PROCESS FOR THE PREPARATION OF 2-(3-N,N- DIISOPROPYLAMINO-l-PHENYLPROPYL)-4-HYDROXYMETHYL- PHENOL AND ITS DERIVATIVES

The present invention concerns a process for the preparation of 2-(3-N,N- diisopropylamino- 1 -phenylpropyl)-4-hydroxymethyl-phenol (I, X=H) and its derivatives (I, X≠ H), key intermediates, as (R)-enantiomers, for the synthesis of Fesoterodine (II) and its salts, in particular of the salt with fumaric acid. The process of the invention involves new amide intermediates of general formula (IIIA) and (IIIB), which by reduction provide new amide intermediates of general formula (IV A) and (IVB); the latter compounds, racemic or enantiomerically enriched, allow the production of (I) by treatment with hydrides. The new intermediates are a further object of the present invention. The invention also concerns processes for the resolution of some derivatives of (R,S)-(I), particularly the trityl derivative (X = trityl), and for the racemization of the corresponding (S) undesired enantiomers. A further embodiment of the invention is a process for the preparation of Fesoterodine involving said intermediates of absolute configuration (R).

(I)

Fesoterodine (10

(II I A) (1 M B) (IV A) (IV B) Background of the invention

( )-2-(3-N,N-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl- phenoxy-isobutyrate (II), known as Fesoterodine, is an anti-cholinergic agent, useful in the treatment of urinary incontinence.

Its salt with fumaric acid resulted particularly interesting for pharmaceutical use and is known on the market with the name TOVIAZ ^® .

Fesoterodine is a pro-drug of 5-hydroxymethyl tolterodine, which is the active metabolite of Tolterodine.

Despite the close structural resemblance, Fesoterodine has been shown to display superior efficacy and tolerability over Tolterodine.

Fesoterodine fumarate was described for the first time in US6858650, which discloses the preparation of Fesoterodine by reaction of (R)-(+)-2-(3-N,N- diisopropylamino- 1 -phenylpropyl)-4-hydroxymethyl-phenol with isobutyryl chloride in the presence of triethylamine. The conversion into fumarate salt is carried out by treating the product with fumaric acid in 2-butanone and cyclohexane. This patent reports the melting point of Fesoterodine fumarate, either crude or recrystallized, but does not disclose the chemical and enantiomeric purity of the product.

The preparation of Fesoterodine is object of many patents.

Among these, US6713464 describes several 3,3-diphenylpropylamino derivatives, processes for their preparation, pharmaceutical compositions and methods for their use.

In this document, Fesoterodine is obtained, as the free base, starting from the deacylated precursor, (R)-2-(3-N,N-diisopropylamino-l-phenylpropyl)-4- hydroxymethyl-phenol [(R)-I, X=H)], according to the Scheme 1, indicated below:

Scheme 1

The compound [(R)-I, X=H)] constitutes the key intermediate. Its preparation, in racemic or optically enriched form, is described in several patents with synthetic processes consisting in numerous steps.

For example, in US5559269 it is prepared from para-bromophenol, using a very long synthetic procedure which utilises reagents that are difficult to use at industrial level such as lithium aluminium hydride and Grignard reagents.

This type of process, shown in a simplified way below {Scheme 2), involves, moreover, the use of protective groups to the OH-phenolic, to avoid secondary reactions:

[( )-I, X=H)]

Scheme 2

WO2007137799, WO2009037569 and WO2011145019 describe improvements to this synthetic scheme which, however, do not eliminate the use of critical reagents to be applied at industrial scale and tend to produce numerous wastes.

US6713464 discloses the preparation of (I, X=H) by means of Heck reaction, to prepare the Ν,Ν-diisopropyl acrylamide, which is then reacted with phenyl cuprate, LiAlH ₄ and A1C1 ₃ {Scheme 3). Subsequently, (I, X=H) is resolved into its optical antipodes and is esterified to get Fesoterodine.

[( ,S)-I, X=H)]

Scheme 3

But also this process suffers from numerous drawbacks and requires the use of reagents difficult to handle, such as acrylamide, LiAlH ₄ and A1C1 ₃ and conditions of reaction which are not suitable to be implemented at industrial level; in particular, the step involving phenyl cuprate must be carried out at a temperature of -78°C. Furthermore, it is necessary to protect the phenolic function as methyl ether and, only at the end, this protection can be removed using A1C1 ₃

Therefore, different synthetic approaches have been developed, aimed at the simplification of the original proceeding.

One of these is the approach via hydrocoumarins, known in the art from the preparation of Tolterodine, which has also been applied to the synthesis of 2-(3-N,N-diisopropylamino- 1 -phenylpropyl)-4-hydroxymethyl-phenol[(I), X=H)], according to Scheme 4, reported below:

[( ,S)-I, X=H)]

Scheme 4

Preparations following this synthetic route, with variations and improvements are described in WO89006644, WO01096279, WO07144097, WO2011282094 and WO2011110556.

Even this synthetic path, however, suffers from some problems.

In US6809214, for example, the process is characterized by the use of reagents that are difficult to handle at industrial level such as Diisobutylaluminium hydride (DIBAL), LiAlH ₄ and expensive resolving agents such as cinchonidine.

A simplification of the process via hydrocoumarins is reported in WO07138440 where the lactol is formed, in a single step, from the trans-cinnamaldehyde and then it is converted into (I, X=H) by reaction with diisopropylamine and H ₂ gas, in the presence of Pd/C.

The formation of lactol, however, is characterized by low yields of reaction and by the formation of many by-products and hence the process requires several purifications that make it less suitable for an industrial application.

WO2011154854 discloses an improved process for the preparation of (I, X=H) which starts from trans-cinnamaldehyde and involves the use of non toxic and easier to handle reagents and claims a new, stable, crystalline form of [(R)-(I), X=H].

The innovative part of the process involves the protection of 4-hydroxymethylphenol, by means of transformation into a silyl ether, and the subsequent reaction with trans-cinnamaldehyde and morpholine, according to Scheme 5, reported below:

Scheme 5

WO07017544 and WO07147547 describe the way traditionally shorter, one -pot, to synthesize Tolterodine, shown in Scheme 6, which comprises the reaction between p-cresol and N,N-diisopropylcinnamylamine (DIPCA) in the presence of a strong acid:

rac-Tolterodine

Scheme 6

This route is not easily applicable to the synthesis of Fesoterodine as the reaction of p-hydroxybenzyl alcohol and DIPCA does not proceed. Likewise, similar reactions fail when conducted on para-substituted phenols having groups convertible into hydroxymethyl, as for example, p-hydroxybenzoic acid or its esters, p-cyanophenol and p-hydroxybenzaldehyde and also reactions with the corresponding O-protected analogues.

The reaction seems to proceed only on the corresponding halogen derivatives which, however, require the Grignard reaction and also the protection of the phenolic group, to be converted into the hydroxymethyl product, as seen in similar processes, described in the documents cited above.

Finally, in WO05012227, [( )-(I), X=H] is prepared by oxidation of Tolterodine using a process with many steps. The oxidation of the methyl group of toluene is not simple and does not easily lead to the hydroxymethyl derivative but to the corresponding aldehyde which then must be reduced, with NaBH ₄ , and also requires the protection of the phenolic -OH and its subsequent deprotection, which evidently lengthens and complicates the synthesis and produces overall not satisfactory yields.

The existence of such a wide and varied literature shows how the current processes are not yet considered to be satisfactory and therefore requires and certainly warrants further study and investigation. Moreover, all the procedures reported in the art, when describe the synthesis of Fesoterodine, use the resolution of an appropriate intermediate, and mainly of the compound [(I), X=H], with methods that produce the (S) enantiomer as a by-product, which is not recovered nor re -used, with obvious cost increases. Even the use of a process to obtain the compound [(I), X=H] in enantiomerically enriched form is not described in the prior art.

Description of the invention

The present invention relates to a new process for the preparation of 2 - (3-N, N-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl-phenol (I, X = H) and its derivatives (I, X≠ H), key intermediates, such as (R)-enantiomers, for the synthesis of Fesoterodine (II) and its salts, in particular the corresponding fumarate. The process of this invention involves new amide intermediates of general formula (IIIA) and (IIIB), which afford, after reduction, new racemic or enantiomerically enriched amide intermediates of general formula (IV A) and (IVB). These latter compounds permit the production of (I) by treatment with hydrides. The new intermediates are a further object of the present invention. The invention also concerns a process for the resolution of some derivatives of (I), and the racemization of the unwanted enantiomer (S) - (I), in particular when X = trityl. Finally the invention is related to the transformation of (R) - (I) with X = trityl in Fesoterodine.

( M I A) ( 1 M B) ( IV A) ( IV B)

The structures (I) and (IV A and B) include either the racemates or the possible enantiomers (R) or (S) or their mixtures, the structure (III A and B) includes the possible geometric isomers E and Z.

The group R is C1-C4 alkyl, phenyl, benzyl. The group X represents hydrogen, benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl.

The process of the invention is shown in Scheme 7:

Fesoterodine

Scheme 7

Starting materials are compounds of formula (V) and (VI).

The synthesis of intermediates (ΙΠΑ) and (IIIB) consists in a Mizoroki- Heck reaction (a detailed review of this reaction is reported in the book "The Mizoroki-Heck Reaction", ed. M.Oestreich, Wiley 2009) and can be carried out, with a high yield and high purity, in the presence of a metal catalyst, preferably Pd, and a base. It should be noted that in the literature a N, N dialkyl- unsaturated amide has never been used as reagent for this reaction and indeed it has been reported that the Mizoroki-Heck is not readily applicable to this type of reactive olefins.

Starting from intermediates (IIIA) and (IIIB), which may be isolated or used in solution, it is possible to produce intermediates (IV A) and (IVB), by treatment with a suitable reducing agent, in the form of racemic mixtures or enantiomerically enriched ( ) or (S) enantiomers.

Although it is preferable that the hydroxymethyl group remains in a protected form, for this reaction, this is not mandatory. Consequently products (IVB) also include the case where X = H.

Subsequently a reaction is carried out with hydrides, such as Vitride ^® , on intermediates (IV A) and (IVB), which can lead to compounds (I) with X = H (which is already known compound), or, depending on the reaction conditions and the protective group used, to compounds (I), with X≠ H, which were never previously described compounds. Also this type of reduction, known per se, has required a detailed study of the reaction conditions with the aim of reducing the amount of by-products when the product obtained is (I) with X = H. In particular, it is preferred in the case where the process leads to the preparation of racemic or enantiomerically enriched (R) or (S) isomers compound (I) where X is a trityl group. The procedure for the resolution of the latter compound is carried out by salification with a suitable acid in enantiomerically pure form, in an appropriate solvent, through the formation and preferably the selective crystallization of the corresponding salt containing the (R) enantiomer (I) with X = trityl. The racemization of enantiomerically enriched (S) - (I) with X = trityl can be conveniently effected by heat treatment with a strong base having a pKa > 26, such as NaNH ₂ , at a temperature exceeding 80°C and preferably in the range 100-150°C.

(S)-(l) or the corresponding salts; X = Tr (R,S)-(I), X=Tr

The obtained racemic mixture of (I) with X = trityl can be conveniently reused in a step of resolution, thus allowing to obtain an overall process improvement which becomes cheaper.

When X≠ trityl there are two possible cases: X = H or X =≠ trityl protecting group.

The process of resolution of the compound (I) with X = H can be performed according to known methods but to recover and recycle the unwanted enantiomer is necessary the use of a protective group X that is stable under basic conditions at high temperature.

When the protective group X is different from trityl, the resolution can be carried out by selecting a suitable enantiomerically pure acid as resolving agent but, if the undesired enantiomer has to be recovered by racemization, this protective group X should be stable under basic conditions and at high temperature.

Preferably, the phenolic group in the of resolution and racemisation processes is used unprotected even if the presence of a protective group of this OH group is not harmful.

The enantiomer ( ) - (I) with X = trityl can be deprotected, under appropriate conditions at acidic pH, before the acylation reaction that leads to Fesoterodine using a known technique.

However, it is also possible to perform the selective deprotection, removing the trityl group, after the protection of the phenolic function as 2-methyl-propyl ester, thus obtaining a totally original process of synthesis of Fesoterodine.

The invention is also characterized in that an enantiomerically enriched molecule can be obtained, not only by the processes of resolution above described, but also through an enantioselective reduction of intermediates (IIIA) or (IIIB), that leads to enantiomerically enriched compounds (IV A) or (IVB), using suitable metal catalysts containing chiral ligands or biocatalysts as suggested by the literature. It has however to be stressed that the teachings of the prior art do not allow easily to the skilled person to envisage the catalysts and/or suitable experimental conditions to obtain an enantiomerically enriched product when the substrate is structurally complex.

The process of the invention is further characterized by the fact that most of the new intermediates can be isolated in solid form. This allows to overcome some of the problems left open by known processes that, on the contrary, often lead to the formation of intermediates of oily consistency, hardly isolable and purifiable, thus creating lower yield, formation of by-products and not allowing the easy isolation of API with high chemical and enantiomeric purity.

The process of the invention is therefore suitable for industrial scale and affords the desired product in good yield and quality.

Brief description of drawings

Figure 1 - shows the X- ay powder diffractogram of the Fesoterodine fumarate polymorph of Example 32.

Figure 2 - shows the X-Ray powder diffractogram numeric pattern of the Fesoterodine fumarate polymorph of Example 32.

Detailed description of the invention

The invention provides intermediates (IIIA), (IIIB), (IV A), (IVB), many of which are novel and have preferably X = trityl, and also intermediates (I) with X≠ H and preferably with X = trityl, which are useful for the synthesis of the key intermediate in the preparation of Fesoterodine namely the compounds (I) wherein X is H, in the racemic or enantiomerically enriched form. The new products were characterized by analytical and spectroscopic techniques such as, for example, HPLC, HPLC-MS, 1H-NMR, ¹³ C-NMR, m.p., [cc] _D and IR.

The intermediate (I) wherein X is H, so produced in an efficient and advantageous way, can then be used as pure enantiomer (R), according to known procedures, in the preparation of pharmaceutical grade Fesoterodine.

The reaction and work-up conditions can be adapted, as exemplified later, to the preparation of the novel intermediates with high yield and chemical purity. A technician expert in this field can easily determine, case by case, the most appropriate conditions, in particular in function of the protective group X and of its stability at different pH conditions.

In particular, the Mizoroki-Heck reaction used for the preparation of novel intermediates (ΙΠΑ) and (IIIB) can be performed using commercially available reagents (V) or easily prepared, such as (VI) and N, N-diisopropylcinnamide, using an unsaturated amide to aromatic halide ratio in the range from 2.5 / 1 to 0.9 / 1, preferably 1.5 / 1 - 0.9 / 1, most preferably 1.1 / 1 - 0.9 / 1. The reaction is carried out in the presence of an organic medium-low polar solvent such as for example 2-methyl-tetrahydrofuran (2-Me-THF), dioxane or toluene. Typically organic solvent to aromatic halide ratio is 2-10/1 w/w. Moreover, the reaction is carried out in the presence of an organic or inorganic base, and preferably in the presence of an organic sterically hindered base as, for example, Ν,Ν-dicyclohexylmethylamine. The base to aromatic halide stoichiometric ratio typically ranges from 1.5 / 1 to 1/1, preferably between 1.3 / 1 and 1/1. The Mizoroki-Heck reaction requires the presence of a catalyst, preferably a commercially available homogeneous catalyst based on Pd (0), e.g. [Pd(t.Bu ₃ P) ₂ ], and/or prepared in situ and/or preformed in a separate vessel and then added to the reaction mixture e.g. t.Bu ₃ P + Pd ₂ (dba) ₃ (where dba is dibenzylideneacetone) in suitable molar ratios. When Pd in a different oxidation state is added to the reaction mixture, example.g. Pd(OAc) ₂ , it has to be reduced in situ to obtain the active Pd(0) catalyst. The most suitable phosphines for this reaction are the hindered electron rich phosphines such as, for example, t-butylphosphine, di-t-butyl(2,2-diphenyl-l-methyl-l-cyclopropyl) phosphine (c-B IDP), di(l-adamantyl)-n-butylphosphine but the technician expert in this field may choose other phosphines, in particular other hindered electron rich phosphines. The aromatic halide to catalyst stoichiometric ratio should range from 100: 1 to 10000: 1, preferably 300: 1 to 5000: 1, more preferably 400: 1 to 2000: 1. It is also to be noted that starting from Ji-unsaturated amide, the obtained product (IIIA) and (IIIB) is predominantly the E isomer, which can be further purified by crystallization. However, even the pure Z isomer or a mixture containing Z and E isomers may be conveniently used for the subsequent reactions. As for the work-up of the reaction mixture, if there is a group X, sensitive to acid or basic pH, which is to be preserved in the molecule (IIIB), the washings should be carried out at a suitable pH and temperature, easily identified by a person skilled in the art.

As concerning to the subsequent reaction for obtaining the intermediates (IV A) and (IVB), the reduction may be effected by means of H ₂ or a hydrogen donor, such as sodium hypophosphite, in the presence of a heterogeneous catalyst, preferably heterogeneous Pd catalyst, at a pressure between 0.5 and 10 bar (although higher pressures are not deleterious), in a solvent, preferably chosen among an alcohol, such as methanol, ethanol or isopropanol, or an ether, such as THF, 2-Me-THF, optionally adding a quantity of water in the range 0.5-10%, with a solvent/unsaturated amide ratio usually in the range 3/1-20/1 w/w. The catalyst to unsaturated amide ratio is in the range of 1/300-1/5 w/w, preferably 1/200-1/10 w/w. The hydrogenation temperature is in the range 30-100°C and preferably 40- 80°C. The conversion and the yield of isolated intermediates (IV A) and (IVB) are >90%, usually >95%, while the reaction time depends on the reaction conditions. When an enantioselective reduction is carried out, a homogeneous chiral catalyst, commercially available or prepared in a separate vessel and then added to the reaction mixture, may be used indifferently. Among the known catalysts containing metals such as u, Rh, Ir, Co, Cu or Zn with suitable chiral ligands, those based on Ru, Rh, Cu or Ir are particularly applicable if the chiral ligand is a phosphine. The result of the reaction depends on the used catalyst, the chemical purity of the olefmic substrate and the reaction conditions. Using, for example, a commercial catalyst based on Ru, such as [RuCl (p-cymene) ((R)-DM- SEGPHOS ^® )]Cl, in a mixture of THF-EtOH (10: 1), working at 60°C and 60 bar of hydrogen, the product [IV A), X = Et] was obtained with e.e. 64% in favour of (R) enantiomer. On the contrary, using [Ru (S)-TMBTP (OCOCF ₃ ) ₂ in EtOH and working at 50°C and 40 bar of hydrogen, (S) [IV A), X = Et] was obtained with e.e 55%. The subsequent reduction to obtain the compounds (I) can be performed using a suitable hydride, such as e.g. Vitride ^® which is commercially available in toluene solution. It was noted that it is appropriate to work at a temperature < 25 °C in order to limit the formation of by-products and thus obtain a product with satisfactory yield and quality, particularly when X = H.

A further aspect of the invention concerns the resolution of the intermediate (I) when X = trityl.

The procedure for the resolution of the latter compound is carried out by salification with a suitable acid in enantiomerically pure form, in an appropriate solvent, through the formation and selective crystallization of the corresponding salt containing the enantiomer (R) - (I) with X = trityl. For example, (S) - mandelic acid or (R)-N-acetyl phenylglycine are used in amounts of 0.4-0.6 equivalents with respect to [(R, S) - (I) with X = trityl]. Suitable solvents are ethers, alcohols, ketones, arenes, esters, and are exemplified as convenient 2-MeTHF, methyl ethyl ketone (MEK) and t.amyl alcohol. Dry solvents or solvents containing 0.1-10% w/w of water may be used. Other solvents, where the intermediate (I) when X = trityl is soluble at room temperature in a concentration of > 10% and the corresponding salts with (S)-mandelic acid or with ( )-N-acetyl phenylglycine appear slightly soluble, may be also used. This procedure offers a unique advantage over similar resolutions previously reported in the state of art in which compound (I) with X = H was used. While in the known processes the enantiomer (S)-(I) with X = H is a waste, in the present case the recovery of (S) enriched enantiomer, protected as trityl derivative and present in the mother liquor, and its racemization can be carried out by a simple procedure: concentration to a residue of such mother liquors, dissolution in a solvent selected from aromatic hydrocarbons or ethers, and treatment with an appropriate base having a pKa > 26, such as e.g. NaNH ₂ , at a temperature comprised between 80 and 170°C and preferably 100-150°C. This procedure allows to recover, with a good yield, the product (R, S) - (I) with X = trityl that may be recycled without any problem. The racemization is carried out using 0.2-6 molar equivalents of sodium amide, and metal hydroxides or alkoxides may optionally be used as ancillary bases to decrease the amount of stronger base.

Another aspect of the invention concerns the preparation of Fesoterodine for acylation of (R)-(I) with X = trityl with a 2-methylpropionic acid derivative, such as 2-methylpropionyl chloride or 2-methylpropionic acid anhydride or 2-methylpropionic acid methyl or ethyl ester, and following removal of trityl group under suitable conditions at acidic pH. Working indeed with aqueous hydrochloric acid, in acetonitrile, at a pH in the range 0.8 - 2.5 the trityl group can be removed selectively and the Fesoterodine thus produced can be recovered with good yield and high chemical and enantiomeric purity. Finally a salt of Fesoterodine can be obtained by addition of an appropriate pharmacologically acceptable acid, in particular fumaric acid. The present procedure offers the additional advantage that the fumarate salt may be obtained in a desired crystalline or amorphous form according to the experimental conditions; as concerning to the crystalline form, having a defined XRD spectral pattern, the high quality of Fesoterodine obtained with the present process makes easier the recovery of fumarate salt as solid.

The enantiomeric excess of Fesoterodine fumarate has been determined using the HPLC technique [Column: Chiralpack AD 4.6 x 250 mm (5 μηι) column. Mobile phase = n-hexane: isopropanol: diethylamine = 400: 20: 0.8; Flow = 0.9 mL/min. Wavelength: 265 nm. Injection volume: 10 μΐ _^ , RT(enantiomer S)=6.9 min, RT(enantiomer R)= 7.4 min]. Sample: mix 50 mg of Fesoterodine fumarate with 2 mL of n-hexane and 2 mL of 10% aq. Na ₂ CO ₃ , dilute 0.5 mL of organic phase with 10 mL of hexane/iPrOH 9/1.

The solid form of Fesoterodine fumarate, obtained following the present invention, was characterized by X-ray Powder Diffraction (XRDP) using a Philips PW1800/10 diffractometer, equipped with software X'Pert High Score - v. 2.0a (PANalytical) and radiation Cu K .

FT-IR spectra were recorded using a Jasco FT/IR 460 plus spectrometer. Where not indicated, the spectra were recorded using the diffuse reflection method and the sample was prepared mixing about 5 mg of product with 500 mg of KBr

(10% w/w). The indication "film" refers to a film of product on NaCl, deposed by evaporation of a dichloromethane solution.

NMR spectroscopy: where not indicated, data was collected using a Bruker Avance 300 MHz spectrometer and using tetramethylsilane (TSM) as reference.

Other two spectrometers were used: Bruker Avance 400 MHz and Bruker 90 MHz.

The multiplicity of signals, in ¹³ C spectra, was assigned by means of a DEPT-135 experiment.

Melting point: melting were determined using a Buchi B400 equipment.

DSC: data was collected using a Mettler-Toledo DSC 822 ^e instrument. Standard DSC experiment: heat 40-300°C at 10 min.

MS spectroscopy: data was collected using a Agilent 6120 quadrupole, coupled with an Agilent 1200 HPLC. The invention is further illustrated by the following examples.

Example 1

Preparation of Compound [(IIIA), R=Et, as (E,Z) mixture]

Ethyl 3-(3-N,N-(diisopropylamino)-3-oxo-l-phenylprop-l-en-l-yl)-4- hydroxybenzoate

In a 500 mL vessel equipped with mechanical stirring 38.3 g of ethyl 3-bromo-4-hydroxybenzoate (0.156 mol), 39.8 g of N,N-diisopropyl-cinnamide (0.172 mol), 33.6 g of N,N-dicyclohexyl-methylamine (0.172 mol) and 170 mL of 2-Me-THF are loaded. After bubbling nitrogen for 5 minutes, the resulting solution is heated, maintaining a gentle nitrogen flow.

When the temperature of 70°C is reached 171 mg of [Pd(Pt-Bu ₃ ) ₂ ] (0.334 mmol) dissolved in 3mL of 2-Me-THF are added and the mixture is refluxed to almost complete conversion of aryl halide (ab. 7h). To the reaction mixture diluted aqueous HCl (85mL of water + 8.5 mL HCl 30%) and 85 mL of 2-Me-THF are loaded. The mixture is heated at 45-50°C. After removal of the aqueous phase, the organic phase is washed twice with water (170 mL at first and then with 85 mL), maintaining the temperature between 45 and 50°C.

After concentration of the organic phase under reduced pressure, the residue is taken up with 70 mL of toluene and the mixture is evaporated under vacuum. The residue is taken up with 200 mL of toluene, the mixture is heated at 50-60°C for 15 minutes, cooled slowly to room temperature then to 0-5°C, stirring for 2-3 hours. The product is isolated by filtration, rinsed with cold toluene and dried under vacuum at 55°C overnight to obtain 55 g (0.139 mol) (c.y. 89%) of the desired product as isomeric mixture E and Z (E/Z 93/7).

Example 2

Preparation of compound [(IIIA), R=Et, isomer (E)]

Ethyl (£ -3-(3-AyV-diisopopylamino-3-oxo-l-phenyl-l-en-l-yl)-4- hydroxybenzoate

A sample of 4.5 g of unsaturated amide (E/Z 93/7) obtained from Example

1 is dissolved in 70 mL of toluene at 80°C. The mixture is cooled to 30°C, promoting the crystallization by rubbing, then the temperature is slowly lowered to 20°C and the mixture is stirred for 1 hour at the same temperature. The product is isolated by filtration on Buchner, washed with cold toluene (2x15 mL) and dried under vacuum at 55°C overnight to give 3.5 g of product containing > 99% of isomer E.

HPLC-MS (m/z): 396 (M+H ⁺ )

IR ^m ^"1 ): 2975, 1716, 1629, 1605, 1562, 1279, 1427, 1371 , 1231 , 1 129, 771 , 696

m.p. (°C): 178-182

NMR (CDC1 ₃ ). ^; H-N R (ppm): 1.20 (6Η, d, J = 7 Hz, CH ₃ ); 1.27 (6H, d, J = 7 Hz, CH ₃ ) 1.38 (3H, t, J = 7 Hz, CH ₃ ); 3.42 (1H, set, J = 7 Hz, H- ); 4.27 (1H, set, J = 7 Hz, H-F'); 4.30 (2H, J = 7 Hz, -CH ₂ O ); 6.69 (1H, s, R-E ; 7.03 (1H, d, J = 9 Hz, H-O; 7.22 - 7.30 (5H, m aromatics); 7.71 (1H, d, J = 2 Hz, R-A); 7.92 (1H, dd, J = 9, 2 Hz, H-5); 9.00 - 950 (1H, broad, OH). C-NMR (ppm): 14.2 (CH ₃ ); 19.9 (CH ₃ ); 20.6 (CH ₃ ); 45.9 (CH-F); 50.5 (CH-F); 60.5 (CH ₂ ); 1 19.1 (CH); 122.2; 124.1 (CH); 126.9 (CH); 127.3; 128.4 (CH); 128.5 (CH); 131.2 (CH); 132.5 (CH): 140.0; 142.3; 159.3; 166.2 (COOR); 168.7 (CONR ₂ ).

Example 3

Preparation of compound [(IIIA), R=Et, isomer Z\

Ethyl (Z)-3-(3-7V,7V-diisopropylamino-3-oxo-l-phenylprop-l-en-l-yl )-4- hydroxybenzoate

The mother liquors of Example 2 are concentrated to residue. Almost 1 g of residue is purified by silica gel column chromatography (L=15 cm D=5 cm) using as eluent a mixture n-hexane/ethyl acetate 60/40. Fractions are controlled by TLC using the same eluent: Rf(Z) 0.35-0.40; Rf(F) 0.25-0.30. Fractions containing only the compound with higher Rf are evaporated under vacuum. The residue is triturated with n-hexane. After drying under vacuum 290mg of product containing 99% of Z isomer are obtained.

HPLC-MS (m/z): 396 (M+H ⁺ )

IR (cm ^"1 ): 2981, 1700, 1587, 1444, 1366, 1302, 1258, 1 1 1 1, 840, 773 m.p. (°C): 190-192°C

NMR (CDC1 ₃ ). ^; H-N R (ppm): 0.87 (6Η, d, J = 7 Hz, CH ₃ ); 1.30 (3H, t, J = 7 Hz, CH ₃ ) 1.41 (6H, d, J = 7 Hz, CH ₃ ); 3.35 (1H, set, J = 7 Hz, H-F); 4.26 (1H, set, J = 7 Hz, H-F'); 4.35 (2H, J = 7 Hz, -CH ₂ OR); 6.13 (1H, s, H-F); 6.64 (1H, d, J = 9 Hz, H-O; 7.18 - 7.24 (5H, m aromatics); 7.84 (1H, d, J = 2 Hz, R-A); 7.89 (1H, dd, J = 9, 2 Hz, H-F); 9.62 (1H, broad, OH). C-NMR (ppm): 14.3 (CH ₃ ); 19.9(CH ₃ ); 20.2 (CH ₃ ); 45.9 (CH- ); 50.6 (CH-F); 60.5 (CH ₂ ); 1 16.3 (CH); 121.0; 124.6 (CH); 127.9 (CH); 128.1 (CH); 128.5 (CH); 128.7; 131.1 (CH); 131.8 (CH): 138.4; 142.5; 159.7; 166.6 (COO ); 168.7 (CONR ₂ ).

Example 4

Preparation of compound [(R,5)(IVA), R=Et]

Ethyl (R,5)-3-(3-7V,7V-diisopropylamino-3-oxo-l-phenylpropyl)-4- hydroxybenzoate

In a 1L vessel equipped with mechanical stirring 52 g (0.131 mol) of ethyl 3-(3-N,N-diisopropylamino-3-oxo- 1 -phenylprop- 1 -en- 1 -yl)-4-hydroxy benzoate (E/Z= 93/7), prepared according to the procedure of Example 1, 500 mL of 2-Me-THF and 15 mL of water are loaded. After 3 vacuum/nitrogen cycles 5 g of 5% Pd/C (moisture 50%) are loaded and after 3 vacuum/hydrogen cycles the mixture is vigorously stirred under hydrogen atmosphere (0.5 bar) at 55°C.

After 21 hours of reaction the conversion is >98%.

The reaction mixture is filtered through celite at 50°C and the filter is rinsed with wet 2-Me-THF (2x50 mL). The filtrate is evaporated under vacuum to a volume of 70-80 mL. To the residue 200 mL of toluene are added and 50 mL of solvent are distilled under vacuum.

The suspension is then heated at 50-60°C and maintained at this temperature for 15 minutes, then cooled slowly to room temperature and finally to 0-5°C, under stirring for 2-3 hours at this temperature. The product is isolated by filtration, washed with cold toluene and dried under vacuum at 55°C overnight to give 49 g (0.123 mol) (c.y. 94%) of the desired product.

HPLC-MS (m/z): 398 (M+H ⁺ )

IR ^m ^"1 ): 2971, 1947, 1933, 1877, 1805, 1706, 1613, 1590, 1493, 1451, 1366, 1285, 1248, 1 1 16, 1043, 909, 771.

m.p. (°C): 184.5-189.0°C

NMR (CDC1 ₃ ). ^; H-N R (ppm): 1.12 (3Η, d, J = 7 Hz, CH ₃ ); 1.17 (3H, d, J = 7 Hz, CH ₃ ) 1.30 (3H, d, J = 7 Hz, CH ₃ ) 1.35 (3H, d, J = 7 Hz, CH ₃ ), 1.36 (3H, t, J = 7 Hz, -CH ₃ ); 3.17 (2H, m, H-F); 3.46 (1H, m, H-F); 4.08 (1H, set, J = 7 Hz, H-F'); 4.29 (2H, J = 7 Hz, -CH ₂ O ); 5.06 (1H, dd, J = 8.5 e 5.5 Hz, H-D); 6.90 (1H, d, J = 9 Hz, H-O; 7.15 - 7.31 (5H, m aromatics); 7.25 (2H, m, H-A e H-F); 10.33 (1H, broad, OH).

¹³ C-NMR (ppm): 14.3 (CH ₃ ); 20.3 (CH ₃ ); 20.4 (CH ₃ ); 20.5 (CH ₃ ); 20,6 (CH ₃ ); 39.0 (CH-D); 40.7 (CH ₂ ); 46.3 (CH-F); 48,9 (CH-F); 60.3 (CH ₂ ); 1 17.3 (CH); 121.8; 126.4 (CH); 128.1 (CH); 128.4 (CH); 129.2 (CH); 139.2 (CH); 131.5; 143.7; 159.5; 166.7 (COOR); 171.4 (CONR ₂ ).

Example 5

Preparation of compound [(R)-(IVA), R=Et]

Ethyl (R)-3-(3-7V,7V-diisopropylamino-3-oxo-l-phenylpropyl)-4- hydroxybenzoate

In an inox 50 mL autoclave, equipped with magnetic stirring,, under inert atmosphere [RuCl ( -cymene) ((R)-DM-Segphos)]Cl (6.0 mg, 0.00583 mmol), ethyl 3-(3-N,N-diisopropylamino-3-oxo- 1 -phenylprop- 1 -en- 1 -yl)-4- hydroxybenzoate (234 mg, 0.592 mmol), prepared according to the procedure described in Example 1 and a degassed mixture of THF-EtOH (10: 1) (4 mL) are loaded.

Hydrogen is introduced at first at a pressure of lObar, then reduced to lbar, carefully venting the autoclave. After repeating this procedure three times, hydrogen is introduced at 30bar and the mixture is stirred at 60°C for 16 hours, then at 60bar for additional 10 hours, obtaining ab. 80% conversion of the starting material. The mixture is filtered on charcoal and celite, then concentrated at reduced pressure and the residue diluted with IPA.

A sample is analyzed by HPLC on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = lmL/min. Wavelength: 280 nm. Injection volume: 10 μΐ _^ , RT(enantiomer S)=7,5 min, RT(enantiomer R)=24,3 min] observing e.e. of 64% in favour of enantiomer (R) of the product [IV A), R=Et].

Example 6

Preparation of compound [(.S')-(IVA), R=Et)

Ethyl (S) 3-(3-7V,7V-diisopropylamino-3-oxo-l-phenylpropyl)-4- hydroxybenzoate

In an inox 50 mL autoclave, equipped with magnetic stirring, under inert atmosphere [Ru(S)-TMBTP(OCOCF ₃ ) ₂ (7 mg, 0.00864 mmol), ethyl 3-(3-NN- diisopropylamino-3-oxo- 1 -phenylprop- 1 -en- 1 -yl)-4-hydroxybenzoate (293 mg, 0.742 mmol), prepared according to the procedure described in Example 1 and degassed EtOH (4 mL), are loaded.

Hydrogen is introduced at first at a pressure of lObar, then reduced to lbar, carefully venting the autoclave. After repeating this procedure three times, hydrogen is introduced at 20bar and the mixture is stirred at 50°C for 16 hours, then at 40bar for additional 8 hours, obtaining ca. 90% conversion of the starting material. The mixture is filtered on charcoal and celite, then concentrated at reduced pressure and the residue diluted with IPA.

A sample is analyzed by HPLC on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = lmL/min. Wavelength: 280 nm. Injection volume: 10 μΐ _^ , RT(enantiomer S)=7,5 min, RT(enantiomer R)=24,3 min] observing e.e. of 55% in favour of enantiomer (S) of the product [IV A), R=Et].

Example 7

Preparation of compound [(R,5)-(I), (X=H)]

2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymethyl- phenol hydrochloride

To a suspension of 20 g (50.3 mmol) of ethyl 3-(3-N,N-diisopropylamino-3- oxo-l-phenylpropyl)-4-hydroxybenzoate prepared according to the procedure described in Example 4, in toluene (200mL) are cautiously added 8mL of Vitride ^® (65-70% w/w in toluene) at 5-10°C. Then additional 60mL of Vitride ^® are added more rapidly at the same temperature. The mixture is then heated to room temperature and stirred for 20 hours. The mixture is then cautiously poured in a vessel containing 200 mL of 2-Me-THF, 200 mL of water and 20 mL of 30% NaOH aq. When quenching is complete the aqueous phase is discarded and the organic phase is washed with NaHCO ₃ aq to have pH=9 and then washed with water. The organic phase is concentrated to residue, taken up with acetonitrile (200 mL) and to this solution 4.3 mL of 36% HC1 aq are added. The suspension is concentrated at small volume, taken up with 100 mL of acetonitrile and stirred at 0-5°C for 1.5 hours. The product is isolated by filtration and washed with cold acetonitrile. Obtained 14.4 g (38.1 mmol)(c.y. 76%)of the compound [(R,S)-(I), (X=H)] as hydrochloride salt having purity 95%.

Example 8

Preparation of compound [(R)-(I), (X=H)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenol

A sample of the product obtained from Example 7 has been resolved in its enantiomers repeating the procedure described in WO2010018484 (Example 3, page 24) to obtain the compound [(R)-(I), (X=H)], having [cc] _D + 137(T= 25°C, CH ₂ C1 ₂ cone.1.0 g/100 mL), m.p. 100-102°C, e.e. >99% determined on Chiralpack IC 4.6 x 250 mm (5 μηι) column [mobile phase = 96:4 heptane / ethanol + 0.5% diethylamine; Flow = lmL/min. Wavelength: 210 nm].

Example 9

Preparation of compound [(R,5)-(I), (X=Tr)]

2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxymethy l-phenol

In a vessel equipped with mechanical stirring 12.3 g (44.2 mmol) of the hydrochloride salt of compound [(R,S)-(I), (X=H)], prepared according to the procedure described in Example 7 and having a purity ~ 95%, 50 mL of anhydrous DMF and 50 mL of anhydrous pyridine are loaded. To the resulting suspension 9.8 g (35.3 mmoles) of trityl chloride are added and the mixture is stirred at room temperature overnight. The resulting solution is then heated at 60°C, additional 1.6 g of trityl chloride are added and the mixture is stirred at 60°C for 3 hours.

The reaction is quenched adding 30% NaOH aq (12 g), water (70 mL) and toluene (120 mL). After 30 minutes the reaction is diluted with 120 mL of toluene and 500 mL of water. After buffering at pH=9 with NaHCO ₃ aq (7%), the aqueous phase is discarded and the organic phase is washed three times with 100 mL of water. The organic phase is evaporated to residue, taken up with toluene and evaporated to residue. This residue is then triturated at room temperature with 300 mL of hexane. The solid is isolated by filtration, washed with hexane and dried under vacuum to give 17 g of raw product. The obtained solid is then triturated at room temperature with 80 mL of isopropanol, filtered, washed with isopropanol and dried under vacuum. Obtained 14.5 g (25 mmol) (c.y 58%.) of pure [(R,5)-(I), (X=Tr)].

HPLC-MS (m/z): 584.3 (M+H ⁺ )

IR (cm ^"1 ): 3059, 3034, 2969, 2969, 2867, 2575, 1956, 1898, 1826, 1777, 1599, 1491 , 1449, 1392, 1372, 1253, 1218, 1 154, 1026, 747, 704.

m.p.(°C): 133-137°C.

Example 10

Preparation of compound [(R)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

In a vessel equipped with mechanical stirring lOg (29.3 mmol) of compound [(R)-(I), (X=H)], prepared according to the procedure described in Example 8, 40 mL of anhydrous DMF and 20 mL of anhydrous pyridine are loaded. To the resulting solution 3.4 g of pyridinium hydrochloride (29.3 mmol), 5.9 g (20.5 mmol) of trityl chloride are added and the mixture is stirred at 55°C for 2 hours. Additional 5.9 g (20.5 mmol) of trityl chloride are added and the mixture is stirred at 55°C for 2 hours; the mixture is then cooled to room temperature.

The reaction is quenched adding 30% NaOH aq (7 mL), water (14 mL) and, after 5 minutes stirring, toluene (300 mL) and water (400 mL). After buffering at pH=9 with Na ₂ CO ₃ aq (10%), the aqueous phase is discarded and the organic phase is washed twice with 50 mL of water. The organic phase is evaporated to residue, taken up with toluene and evaporated to residue. The residue is taken up with hexane and evaporated to residue. This residue is then triturated at room temperature with lOOmL of hexane. The solid is isolated by filtration, washed with hexane and dried under vacuum to give 18.1 g of raw product. The obtained solid is then triturated at 60°C with 90 mL of isopropanol; the suspension is slowly cooled to room temperature and stirred at this temperature for 1 hour. The solid is filtered, washed with isopropanol and dried under vacuum to obtain 14.8 g (25.3 mmol) (c.y 86%) of pure [(R)-(I), (X=Tr)] having e.e. 99%.

HPLC-MS (m/z): 584.3 (M+H ⁺ )

IR (cm ^"1 ): 3057, 3031 , 2967, 2874, 2761, 2601, 1969, 1885, 1597, 1585,

1494, 1448, 1373, 1250, 1 156, 1046, 1027, 899, 746, 707.

m.p. (°C): 146-147°C

NMR (CDC1 ₃ ). ^; H-N R (ppm, 400 MHz): 1.17 (6H, d, J = 7 Hz, CH ₃ ); 1.12 (6H, d, J = 7 Hz, CH ₃ ); 2.20 and 2.46 (2H, m, H-/±); 2.46 and 2.81 (2H, m, H- ); 3.32 (2H, set, J = 7 Hz, H-G); 4.03 (2H, AB system, J = 12 Hz, -CH ₂ O ); 4.59 (1H, dd, J = 10 e 4 Hz, H-D); 6.91 (1H, d, J = 2 Hz, R-A): 6.97 (1H, d, J = 9 Hz, H-G); 7.13 (1H, dd, J = 9, 2 Hz, H-5); 7.29 - 7.50 (20H, m, aromatics); 10.30 (1H, broad, OH). ¹³ C-NMR (ppm): 19.5 (2 CH ₃ ); 19.8 (2 CH ₃ ); 33.2 (CH ₂ - E) 39.6 (CH-D); 42,2 (CH ₂ - F) 48.1 (CH-G); 65.5 (CH ₂ -O ); 86.6; 1 17.9 (CH-Q; 125.8 (CH); 126.1 (CH); 126.7 (CH); 127.0 (CH); 127.6 (CH); 128.2 (CH); 128.5 (CH); 128.6 (CH); 130.5; 132.2; 144.1 ; 144.5; 154.6.

Example 11

Resolution of compound [(R,5)-(I), (X=Tr)]

(5)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

In a vessel equipped with mechanical stirring 0.5 g of [(R,S)-(I), (X=Tr)], prepared following the procedure described in Example 9, and 4 mL of t-amyl alcohol are loaded. To the solution obtained heating the mixture at 70°C 91 mg of (R)- acetoxymandelic acid dissolved in 2.2 mL of t-amyl alcohol are added. The mixture is left to reach room temperature, the solid is filtered and washed with t-amyl alcohol (2x2 mL).

By HPLC analysis on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = 1 mL/min. Wavelength: 280 nm. Injection volume: 10 Ε, RT(enantiomer S)= 12, 1 min, RT(enantiomer R)=10,6 min] on a sample of free base obtained after treatment with Na ₂ CO , 20% e.e. in favour of [(S)-(I), (X=Tr)] is determined. Example 12

Resolution of compound [(R,S)-(I), (X=Tr)]

(R)-2-(3-N,N-diisopropylamino-l-phenylpropyl)-4-trityloxymet hyl- phenol

Operating as described in Example 1 1, but using 71 mg of (S)-mandelic acid instead of 91 mg of (R)-acetoxymandelic acid, a solid is obtained after filtering and washing with t-amyl alcohol (2x2 mL).

By HPLC analysis on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = 1 mL/min. Wavelength: 280 nm. Injection volume: 10 μΐ _^ , RT(enantiomer S)= 12,1 min, RT(enantiomer R)=10,6 min] on a sample of free base obtained after treatment with Na ₂ CO ₃ , 71% e.e. in favour of [(R)-(I), (X=Tr)] is determined.

Example 13

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

Operating as described in Example 12, but using 6mL of 2-Me-THF instead of 4 mL of t-amyl alcohol, a solid is obtained after filtering and washing with 2-Me-THF (2x2 mL).

By HPLC analysis on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = 1 mL/min. Wavelength: 280 nm. Injection volume: 10 μΐ _^ , RT(enantiomer S)= 12, 1 min, RT(enantiomer R)=10,6 min] on a sample of free base obtained after treatment with Na ₂ CO ₃ , 96% e.e. in favour of [(R)-(I), (X=Tr)] is determined.

Example 14

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

Operating as described in Example 13, but using 6 mL of toluene instead of 6 mL of 2-Me-THF, a solid is obtained after filtering and washing with toluene (2x4 mL).

By HPLC analysis on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = 1 mL/min. Wavelength: 280 nm. Injection volume: 10 μΐ _^ , RT(enantiomer S)= 12, 1 min, RT(enantiomer R)=10,6 min] on a sample of free base obtained after treatment with Na ₂ CO , 24% e.e. in favour of [(R)-(I), (X=Tr)] is determined.

Example 15

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

Operating as described in Example 12, but using 6mL of t-amyl alcohol instead of 4 mL and 85 mg of (R)-N-acetylphenylglycine instead of 71 mg of (S)-mandelic acid, a solid is obtained after filtering and washing with t-amyl alcohol (2x2 mL).

By HPLC analysis on Chiralpack AD 4.6 x 250 mm (5 μηι) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1 ; Flow = 1 mL/min. Wavelength: 280 nm. Injection volume: 10 μΐ _^ , T(enantiomer S)= 12,1 min, RT(enantiomer R)=10,6 min] on a sample of free base obtained after treatment with Na ₂ CO ₃ , 60% e.e. in favour of [(R)-(I), (X=Tr)] is determined.

Example 16

Racemization of compound [(R)-(I), (X=Tr)]. (R,S)-2-(3-7V,7V- diisopropilamino-l-phenylpropyl)-4-trityloxymethyl-phenol

3,0 g (5.14 mmol) of [(R)-(I), (X=Tr)] (prepared following Example 10) and 20 mL of anisole are heated to 90-100°C and 585 mg (15 mmol) of sodium amide are added portion-wise. Then the mixture is heated to 125°C for 3 hrs.

After cooling to room temperature, water is added with caution to the reaction and the mixture is diluted with NaHCO aq (7%, 35 mL) and methylene chloride (40 mL). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to an oil residue (4 g). Calculated yield 77% (HPLC). The residue is taken up with 2-propanol (12 mL) heating gently. Then the mixture is allowed to cool to room temperature prior to be cooled to 0-5 °C and finally stirred for lh at this temperature.. The product is filtered off, washed with cool 2-propanol and dried in vacuo to give 2.0 g (3.43 mmol) (c.y. 67%) of [(R,S)-(I), (X=Tr)], with enantiomeric ratio: R / S = 50.1 : 49.9. Example 17

Racemization of compound [(R)-(I), (X=Tr)], trityl-cleavage and isolation of (R,S)-2-(3-7V,7V-diisopropilamino-l-phenylpropyl)-4- hydroxymethyl-phenol as hydrochloride salt

8,0 g (13.7 mmol) of [( )-(I), (X=Tr)] (prepared following Example 10) and 55 mL of anisole are heated to 90-100°C and 909 mg of sodium amide are added portion-wise. Then the mixture is heated to 125°C for 3hrs.

After cooling to room temperature, water is added with caution to the reaction and the mixture is diluted with NaHCO ₃ aq (7%, 76 mL) and methylene chloride (70 mL). The organic layer is separated, dried over anhydrous Na ₂ SO ₄ and concentrated in vacuo to an oil residue (16 g).

The residue is taken up with acetonitrile (80 mL) and the solution is treated with 7.0-7.5 mL of 1.9 M aq. HC1. (to pH 2.0-2,5).

The mixture is heated to 50°C for 1 h prior to be cooled to room temperature and charged with 240 mL of water and 40 mL of toluene. The organic phase is discarded while the aqueous phase is washed with another portion of toluene (40 mL). The aqueous phase is charged with 10% aq. Na ₂ CO ₃ (to basic pH), concentrated under reduced pressure, to distill off acetonitrile and extracted with methylene chloride. The organic extracts, containing about 3,3 g of (R,S)-(I) con X=H are collected and concentrated. The residue is dissolved with 30 mL of acetonitrile and concentrated HC1. The solution is reduced under vacuum to small volume and the residue is diluted with fresh acetonitrile (15 mL). After stirring, the product is filtered, washed with fresh acetonitrile and dried in vacuo to give 3.8 g (9.97 mmol) (c.y. 73%) of (R,S)-(I) con X=H as hydrochloride salt. Example 18

De-tritylation of compound [(R)-(I), (X=Tr)].

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenol [(R)-(I), (X=H)] as hydrochloride salt

To a suspension of 3.0 g (5.14 mmol) of [(R)-(I), (X=Tr)], obtained following the procedure described in Example 10, in 30 mL of acetonitrile and 15 mL of water, 0.45 mL of 1.9M HCI aq are added, verifying that the final pH is 2-2.5. The mixture is heated at 50°C for 1.5 hours and then cooled to room temperature observing complete de-tritylation.

To the formed suspension 80mL of water are slowly added; the mixture is left on stirring for 5-10 minutes. The solid is filtered and washed with slightly acidic 70/30 water/acetonitrile mixture recovering the mother liquors. The pH of these mother liquors is set at value equal to 9 with Na ₂ CO ₃ aq. After evaporation under vacuum to remove acetonitrile the residue is extracted with methylene chloride (2x30 mL) and the organic phase is again evaporated under vacuum to give 1.6 g of product.

The residue is taken up with 30mL of acetonitrile acidified with 36% HCI, concentrated to small volume and finally taken up with 15mL of acetonitrile. The product is filtered, washed with acetonitrile and dried under vacuum to give 1.5 g (3.97 mmol) (c.y 77%) [(R)-(I), (X=H)] as hydrochloride salt, having high purity and e.e > 99%.

Example 19

(R)-2-(3-/V,/V-diisopropiylamino-l-phenylpropyl)-4-trityloxy methyl- phenoxy-isobutyra

0.84 mL of triethylamine and 0.6 mL of pyridine are added to a solution of 2.22 g (3.80 mmol) of (R)-2-(3-N,N-diisopropylamino-l-phenylpropyl)-4- trityloxymethyl-phenol [(R)-(I), X=trityl], obtained following the procedure described in Example 10, in 20 mL of methylene chloride; the mixture is cooled to 10-15°C. After addition of 0.53 mL (4.94 mmol) of 2-methylpropionyl chloride the mixture is brought and maintained to room temperature under stirring for 2.5 hours. 10 mL of water and 2 mL of 10% Na ₂ CO ₃ aq are added. The organic phase is separated, washed with water at neutral pH and concentrated under vacuum. The residue is purified by silica gel column chromatography (4x10 cm). Eluent: from n-hexane/ethyl acetate 1/1 to ethyl acetate/2 -propanol 9/1. The fractions containing the desired product are merged and concentrated to residue to give 2.3 g (3.52 mmol) (c.y. 93%) of product.

HPLC-MS (m/z): 654.5 (M+H ⁺ )

[cc] _D : -1 1.2 (cone. 1, CH ₂ C1 ₂ , 25°C)

IR (film, cm ^"1 ): 3058, 3026, 2965, 2933, 2867, 1765, 1491, 1467, 1448, 1387, 1358, 1222, 1 120, 1089, 764, 745, 702

NMR (CDC1 ₃ ). ^] H.-NMR (ppm, assigned by COSY experiment): 1.03 (12H, bs, 4 CH ₃ ); 1.36 (3H, d, J = 7 Hz, CH ₃ ); 1.37 (3H, d, J = 7 Hz, CH ₃ ); 2.27 (2H, m, H-E); 2.47 (2H, m, H- ); 2.86 (1H, set, J = 7 Hz, H-H); 3.1 1 (2Η, m, Η- G); 4.16 (3Η, m, H-D e -C¾OR); 7.00 (1Η, d, J = 9 Hz, H-Q; 7.25 - 7.55 (22H, m, aromatic s). C-NMR (ppm): 18.9 (2 CH ₃ ); 19.0 (2 CH ₃ ); 20.1 (2 CH ₃ ); 34.1 (CH-H); 36.1 (CH ₂ - E) 41.7 (CH-D); 44.1 (CH ₂ - F) 49 A (CH-G); 65.3 (CH ₂ -O ); 87.0

122.2 (CH-G); 125.5 (CH); 126.1 (CH); 126.9 (CH); 127.7 (CH); 127.8 (CH)

128.3 (CH); 128.6 (CH); 136.1 ; 136.8; 143.6; 143.9; 147.5; 175.3 (COOR).

Example 20

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenoxy-isobutyrate

To a solution of 2.1 g (3.21 mmol) of (R)-2-(3-N,N-diisopropylamino-l- phenylpropyl)-4-trityloxymethyl-phenoxy-isobutyrate, prepared following the procedure reported in Example 19, in 20 mL of acetonitrile, 2 mL of water and 1.6 mL of 1.9M HCl aq are added, verifying that the obtained pH is in the range 2-2.5. The mixture is then heated at 50°C for 1 hour then cooled at room temperature, diluted with 55 mL of water and filtered to eliminate trityl alcohol. The filtrate is made basic and evaporated under vacuum to residue and taken up with methylene chloride. The organic phase is dried on Na ₂ SO ₄ , filtered and evaporated to residue to obtain 1.3 g (3.16 mmol) of the desired product (c.y 98%).

HPLC-MS (m/z): 412.3 (M+H ⁺ )

tf-NMR (CDC1 ₃₎ Bruker 90 MHz, ppm, reference TMS): 1.05 (12H, d, 7 Hz, CH ₃ ); 1.4 (6H, 2d, 7 Hz, CH ₃ ); 2.4 (4H, m, CH ₂ -CH ₂ ) 3.0 (3H, m, CHMe ₂ ); 4.15 (1H, bt, 7 Hz, CH-Ph); 4.7 (2H, s, -CH ₂ OH); 7.0 (1H, d, 9Hz, Ar); 7.3 (21H, m, Ar); 7.5 (1H, bs, Ar). Example 21

Preparation of compound [(VI), (X=Tr)]

2-Bromo-4-trityloxymethyl-phenol

197 g (684 mmol) of trityl chloride are added, over 2hrs, in three portions, to a solution of pyridinium chloride (22.6 g, 196 mmol) and 2-bromo-4- hydroxymethyl-phenol (133 g, 653 mmol) in 530 mL of dry DMF and 265 mL of dry pyridine. The mixture is stirred overnight at the same temperature.

The reaction is diluted with water (1.3L) and Toluene (1.3L), let to separate and the aqueous layer is discarded. After removal of most of pyridine under reduced pressure, the remaining mixture is diluted with ethyl acetate and the organic phase is washed, in order, with 5% aq. sodium bisulphate, 7% aq. sodium bicarbonate and finally with water. The organic phase is treated with active charcoal and then concentrated to a solid residue, under vacuum. The product is slurried with methanol (1500 mL) at reflux and finally isolated at room temperature, affording 259 g (581 mmol) (c.y 85%).of pure compound [(VI), (X=Tr)].

HPLC-MS (m/z): 443 (M-H ⁺ )

IR (cm ^"1 ): 3328, 3079, 3059, 3020, 2936, 2881, 1815, 1723, 161 1, 1509,

1489, 1446, 1419, 1375, 1284, 1218, 1001, 769, 751, 705.

m.p. (DSC, onset-peak-endset, °C): 156-159-162.

NMR (CDC1 ₃ ). ^; H-N R (ppm, 400 MHz): 4.12 (2H, s, -CH ₂ O ); 5.51 (1H, broad, OH);: 7.02 (1H, d, J = 9 Hz, H-Q; 7.25 (1H, dd, J = 9, 2 Hz, H-5); 7.50 (1H, d, J = 2 Hz, R-A) 7.28 - 7.60 (15H, m, Ph ₃ C-). Example 22

Preparation of Compound [ (IIIB), X=H, as (E,Z) mixture]

3-(2-hydroxy-5-(hydroxymethyl)phenyl)-N,N-diisopropyl-3- phenylacrylamide

In a vessel, under nitrogen atmosphere, N,N-diisopropylcinnamamide (66.0 g, 0.285 mol), 2-bromo-4-hydroxymethyl-phenol (55.0g, 0.271 mol), N,N-dicyclohexylmethylamine (58.6 g, 0.297 mol) and 2-Me-THF (290 mL) are loaded and the mixture is heated at 70-80°C. The catalyst, bis(tri-tert- butylphosphine)Pd, (130 mg, 0.25 mmol) is added and the reaction mixture is heated to about 86°C. Two more portions of catalyst (2x130 mg) are added after 1 and 2 hours, then, the mixture is maintained at the same temperature for two more hours, finally cooled at room temperature and diluted with 150 mL of 2-Me-THF. Then an aqueous solution of hydrochloric acid (3% w/w, 200mL) is added (pH =1) and the phases are let to separate. The water phase is discarded and the organic phase is washed again with dil. HC1 (3%, 100 mL) and, in order with water, aqueous 7% NaHCO ₃ and twice with water. The organic solution is treated with active carbon and celite, filtered and concentrated under vacuum to an oil residue.

The residue is taken up with methyl-tert-butyl-ether (MTBE) at 30°C and stirred until the product crystallizes. Then 120 mL of hexane is added slowly, the suspension is cooled to room temperature and stirred for 2 hrs. The product is filtered, washed with MTBE/hexane (2 x 25 m of 3/1 mixture) and dried under vacuum (HPLC purity A%= 96%, E/Z > 51 :1) to give 72.5 g (0.205 mol) (c.y.72%) of the product.

HPLC-MS (m/z): 354 (M+H ⁺ ), 352 (M-H ⁺ ). IR (cm ^"1 ): 3183, 2971 , 2876, 1584, 1444, 1373, 1350, 1270, 1203, 1044, 823, 699.

m.p. (°C): 59-71

NMR (CDC1 ₃ ). ^; H-N R (ppm, 400 MHz): 0.90 (6H, d, J = 7 Hz, CH ₃ ); 1.39 (6H, d, J = 7 Hz, CH ₃ ); 3.44 (2H, set, J = 7 Hz, H-E); 3.60 - 3.90 (broad, OH); 4.24 (1H, set, J = 7 Hz, H-E '); 4.56 (2H, s, -CH ₂ OH); 6.04 (1H, s, H-D); 6.84 (1H, d, J = 9 Hz, H-Q: 6.98 (1H, d, J = 2 Hz, Η- ); 7.13 (1H, i¾ J = 9, 2 Hz, H-5); 7.15 - 7.31 (5H, m, Ph-); 8.00 (1H, broad, OH).

¹³ C-NMR (ppm): 19.6 (2 CH ₃ ); 20.0 (2 CH ₃ ); 45.4 (CH-N ₂ ); 50.2 (CH-NR ₂ ); 64.2 (CH ₂ -OH); 1 16.6 (CH); 125.1 (CH); 127.7 (CH); 127.8 (CH); 127.9 (CH); 128.4 (CH); 129.2; 131.8; 138.2; 141.6; 153.6; 168.3 (CONR ₂ ).

Example 23

Preparation of Compound [(IIIB), X=Tr]

^-S-i -h drox -S-itrit lox meth ^phen ^-N^-diisoprop l-S- phenylacrylamide

In a vessel, under nitrogen atmosphere, N,N-diisopropylcinnamamide (95.1 g, 0.467 mol), 2-bromo-4-trityloxymethyl-phenol (174.3 g, 0.391 mol), NN-dicyclohexylmethylamine (84.1 g, 0.431 mol) and 2-Me-THF (785 mL) are loaded. The mixture is heated at 70-80°C, the catalyst, bis(tri-tert- butylphosphine)Pd, (400 mg, 0.78 mmol) is added and the reaction is heated to reflux. After 2h another portion of catalyst (200 mg, 0.39 mmol) is added, the reflux is maintained for three more hours and then the reaction is cooled to room temperature. After the addition of water (780 mL), the mixture is stirred for 1 h at room temperature, then, the product is filtered off, washed with water (3 x 100 mL), washed with 2-Me-THF (3x100 mL) and finally dried under vacuum to give 199.7g (0.335 mol) (c.y. 86%) of the product, HPLC purity A%= 96%).

HPLC-MS (m/z): 356 (M+H ⁺ ), 354 (M-H ⁺ ).

IR (cm ^"1 ): 3079, 2972, 2752, 1964, 1895, 1826, 1577, 1490, 1444, 1367, 1346, 989, 830, 786, 700.

m.p. (DSC: onset-peak-endset, °C): 210-213-215

NMR (DMSO-CDCI ₃ ). ^; H.-N R (ppm, 300 MHz): 0.980 (6H, d, J = 7 Hz, CH ₃ ); 1.28 (6H, d, J = 7 Hz, CH ₃ ); 3.33 (1H, set, J = 7 Hz, H-/±); 3.95 (2H, s, - CH ₂ OR); 4.27 (1H, set, J = 7 Hz, H-E '); 6.24 (1H, s, H-D); 6.84 (1H, d, J = 9 Hz, H-Q: 6.94 (1H, d, J = 2 Hz, R-A); 7.10 (1H, dd, J = 9, 2 Hz, H-5); 7.15 - 7.35 (20H, m, Ph ₃ C- and Ph-); 9.30 (1H, bs, OH).

¹³ C-NMR (ppm): 19.9 (2 CH ₃ ); 20.1 (2 CH ₃ ); 44.3 (CH-NR ₂ ); 49.5 (CH- NR ₂ ); 64.8 (CH ₂ -OR); 86.3; 1 15.7 (CH-Q; 125.8 (CH); 126.9 (CH); 127.3 (CH); 127.5 (CH); 127.6 (CH); 127.8 (CH); 127.9; 128.1. (CH); 128.4 (CH); 128.5; 129.3 (CH); 139.6; 139.8; 143.7; 154.2; 166.9 (CONR ₂ ).

Example 24

Preparation of Compound [(IVB), X=H]

(R,5)-3-(2-hydroxy-5-(hydroxymethyl)phenyl)-N,N-diisopropyl- 3- phenylpropanamide

Compound (IIIB, X=H), prepared according to Example 22, (17 g, .1 mmol), 2-Me-THF (315 mL) and ethanol (35 mL) are loaded into a 1L round bottomed flask, fitted with a mechanical stirrer. The flask is washed three times with nitrogen, 5% Pd/C (2.3 g, 50% wet) and sodium carbonate (9.2 g) are added and the reaction mixture is stirred under hydrogen atmosphere (1 bar) at 50°C until the hydrogenation of the starting material is complete. After cooling the mixture to room temperature the catalyst and the salt are filtered off and washed with 2-MeTHF-Ethanol mixture.

The solution is concentrated under reduced pressure, the residue is suspended with toluene and concentrated again and then slurried with 100 mL of toluene, at room temperature. The product is filtered off, washed with toluene and dried under reduced pressure, at 50°C, overnight. 15.7 g (44.2 mmol) (c.y. 92%) are obtained.

HPLC-MS (m/z): 356 (M+H ⁺ ), 354 (M-H ⁺ ).

IR (cm ^"1 ): 3607, 3435, 2965, 3100, 2924, 1601, 1578, 1507, 1475, 1433, 1338, 1272, 1261, 1207, 1 156, 1 102, 1042, 891, 816, 699, 610.

m.p. (DSC: onset-peak-endset, °C): 185-187-189.

NMR (CDC1 ₃ . ^; H-N R (ppm, 400 MHz): 1.12 (3H, d, J = 7 Hz, CH ₃ ); 1.16 (3H, d, J = 7 Hz, CH ₃ ) 1.28 (3H, d, J = 7 Hz, CH ₃ ) 1.37 (3H, d, J = 7 Hz, CH ₃ ); 3.14 (2H, m, H-F); 1.90 (broad, OH); 3.47 (1H, m, H-F); 4.06 (1H, set, J = 7 Hz, H-F'); 4.42 (2H, s, -CH ₂ OH); 5.02 (1H, dd, J = 8.5 e 5.5 Hz, H-D); 6.84 (1H, d, J = 2 Hz, H-A) 6.93 (1H, d, J = 9 Hz, H-Q; 7.04 (1H, dd, J = 9,2 Hz, H-5); 7.15 - 7.31 (5H, m, Ph-); 10.50 (1H, broad, OH).

¹³ C-NMR (ppm): 20.3 (CH ₃ ); 20.4 (CH ₃ ); 20.5 (2 CH ₃ ); 38.5 (CH- ); 41.0 (CH ₂ - F); 46.3 (CH-F); 48.7 (CH-F); 65.1 (CH ₂ -OH); 1 18.4 (CH); 126.3 (CH); 126.6 (CH); 127.8 (CH); 128.1 (CH); 128.4 (CH); 132.2; 132.6; 144.3; 154.2;

Example 25

Preparation of Compound [(IVB), X=Tr]

(R,5)-3-(2-hydroxy-5-(trityloxymethyl)phenyl)-N,N-diisopropi l-3- phenylpropanamide

Compound (IIIB, X=Tr) (100 g, 0.168 mol), prepared according to Example 23, Toluene (1200 mL), sodium carbonate (10 g) and water (100 mL) are loaded into a 2L round bottomed flask, fitted with a mechanical stirrer. The flask is washed three times with N ₂ , 5% Pd/C (10 g, 50% wet) are added and the reaction mixture is stirred under H ₂ atmosphere (1 bar) at 50-55°C until the hydrogenation of the starting material is complete (about 24h). After the cooling to room temperature the catalyst is filtered off and washed with toluene. The mixture is let to separate, the aqueous layer is discarded and the organic phase is washed with water (3x100 mL).

The solution is concentrated under reduced pressure, and the residue is taken up with methanol (400 mL) and concentrated again than slurried with methanol (500 mL). The product is filtered off, washed with methanol (2 x 50 mL) and dried under reduced pressure, at 50°C, overnight to give 81.5 g (0.136 mol) (c.y. 81%) of the product.

HPLC-MS (m/z): 596 (M-H ⁺ ).

IR (cm ^"1 ): 3086, 2972, 2938, 1587, 1512, 1490, 1447, 1340, 1277, 1220, 1208, 1 158, 1 102, 1075, 1027, 822, 764, 747, 702.

m.p. (DSC: onset-peak-endset, °C): 161-164-166.

NMR (CDC1 ₃ ). ^; H-N R (ppm, 400 MHz): 1.14 (3H, d, J = 7 Hz, CH ₃ ); 1.22 (3H, d, J = 7 Hz, CH ₃ ) 1.32 (3H, d, J = 7 Hz, CH ₃ ) 1.42 (3H, d, J = 7 Hz, CH ₃ ); 3.18 (2H, d, J = 7 Hz, H-/±); 3.51 (1H, m, H- ); 4.01 (2H, AB system, J = 12 Hz, -CH ₂ O ); 4.09 (1H, set, J = 7 Hz, H-F'); 5.08 (1H, t, J = 7 Hz, H-D); 6.96 (1H, d, J = 9 Hz, H-Q: 6.98 (1H, , J = 2 Hz, Η- ); 7.06 (1H, <¾ J = 9,2 Hz, H- B); 7.22 - 7.45 (20H, m, aromatics); 9.61 (1H, bs, OH).

¹³ C-NMR (ppm): 20.3 (CH ₃ ); 20.5 (CH ₃ ); 20.6 (CH ₃ ); 20.65 (CH ₃ ); 38.5 (CH-D); 41.1 (CH ₂ - E) 46.3 (CH- ); 48.6 (CH- ); 65.5 (CH ₂ -O ); 86.7; 1 18.2 (CH-O; 126.1 (CH); 126.2 (CH); 126.7 (CH); 127.4 (CH); 127.6 (CH); 128.1 (CH); 128.3 (CH); 128.5 (CH); 130.7; 132.0; 144.1 ; 144.5; 153.7; 171.7 (CONR ₂ ).

Example 26

Preparation of Compound [(I), X=Tr]

(R,S)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-tritylox ymethyl- phenol

A well dried 1L round bottomed flask, fitted with a mechanical stirrer, is purged with nitrogen and loaded with Compound (IVB, X=Tr), prepared according to Example 25, (20 g, 33.5 mmol) and anhydrous toluene (200 mL). The suspension is cooled with an ice bath and a first portion of Vitride ^® (5.4 g, > 65% w/w in toluene) is added, drop-wise, at 5-10°C (exothermic reaction and H ₂ evolution occur). Then the second portion of Vitride ^® (39.5 g, > 65% w/w in toluene) is added, the reaction is warmed gently to 25 °C and stirred at the same temperature overnight. Acetone (4.4 mL) is slowly dropped allowing the temperature to rise to 30-35°C. After 5 min 10%NaOH (200 mL) is added and the mixture is stirred for 10 min at room temperature. Then, the aqueous phase is separated and the organic phase washed, in order, with dil. NaOH (10% w/w, 100 mL) and water (3 x 100 mL). The final organic solution is evaporated under reduced pressure using a water bath (Tmax 50-60°C). The residue (ab. 18.6 g) is taken up with isopropanol (100 mL) at 60-65 °C and the suspension obtained is stirred while is cooled to room temperature. The mixture is stirred for 30min-lh and filtered to afford 16.1 g (27.6 mmol) (82%) of the product.

HPLC-MS (m/z): 584.3 (M+H ⁺ )

Example 27

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

In a round bottomed flask, equipped with mechanical stirrer, 10.0 g (17.1 mmol) of [(R,S)-(I), (X=Tr),], prepared following the procedure described in Example 9, and 100 mL of methyl-ethyl ketone (MEK) are loaded and the mixture is heated to 60°C. To the solution obtained half of a solution of 1.25 g (8.2 mmol) of (S)-(+)-mandelic acid in 5 mL of MEK is added before seeding with pure (R)-(I) (X=Tr) (S)-mandelate salt, then, the rest of the mandelic acid solution is dropped in 10 min and the suspension maintained for 30 min. at 60°C. The mixture is cooled slowly at RT (20-25 °C), stirred for lh, and the product is filtered, washed with MEK and dried under vacuum at 40/50°C. 5.1g (6.9 mmol) (c.y 40%) of mandelate salt. A sample of free base shows a 96% e.e. in favour of [(R)-(I), (X=Tr)].

Example 28

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol In a round bottomed flask, equipped with mechanical stirrer, 10.0 g (17.1 mmol) of [(R,S)-(I), (X=Tr),], prepared following the procedure described in Example 9, and 40 mL of MEK are loaded and the mixture is heated to 60°C. To the solution obtained about 1/4 of a solution of (S)-(+)-mandelic (1.25 g, 8.2 mmol) in MEK (6 mL) is added before seeding with pure (R)-(I) (X=Tr) (S)-mandelate salt. Then, the rest of the mandelic acid solution is dropped in 10 min and the suspension maintained for lh at 65°C. 2.0 mL of water is added and the suspension is heated at reflux (about 75 °C) for lh, before being cooled to room temperature in about lh and stirred for 30 min. The product is filtrated off, washed with MEK and dried under vacuum at 40/50°C to give 3.2 g (4.3 mmol) (c.y 25%) of mandelate salt. A sample of free base shows a 97% e.e. in favour of [(R)-(I), (X=Tr)].

Example 29

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-/V,/V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

Operating as described in Example 27, but using 2-MeTHF instead of MEK, 5.1 g of mandelate salt is obtained. A sample of free base shows 86% e.e. in favour of [(R)-(I), (X=Tr)]. Example 30

Resolution of compound [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

Operating as described in Example 27, but using wet 2-MeTHF (containing 2% of water) instead of MEK, 3.8 g of mandelate salt is obtained. A sample of free base shows 96% e.e. in favour of [(R)-(I), (X=Tr)].

Example 31

Resolution of [(R,5)-(I), (X=Tr)]

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-trityloxym ethyl- phenol

In a round bottomed flask, equipped with mechanical stirrer, 135 g (0.231 mol) of [(R,S)-(I), (X=Tr)], prepared following the procedure described in Example 9, and 1350 mL of methyl-ethyl ketone (MEK) are loaded and the mixture is heated to 60-65°C. To the solution obtained 1/4 of a solution of 17.2 g (0.1 13 mmol) of (S)-(+)-mandelic acid in 85 mL of MEK is added before seeding with pure (R)-(I) (X=Tr) (S)-mandelate salt, then, the rest of the mandelic acid solution is dropped in 30 min. The suspension is heated at reflux temperature, for lh, cooled to room temperature (20-25°C) in lh and stirred for 30 min. The product is filtered, washed with MEK (2x40 mL). The product (83 g wet) is suspended in 800 mL of MEK, heated at reflux temperature, cooled to 70°C and stirred for 45 min, cooled to room temperature in lh and stirred for 30 min. The product is filtered, washed with MEK (2x40 mL). The product (70 g wet) is finally slurried using 660 mL of MEK and 13 mL of water. The product is filtered, washed with MEK (2x30 mL) and dried under vacuum to give 54 g of mandelate salt. A sample of free base shows 98.2% e.e. in favour of [(R)-(I), (X=Tr)].

The salt is then mixed with 250 mL of 2-MeTHF, 100 mL of water and 20 g of 30% aq. NaOH and stirred until two clear phases are obtained. After the correction of pH to 9-10 with the addition of NaHCO ₃ , the aqueous phase is discarded. The organic phase is washed with water (3x50 mL) and evaporated under reduced pressure to a thick residue that is taken up with 300 mL of methanol and stirred at room temperature for lh. The free base is filtered off, washed with methanol and dried under vacuum. 40.5 g (69.4 mmol) (c.y 30%) of [(R)-(I), (X=Tr)] having e.e. 99.4% is obtained.

Example 32

Fesoterodine fumarate

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenoxy-isobutyrate/fumaric acid (1/1)

A solution of [(R)-(I), X=trityl, e.e.99.4%] (20 g, 34.3 mmol), prepared according to Example 30, in 140 mL of toluene is charged with 7.2 mL of triethylamine and 0.3 mL of pyridine. The mixture is cooled to 10-15°C and a solution of 4.0 g (37.7 mmol) of 2-methylpropionyl chloride in 20 mL of toluene is dropped, over about 30 min, maintaining the temperature in the range 10-15°C. Then the reaction is stirred and allowed to reach room temperature. Water (70 mL) is added, the mixture is stirred for 30 min and poured in a separating funnel. The aqueous phase is discarded and the organic one is washed with water (2 x 50 mL) and evaporated under reduced pressure. The oily residue obtained (26 g) is loaded in a 1-L round bottomed flask with 200 mL of acetonitrile. The solution is charged with 18 mL of water, heated at 50°C, charged with about 27 mL of aq. HC1 (6%) and stirred for 30-45 min. After cooling to room temperature, water (580 mL) is added and the suspension is stirred for about 15 min, then the solid (trityl alcohol) is filtered off and washed with water-acetonitrile mixture on filter. The filtrate is neutralized adding NaHCO ₃ and acetonitrile is evaporated under reduced pressure. The pH is then set to about 9 with the addition of Na ₂ CO (2.5-3 g...g) and methylene chloride (200 mL) is added while mixing. Then the organic phase is separated and the aqueous one is extracted with a second portion of methylene chloride (70 mL). The organic phases are merged, dried over anhydrous Na ₂ CO and filtered. The filtrated is concentrated under reduced pressure to a oily residue (15 g, containing 14.1 g of Fesoterodine as base).

A sample of 3.53 g (8.56 mol) of Fesoterodine base prepared as above is dissolved in 7.6 mL of MEK, 0.99 g (8.56 mol) of fumaric acid are added and the mixture heated to 40°C to obtain a clear solution. Cyclohexane (1.9 mL) is dropped and the mixture was allowed to cool to room temperature and maintained under stirring for 16 h before being cooled to 0-5°C. After 9 h at this temperature a crystalline product is observed. The dense suspension is diluted with a MEK/cyclohexane mixture (15 mL/4 mL) and stirred overnight allowing to warm up to room temperature. Then it was stirred for 8 h again at 0-5 °C and the product is filtered, washed with cyclohexane/MEK mixture (9/1) and dried under vacuum to give Fesoterodine fumarate 3.6 g (6.82 mmol)(c.y. 80%) that shows HPLC purity: A% > 99% and e.e. 99.94.

m.p. (DSC: onset-peak-endset, °C): 106-109-1 14. In Figure 1 the X-Ray powder diffractogram of a sample of this compound and in Fig corresponding X-Ray powder diffractogram numeric pattern are reported.

Example 33

Fesoterodine fumarate

(R)-2-(3-/V,/V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenoxy-isobutyrate/fu

A sample of Fesoterodine base (about 10.6 g, 25.7 mmol), obtained in the previous Example, is dissolved in 10 mL of MEK. The mixture is charged with 2.98 g (25.7 mmol) of fumaric acid and heated to 65°C to obtain an almost clear solution, that is allowed to cool to room temperature in about lh. The product crystallizes within lh. Then, the dense suspension is diluted with 12 mL of MEK, cyclohexane (6 mL) is dropped in 30 min and the mixture stirred at room temperature overnight. Then the product is filtered off, washed with MEK/cyclohexane mixture (2/1) and dried under vacuum to give 10.6 g (20.1 mmol) of Fesoterodine fumarate (c.y. 78%), having e.e. > 99.9%.

m.p. (DSC: onset-peak-endset, °C): 107-1 1 1-1 14.

Example 34

Fesoterodine fumarate

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenoxy-isobutyrate/fu

Fesoterodine base (14. lg, 34.3 mmol, e.e >99%), prepared using the same procedure described in Example 32, is dissolved in 30 mL of MEK. The mixture is charged with 3.98 g (34.3 mmol) of fumaric acid and heated to 40°C to obtain a clear solution. Cyclohexane (8 mL) is dropped slowly and the mixture is allowed to cool to room temperature under stirring-and then concentrated under reduced pressure. The thick residue is charged with MEK (20 mL) and stirred at room temperature overnight.

The dense suspension obtained is diluted with 10 mL of MEK and cyclohexane (8 mL) is dropped in 30 min. Then, the mixture is stirred for 4 h at room temperature, cooled to 0-5°C and maintained under stirring overnight to obtain a solid product which is filtered, washed with a MEK/cyclohexane mixture (2/1) and dried under vacuum to afford Fesoterodine fumarate 15.0 g (28.4 mmol) (c.y. 83%) having e.e. > 99.9%.

m.p. (DSC: onset-peak-endset, °C): 106-1 10-1 13.

Example 35

Fesoterodine fumarate

(R)-2-(3-7V,7V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenoxy-isobutyrate/fumaric acid (1/1)

Fesoterodine base (10.6 g, 25.7 mmol), having e.e. 96%, prepared using the same procedure described in Example 32, is dissolved in 23 mL of MEK. The mixture is charged with 2.98 g (25.7 mmol)of fumaric acid heated to 40°C to obtain a clear solution. Cyclohexane (6 mL) is dropped slowly and the mixture is allowed to cool to room temperature and maintained under stirring for 16 h before being cooled to 0-5°C. Since crystallization does not occur even after many hours at 0°C, the mixture is evaporated to dryness under reduced pressure. The thick residue is charged with MEK (15 mL) and stirred at room temperature overnight. Then the mixture was evaporated again and the residue is charged with 10 mL of MEK and stirred at room temperature to obtain a solid product within 30 min. The dense suspension is diluted with 12 mL of MEK, cyclohexane (6 mL) is dropped in 30 min. and the mixture stirred at room temperature overnight. After being cooled to 0-5 °C, the suspension is stirred 4 h before filtering off the product, which is washed with MEK/cyclohexane mixture (2/1) and dried under vacuum to give 1 1.3 (21.4 mmol) (c.y. 83%) of Fesoterodine fumarate having e.e.=99.46%.

m.p. (DSC: onset-peak-endset, °C): 107-1 10-1 13.

Example 36

Fesoterodine fumarate

(R)-2-(3-/V,/V-diisopropylamino-l-phenylpropyl)-4-hydroxymet hyl- phenoxy-isobutyrate/fumaric acid (1/1)

Fesoterodine base (8.0 g, 19.3 mmol) having e.e. >99%, prepared using the same procedure described in Example 32, is dissolved in 100 mL of 2-MeTHF. The mixture is charged with 2.24 g (19.3 mmol) of fumaric acid and heated to 50°C to obtain a clear solution, that was allowed to cool to room temperature in about lh. The product, initially separated as a dispersed oil, solidifies spontaneously within 2h. The mixture is then heated again to 50°C to obtain a suspension and finally is cooled to room temperature and maintained under stirring overnight. Then the product is filtered off, washed with 2-MeTHF and dried under vacuum to give 8.0 g (15.2 mmol) (c.y. 79%) of Fesoterodine fumarate having e.e > 99.9%.

m.p. (DSC: onset-peak-endset, °C): 106-1 10-1 12.