, to obtain the 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) to be used as a starting material.
  • the present application is directed to a process for preparing sodium 4-phenylbutyrate of formula (I): comprising: forming a solution of 4-phenylbutyric acid of formula (IV): salifying 4-phenylbutyric acid of formula (IV) to obtain sodium 4-phenylbutyrate of formula (I), recovering sodium 4-phenylbutyrate of formula (I) as a solid by freeze-drying.
  • Phenylbutyric acid of formula (IV) is a known compound. It can be prepared by known methods or it can be obtained according to the procedures disclosed in the present application. Phenylbutyric acid of formula (IV), used as the starting material, may be in any form, for instance in non-crystalline form, in anhydrous, hydrated or solvated crystalline form or in solution, for instance in the solution of the decarboxylation step of 2-(2- phenylethyl)propanedioic acid of formula (II), as disclosed herein.
  • the solution of phenylbutyric acid of formula (IV) may be prepared in a solvent selected from an aprotic dipolar solvent, for example dimethylformamide (DMF), dimethylacetamide (DMA A-methylpyrrolidone (NMP), acetonitrile or dimethyl sulfoxide (DMSO); a cyclic or acyclic ether, for example tetrahydrofuran (THF), methyl-tetrahydrofuran (methyl-THF), diethylether, methyl tert-butyl ether (MTBE), or dioxane; a linear or branched Ci-Cs alcohol, for example methanol, ethanol, isopropanol, n-butanol, isobutanol, tert-butanol, 1 -pentanol, 2- pentanol, 3-pentanol, or 1-heptanol; an apolar aprotic solvent, typically toluene;
  • Lyophilization of sodium 4-phenylbutyrate of formula (I) comprises a freezing step of sodium 4-phenylbutyrate of formula (I) in the solvent or solvent mixture used in the salification step, as defined above, and subsequently a drying step to obtain sodium 4-phenylbutyrate of formula (I).
  • Freezing is carried out at a temperature and for an appropriate time so that the solution is completely frozen, and no more liquid is observed.
  • the freezing temperature of an aqueous solution is below 0°C.
  • the freezing temperature of an aqueous solution is about -10°C, about -20°C, about -30°C, about -40°C, about -50°C or lower, for example -60°C, -70°C or -78°C.
  • the freezing temperature of a mixture of acetonitrile and water is about -48°C or lower.
  • the freezing temperature of an acetonitrile and water mixture is about -54°C or lower, for example -60°C, -70°C or -78°C.
  • the freezing time of the mixture may be at least about 30 minutes, for example from about 30 minutes to about 20 hours, from about 1 to about 18 hours, from about 2 to about 16 hours, from about 3 to about 14 hours, from about 4 to about 10 hours, from about 5 to about 8 hours or from about 6 to about 7 hours.
  • the freezing time of the mixture is about 6 hours.
  • the temperature and freezing time can depend on several factors, such as the volume of the solution, the solvent or mixture of solvents used.
  • the drying step of the product may comprise a primary drying phase and a secondary drying phase.
  • the drying step comprises a primary drying step, wherein the frozen solvent or the mixture of the frozen solvents is removed by sublimation, i.e. by direct conversion of the frozen solvents from the solid to the gas state.
  • the primary drying step may be carried out at a temperature between about -100°C and about 20°C, or between about -90°C and about 10°C, or between about -80°C and about 0°C.
  • the primary drying step is carried out at about -80°C.
  • the primary drying step may be carried out at a temperature between about -35°C and about 20°C, or between about -25°C and about 10°C, or between about -20°C and about 0°C.
  • the primary drying step is carried out at about 0°C.
  • the primary drying step may be carried out for at least about 1 hour, for example from about 1 hour to about 1 week, from about 10 hours to about 4 days or from about 20 hours to about 40 hours.
  • the primary drying step comprises the drying at a pressure of 0 mbar to about 200 mbar, for example at 10 mbar, 50 mbar, 100 mbar or 150 mbar.
  • the drying can be carried out by varying the temperature, for example by increasing or decreasing the temperature at a rate between about 0.1 °C and about 10°C per minute.
  • the primary drying step may be carried out for a sufficient time to ensure that substantially all frozen solvent or frozen solvent mixture is removed from the sample.
  • An expert in the field is aware of the possibility that the primary drying time may vary, since the length of primary drying may depend on the volume, type of freeze dryer and geometry of the lyophilisate.
  • the primary drying step may be about 5 hours or more than 5 hours, such as from about 5 hours to about 100 hours, from about 10 hours to about 80 hours, from about 30 hours to about 60 hours, and from about 40 hours to about 50 hours.
  • the primary drying process can be monitored by different methods, for example by observing product temperature changes during freeze-drying. Another method is to observe pressure changes during freeze-drying.
  • the end of the primary drying phase can be established, for example, when a significant change in the slope of the product temperature trace due to the reduction of the sublimation rate is observed.
  • evaporative cooling ends, too. If necessary, drying can be prolonged, for example for further 2 or 3 hours.
  • Another method to monitor primary drying is a pressure rise test: once the vacuum source is disconnected and an increase in chamber pressure occurs, then this indicates that there is still moisture present in the product.
  • the conclusion of the primary drying can be established, when the rate of the pressure increase is below a specified value.
  • Another method for determining the end of the primary drying step is the measurement of the heat transfer rate.
  • the composition directly before the primary drying step, can be placed under vacuum. Once evaporation has started, the vacuum can remain fixed for the rest of the freeze-drying process, or it can be varied, if desired.
  • the drying procedure may also comprise one or more secondary drying steps to further reduce the level of the solvent or the mixture.
  • each secondary drying step may be carried out at a temperature of about 0°C or higher, for example from about 0°C to about 100°C, from about 10°C to about 90°C, from about 20°C to about 80°C, from about 30°C to about 70°C, for example at about 40°C, at about 45°C, at about 50°C or at about 60°C.
  • secondary drying may last about 1 hour or more than 1 hour, for example from about 5 hours to about 100 hours, from about 10 hours to about 80 hours, from about 30 hours to about 60 hours, or from about 40 to about 50 hours.
  • Each secondary drying step may be carried out for a sufficient time to reduce the level of solvent or residual solvents in the lyophilised product.
  • the final residual solvent level is about 10% (w/w) or less, for example about 9% or less, about 8% or less, about 7% or less, about 6% or less, about 5% or less, about 4% or less, about 3% or less, about 2% or less, about 1% or less, about 0.8% or less, about 0.6% or less, about 0.5% or less, about 0.2% or less or about 0.1% or less.
  • Sodium 4-phenylbutyrate of formula (I), as obtainable according to the present disclosure, has a high purity, typically > 99.95% measured at 245 nm in HPLC, for example of 99.99% or 100.00%.
  • the impurities are present in an amount lower than or equal to 0.03%, preferably lower than or equal to 0.01% measured at 245 nm in HPLC.
  • sodium 4-phenylbutyrate of formula (I) obtained by the present lyophilization process has a content of the impurity of formula (VIII), described in the European Pharmacopoeia as impurity A: lower than 0.01%, preferably lower than 0.008%, for example, lower than 0.005%, 0.001%, or 0.0005%.
  • the 1 H NMR spectra were acquired with a Varian 500 MHz instrument.
  • the chemical shifts are expressed in parts per million (ppm).
  • the coupling constants are expressed in Hertz (Hz) and the splitting patterns are described as s (singlet), bs (broad signal), d (doublet), t (triplet), q (quartet), quint (quintet), m (multiplet).
  • HPLC analyses were carried out on a Waters Alliance or Agilent 1260 HPLC at the following conditions: Symmetry C18 column (250 x 4.6 mm, 5 pm); Eluent A: acetonitrile; eluent B: phosphoric acid 1% in water; eluent C: methanol; flow rate: 1.0 mL/min; UV detector.
  • the reaction mixture is cooled down to 50°C and 156.6 g (180 mL) of toluene and 360 g (360 mL) of water are added. The mixture is stirred for 1 hour or until the salts are completely dissolved. The aqueous phase is separated, and the organic phase is distilled off. The remaining mixture is kept at about 20-25°C and 25.9 g (648 mmol) of NaOH in 180 g (180 mL) of water are added and the mixture is stirred at a temperature of 20-25°C for 6 hours. 133.2 g (180 mL) of methyl-te/7-butyl ether (MTBE) is added and the reaction mixture is stirred for 1 hour and then left to settle for 1 hour.
  • MTBE methyl-te/7-butyl ether
  • the phases are separated and 133.2 g (180 mL) of MTBE and 63.8 g (648 mmol) of an aqueous solution of 37% HC1 are added to the aqueous phase at a temperature between 20-25°C.
  • the mixture is stirred for 1 hour, then decanted for 1 hour.
  • the organic phase is separated and washed with 180 mL of water.
  • the organic phase is concentrated under vacuum at a temperature between 55-60°C.
  • 208.8 g (240 mL) of toluene is added and the mixture is concentrated under vacuum at a temperature between 55-60°C. Further 240 mL of toluene is added, and the mixture is heated up to 85-90°C and stirred until complete dissolution.
  • the mixture is then cooled down to 80°C, and a precipitate can be observed. Then, the mixture is heated up to 83°C to fluidize and kept at 83°C for 2 hours. Then, the mixture is cooled down to 20°C within 4 hours and maintained at that temperature for another 2 hours.
  • the obtained product is filtered off, the solid is washed with 52.2 g (60 mL) of toluene and the product is dried in a vacuum oven at 40°C providing 2-(2-phenylethyl)propanedioic acid of formula (II) (molar yield 60%) with a purity of 100.00% (HPLC detector at 220 nm).
  • the obtained product has an XRPD spectrum as shown in Figure 1 and is characterized by the following peaks obtained using CuKa radiation:
  • the organic phase is concentrated, the residue cooled down to 50-55°C and diluted with 1 L of isopropanol. 15.2 g of NaOH in 30% aqueous solution is added, the obtained solution is heated to reflux and filtered on a perlite panel. After concentration of the solution, the mixture is first cooled down to 46°C, then heated to 52°C for 4 hours and finally cooled down to 20°C within 6 hours.
  • reaction mixture is cooled down to 50°C and 156.6 g (180 mL) of toluene and 360 g (360 mL) of water are added. The mixture is stirred for 1 hour or until the salts are completely dissolved. The aqueous phase is separated and the organic phase is distilled off. The remaining mixture is kept at about 20-25°C and 25.9 g (648 mmol) of NaOH in 180 g (180 mL) of water are added and the mixture is stirred at a temperature of 20-25°C for 6 hours. 133.2 g (180 mL) of methyl-te/7-butyl ether (MTBE) are added and the reaction mixture is stirred for 1 hour and then left to settle for 1 hour.
  • MTBE methyl-te/7-butyl ether
  • the phases are separated, and the aqueous phase is concentrated at reduced pressure to an internal volume of 120 mL. 7 mL of HC1 37% are added to the suspension until reaching a pH value of about 6. 120 mL of isopropanol and 16 mL of demineralized water are then added, and the suspension is heated to about 65 to 70°C until a clear solution is obtained. About 75 mL of the solvent mixture is distilled off and about the same amount of pure isopropanol is added.
  • the solution is then concentrated to a volume of distillate equal to 1.1 L.
  • Isopropanol is added and the crystallization mixture is cooled down to 20°C in 5 hours and stirred for a further 2 hours.
  • the suspension is filtered on paper by washing the panel with 190 mL of isopropanol.
  • the wet solid is dried at 50°C in stove overnight and 119.2 g of sodium 4-phenylbutyrate of formula (I) is obtained as a white solid with a yield of 70% starting from 2-(2-phenylethyl)propanedioic acid of formula (II).
  • the content of sodium 4-phenylbutyrate of formula (I) in the mother liquors of crystallization is 22%, so the yield of the crystallization step alone is 78%.
  • the purity of sodium 4-phenylbutyrate of formula (I) is greater than 99.99% and the content of the impurity of formula (VIII) is 0.008% (measured at 245 nm in HPLC).
  • the frozen solution is dried for about 16 hours by freeze-drying (the internal pressure reached in a time of about 10 minutes is less than 133 mbar, the condenser temperature is at - 80°C) providing 1.1 g of sodium 4-phenylbutyrate of formula (I) as a white solid and with a yield of 97% starting from phenylbutyric acid of formula (IV).
  • the purity of sodium 4-phenylbutyrate of formula (I) is greater than 99.99% and the content of the impurity of formula (VIII) is 0.005% (measured at 245 nm in HPLC).

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Abstract

La présente invention concerne un procédé de préparation et de purification de 4-phénylbutyrate de sodium de formule (I).
PCT/EP2024/058427 2023-03-28 2024-03-28 Procédé et intermédiaires pour la préparation d'un médicament pour le traitement de troubles du cycle de l'urée Pending WO2024200617A1 (fr)

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IN2012MU01279A (fr) 2012-04-23 2013-12-06 Sequent Scientific Limited
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