WO2024200617A1

WO2024200617A1 - Process and intermediates for preparing a drug for the treatment of urea cycle disorders

Info

Publication number: WO2024200617A1
Application number: PCT/EP2024/058427
Authority: WO
Inventors: Francesco LANZA; Giuseppina TRUGLIO; Davide Rossi; Alessandro Restelli; Matteo PANZA; Chiara Vladiskovic; Gabriele Razzetti; Anna SIMONETTO; Giovanni Battista Giovenzana
Original assignee: Dipharma Francis S.R.L.
Priority date: 2023-03-28
Filing date: 2024-03-28
Publication date: 2024-10-03

Abstract

The present invention relates to a process for the preparation and the purification of sodium 4-phenylbutyrate of formula (I).

Description

PROCESS AND INTERMEDIATES FOR PREPARING A DRUG FOR THE TREATMENT OF UREA CYCLE DISORDERS

FIELD OF THE INVENTION

The present invention relates to a process for the preparation and the purification of sodium 4-phenylbutyrate.

STATE OF THE ART

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. These disorders of the urea cycle are characterized by hyperammonemia in conditions of catabolic or protein load. The clinical manifestations vary from moderate, with episodic hyperammonemia events, possible alterations of different degrees of cognitive functions, behavioral disorders, and growth difficulties, to severe, with encephalopathy with neurological sequelae and psychomotor retardation, coma, and death.

Current treatments of urea cycle diseases comprise dietary protein restrictions, supplementing arginine or citrulline, treatment with sodium phenylbutyrate of formula (I) or even liver transplantation.

In addition, clinical studies are ongoing to evaluate the efficacy of the combination of sodium phenylbutyrate of formula (I) with taurursodiol as neuroprotective agents in the therapy of neurodegenerative diseases such as ALS (amyotrophic lateral sclerosis). Such combination of sodium phenylbutyrate of formula (I) and taurursodiol showed to protect neurons by slowing or preventing motor neuron cell death.

There are several known methods for the preparation of sodium phenylbutyrate of formula (I).

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.

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).

Luan et al. describe in J. Am. Chem. Soc. 2020, 142, 50, 20942-20947 the preparation of 2-(2-phenylethyl)propanedioic acid of formula (II) by treating 2-bromo-ethylbenzene and diethylmalonate in absolute THF and in the presence of NaH. The formed diethyl ester is hydrolysed with aqueous sodium hydroxide and subsequently acidified and extracted with ethyl acetate 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. In fact, as expressed in the ICH guidelines: Q3A (R2), the active pharmaceutical ingredient must be particularly pure and even known impurities must be lower than 0.05%.

However, the purification of sodium phenylbutyrate of formula (I) was found to be problematic, particularly when scaling up the process. Thus, there is a need to have alternative methods for obtaining sodium phenylbutyrate of formula (I) with a purity that meets the regulatory requirements. These methods have to be efficient, provide the product with high yields, have to be cost-effective and suitable for the production and purification at an industrial scale.

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).

SUMMARY OF THE INVENTION

In a first aspect, 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)propanedioic acid monosodium salt of formula (III) and optionally salifying to obtain sodium 4-phenylbutyrate of formula (I).

In a further aspect, 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.

In a further aspect, 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.

BRIEF DESCRIPTION OF THE FIGURES AND ANALYTICAL METHODS

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).

X-ray diffraction spectra (XRPD) were run on a Bruker D8 Advance diffractometer having a goniometer radius of 280 mm and working in the following conditions: CuKa radiation filtered by Nickel filter (X = 1.54 A), Bragg-Brentano geometry, scanning with angular range 3-40° in 20 with angular pitch of 0.02°. The diffractogram obtained was evaluated using Diffrac. Eva version 4.3.0.1 (Bruker AXS).

Differential Scanning Calorimetry (DSC) analysis were run on a Mettler-Toledo DSC1 scanning differential calorimeter, under the following operating conditions: open aluminium capsule, heated at 10°C/min from 30°C to 300°C under nitrogen flow.

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.

DETAILED DESCRIPTION OF THE INVENTION

According to the present disclosure, by "comprising" herein is meant that additional steps may be taken in the process, which do not substantially change the product produced by the reaction. The term comprising encompasses the terms "consisting of and "consisting essentially of.

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.

In a preferred aspect, 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.

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.

In one aspect, the polar solvent may be a mixture of two or more polar solvents, preferably two or three of the polar solvents listed above.

In a preferred aspect, 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.

In a preferred aspect, 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.

In a preferred aspect, 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.

In a more preferred aspect, 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.

In one aspect, 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.

In one aspect, 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.

In one aspect, 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.

In a further aspect, 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.

In one aspect, the precipitate obtained after cooling or concentration is 2-(2- phenylethyl)propanedioic acid of formula (II) in crystalline form.

In a further aspect, the precipitate obtained after cooling or concentration is 2-(2- phenylethyl)propanedioic acid of formula (II) in crystalline form 1 as defined below.

In a further aspect, 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is an anhydrous crystalline form.

In a further aspect, 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.

In another aspect, 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

20.77 and about 21.18° ± 0.20° in 29.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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

20.77 and about 21.18° ± 0.20° in 29.

In another aspect, 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

20.77 and about 21.18° ± 0.20° in 29.

In another aspect, 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.

In another aspect, 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.

In another aspect, 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. According to a further aspect, 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by nine or more peaks obtained using CuKa radiation:

In another aspect, 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 is characterized by one or more of the following characteristics:

(i) an XRPD spectrum substantially similar to, or corresponding to, the one shown in FIG. 1;

(ii) a DSC spectrum substantially similar to, or corresponding to, the one shown in FIG. 2 with a melting point at about 135°C. 2-(2-Phenylethyl)propanedioic acid of formula (II) in crystalline form 1 has a water content between about 0 and about 1% w/w (weight/weight), preferably between about 0.05 and 0.5%, more preferably between 0.1 and 0.3%, so that it can be defined substantially anhydrous. The product has a melting point of about 135°C.

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%).

Surprisingly, the authors of this invention have found that the crystallization of 2-(2- phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (HI), for example to obtain crystalline form 1 of 2-(2- phenylethyl)propanedioic acid of formula (II) as defined below, is particularly suitable for preparing particularly pure sodium 4-phenylbutyrate of formula (I), with a typical purity > 99.95%, measured at 220 nm or at 245 nm in HPLC (HPLC-UV, Area% - A%), for example at 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).

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.

In a preferred aspect, the mineral acid is an aqueous solution of hydrochloric acid, for example at concentrations of about 2 molars, 6 molars or 12 molars.

The decarboxylation, for instance of 2-(2-phenylethyl)propanedioic acid of formula (II) forming phenylbutyric acid of formula (IV):

(IV), can be carried out in a solvent.

In one aspect, 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.

In a preferred aspect, 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.

In a particularly preferred aspect, the solvent is toluene.

According to a further aspect, 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 authors of the present invention surprisingly found that the decarboxylation of 2- (2-phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) occurs much more rapidly in the presence of an organic base.

The process for preparing sodium 4-phenylbutyrate of formula (I) comprising 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 is a further aspect of the present invention.

In one aspect, the organic base may be an aliphatic tertiary amine or a heteroaromatic amine.

In one aspect, 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.

In one aspect, the organic base may be pyridine or Ci-Ce alkyl pyridine.

In a preferred aspect, the organic base is triethylamine.

The term "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.

In a preferred aspect, 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. For example, 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 or more, preferably two or three, solvents selected from the solvents listed above.

In a preferred aspect, 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.

In a more preferred aspect, 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.

If desired, 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.

In one aspect, 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 R¹ and R² 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 R¹ and R² are defined as above; and subsequently hydrolysing the compound of formula (VII) to form 2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III).

The halogen may be fluorine, chlorine, bromine, or iodine.

In a preferred aspect, the halogen is chlorine or bromine, more preferably bromine.

The "Ci-Ce alkyl" group is as defined above.

The "C3-C8 cycloalkyl" group refers to a cyclic hydrocarbon chain, consisting only of carbon and hydrogen atoms and having three to eight carbon atoms.

Examples of a "C3-C8 cycloalkyl" are cyclopropyl, cyclobutyl, or cyclohexyl.

The term "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.

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. Examples of 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.

In a preferred aspect, the base is potassium carbonate.

The 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.

In a preferred aspect, 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.

In a particularly preferred aspect, 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.

The 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).

In a preferred aspect, the 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).

In a particularly preferred aspect, the 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.

In one aspect, 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.

In one aspect, 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.

At the end of hydrolysis, an acid, for example hydrochloric acid, 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 authors surprisingly found that, if a solvent other than an apolar aprotic solvent is used in the synthesis of 2-(2-phenylethyl)propanedioic acid of formula (II), an azeotropic distillation with an apolar aprotic solvent does not only allow to increase the yields of the product in the subsequent crystallization step as disclosed herein but also provides crystals that are more easily filtrable.

According to a further aspect, 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.

According to a further aspect, at the end of hydrolysis with sodium hydroxide or sodium carbonate, an acid, for example hydrochloric acid, 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.

comprising: forming a solution of 4-phenylbutyric acid of formula (IV):

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; 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 or more, preferably two or three, solvents selected from the solvents listed above.

The salification of phenylbutyric acid of formula (IV) into sodium 4-phenylbutyrate of formula (I) can be carried out as described above.

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.

In one aspect, the freezing temperature of an aqueous solution is below 0°C.

In another aspect, 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.

In one aspect, the freezing temperature of a mixture of acetonitrile and water is about -48°C or lower.

In another aspect, the freezing temperature of an acetonitrile and water mixture is about -54°C or lower, for example -60°C, -70°C or -78°C.

In another aspect, 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.

In one preferred aspect, 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.

In one aspect, 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.

In one aspect, 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.

In one preferred aspect, the primary drying step is carried out at about -80°C.

In one aspect, if the solvent is water, 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.

In one preferred aspect, if the solvent is water, the primary drying step is carried out at about 0°C.

In one aspect, 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.

In one aspect, 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.

Optionally, 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.

In one aspect, 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. When sublimation ends, 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.

In one aspect, 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.

In one aspect, directly before the primary drying step, the composition 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.

In one aspect, the drying procedure may also comprise one or more secondary drying steps to further reduce the level of the solvent or the mixture.

In one aspect, 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.

In one aspect, 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.

In some aspects, 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.

Surprisingly it was found that thanks to isolation by freeze-drying, sodium 4- phenylbutyrate of formula (I) not only was recovered quantitatively, but it was also found that the obtained product has a purity equal to or greater than a product purified by crystallization, for example from isopropanol.

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.

It has been surprisingly found that 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 examples below further illustrate the invention.

Experimental Part

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.

Example 1: Synthesis of 2-(2-Phenylethyl)propanedioic Acid of Formula (II)

55.69 g (421 mmol) of dimethylmal onate of formula (VI), 226 g (240 mL) of dimethylacetamide (DMA) and 58.2 g (421 mmol) of K2CO3 are placed under a nitrogen atmosphere in a 1 L reactor equipped with a mechanical stirrer at a temperature between 20°C and 25°C. The reaction mixture is heated to a temperature of 85 to 90°C. 60.0 g (324 mmol) of 2 -bromo-ethylbenzene of formula (V) is added within 4 hours and the mixture is stirred for 16 hours. 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. 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. Then, 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).

'H NMR (500 Hz, DMSO) 5: 7.29-7.29 (m, 2H), 7.19-7.15 (m, 3H), 3.17 (t, J=7 Hz, 1H), 2.56 (t, J=8 Hz, 2H), 1.98 (q, J=4 Hz, 2H).

The obtained product has an XRPD spectrum as shown in Figure 1 and is characterized by the following peaks obtained using CuKa radiation:

Example 2: Synthesis of Sodium 4-Phenylbutyrate of Formula (I)

25 g (120 mmol) of 2-(2-phenylethyl)propanedioic acid of formula (II), obtained as described in Example 1, 75 mL of toluene and 12.1 g (16.6 mL, 120 mmol) of triethylamine are placed under nitrogen atmosphere and at a temperature between 20°C and 25°C in a 250 mL reactor, equipped with a mechanical stirrer. The solution is heated to 90-95°C for 60 minutes, then cooled down to 20-25°C and 50 mL of water and 17.7 g (180 mmol) of HC1 37% are added. The mixture is vigorously stirred for 15 minutes, after that the phases are allowed to separate. 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. After stirring for further 2 hours, the solid is filtered off, washed twice with 50 mL of isopropanol and the wet solid is dried in an oven at 40°C overnight to furnish 10 g of sodium 4-phenylbutyrate of formula (I) as a white solid and with a yield of 44% and a purity of 99.99% (HPLC detector at 245 nm).

'H NMR (500 MHz, CD₃OD) 5: 7.26-7.19 (m, 2H), 7.23-7.15 (m, 2H), 7.15-7.08 (m, 1H), 2.65-2.59 (m, 2H), 2.22-2.15 (m, 2H), 1.94-1.84 (m, 2H).

Example 3: Synthesis of Sodium 4-Phenylbutyrate of Formula (I)

The reaction described in Example 2 is carried out varying the content of triethylamine relative to 2-(2-phenylethyl)propanedioic acid of formula (II):

Table 1. Percentage of conversion of 2-(2-phenylethyl)propanedioic acid of formula (II) to phenylbutyric acid of formula (IV).

As shown in Table 1, in the absence of tri ethylamine even after 24 hours at reflux only 55% of 2-(2-phenylethyl)propanedioic acid of formula (II) is converted, whereas surprisingly even 0.1 equivalents of triethylamine allow to obtain phenylbutyric acid of formula (IV) quantitatively within 7 hours. Increasing the organic base results in an acceleration of the reaction. For example, the conversion is quantitative in one hour with 1.0 triethylamine equivalents.

Example 4: Synthesis of 2-(2-Phenylethyl)propanedioic Acid Monosodium Salt of Formula (III)

55.69 g (421 mmol) of dimethylmal onate of formula (VI), 226 g (240 mL) of dimethylacetamide (DMA) and 58.2 g (421 mmol) of K2CO3 are placed under a nitrogen atmosphere in a 1 L reactor equipped with a mechanical stirrer at a temperature between 20°C and 25°C. The reaction mixture is heated to a temperature of 85 to 90°C. 60.0 g (324 mmol) of 2 -bromo-ethylbenzene of formula (V) are added within 4 hours and the mixture is stirred for 16 hours. 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) are added and the reaction mixture is stirred for 1 hour and then left to settle for 1 hour. 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 becomes opalescent and is then cooled down to about between 20 and 25°C within about 1 hour and the resulting suspension is filtered off and dried to provide 37 g of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) with a yield of 50% and a purity of 98.00% (HPLC detector at 245 nm).

¹H NMR (500 Hz, DMSO) 5: 7.27-7.20 (m, 2H), 7.16-7.10 (m, 3H), 2.66 (td, J=5.5, 1.8 Hz, 1H), 2.52-2.46 (m, 2H), 2.05-1.95 (m, 2H).

Example 5: Synthesis of Sodium 4-Phenylbutyrate of Formula (I)

37.0 g (161 mmol) of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (HI), obtained as described in Example 4, is suspended in 110 mL of toluene and 110 mL of MTBE. A solution of 37% HC1 is added to the stirred mixture until reaching a pH of 1. The phases are separated and the organic phase is concentrated providing 2-(2- phenylethyl)propanedioic of formula (II) as a white solid, which can be converted to sodium 4-phenylbutyrate of formula (I) according to the procedures described in Examples 2 or 3.

Example 6: Synthesis and Purification by Crystallization of Sodium 4- Phenylbutyrate of Formula (I)

190 g (913 mmol) of 2-(2-phenylethyl)propanediol acid of formula (II), obtainable according to the procedure described in Example 1, and 570 mL of toluene are placed under inert atmosphere and at a temperature between 20°C and 25°C in a 250 mL reactor, equipped with a mechanical stirrer. The solution is heated to 90-95°C and 46.2 g (456 mmol) of triethylamine are added within 2 hours. After further 2 hours at 90-95°C, the reaction mixture is cooled down to 20-25°C and 380 mL of water and 182.5 g (1369 mmol) of NaOH in 30% aqueous solution are added. The mixture is stirred vigorously for 15 minutes, then the organic phase is discarded, and the aqueous phase is washed twice with 190 mL of toluene. 380 mL of toluene and 152.8 g (1551 mmol) of HC1 37% are added, the phases are separated, and the organic phase is washed twice with 190 mL of water. The organic phase is diluted with 1310 mL of isopropanol and filtered on perlite. The solution comprising phenylbutyric acid of formula (IV) is combined with a solution of 3200 mL of isopropanol and 164.0 g of a 5 M sodium methylate solution in methanol and heated to 50°C. 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).

'H NMR (500 Hz, CD₃OD) 5: 7.10-7.24 (m, 5H), 2.62 (t, J=8 Hz, 2H), 2.18 (t, J=8 Hz, 2H), 1.89 (q, J=8 Hz, 2H).

Example 7: Freeze-Drying Purification of Sodium 4-Phenylbutyrate of Formula (I)

1.0 g (6.1 mmol) of phenylbutyric acid of formula (IV), prepared as described in Example 6 and obtained as a solid after evaporation of the solvent, is dissolved in 20 mL of an acetonitrile/water mixture (3/1, v/v). In addition, 2.4 mL (6.1 mmol) of a 2 M solution of NaOH in water is added (VWR, batch 19G1156744; Batch = BDH7223-1) and the mixture is stirred for 2 hours, and then frozen by immersion in a dry ice/isopropanol bath until no more liquid is observed. 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).

'H NMR (400 Hz, DMSO) 5: 7.29-7.31 (m, 2H), 7.20-7.17 (m, 3H), 2.59 (t, J=7.2 Hz, 2H), 2.21 (t, J=7.2 Hz, 2H), 1.81 (q, J=7.2 Hz, 2H).

Reference Example: Repeating of the Procedure Described in IN 1279/MUM/2012

22.4 g (162 mmol, 2 equivalent) of K2CO3, 0.20 g (1.3 mmol) of tetrabutylammonium bromide and 15 g (81 mmol, 1 equivalent) of (2-bromoethyl)benzene are added to 10.7 g (81.1 mmol) of sodium dimethylmalonate placed under nitrogen atmosphere.

The procedure of IN 1279/MUM/2012 describes that the reaction mixture is heated between 25 and 30°C for 2-2.5 hours and at the end of the reaction the mixture is cooled between 25 and 30°C providing phenylbutyric acid of formula (IV) with a yield of 70%. However, the authors of this invention found that maintaining the stirred reaction mixture for even after 5 days between 20 and 25°C led only to a partial conversion (61%). Thus, it was found that the conversion as described in IN 1279/MUM/2012 proceeds much slower than the procedures of the present application.

Claims

1. 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)

2. The process according to claim 1, wherein 2-(2-phenylethyl)propanedioic acid of formula (II) obtained after cooling is in crystalline form 1 having an XRPD spectrum characterized by one 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 20.

3. The process according to claims 1 or 2, wherein the apolar aprotic solvent is selected from the group comprising hexane, heptane, toluene, o-xylene, m-xylene or p-xylene, or a mixture of two or three of these solvents; and the polar solvent is a dipolar aprotic solvent or a polar protic solvent, wherein the dipolar aprotic solvent is selected from the group comprising dimethylformamide (DMF), dimethylacetamide (DMA), N-methyl-pyrrolidone (NMP), acetonitrile or dimethylsulfoxide (DMSO); a cyclic or acyclic ether, for example tetrahydrofuran (THF), methyl-THF, diethylether, methyl tert-butyl ether or dioxane; a ketone, for example methyl ethyl ketone, methyl isobutyl ketone or acetone; and the polar protic solvent is 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.

4. The process according to claims 1 to 3, wherein the dissolution of 2-(2- phenylethyl)propanedioic acid of formula (II) is carried out in toluene at a temperature between about 80°C and 100°C for a time between 15 minutes and 5 hours.

5. The process according to claims 1 to 4, wherein the decarboxylation of 2-(2- phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) is carried out in a solvent selected from hexane, heptane, cyclohexane, toluene, o-xylene, m-xylene, p-xylene, dimethylacetamide, acetonitrile, 1- methyl-2 -pyrrolidone or in a mixture of two or more, for instance two or three, of these solvents.

6. The process according to claim 5, wherein the decarboxylation of 2-(2- phenylethyl)propanedioic acid of formula (II) or of 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III) is carried out in presence of an organic base.

7. The process according to claim 6, wherein the organic base is triethylamine.

8. The process according to claims 1 to 7, further comprising reacting a compound of formula (V):

wherein X is a halogen, with a compound of formula (VI):

wherein R¹ and R² are independently selected from Ci-Ce alkyl or C3-C8 cycloalkyl, and wherein the Ci-Ce alkyl or C3-C8 cycloalkyl are 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 R¹ and R² are defined as above; and subsequently hydrolysing the compound of formula (VII) to form

2-(2-phenylethyl)propanedioic acid of formula (II) or 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III).

9. A compound selected from:

- 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 as defined in claim

2, with a purity > 99.95% measured at 220 nm in HPLC;

- 2-(2-phenylethyl)propanedioic acid monosodium salt of formula (III):

Na

(III).

10. Use of 2-(2 -phenyl ethyl)propanedioic acid monosodium salt of formula (III) as defined in claim 9 or of 2-(2-phenylethyl)propanedioic acid of formula (II) in crystalline form 1 having an XRPD spectrum characterized by one or more peaks, obtained using CuKa radiation, 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, to prepare sodium 4-phenylbutyrate of formula (I).

11. A process for purifying sodium 4-phenylbutyrate of formula (I):

comprising: forming a solution of 4-phenylbutyric acid of formula (IV):

12. The process according to claim 11, wherein 4-phenylbutyric acid of formula (IV) is salified with NaOH, NaHCCh, Na2COs, sodium methoxide, sodium ethoxide or sodium 2- ethylhexanoate.

13. The process according to claim 11 or 12, wherein the salification of phenylbutyric acid of formula (IV) to sodium 4-phenylbutyrate of formula (I) is carried out in a solvent selected from an aprotic dipolar solvent, typically 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; an ester, for example ethyl acetate; or a mixture of two or more, preferably two or three, of such solvents; or in water or in an aqueous solution comprising one or more said solvents.

14. The process according to claims 11 to 13, wherein the salification of phenylbutyric acid of formula (IV) to sodium 4-phenylbutyrate of formula (I) is carried out in water or in a mixture of water and acetonitrile.

15. The process according to claim 13 or 14, comprising freezing the solution of sodium 4- phenylbutyrate of formula (I) in the solvent or solvent mixture of salification, as defined in claims 13 or 14, and subsequent drying to obtain sodium 4-phenylbutyrate of formula (I) as solid.