Patent Description:
Solriamfetol, whose chemical name is (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate, is a drug used for the treatment of excessive sleepiness associated with narcolepsy and sleep apnea, and is marketed under the trade name Sunosi, in the form of the hydrochloride of formula (I)
<CHM>.

Different methods of synthesis of solriamfetol are known in the literature, which involve various intermediate products, such as D-phenylalanine, of formula (II), and D-phenylalaninol, i.e. (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol, of formula (III)
<CHM>
which, for example, can be obtained starting from the corresponding amino acid of natural origin, L-phenylalanine, a compound of formula (IV).

<CIT> describes the preparation of solriamfetol from its acid salt.

The Applicant found that the synthesis methods of solriamfetol, which provide for said intermediate products of formula (II) and (III), have technological limits linked to the difficulty of achieving high yields and competitive costs, also due to the chiral nature of the same being reversed with respect to the corresponding amino acid of natural origin, L-phenylalanine.

The Applicant found that the chiral nature of D-phenylalanine and D-phenylalaninol requires, in fact, the adoption of particular technical solutions in order to drive the stereospecificity of their preparation process, and that these particular technical solutions have a negative impact on the yield and on the overall costs of the synthesis of Solriamfetol hydrochloride.

The object of the present invention is therefore to provide a new process for the synthesis of solriamfetol hydrochloride capable of overcoming current difficulties and limits in obtaining the intermediates D-phenylalanine and D-phenylalaninol with high chemical and optical purity, thus reducing the impact on the yield and overall process costs of the final product.

According to the present invention, the Applicant has surprisingly found that it is possible to pursue the aforementioned object by using particular reaction conditions and expedients for obtaining the intermediates D-phenylalanine and D-phenylalaninol, starting from the corresponding starting amino acid of natural origin, L-phenylalanine.

In particular, the Applicant has discovered the possibility of obtaining in a simple way and in high yields a D-phenylalanine:(R)-mandelic acid complex with a particularly high diastereoisomeric ratio starting from L-phenylalanine. This allows the chirality of the latter to be substantially fully reversed in a single step, thus overcoming the current difficulties and limits in obtaining the intermediates D-phenylalanine and D-phenylalaninol, which can therefore be advantageously obtained with high optical and chemical purity, thus reducing their impact on the yield and overall costs of solriamfetol hydrochloride preparation. The process according to the present invention is therefore more competitive with respect to existing processes for the synthesis of solriamfetol hydrochloride.

Therefore, in a first aspect, the present invention relates to a process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride of formula (I)
<CHM>
comprising the steps of:.

In fact, it was surprisingly discovered that, thanks to the addition of (R)-mandelic acid and at least one aldehyde, it is possible to obtain in high yields a D-phenylalanine:(R)-mandelic acid complex with a particularly high diastereoisomeric ratio, starting from a suspension of L-phenylalanine in acetic acid.

Without being bound to a specific theory, the Applicant believes that the aldehyde reacts with the starting L-phenylalanine generating an imine species which, in the presence of acetic acid, leads to the formation of an iminium ion and racemization of its stereocenter, thus giving rise, after hydrolysis of the imine species, to in situ formation of the DL-phenylalanine racemic mixture. In the presence of mandelic acid, the D-phenylalanine thus formed reacts to form the D-phenylalanine:(R)-mandelic acid complex which, being slightly soluble in the reaction environment and also less soluble than the L-phenylalanine:(R)-mandelic acid complex, is easy to isolate. Furthermore, the hydrolysis of the imine species leads to regeneration of the starting aldehyde which is therefore not wasted during step a. and can further convert the L-phenylalanine remaining in the reaction medium, thereby progressing the dynamic kinetic resolution of the racemic mixture formed in situ and obtaining the D-phenylalanine:(R)-mandelic acid complex with a particularly high diastereoisomeric ratio.

This advantageously allows to effectively reverse the chirality of the starting L-phenylalanine in a single step, without any further particular technical solutions, in order to drive the stereospecificity of the reaction for obtaining D-phenylalanine and D-phenylalaninol, thus improving the process for preparing solriamfetol hydrochloride.

In a further aspect, the present invention also relates to a process for preparing a D-phenylalanine:(R)-mandelic acid complex, wherein the D-phenylalanine:(R)-mandelic acid molar ratio is <NUM>:<NUM>, comprising the addition of (R)-mandelic acid and at least one aldehyde to a suspension of L-phenylalanine in acetic acid.

The advantages of the process for preparing said complex according to this further aspect have already been outlined with reference to the process according to the first aspect of the invention and are not replicated here.

The D-phenylalanine:(R)-mandelic acid complex obtained from the process according to the present invention, shows a particularly high diastereoisomeric ratio and therefore allows to obtain D-phenylalanine in high yields and in a simple way, thus representing a key intermediate in the synthesis of solriamfetol hydrochloride.

In a still further aspect, the present invention therefore also refers to a D-phenylalanine:(R)-mandelic acid complex, wherein the D-phenylalanine:(R)-mandelic acid molar ratio is <NUM>:<NUM>, wherein said complex has a diastereoisomeric ratio higher than or equal to <NUM>/<NUM>.

The high diastereoisomeric ratio of the complex according to this aspect of the invention represents, in fact, an advantage in preparing solriamfetol hydrochloride, as it allows to obtain D-phenylalanine and D-phenylalaninol with a high enantiomeric purity which, as observed by the Applicant, represent a key step for obtaining solriamfetol hydrochloride.

Therefore, in a further and advantageous aspect, the present invention also relates to a process for preparing D-phenylalanine of formula (II)
<CHM>
comprising the steps of:.

The advantages of the process for preparing D-phenylalanine according to this further aspect have already been outlined with reference to the process according to the first aspect of the invention and are not replicated here. D-phenylalanine represents a key intermediate product for the synthesis of solriamfetol hydrochloride and the Applicant has found that an improved process for obtaining it can therefore contribute to making the synthesis of solriamfetol hydrochloride more competitive than existing processes.

In a further and advantageous aspect, the present invention also relates to a process for preparing (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol of formula (III)
<CHM>
comprising the steps of:.

The advantages of the process for preparing (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol (D-phenylalaninol) according to this further aspect have already been outlined with reference to the process according to the first aspect of the invention and are not replicated here. D-phenylalaninol represents a key intermediate product for the synthesis of solriamfetol hydrochloride and the Applicant has found that an improved process for obtaining it can therefore contribute to making the synthesis of solriamfetol hydrochloride more competitive than existing processes.

In a first aspect, the present invention relates to a process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride of formula (I)
<CHM>
comprising the steps of:.

Without being bound to a specific theory, the Applicant believes that the aldehyde reacts with the starting L-phenylalanine generating an imine species which, in the presence of acetic acid, leads to the formation of an iminium ion and to racemization of its stereocenter, thus giving rise, after hydrolysis of the imine species, to the in situ formation of the DL-phenylalanine racemic mixture. In the presence of mandelic acid, the D-phenylalanine thus formed reacts to form the D-phenylalanine:(R)-mandelic acid complex which, being poorly soluble in the reaction environment and also less soluble than the L-phenylalanine:(R)-mandelic acid complex, is easy to isolate. Furthermore, the hydrolysis of the imine species leads to regeneration of the starting aldehyde which is therefore not wasted during step a. and can further convert the L-phenylalanine remaining in the reaction medium, thereby progressing the dynamic kinetic resolution of the racemic mixture formed in situ, and obtaining the D-phenylalanine:(R)-mandelic acid complex with a particularly high diastereoisomeric ratio.

This advantageously allows to effectively reverse the chirality of the starting L-phenylalanine in a single step, without any further particular technical solutions in order to drive the stereospecificity of the reaction for obtaining D-phenylalanine and D-phenylalaninol, thus improving the process for preparing solriamfetol hydrochloride.

Within the scope of the present description and in the subsequent claims, all numerical quantities indicating amounts, parameters, percentages, and so on, are to be intended in all circumstances as preceded by the term "about", unless otherwise stated. Furthermore, all ranges of numerical quantities include all possible combinations of the maximum and minimum numerical values and all possible intermediate ranges, in addition to those specifically indicated below.

Within the scope of the present description and in the subsequent claims, the expression "diastereoisomeric ratio" (also abbreviated "d. ") means the molar ratio between the D-phenylalanine:(R)-mandelic acid complex and the L-phenylalanine:(R)-mandelic acid complex, expressed as D-phenylalanine:(R)-mandelic acid complex/ L-phenylalanine:(R)-mandelic acid complex. For example, a diastereoisomeric ratio of <NUM>/<NUM> indicates a product in which <NUM> parts by moles of D-phenylalanine:(R)-mandelic acid complex and <NUM> parts by moles of L-phenylalanine:(R)-mandelic acid complex are present.

The present invention may present in one or more of its aspects one or more of the preferred characteristics reported hereinafter, which can be combined with each other according to the application requirements.

The process according to the present invention comprises the step a. of adding (R)-mandelic acid and at least one aldehyde to a suspension of L-phenylalanine in acetic acid, thus obtaining a D-phenylalanine:(R)-mandelic acid complex, wherein the D-phenylalanine:(R)-mandelic acid molar ratio is <NUM>:<NUM>.

Preferably, in said step a. , said at least one aldehyde is selected from the group consisting of salicylaldehyde, benzaldehyde, picolinaldehyde (<NUM>-formyl pyridine), isonicotinaldehyde (<NUM>-formyl pyridine), propionaldehyde, and butyraldehyde.

In a preferred embodiment, in said step a. , said at least one aldehyde is salicylaldehyde.

Preferably, in said step a, from <NUM> to <NUM> equivalents of (R)-mandelic acid per <NUM> equivalent of L-phenylalanine, more preferably from <NUM> to <NUM> equivalents of (R)-mandelic acid per <NUM> equivalent of L-phenylalanine are added.

Preferably, in said step a, from <NUM> to <NUM> equivalents of said at least one aldehyde per <NUM> equivalent of L-phenylalanine, more preferably from <NUM> to <NUM> equivalents of said at least one aldehyde per <NUM> equivalent of L-phenylalanine are added.

Preferably, in said step a. , said dispersion of L-phenylalanine in acetic acid, comprises from <NUM>% to <NUM>% by weight of L-phenylalanine, with respect to the weight of acetic acid.

Preferably, said step a. is carried out at a temperature between <NUM> and <NUM>.

Preferably, said step a. it is carried out without adding water. Although step a. may also be carried out in the presence of water, the Applicant has in fact observed that water slows down the reaction kinetics in step a. , making the process less productive.

Preferably, in said step a. , the mixture is kept under stirring at a temperature ranging from <NUM> to <NUM>, preferably for a time ranging from <NUM> hour to <NUM> hours. Subsequently, the mixture thus obtained is then preferably brought to a temperature ranging from <NUM> to <NUM>, preferably over a period of time ranging from <NUM> hours to <NUM> hours, and then kept at said temperature, under stirring, for a time ranging from <NUM> hours to <NUM> hours.

Preferably, said step a. comprises isolating said D-phenylalanine:(R)-mandelic acid complex from the reaction mixture.

Preferably, said isolating step comprises at least one operation selected from the group consisting of washing with acetic acid, filtering, and drying said D-phenylalanine:(R)-mandelic acid complex.

Preferably said drying step is carried out at a temperature ranging from <NUM> to <NUM>, preferably for a time ranging from <NUM> to <NUM> hours.

The process according to the present invention comprises the step b. of isolating the D-phenylalanine of formula (II)
<CHM>
from the D-phenylalanine:(R)-mandelic acid complex obtained from step a.

The D-phenylalanine:(R)-mandelic acid complex obtained from said step a. advantageously shows a D-phenylalanine:(R)-mandelic acid molar ratio of <NUM>:<NUM>, and preferably a diastereoisomeric ratio (d. ) higher than or equal to <NUM>/<NUM>, even more preferably higher than or equal to <NUM>/<NUM>.

Said diastereoisomeric ratio may be determined by chiral HPLC analysis.

Preferably, said step b. is carried out at a temperature between <NUM> and <NUM>.

Preferably, said step b. comprises adding at least one base to a solution of said complex in at least one polar solvent.

The Applicant has in fact also surprisingly discovered that, thanks to the addition of at least one base to a solution of a D-phenylalanine:(R)-mandelic acid complex in at least one protic solvent, wherein the molar ratio D-phenylalanine:(R)-mandelic acid is <NUM>:<NUM>, it is possible to isolate D-phenylalanine in high yields. This advantageously allows to easily have an ideal starting product for the reaction of obtaining D-phenylalaninol, thus improving the process for preparing solriamfetol hydrochloride.

Preferably, in said step b. , said at least one base is selected from the group consisting of an amine, aqueous ammonia.

Preferably, in said step b. , said amine is selected from the group consisting of triethylamine, diisopropylethylamine, more preferably said amine is triethylamine.

Preferably, in said step b. , said at least one base is added to said solution at a temperature ranging from <NUM> to <NUM>, preferably over a period of time ranging from <NUM> minutes to <NUM> hours.

Preferably, in said step b, from <NUM> to <NUM> equivalents, more preferably from <NUM> to <NUM> equivalents, of said at least one base per <NUM> equivalent of said complex are added.

Preferably, in said step b. , said at least one polar solvent is protic, more preferably selected from the group consisting of water, methanol, ethanol, iso-propanol, n-propanol.

Preferably, in said step b. , said at least one polar solvent is a binary water/ethanol mixture.

Preferably, in said step b. , once the addition of said base is completed, the mixture thus obtained is kept under stirring at a temperature ranging from <NUM> to <NUM>, preferably for a time ranging from <NUM> hours to <NUM> hours. Subsequently, in said phase b. , the mixture thus obtained is preferably filtered and the D-phenylalanine thus separated is washed with at least one polar solvent and dried.

Preferably, said at least one polar solvent is selected from the group consisting of water, methanol, ethanol, iso-propanol, n-propanol.

Preferably, D-phenylalanine is dried at a temperature ranging from <NUM> to <NUM>, preferably for a time ranging from <NUM> hours to <NUM> hours.

Withing the scope of the present description and subsequent claims, the expression "chemical purity" means the relationship between a product and related substances, and the expression "optical purity" means the relationship between a product and its enantiomer.

At the end of step b. of the process according to the present invention, it is possible to obtain said D-phenylalanine with an optical purity ><NUM>/<NUM>, i.e. a product wherein the molar ratio D-phenylalanine/L-phenylalanine is greater than <NUM>/<NUM>.

The process according to the present invention comprises the step c. of reacting the D-phenylalanine obtained from step b. with a reducing agent, thus obtaining (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol of formula (III)
<CHM>.

Preferably, said step c. comprises reacting the D-phenylalanine obtained from step b. with a reducing system consisting of sodium borohydride and boron trifluoride, wherein said sodium borohydride is used in amounts ranging from <NUM> to <NUM> equivalent with respect to said D-phenylalanine.

The Applicant has, in fact, also surprisingly discovered that it is possible to effectively reduce D-phenylalanine to D-phenylalaninol ((R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol) by using a reducing system consisting of sodium borohydride and boron trifluoride, wherein said sodium borohydride is added in limited and specific amounts with respect to the D-phenylalanine to be reduced. The combined use of sodium borohydride and boron trifluoride allows the formation, even in situ, of borane species capable of reducing D-phenylalanine to D-phenylalaninol, and the use of limited amounts of sodium borohydride with respect to D-phenylalanine reduces significantly, and almost completely eliminates, the formation of hydrogen in the reaction medium. At the same time, this eliminates the safety issues associated with the presence of a flammable gas and allows a better control of the reaction for obtaining D-phenylalaninol, thus improving the process for preparing solriamfetol hydrochloride.

Preferably, in said step c. , said D-phenylalanine is suspended in at least one aprotic solvent.

Preferably, said at least one aprotic solvent is tetrahydrofuran (THF).

Preferably, said at least one aprotic solvent is anhydrous.

Preferably, in said step c. , said sodium borohydride is used in amounts ranging from <NUM> to <NUM> equivalents per <NUM> equivalent of said D-phenylalanine.

Preferably, in said step c. , said boron trifluoride is used in amounts ranging from <NUM> to <NUM> equivalent with respect to <NUM> equivalent of said D-phenylalanine.

Preferably, in said step c. , said sodium borohydride and said boron trifluoride are added to the reaction mixture separately.

In one embodiment, said sodium borohydride is added before said boron trifluoride.

In a further embodiment, said boron trifluoride is added before said sodium borohydride.

Preferably, when the reducing agent is a reducing system consisting of sodium borohydride and boron trifluoride, said step c. is carried out at a temperature between <NUM> and <NUM>.

Preferably, in said step c. , said sodium borohydride and said boron trifluoride are added to D-phenylalanine at a temperature ranging from <NUM> to <NUM>, preferably over a period of time ranging from <NUM> to <NUM> hours.

Preferably, in said step c. , after completing the addition of the reducing agent, the reaction mixture is kept under stirring at a temperature ranging from <NUM> to <NUM>, preferably for a time ranging from <NUM> to <NUM> hours.

Subsequently, water is added in said step c. Said addition of water quenches the reaction and then a basic aqueous solution is advantageously added, more preferably an aqueous solution of an alkaline or alkaline earth metal hydroxide, more preferably sodium hydroxide. Preferably, the addition of said aqueous solution of an alkaline or alkaline earth metal hydroxide is carried out over a period of time ranging from <NUM> to <NUM> hours.

Preferably, said step c. comprises isolating said (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol.

Preferably, said isolating step comprises extracting with an organic solvent and crystallizing said (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol.

Preferably, said organic solvent is selected from the group consisting of <NUM>-methyltetrahydrofuran (MeTHF), dichloromethane, iso-butanol, normal-butanol, toluene, isopropyl acetate, ethyl acetate, tert-butyl acetate, tetrahydrofuran.

In a preferred embodiment, said step c. comprises crystallizing said D-phenylalaninol. Preferably said crystallization is carried out by dissolution of D-phenylalaninol from step c. in a solvent, advantageously in toluene, and subsequent precipitation of D-phenylalaninol by cooling.

The Applicant has in fact surprisingly found that, in this way, it is possible to obtain D-phenylalaninol in particularly high yield, chemical purity, and optical purity.

At the end of step c. of the process according to the present invention, it is possible to obtain said D-phenylalaninol with an optical purity ><NUM>/<NUM>, i.e. a product wherein the molar ratio between D-phenylalaninol and L-phenylalaninol is higher than <NUM>/<NUM>.

The process according to the present invention comprises the step d. of reacting (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol obtained from step c. with an acid, thus obtaining (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate of formula (IV)
<CHM>.

Preferably, said step d. is carried out at a temperature between -<NUM> and <NUM>.

Preferably, in said step d. , the reaction between (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol obtained from step c. and an acid occurs in an anhydrous organic solvent.

Preferably, in said step d. , said acid is generated in situ by the reaction between a cyanate and a strong acid.

Preferably said cyanate is an alkali metal cyanate, even more preferably sodium cyanate.

Preferably, said strong acid is anhydrous.

Preferably, in said step d. , said strong anhydrous acid is added over a period of time ranging from <NUM> hours to <NUM> hours. Preferably, during said addition the reaction mixture is kept at a temperature ranging from -<NUM> to <NUM>.

Preferably, said strong acid is selected from the group consisting of methanesulfonic acid, hydrochloric acid.

Preferably, in said step d. , said strong acid is used in amounts ranging from <NUM> to <NUM> equivalents per <NUM> equivalent of (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol.

Preferably, in said step d. , said anhydrous organic solvent is dichloromethane.

Preferably, in said step d. , said acid is mixed with (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol in the presence of an anhydrous organic solvent, under stirring at a temperature ranging from -<NUM> to <NUM>. Preferably said acid is added to a solution of (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol in said anhydrous organic solvent.

Preferably, to terminate the reaction, a basic aqueous solution is added to bring the mixture to a pH greater than <NUM>, more preferably an aqueous solution of an alkaline or alkaline earth metal hydroxide, more preferably sodium hydroxide.

Preferably, said step d. comprises isolating said (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate from the reaction mixture.

Preferably, said isolating step comprises at least one operation selected from the group consisting of extracting with an organic solvent, washing, filtering, drying, and concentrating said (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate.

Preferably, said organic solvent is selected from the group consisting of dichloromethane, MeTHF, iso-butanol, normal-butanol, toluene, isopropyl acetate, ethyl acetate, tert-butyl acetate, tetrahydrofuran.

The process according to the present invention comprises the step e. of converting the (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate obtained from step d. into ((2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride of formula (I)
<CHM>.

Preferably, said step e. comprises bubbling gaseous HCl into a solution of said (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate in a polar protic solvent.

Preferably, in said step e. , said polar protic solvent is selected from the group consisting of an alcohol.

Preferably, said alcohol is isopropanol.

Preferably, in said step e. , said polar protic solvent is anhydrous.

Preferably, in said step e. , said bubbling of gaseous HCl is carried out at a temperature below <NUM>.

Preferably, in said step e. , the mixture thus obtained is kept under stirring at a temperature ranging from <NUM> to <NUM>, preferably for a time ranging from <NUM> hour to <NUM> hours.

Preferably, said step e. comprises isolating said (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride from the reaction mixture.

Preferably, said isolating step comprises at least one operation selected from the group consisting of washing with an aprotic polar solvent, filtering, and drying said (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride.

Preferably, said polar protic solvent is isopropanol.

Preferably, said drying is carried out under vacuum, at a pressure from <NUM> to <NUM> mBar, at a temperature from <NUM> to <NUM>.

In a further aspect, the present invention further relates to a process for preparing a D-phenylalanine:(R)-mandelic acid complex, wherein the D-phenylalanine:(R)-mandelic acid molar ratio is <NUM>:<NUM>, comprising the addition of (R)-mandelic acid and at least one aldehyde to a suspension of L-phenylalanine in acetic acid.

Preferably, the process for preparing the D-phenylalanine:(R)-mandelic acid complex according to the present invention may have one or more of the preferred characteristics of step a. of the process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride according to the first aspect of the present invention, which can be combined with each other according to the application requirements.

The D-phenylalanine:(R)-mandelic acid complex obtained from the process according to the present invention shows a particularly high diastereoisomeric ratio, and therefore allows to obtain D-phenylalanine in high yields and in a simple way, representing therefore a key intermediate in the synthesis of solriamfetol hydrochloride.

The high diastereoisomeric ratio of the complex according to this aspect of the invention represents, in fact, an advantage for the preparation of solriamfetol hydrochloride, as it allows to obtain D-phenylalanine and D-phenylalaninol having high enantiomeric purity, which, as found by the Applicant, represent a key step for obtaining solriamfetol hydrochloride.

The advantages of the process for preparing D-phenylalanine according to this further aspect have already been outlined with reference to the process according to the first aspect of the invention and are not replicated here. D-phenylalanine represents a key intermediate product for the synthesis of solriamfetol hydrochloride, and the Applicant has found that an improved process for obtaining it can therefore contribute to making the synthesis of solriamfetol hydrochloride more competitive with respect to existing processes.

Preferably, step i. of the process for preparing D-phenylalanine according to the present invention may have one or more of the preferred characteristics respectively of step a. of the process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride according to the first aspect of the present invention, which can be combined with each other according to the application requirements.

Preferably, step ii. of the process for preparing D-phenylalanine according to the present invention may have one or more of the preferred characteristics respectively of step b. of the process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride according to the first aspect of the present invention, which can be combined with each other according to the application requirements.

The advantages of the process for preparing (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol (D-phenylalaninol) according to this further aspect have already been outlined with reference to the process according to the first aspect of invention and are not replicated here. D-phenylalaninol represents a key intermediate product for the synthesis of solriamfetol hydrochloride, and the Applicant has found that an improved process for obtaining it can therefore contribute to making the synthesis of Solriamfetol hydrochloride more competitive with respect to existing processes.

Preferably, step <NUM>. of the process for preparing (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol according to the present invention may have one or more of the preferred characteristics respectively of step a. of the process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride according to the first aspect of the present invention, which can be combined with each other according to the application requirements.

Preferably, step <NUM>. of the process for preparing (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol according to the present invention may have one or more of the preferred characteristics respectively of step b. of the process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride according to the first aspect of the present invention, which can be combined with each other according to the application requirements.

Preferably, step <NUM>. of the process for preparing (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol according to the present invention may have one or more of the preferred characteristics respectively of step c. of the process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride according to the first aspect of the present invention, which can be combined with each other according to the application requirements.

The invention will be now illustrated by means of some Examples to be intended for illustrative and not limitative purposes of the same.

Chiral HPLC analysis: to perform the analysis, the sample is dissolved at a concentration of <NUM> milligrams/milliliter in a solution consisting of <NUM> parts by volume of a solution of perchloric acid at <NUM>% by volume in water and <NUM> parts by volume of acetonitrile, and is then analyzed according to the following method:.

<NUM> NMR: spectra were recorded with a BRUKER AV400 instrument in DMSO-d6. <NUM> microliters of trifluoroacetic acid were added to the samples in order to salify the amines present in the structure.

<NUM> grams of salicylaldehyde (<NUM> mmol, <NUM> eq) were added to a suspension of L-phenylalanine (<NUM>, <NUM> mmol, <NUM> eq) and (R)-mandelic acid (<NUM>. g, <NUM> mmol, <NUM> eq) in <NUM> of acetic acid. The reaction mixture was heated to <NUM> and stirred at the same temperature for <NUM> hours until almost complete racemization, as determined by chiral HPLC analysis according to the method described above. After one hour of reaction, the complete dissolution of the reagents was observed.

<FIG> shows the HPLC chromatogram obtained after complete dissolution of the reagents, in which the peaks related to (L)-phenylalanine (RT <NUM>) and (D)-phenylalanine (RT <NUM>) of the obtained racemic mixture are identifiable.

The reaction mixture was then allowed to spontaneously cool to <NUM> for <NUM> hours, then stirred at the same temperature for a further <NUM> hours. The formation of a precipitate was observed about <NUM> minutes after reaching the temperature of <NUM>.

The reaction mixture thus obtained was then filtered; the solid was washed with acetic acid (<NUM>) and dried at <NUM> for <NUM> hours. A D-phenylalanine:(R)-Mandelic Acid complex (<NUM>, <NUM>% yield, diastereoisomeric ratio (d. )> <NUM>/<NUM>) was obtained as a white solid.

The product thus obtained was analyzed by chiral HPLC and <NUM> NMR, showing no more than <NUM>% of L-phenylalanine.

<FIG> shows the HPLC chromatogram obtained, in which there is the peak corresponding to (D)-phenylalanine (RT <NUM>) and the substantial disappearance of the peak related to (L)-phenylalanine, thus confirming the inversion with respect to the start of the reaction.

<FIG> shows the obtained <NUM> NMR spectrum (<NUM>, DMSO-d6 + TFA) which allows to confirm the D-phenylalanine:(R)-mandelic acid molar ratio of <NUM>:<NUM>. The following is the assignment of the related peaks: δ (ppm) <NUM> (bs, <NUM>, NH), <NUM>-<NUM> (m, <NUM>), <NUM> (s, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>).

<NUM> grams of salicylaldehyde (<NUM> mmol, <NUM> eq) were added to a suspension of L-phenylalanine (<NUM>, <NUM> mmol, <NUM> eq) and (R)-mandelic acid (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> milliliters of acetic acid. The reaction mixture was heated to <NUM> and stirred at the same temperature for <NUM> minutes until almost complete racemization was detected by chiral HPLC analysis according to the method described above. The reaction mixture was then allowed to spontaneously cool to <NUM> for <NUM> hours, then stirred at the same temperature for a further <NUM> hours. The reaction mixture was filtered, the solid was washed with acetic acid (<NUM>) and dried at <NUM> for <NUM> hours. A D-phenylalanine:(R)-mandelic acid complex was obtained as a white solid (<NUM>, <NUM>% yield, d. <NUM>/<NUM>), whose identification and characterization by HPLC and <NUM> NMR was carried out according to the methods described above, obtaining results fully similar to those of the second complex of Example <NUM>.

<NUM> grams of salicylaldehyde (<NUM> mmol, <NUM> eq) were added to a suspension of L-phenylalanine (<NUM>, <NUM> mmol, <NUM> eq) and (R)-mandelic acid (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> milliliters of acetic acid. The reaction mixture was heated to <NUM> and stirred at the same temperature for <NUM> minutes until almost complete racemization was detected by chiral HPLC analysis according to the method described above. The reaction mixture was allowed to spontaneously cool to <NUM> for <NUM> hours, then stirred at the same temperature for a further <NUM> hours. About <NUM> hours after reaching the temperature of <NUM> the formation of a precipitate was observed. The reaction mixture was then filtered, the solid was washed with acetic acid (<NUM>) and dried at <NUM> for <NUM> hours. A D-phenylalanine-mandelic acid (R) complex was obtained as a white solid (<NUM>, <NUM>% yield, d. <NUM>/<NUM>), whose identification and characterization by HPLC and <NUM> NMR was carried out according to the methods described above, obtaining results fully similar to those of the second complex of Example <NUM>.

<NUM> grams of salicylaldehyde (<NUM> mmol, <NUM> eq) were added to a suspension of L-phenylalanine (<NUM>, <NUM> mmol, <NUM> eq) and (R)-mandelic acid (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> milliliters of acetic acid. The reaction mixture was heated to <NUM> and stirred at the same temperature for <NUM> hours until almost complete racemization was detected by chiral HPLC analysis according to the method described above. The reaction mixture was allowed to spontaneously cool to <NUM> for <NUM> hours, then stirred at the same temperature for a further <NUM> hours. The reaction mixture was filtered, the solid was washed with acetic acid (<NUM>) and dried at <NUM> for <NUM> hours. A D-phenylalanine-mandelic acid (R) complex was obtained as a white solid (<NUM>, <NUM>% yield, d. <NUM>/<NUM>), whose identification and characterization by HPLC and <NUM> NMR was carried out according to the methods described above, obtaining results fully similar to those of the second complex of Example <NUM>.

<NUM> grams of triethylamine (<NUM> mmol) were slowly added, over <NUM> hour, to a suspension of D-phenylalanine:(R)-mandelic acid complex according to Example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> of an EtOH/water mixture (<NUM>:<NUM> v/v), while keeping the temperature between <NUM> and <NUM>. After the addition was complete, the mixture was stirred at <NUM> for <NUM> hours and then filtered; the solid was washed with EtOH (<NUM> x <NUM>) and dried at <NUM> for <NUM> hours.

<NUM> grams of D-phenylalanine (<NUM>% yield) were thus obtained as a white solid. The product was analyzed by <NUM> NMR (<NUM>, DMSO-d6 + TFA) according to the method described above. <FIG> shows the <NUM> NMR spectrum obtained, and the assignment of the related peaks is as follows: δ (ppm) <NUM> (bs, <NUM>, NH), <NUM>-<NUM> (m, <NUM>), <NUM> (t, <NUM>), <NUM> (d, <NUM>).

<NUM> grams of triethylamine (<NUM> mmol) were slowly added, over <NUM> hour, to a suspension of D-phenylalanine:(R)-mandelic acid complex according to Example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> of EtOH, while keeping the temperature between <NUM> and <NUM>. After the addition was complete, the mixture was stirred at <NUM> for <NUM> hours and then filtered; the solid was washed with MeOH (<NUM> x <NUM>) and dried at <NUM> for <NUM> hours. <NUM> grams of D-phenylalanine (<NUM>%yield) were thus obtained as a white solid, whose identification and characterization by <NUM> NMR were carried out according to the method described above, obtaining results fully similar to those of D-phenylalanine according to Example <NUM>.

<NUM> grams of triethylamine (<NUM> mmol) were slowly added, over <NUM> hour, to a suspension of D-phenylalanine:(R)-mandelic acid complex according to Example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> of MeOH, while keeping the temperature between <NUM> and <NUM>. After the addition was complete, the mixture was stirred at <NUM> for <NUM> hours and then filtered; the solid was washed with MeOH (<NUM> x <NUM>) and dried at <NUM> for <NUM> hours. <NUM> grams of D-phenylalanine (<NUM>%yield) were thus obtained as a white solid, whose identification and characterization by <NUM> NMR were carried out according to the method described above, obtaining results fully similar to those of D-phenylalanine according to Example <NUM>.

<NUM> grams of triethylamine (<NUM> mmol) were slowly added over <NUM> hour to a suspension of D-phenylalanine-(R)-mandelic acid complex according to Example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> of MeOH, while keeping the temperature between <NUM> and <NUM>. After the addition was complete, the mixture was stirred at <NUM> for <NUM> hours and then filtered; the solid was washed with MeOH (<NUM> x <NUM>) and dried at <NUM> for <NUM> hours. <NUM> grams of D-phenylalanine (<NUM>%yield) were thus obtained as a white solid, whose identification and characterization by <NUM> NMR were carried out according to the method described above, obtaining results fully similar to those of D-phenylalanine according to Example <NUM>.

<NUM> milliliters of a <NUM>% by weight aqueous solution of NH<NUM> (<NUM> mmol) were slowly added, over <NUM> minutes, to a suspension of D-phenylalanine-(R)-mandelic acid complex according to Example <NUM> (<NUM>, <NUM> mmol, 1eq) in <NUM> of EtOH, while keeping the temperature between <NUM> and <NUM>. After the addition was complete, the mixture was stirred at <NUM> for <NUM> hours and then filtered; the solid was washed with EtOH (<NUM> x <NUM>) and dried at <NUM> for <NUM> hours. <NUM> grams of D-phenylalanine (<NUM>% yield) were thus obtained as a white solid, whose identification and characterization by <NUM> NMR were carried out according to the method described above, obtaining results fully similar to those of D-phenylalanine according to Example <NUM>.

<NUM> milliliters of a <NUM>% by weight aqueous solution of NH<NUM> (<NUM> mmol) were slowly added, over <NUM>, to a suspension of D-phenylalanine-(R)-mandelic acid complex according to Example <NUM> (<NUM>, <NUM> mmol, <NUM> eq) in <NUM> of MeOH, while keeping the temperature between <NUM> and <NUM>. After the addition was complete, the mixture was stirred at <NUM> for <NUM> hours and then filtered; the solid was washed with MeOH (<NUM> x <NUM>) and dried at <NUM> for <NUM> hours. <NUM> grams of D-phenylalanine (<NUM>% yield) were thus obtained as a white solid, whose identification and characterization by <NUM> NMR were carried out according to the method described above, obtaining results fully similar to those of D-phenylalanine according to Example <NUM>.

<NUM> grams of D-phenylalanine obtained according to Example <NUM> (<NUM> mmol, <NUM> eq) were suspended in <NUM> grams of anhydrous THF, under a N<NUM> atmosphere. The suspension was heated to <NUM> and NaBH<NUM> (<NUM>, <NUM> mmol, <NUM> eq) was added. After the last addition, the reaction mixture was kept under stirring at the same temperature for another hour until no gas evolution was detected anymore. <NUM> grams of BF<NUM>-THF complex (<NUM> mmol, <NUM> eq) were then added over <NUM> hours while keeping the temperature at <NUM>. At the end of the addition, the reaction mixture was still kept at the same temperature for a further <NUM> hours, then water (<NUM>) was added to quench the reaction and stirring was continued for a further <NUM> hour, while keeping the temperature at <NUM>, detecting the evolution of H<NUM>. The resulting mixture was stirred at the same temperature for another <NUM> minutes, then <NUM>% w/w NaOH (<NUM>) was slowly added over <NUM> hour. The reaction was kept under stirring at <NUM> for <NUM> hours, then the organic solvent was distilled and replaced with MeTHF (<NUM>). The obtained biphasic mixture was still kept under stirring at the same temperature and separated. The aqueous layer was extracted with additional MeTHF (<NUM>). Finally, the combined organic layers were washed with <NUM> grams of a solution obtained by combining <NUM> part by volume of a <NUM>% by weight aqueous solution of NaOH and <NUM> part by volume of a <NUM>% by weight aqueous solution of NaCl.

After concentration of the solvent and crystallization from toluene, <NUM> grams of D-phenylalaninol (<NUM>% yield) were obtained as a colorless crystal. The product was analyzed by chiral HPLC and by <NUM> NMR (<NUM>, DMSO-d6 + TFA) according to the methods described above.

<FIG> shows the HPLC chromatogram obtained, in which the peak corresponding to (D)-phenylalaninol (RT <NUM>) is present and in which it is possible to detect the substantial absence of the peak corresponding to (L)-phenylalaninol (RT <NUM>) and the negligible percentage area of the same with respect to D-phenylalaninol.

<FIG> shows the <NUM> NMR spectrum obtained and then relative peaks assignment: δ (ppm) <NUM> (bs, <NUM>, NH), <NUM>-<NUM> (m, <NUM>), <NUM> (bs, <NUM>, OH), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>).

<NUM> grams of D-phenylalanine (<NUM> mmol, 1eq) were suspended in <NUM> grams of anhydrous THF under a N<NUM> atmosphere. <NUM> grams of BF<NUM>-THF complex (<NUM> mmol, <NUM> eq) were added over <NUM> minutes, while keeping the temperature at <NUM>. The reaction mixture was heated to <NUM> and the mixture stirred for <NUM> minutes, then NaBH<NUM> (<NUM>, <NUM> mmol, <NUM> eq) was added. After the last addition, the reaction mixture was kept under stirring at the same temperature for a further <NUM> hours, then water (<NUM>) was added to quench the reaction and stirring was continued for a further <NUM> hour, while keeping the temperature at <NUM>, observing evolution of H<NUM>. The obtained mixture was kept under stirring at the same temperature for another <NUM> minutes, then <NUM>% w/w NaOH (<NUM>) was slowly added over <NUM> hour. The reaction was kept under stirring at <NUM> for <NUM> hours, then the organic solvent was distilled and replaced with MeTHF (<NUM>). The resulting biphasic mixture was kept under stirring at the same temperature and separated. The aqueous layer was extracted with additional MeTHF (<NUM>). Finally, the combined organic layers were washed with <NUM> grams of a solution obtained by combining <NUM> part by volume of a <NUM>% by weight aqueous solution of NaOH and <NUM> part by volume of a <NUM>% by weight aqueous solution of NaCl. After concentration of the solvent and crystallization from toluene, <NUM> grams of D-phenylalaninol (<NUM>% yield) were obtained as a colorless crystal, whose identification and characterization by HPLC and by <NUM> NMR was carried out according to the methods described above, obtaining results fully similar to those of D-phenylalaninol according to Example11.

<NUM> grams of D-phenylalanine (<NUM> mmol, <NUM> eq) were suspended in <NUM> grams of anhydrous THF, under a N<NUM> atmosphere. <NUM> grams of BF<NUM>-THF complex (<NUM> mmol, <NUM> eq) were added over <NUM> minutes, while keeping the temperature at <NUM>. The reaction mixture was heated to <NUM> and stirred for <NUM> hour, and <NUM> grams of NaBH<NUM> (<NUM> mmol, <NUM> eq) were added over <NUM> hours. After the last addition, the reaction mixture was kept under stirring at the same temperature for a further <NUM> hour, then further BF<NUM>-THF complex (<NUM>, <NUM> mmol, <NUM> eq) was added over <NUM> hours, while keeping the temperature at <NUM>. After the last addition, the reaction mixture was kept under stirring at the same temperature for another <NUM> hours, then water (<NUM>) was added to quench the reaction and stirring was continued for a further <NUM> hour, while keeping the temperature at <NUM>. The resulting mixture was kept under stirring at the same temperature for another <NUM> minutes, then a <NUM>% by weight aqueous solution of NaOH (<NUM>) was slowly added over <NUM> hour. The resulting mixture was kept under stirring at <NUM> for <NUM> hours, then the organic solvent was distilled and replaced with MeTHF (<NUM>). The biphasic mixture obtained was kept under stirring at the same temperature and separated. The aqueous layer was extracted with additional MeTHF (<NUM>). Finally, the combined organic layers were washed with <NUM> grams of a solution obtained by combining <NUM> part by volume of a <NUM>% by weight aqueous solution of NaOH and <NUM> part by volume of a <NUM>% by weight aqueous solution of NaCl. After concentration of the solvent and crystallization from toluene, <NUM> grams of D-phenylalaninol (<NUM>% yield) were obtained as a colorless crystal, whose identification and characterization by HPLC and by <NUM> NMR were carried out according to the methods described above, obtaining results fully similar to those of D-phenylalaninol according to Example <NUM>.

<NUM> grams of D-phenylalaninol (<NUM> mmol, <NUM> eq) and <NUM> grams of sodium cyanate (<NUM> mmol, <NUM> eq) were suspended in <NUM> milliliters of anhydrous DCM and the reaction mixture was cooled to <NUM>-<NUM> with a ice bath. <NUM> grams of methanesulfonic acid (<NUM> mmol, <NUM> eq) were slowly added, over <NUM> hours, while keeping the temperature below <NUM>. After the addition, the reaction mixture was allowed to warm to <NUM> and kept under stirring at the same temperature for <NUM> hours, then a <NUM>% by weight aqueous solution of NaOH was added to quench the reaction, while keeping the temperature below <NUM> and until reaching a pH of <NUM>-<NUM>. The two layers were then brought back to <NUM> and then separated. The aqueous layer was extracted with DCM (<NUM> x <NUM>). The combined organic layers were washed with a <NUM>% by weight aqueous solution of sodium chloride, dried over Na<NUM>SO<NUM>, filtered and concentrated. <NUM> grams of (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate (<NUM>% yield) were thus obtained as a colorless oil, which were used without further purification.

<NUM> grams of D-phenylalaninol (<NUM> mmol, <NUM> eq) and <NUM> grams of sodium cyanate (<NUM> mmol, <NUM> eq) were suspended in <NUM> milliliters of anhydrous DCM and the reaction mixture was cooled to -<NUM> with an ice and salt bath. Anhydrous HCl (<NUM> eq) was bubbled for <NUM> hours, while keeping the temperature below <NUM>. After the addition, the reaction mixture was allowed to warm to <NUM> and kept under stirring at the same temperature for a further <NUM> hours; a <NUM>% by weight aqueous solution of NaOH was added to quench the reaction, while keeping the temperature below <NUM> and until a pH of <NUM>-<NUM> is reached. The two layers were then brought back to <NUM>, and then separated. The aqueous layer was extracted with DCM (<NUM> x <NUM>). The combined organic layers were washed with a <NUM>% by weight aqueous solution of sodium chloride, dried over Na<NUM>SO<NUM>, filtered and concentrated. <NUM> grams of (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate (<NUM>% yield) were thus obtained as a colorless oil, which were used without further purification.

<NUM> grams of (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate according to Example <NUM> were dissolved in <NUM> milliliters of anhydrous isopropanol and the resulting mixture was heated to <NUM>. Gaseous HCl (<NUM> eq) was then bubbled into the mixture, while keeping the temperature below <NUM>. The reaction was kept under stirring at <NUM> for a further <NUM> hours, then allowed to cool to <NUM> and further stirred for <NUM> hour before recovering the solid by filtration. The filter cake was washed with <NUM> milliliters of isopropanol and dried in vacuo to give (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride as a white crystalline solid (<NUM>, <NUM>% yield).

<FIG> shows the <NUM> NMR spectrum obtained, and the relative peaks assignment is as follows: δ (ppm) <NUM> (bs, <NUM>, NH), <NUM>-<NUM> (m, <NUM>), <NUM> (bs, <NUM>, NH), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>), <NUM> (m, <NUM>).

Example <NUM> was repeated without adding salicylaldehyde. The solid obtained after filtration of the reaction mixture, subsequent washing with acetic acid and drying, was analyzed by chiral HPLC and did not show the formation of the D-phenylalanine:(R)-mandelic acid complex. <FIG> shows the HPLC chromatogram obtained, in which only the peak corresponding to (L)-phenylalanine (RT <NUM>) is present.

The test performed, when compared with Example <NUM>, therefore confirmed the relevance of the aldehyde presence in the reaction mixture to obtain the D-phenylalanine:(R)-mandelic acid complex starting from L-phenylalanine under the investigated reaction conditions.

The racemic phenylalanine separation process described in the publication "<NPL>, was replicated starting from <NUM> grams of DL-phenylalanine racemic mixture (Fluorochem, product code <NUM>), in order to verify the reaction yield and to determine the diastereoisomeric ratio of the D-phenylalanine:(R)-mandelic acid complex obtained.

In particular, <NUM> grams of DL-phenylalanine racemic mixture and <NUM> grams of (R)-mandelic acid were dissolved in <NUM> milliliters of hot water. The solution was slowly cooled and brought to room temperature, obtaining <NUM> grams of a white solid after one day. The solid was analyzed by chiral HPLC (<FIG>) observing the formation of the D-phenylalanine:(R)-mandelic acid complex (<NUM>, <NUM>% yield, diastereoisomeric ratio (d. ) = <NUM>/<NUM>).

The solid was then recrystallized in aqueous solution, isolating by filtration <NUM> grams of white solid which was also analyzed by chiral HPLC (<FIG>), observing the obtaining of D-phenylalanine:(R)-mandelic acid complex with a diastereoisomeric ratio of <NUM>/<NUM>, with an overall reaction yield of <NUM>%.

Claim 1:
A process for preparing (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride of formula (I)
<CHM>
comprising the steps of:
a. adding (R)-mandelic acid and at least one aldehyde to a suspension of L-phenylalanine in acetic acid, thus obtaining a D-phenylalanine:(R)-mandelic acid complex, wherein the D-phenylalanine:(R)-mandelic acid molar ratio is <NUM>:<NUM>;
b. isolating the D-phenylalanine of formula (II)
<CHM>
from the D-phenylalanine:(R)-mandelic acid complex obtained from step a;
c. reacting the D-phenylalanine obtained from step b. with a reducing agent, thus obtaining (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol of formula (III)
<CHM>
d. reacting (R)-(+)-<NUM>-amino-<NUM>-phenyl-<NUM>-propanol obtained from step c. with an acid thus obtaining (2R)-<NUM>-amino-<NUM>-phenylpropilcarbamate of formula (IV)
<CHM>
e. converting (2R)-<NUM>-amino-<NUM>-phenylpropilcarbamate obtained from step d. into said (2R)-<NUM>-amino-<NUM>-phenylpropylcarbamate hydrochloride of formula (I).