ITMI20121232A1 - PROCEDURE FOR THE PREPARATION OF 2- (3-N, N-DIISOPROPYLAMINO-1-PHENYLPROPYL) -4-HYDROXYMETHYL-PHENOL AND ITS DERIVATIVES - Google Patents

Description

Description of the patent for industrial invention entitled:

â € œPROCESS FOR THE PREPARATION OF 2- (3-N, N-DIISOPROPYLAMINO-1-PHENYLPROPYL) -4-HYDROXIMETHYL-PHENOL AND ITS DERIVATIVESâ €

The present invention refers to a process for the preparation of 2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol (I, X = H) and its derivatives (I, X â ‰ H), key intermediates, such as (R) -enantiomers, of the synthesis of Fesoterodina (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 lead by reduction to new amide intermediates of general formula (IVA) and (IVB) racemes or enantiomerically enriched which allow the production of (I) for treatment with hydrides. The new intermediates are a further object of the invention. The invention also concerns a resolution process of some derivatives of (I) and the racemization of the undesired enantiomers (S) - (I). A further object of the invention is a process for the preparation of Fesoterodina starting from said intermediates of absolute configuration (R).

<(I)> Fesoterodine (II)

(III A) (III B) (IV A) (IV B)

State of the art

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethyl-phenoxyisobutyrate (II), known as Fesoterodina, is an anticholinergic agent useful in the treatment of urinary incontinence.

Its salt with fumaric acid was particularly interesting for pharmaceutical use and is known on the market under the name TOVIAZ <®>.

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

Although the structure of Fesoterodine is very similar to that of Tolterodine, Fesoterodine was found to be superior in efficacy and tolerability.

Fesoterodine fumarate is described in US6858650 which describes the preparation of Fesoterodine by reaction of (R) - (+) - 2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethyl-phenol with isobutyryl chloride in presence of triethylamine. The conversion into fumarate is carried out by treating the product with fumaric acid in 2-butanone and cyclohexane. This patent reports the melting point of raw and recrystallized Fesoterodina Fumarate but does not mention purity.

The preparation of Fesoterodina is the subject of many patents.

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

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

OR

Cl O

OH

O O N O N H H

TEA

Scheme 1

The compound [(R) -I, X = H)] is therefore the key intermediate. Its preparation in its racemic or optically enriched form is described in several patents using multistage processes.

For example, US5559269 reports its preparation from 4-bromophenol, by means of a very long synthetic process and which uses reagents that are difficult to apply on an industrial scale due to their dangerousness such as LiAlH4 and Grignard reagents. This type of process, shown in a simplified way below (Scheme 2), also involves the use of protective OH-phenolic groups, to avoid secondary reactions:

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

Scheme 2

WO2007137799, WO2009037569 and WO2011145019 describe improvements of this synthetic scheme which in any case do not eliminate critical reagents to be applied on an industrial scale and tend to produce numerous wastewater.

US6713464 describes the preparation of (I, X = H) by Heck reaction, to prepare N, N-diisopropyl acrylamide which is then reacted in order with a phenylcuprate, LiAlH4 and AlCl3 (Scheme 3). Subsequently (I, X = H) is resolved in its optical antipodes and esterified to obtain Fesoterodina.

OCH3OCH3

Pd

NiPr2 H3COOC <Br> H

NiPr3COOC

2

OR

OR

OH OCH3

I <NiPr> 2NiPr2

H3COOC

OR

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

Scheme 3

As is evident, this process also suffers from numerous drawbacks and requires the use of difficult to handle reagents such as acrylamide, LiAlH4 and AlCl3 and reaction conditions unsuitable for industrial development; in particular, the passage with phenylcuprate which 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 deprotection is removed using AlCl3.

Several synthetic approaches have therefore been developed aimed at simplifying the original procedure.

One of these is the approach via hydrocumarins, known from the preparations 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 below:

O OH OH

Pd / C

H O H <2> HO N

DIISOPROPYLAMINE

[(R, S) -I, X = H)] Scheme 4

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

However, this route also suffers from some critical issues.

In US6809214, for example, the process is characterized by the use of reagents of difficult industrial use such as Diisobutylaluminium hydride (DIBAL), LiAlH4 and non-economic resolving agents, such as Cinconidine.

A simplification of the hydrocumarine pathway is the process reported in WO07138440 in which the lactol is formed, in a single step, from the transcinnamaledehyde and is then transformed into (I, X = H) by reaction with diisopropylamine and H2gas, in the presence of Pd / C.

The formation of lactol is however characterized by low reaction yields and by the formation of many by-products and therefore the process requires several purifications that make it unsuitable for an industrial process.

Still starting from trans-cinnamaldehyde, WO2011154854 describes an improvement process to synthesize (I, X = H) which uses non-toxic and more easily handled reagents and claims a new stable crystalline form for [(R) - (I), X = H].

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

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

Scheme 5

The traditionally shortest, one-pot way to synthesize Tolterodine described in WO07017544 and WO07147547, reported in Scheme 6, involves the reaction between p-cresol and N, N-diisopropylcinnamylamine (DIPCA) in the presence of a strong acid:

Scheme 6

However, this route is not easily applicable to the synthesis of Fesoterodina as the reaction of p-hydroxybenzyl alcohol and DIPCA does not proceed. Similarly, similar reactions carried out on para-substituted phenols with hydroxymethyl convertible groups such as, e.g., p-hydroxybenzoic acid, p-hydroxybenzoic ester, p-cyanophenol and para hydroxybenzaldehyde and also reactions with the corresponding O-protected analogues fail.

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

Finally in WO05012227, [(R) - (I), X = H] is prepared by oxidation of Tolterodine, by means of a process with many steps. The oxidation of the methyl group of toluene is not simple, it does not easily lead to the hydroxymethyl derivative but to the corresponding aldehyde which must then be reduced, with NaBH4, and also requires the protection of the phenolic -OH and the its subsequent deprotection, which evidently lengthens and complicates the synthesis and produces unsatisfactory global yields.

The existence of such a large and articulated patent bibliography demonstrates how much the current procedures are not yet to be considered satisfactory and therefore certainly requires and justifies further studies and in-depth studies. Furthermore, all the procedures reported so far use, in the synthesis of Fesoterodine, the resolution of a suitable intermediate and mainly in the compound [(I), X = H] with methods that produce the enantiomer (S) as waste, which is not recovered or reused, with evident cost increases. Nor is any process used to obtain the compound [(I), X = H] in an enantiomerically enriched form.

Description of the invention

The present invention refers to a new process for the preparation of 2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol (I, X = H) and its derivatives (I, X â ‰ H) , key intermediates, such as (R) -enantiomers, of the synthesis of Fesoterodina (II) and its salts, in particular of fumarate. The process of the invention involves new amide intermediates of general formula (IIIA and IIIB) which lead by reduction to new amide intermediates of general formula (IVA and IVB) racemes or enantiomerically enriched. The latter allow the production of (I) by treatment with hydrides. The new intermediates are a further object of the invention. The invention also relates to a process for the resolution of some derivatives of (I), and the racemization of the undesired enantiomers (S) - (I), in particular when X = trityl. Finally, the invention also has as its object the transformation of (R) - (I) with X = trityl in Fesoterodina.

<(I)> Fesoterodine (II)

(III A) (III B) (IV A) (IV B)

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

The R group is C1-C4alkyl, phenyl, benzyl. Group X represents hydrogen, benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl, acyl (COR) or silyl (SiTTâ € ™ Tâ € where T, Tâ € ™, Tâ € equal or different from each other are C1-C4alkyl, phenyl or benzyl).

The process of the invention is illustrated in Scheme 7:

O OH

Br <N>

OHOOH O OH O

hydrides

N red. N NOO <cat.>

<Pd cat.>, Base

R OOO O O

R R H

(V) (III A) <(IV A)> (I) (X = H)

hydrides

protection

O OH

Br N

OH O OH O OH

hydrides H

N red. N N

O <cat.>

<Pd cat.>, Base

X O O O

X X X

(VI) (III B) <(IV B)> (I) (X = H)

Base ∠†

resolution

Chiral Chiral

OH OH

HH

N N

O X O X

(S) - (I) (R) - (I)

Chiral

O OH

No.

OR

H.

Fesoterodine

(II)

Scheme 7

The starting products are the compounds of formula (V) and (VI) (with the exclusion of (VI) when X = H).

The synthesis of the intermediates (IIIA) and (IIIB) consists of 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 it can be carried out, with a high yield and a high degree of purity, in the presence of a metal catalyst, preferably Pd, and of a base. It should be emphasized that in literature an unsaturated N, N dialkylated amide has never been used as a reagent for this reaction, and indeed it has been reported that Mizoroki-Heck is not easily applicable to this type of reactive. olefinics. Furthermore, it has been surprisingly found that, in the synthesis of intermediates (IIIB), it is necessary that the hydroxymethyl group be suitably protected in order to have satisfactory yields.

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

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

Subsequently a reaction is carried out with hydrides, such as Vitride <TM>, on the intermediates (IVA) and (IVB) which can lead to compounds (I) with X = H, already known, or, depending on the reaction conditions and of the protective group used, to products (I), with Xâ ‰ H, never previously described. Also this type of reaction, known per se, required a detailed study of the reaction conditions aimed at reducing the quantity of by-products if the product obtained is (I) with X = H.

In particular, it is preferred the case in which the process scheme leads to the preparation of the racemic or enantiomerically enriched compound (I) in its isomers (R) or (S) where the group X = trityl. The resolution procedure of this last compound is carried out by salification with a suitable acid in an enantiomerically pure form, in a suitable solvent, through the formation and preferably the selective crystallization of the corresponding salt containing the enantiomer (R) (I) with X = trityl.

The racemization of the enantiomer enriched in the form (S) of the compound (I) with X = trityl can be conveniently carried out by heat treatment with a strong base having a pKa â ¥ 26, such as NaNH2 or NaH, at a temperature above 80 ° C.

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

When Xâ ‰ trityl, two cases can occur: X = H or X = protective group â ‰ trityl.

The process of resolving compound (I) with X = H can be performed according to known methods but to recover and recycle the unwanted enantiomer it is necessary to use a protective group X which is stable in basic and hot conditions .

When the protective group X is different from trityl, the resolution can be carried out by appropriately choosing an enantiomerically pure acid resolving agent but it is then necessary, if the undesired enantiomer is to be recovered by racemization, that this protective group X is stable under the conditions basic and hot.

The phenolic group in the resolution and racemization processes is preferentially used as unprotected even if the presence of a protective group on this hydroxyl function is not harmful.

The (R) - (I) enantiomer with X = trityl can be deprotected, under suitable conditions at acid pH, before the acylation reaction that leads to Fesoterodine according to the known technique.

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

The invention is also characterized by the fact that it is possible to introduce the chirality of the molecule, as well as through the resolution processes indicated above, also through an enantioselective reduction procedure of the intermediate (IIIA) or (IIIB) which leads to enantiomerically enriched mixtures of the corresponding intermediates (IVA) or (IVB), using suitable metal catalysts containing chiral ligands or biocatalysts as suggested by the literature. However, it should be emphasized that the teachings of the state of the art do not easily allow the person skilled in the art to foresee the catalysts and / or the experimental conditions suitable for obtaining an enantiomerically enriched product when the substrate is structurally complex.

The process of the invention is further characterized in that most of the new intermediates are isolable in solid form. This allows to overcome some of the problems left open by the known processes which instead often lead to the formation of intermediates with an oily consistency or syrup, which are difficult to isolate and purify, thus creating problems of yield, formation of by-products and not allowing the easy isolation of a finished product with a high degree of purity.

The process of the invention is therefore suitable for being carried out on an industrial scale and provides the desired product in good yield and quality.

Detailed description of the invention

The invention provides new intermediates (IIIA), (IIIB) and (IVA), (IVB) and (I) with Xâ ‰ H and preferably with X = trityl, useful for the synthesis of the key intermediate of the preparation of Fesoterodine and that is, compounds (I) in which X is H, in racemic or enantiomerically enriched form. The new products were characterized by analytical and spectroscopic techniques such as, for example, HPLC, HPLC-MS, <1> H-NMR, <13> C-NMR, m.p., [Î ±] De IR.

The intermediate (I) in which X is H, thus produced in an efficient and advantageous way, can then be used as a pure (R) enantiomer for the preparation of Fesoterodine, with specific requirements for this pharmaceutical product, according to known procedures. .

The reaction and processing conditions can be adapted, as exemplified below, to the preparation of the new intermediates with high yield and chemical purity. The person skilled in the art will be able to easily evaluate, from time to time, the most suitable conditions, in particular as a function of the protective group X and its stability as a function of pH.

In particular, the Mizoroki-Heck reaction used for the preparation of the new intermediates (III A and B), can be carried out using commercially available (V) or easily prepared reagents, such as (VI) and N, N-diisopropylcinnamide, using a ratio between the unsaturated amide and the aromatic halide included in the range from 2.5 / 1 to 0.9 / 1, preferably 1.5 / 1 - 0.9 / 1, even more preferably 1.1 / 1 - 0.9 / 1. The reaction is carried out in the presence of a medium-low polarity organic solvent such as 2-methyl-tetrahydrofuran (2-Me-THF), dioxane or toluene. Typically the ratio between the organic solvent and the aromatic halide is 2-10 / 1 weight / weight. Furthermore, the reaction is carried out in the presence of an organic or inorganic base and, preferably, in the presence of a sterically encumbered organic base such as, for example, N, N-dicyclohexylmethylamine. The stoichiometric ratio between the base and the aromatic halide is typically between the values of 1.5 / 1 and 1/1, preferably between 1.3 / 1 and 1/1. The Mizoroki-Heck reaction requires the presence of a catalyst, preferably a homogeneous catalyst based on Pd (0), commercially available, such as e.g. [Pd (t.Bu3P) 2], and / or prepared in situ and / or preformed in a separate vessel and then added to the reaction mixture such as eg. t.Bu3P Pd2 (dba) 3 (where dba is dibenzylideneacetone) in suitable molar ratios. When palladium is in a different oxidation state, for example Pd (OAc) 2, it needs to be reduced in situ to obtain the catalytically active Pd (0). The most suitable phosphines for this reaction are, for example, t-butylphosphine, di-t-butyl (2,2-diphenyl-1-methyl-1-cyclopropyl) phosphine (c-BRIDP), di (1-adamantyl) - n-butylphosphine, but the person skilled in the art can choose others and preferably among the electron rich and sterically cluttered ones. The stoichiometric ratio between the aromatic halide and the catalyst is between the values 100: 1 and 10000: 1, preferably 300: 1 and 5000: 1, more preferably 400: 1 and 2000: 1. It should also be noted that starting from the E isomer of the unsaturated amide, the product (IIIA and B) is obtained mainly as the E isomer, which can be further purified by crystallization. However, also the pure Z isomer or present in mixture with the E isomer can be conveniently used for the subsequent reactions. As for the processing of the mixture at the end of the reaction, if there is a group X sensitive to the acidic or basic pH that you want to preserve in the molecule (IIIB) thus obtained, it is advisable that the washes are carried out at controlled pH and temperature. , second conditions easily identifiable by the person skilled in the art.

As regards the subsequent reaction to obtain the intermediates (IV A and B), the reduction can be carried out by means of H2o with a hydrogen donor, such as sodium hypophosphite, in the presence of heterogeneous catalysts, preferably based on Pd, at a pressure between 0.5 and 10 bar (even if higher pressures are not deleterious), in a preferably alcoholic solvent, such as methanol, ethanol or isopropanol, or ethereal, such as THF, 2-Me-THF, optionally adding a quantity of water between 0.5-10%, with a solvent / unsaturated amide ratio usually between 3 / 1-20 / 1 weight / weight.

The weight ratio between the catalyst and the unsaturated amide is between 1 / 300-1 / 5, preferably 1 / 200-1 / 10.

The hydrogenation temperature is between 30-100 ° C and preferably between 40-80 ° C.

The conversion and yield of isolated intermediate (IV A and B) are> 90%, usually> 95%, while the reaction time depends on the reaction conditions used.

When enantioselective reduction is performed, a commercially available chiral homogeneous catalyst can either be used or prepared in a separate reactor and then added to the reaction mixture. Among the known metal-based catalysts such as Ru, Rh, Ir, Co, Cu or Zn with suitable chiral ligands, those based on Ru, Rh, Cu or Ir are particularly applicable if the ligand is a phosphine derivative. The result of the reaction depends both on the catalyst used, both on the chemical purity of the olefin substrate, and on the reaction conditions. Using, for example, a commercial Ru-based catalyst, such as [RuCl (p-cymene) ((R) -DM-Segphos ®)] Cl, in a mixture of THF-EtOH (10: 1), by operating at 60 ° C and 60 bar of hydrogen, an e.e. 64% in favor of the configuration enantiomer (R) of the product [IVA), X = Et]. Using instead [Ru (S) -TMBTP (OCOCF3) 2in EtOH, operating at 50 ° C and 40 bar of hydrogen, an e.e. 55% in favor of the configuration enantiomer (S) of the product [IVA), X = Et].

The subsequent reduction to obtain compounds (I) can be carried out using a suitable hydride, such as e.g. Vitride ® commercially available in toluene. It has been observed that it is advisable to work at a temperature of â ¤ 25 ° C in order to limit the formation of by-products and thus obtain a product with satisfactory yield and quality, in particular when X = H.

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

The resolution procedure of this last compound is carried out by salification with a suitable acid in an enantiomerically pure form, in a suitable 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 quantities 0.4-0.6 equivalent to [(R, S) - (I) with X = trityl ]. Suitable solvents can be ethers, alcohols, arenes, esters, and 2-MeTHF and t.amyl alcohol are exemplified as suitable. Other solvents, where the intermediate (I) when X = trityl is soluble at room temperature in a concentration of 10% and the corresponding salt with the (S) -mandelic acid or with the (R) - N-acetyl phenylglycine is not very soluble, they can be equally advantageous. This procedure offers a peculiar advantage, compared to similar known resolutions in which (I) has been used with X = H. While in the known processes the enantiomer (S) - (I) with X = H turns out to be an unusable waste, in the present process the racemization and therefore the recovery of the enantiomer enriched in the (S) form, already protected as trityl , and present in the mother liquors, can occur by simple residue concentration of these mother liquors, dissolution in a solvent selected from aromatic hydrocarbons or ethers and treatment with a suitable base having a pKa â ‰ ¥ 26, such as eg. NaH or NaNH2, at a temperature 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 = tritile which can be recycled without any problem. Racemization is performed using 0.2-6 molar equivalents of sodium amide or sodium hydride, while metal hydroxides or alkoxides can optionally be used as ancillary bases to decrease the consumption of the strong base.

Another aspect of the invention concerns the preparation of fesoterodine by acylation with a derivative of the 2-methylpropionic acid of the enantiomer (R) - (I) with X = trityl subsequently deprotected under selective conditions in an acid environment. In fact, by operating with aqueous hydrochloric acid, in acetonitrile, at a pH between 2 and 2.5, it is possible to selectively remove the trityl group and the Fesoterodine thus produced can be recovered with good yield and satisfactory chemical purity. It is then possible to obtain a Fesoterodina salt by salifying it with a suitable pharmacologically acceptable acid, in particular fumaric acid.

The following examples illustrate the various aspects of the present invention. Example 1

Compound preparation [(IIIA), mixture (E, Z), X = Et]

Ethyl 3- (3-N, N- (diisopropylamino) -3-oxo-1-phenylprop-1-en-1-yl) -4-hydroxybenzoate

And

38.3 g of ethyl 3-Bromo-4-hydroxy-benzoate (0.156 mol), 39.8 g of N, N-diisopropyl-cinnamide (0.172 mol) are loaded into a 500 ml flask equipped with mechanical stirring. ), 33.6 g of N, N-dicyclohexylmethylamine (0.172 mol) and 170 mL of 2-Me-THF. After vigorously bubbling nitrogen for 5 minutes, the solution is heated, maintaining a gentle nitrogen flow.

Once the temperature of 70 ° C is reached, 171 mg of [Pd (Pt-Bu3) 2] (0.334 mmol) in a MeTHF solution (3 mL) are added and the mixture is heated under reflux until almost complete conversion of the aryl halide (about 7h). A solution of diluted HCl (85 mL water 8.5 mL 30% HCl) and 85 mL of 2-Me-THF is then added to the reaction and the mixture is heated to 45-50 ° C. After eliminating the aqueous phase, the organic phase is washed twice with water (170 mL and then 85 mL), keeping the temperature between 45 and 50 ° C.

After having concentrated the organic phase under reduced pressure, the residue is taken up with 70 mL of toluene and the mixture is again evaporated under vacuum. The residue is taken up with 200 mL of toluene, the mixture is heated to 50-60 ° C for 15 ', gradually cooled to room temperature and then to 0-5 ° C, stirring it for 2-3h.

The product is isolated by filtration, washed on the filter with cold toluene and dried under vacuum at 55 ° C for one night. 55 g (0.139 moles) of the desired product are obtained as an isomeric mixture E and Z (E / Z = 93/7) (yield 89%).

Example 2

Compound preparation [(IIIA), isomer E, X = Et]

Ethyl (E) -3- (3-N, N-diisopropylamino-3-oxo-1-phenylprop-1-en-1-yl) -4-hydroxybenzoate

A 4.5 g sample of unsaturated amide (E / Z = 93/7) obtained in Example 1 are dissolved in 70 mL of toluene, at 80 ° C. The mixture is cooled to 30 ° C, primed by rubbing, slowly cooled to 20 ° C and stirred for 1 hour at the same temperature. The product is isolated by filtration on buchner, washed with cold toluene (2x 15 mL) and dried under vacuum at 55 ° C for one night to give 3.5 g of product with an E â ‰ ¥ 99% isomer content.

HPLC-MS (m / z): 396 (M + H <+>)

IR (cm <-1>): 2975, 1716, 1629, 1605, 1562, 1279, 1427, 1371, 1231, 1129, 771, 696

m.p. (° C): 178-182

NMR (Solvent: CDCl3, Instrument used: Bruker Avance 300 MHz)

<1> H-NMR (in ppm with respect to the TMS): 1.20 (6H, d, J = 7 Hz, CH3); 1.27 (6H, d, J = 7 Hz, CH3) 1.38 (3H, t, J = 7 Hz, CH3); 3.42 (1H, set, J = 7 Hz, H-F); 4.27 (1H, set, J = 7 Hz, H-Fâ € ™); 4.30 (2H, J = 7 Hz, -CH2OR); 6.69 (1H, s, H-E); 7.03 (1H, d, J = 9 Hz, H-C); 7.22 â € “7.30 (5H, aromatic m); 7.71 (1H, d, J = 2 Hz, H-A); 7.92 (1H, dd, J = 9.2 Hz, H-B); 9.00 - 950 (1H, broad, OH).

<13> C-NMR (in ppm with respect to the TMS): 14.2 (CH3); 19.9 (CH3); 20.6 (CH3); 45.9 (CH-F); 50.5 (CH-Fâ € ™); 60.5 (CH2); 119.1 (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 (CONR2).

Example 3

Compound preparation [(IIIA), isomer Z, X = Et]

Ethyl (Z) -3- (3-N, N-diisopropylamino-3-oxo-1-phenylprop-1-en-1-yl) -4-hydroxybenzoate

COOEt

B A O

F '

D.

C N

And

F OH Ph

The mother liquors of the previous preparation (Example 2) are concentrated to residue. 1 g of residue is purified by chromatography on a silica gel column (L = 15 cm D = 5 cm) using a mixture of n.hexane / ethyl acetate = 60/40 as eluent. The fractions are controlled by TLC using the same eluent: Rf (Z) 0.35-0.4; Rf (E) 0.25-0.3. The fractions containing only the compound with the highest Rf were evaporated under vacuum, to residue and the latter was then shelled with n.hexane. After drying under vacuum, 290 mg of product are obtained with a content of isomer Z at 99%.

HPLC-MS (m / z): 396 (M + H <+>)

IR (cm <-1>): 2981, 1700, 1587, 1444, 1366, 1302, 1258, 1111, 840, 773

m.p. (° C): 190-192 ° C

NMR (Solvent: CDCl3, Instrument used: Bruker Avance 300 MHz)

<1> H-NMR (in ppm with respect to the TMS): 0.87 (6H, d, J = 7 Hz, CH3); 1.30 (3H, t, J = 7 Hz, CH3) 1.41 (6H, d, J = 7 Hz, CH3); 3.35 (1H, set, J = 7 Hz, H-F); 4.26 (1H, set, J = 7 Hz, H-Fâ € ™); 4.35 (2H, J = 7 Hz, -CH2OR); 6.13 (1H, s, H-E); 6.64 (1H, d, J = 9 Hz, H-C); 7.18 â € “7.24 (5H, aromatic m); 7.84 (1H, d, J = 2 Hz, H-A); 7.89 (1H, dd, J = 9.2 Hz, H-B); 9.62 (1H, broad, OH).

<13> C-NMR (in ppm with respect to the TMS): 14.3 (CH3); 19.9 (CH3); 20.2 (CH3); 45.9 (CH-F); 50.6 (CH-Fâ € ™); 60.5 (CH2); 116.3 (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 (COOR); 168.7 (CONR2).

Example 4

Compound preparation [(R, S) (IVA), X = Et]

Ethyl (R, S) -3- (3-N, N-diisopropylamino-3-oxo-1-phenylpropyl) -4-hydroxybenzoate

And

F '

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

After a total of 21h of reaction the conversion results> 98%.

The reaction is filtered on celite at a temperature of about 50 ° C and the panel is washed with wet MeTHF (2x50 mL) and the filtrate evaporated under vacuum to a volume of 70-80 mL.

To the residue are added 200 mL of toluene and 50 mL of solvent is distilled under vacuum.

The suspension is then brought to 50-60 ° C and kept at this temperature for 15â € ™, then slowly cooled to room temperature and then to 0-5 ° C, stirring it for 2-3h. The product is isolated by filtration, washed on the filter with cold toluene and dried under vacuum at 55 ° C overnight to give 49 g (0.123 moles) of the desired product (94%).

HPLC-MS (m / z): 398 (M + H <+>)

IR (cm <-1>): 2971, 1947, 1933, 1877, 1805, 1706, 1613, 1590, 1493, 1451, 1366, 1285, 1248, 1116, 1043, 909, 771.

m.p. (° C): 184.5-189.0 ° C

NMR (Solvent: CDCl3, Instrument used: Bruker Avance 300 MHz)

<1> H-NMR (in ppm with respect to the TMS): 1.12 (3H, d, J = 7 Hz, CH3); 1.17 (3H, d, J = 7 Hz, CH3) 1.30 (3H, d, J = 7 Hz, CH3) 1.35 (3H, d, J = 7 Hz, CH3), 1.36 (3H, t, J = 7 Hz , -CH3); 3.17 (2H, m, H-E); 3.46 (1H, m, H-F); 4.08 (1H, set, J = 7 Hz, H-Fâ € ™); 4.29 (2H, J = 7 Hz, -CH2OR); 5.06 (1H, dd, J = 8.5 and 5.5 Hz, H-D); 6.90 (1H, d, J = 9 Hz, H-C); 7.15 â € “7.31 (5H, aromatic m); 7.25 (2H, m, H-A and H-B); 10.33 (1H, broad, OH).

<13> C-NMR (in ppm with respect to the TMS): 14.3 (CH3); 20.3 (CH3); 20.4 (CH3); 20.5 (CH3); 20.6 (CH3); 39.0 (CH-D); 40.7 (CH2); 46.3 (CH-F); 48.9 (CH-Fâ € ™); 60.3 (CH2); 117.3 (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 (CONR2).

Example 5

Compound preparation [(R) - (IVA), X = Et]

Ethyl (R) -3- (3-N, N-diisopropylamino-3-oxo-1-phenylpropyl) -4-hydroxybenzoate

In a 50-mL stainless steel autoclave equipped with a Teflon-coated magnetic stirrer, [RuCl (pcimene) ((R) -DM-Segphos)] Cl (6.0 mg, 0.00583 mmoles), Ethyl 3- (3-N, N-diisopropylamino-3-oxo-1-phenylprop-1-en-1-yl) -4-hydroxybenzoate (234 mg, 0.592 mmol), prepared according to example 1, and a mixture of THF-EtOH (10: 1) (4 mL) previously deaerated. The hydrogen is initially introduced into the autoclave at a pressure of 10 bar, before being reduced to 1 bar by carefully venting the autoclave. After this procedure is repeated three times, hydrogen is introduced at a pressure of 30 bar and the mixture is stirred at 60 ° C for 16h and then at 60 bar for another 10h obtaining a conversion of approx. 80% of the starting product. The reaction mixture is filtered on carbon and celite, then concentrated under reduced pressure and the residue diluted with IPA. A sample is analyzed by HPLC on a Chiralpack AD 4.6 x 250 mm (5 µm) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1; Flow = 1mL / min. Wavelength: 280 nm. Loop volume: 10 µL, RT (S enantiomer) = 7.5 min, RT (R enantiomer) = 24.3 min] observing an e.e. 64% in favor of the configuration enantiomer (R) of the product [IVA), X = Et].

Example 6

Compound preparation [(S) - (IVA), Y = CO, X = Et]

Ethyl (S) 3- (3-N, N-diisopropylamino-3-oxo-1-phenylpropyl) -4-hydroxybenzoate

In a 50 mL stainless steel autoclave equipped with a Teflon-coated magnetic stirrer, [Ru (S) -TMBTP (OCOCF3) 2 (7 mg, 0.00864 mmol), 3- (3-N, N-diisopropylamino Ethyl -3-oxo-1-phenylprop-1-en-1-yl) -4-hydroxybenzoate (293 mg, 0.742 mmoles), prepared according to example 1, and EtOH (4 mL) previously deaerated. The hydrogen is initially introduced into the autoclave at a pressure of 10 bar, before being reduced to 1 bar by carefully venting the autoclave. After this procedure is repeated three times, hydrogen is introduced at a pressure of 20 bar and the mixture is stirred at 50 ° C for 16 h and then at 40 bar for another 8 h obtaining a conversion of approx. 90% of the starting product. The reaction mixture is filtered on carbon and celite, then concentrated under reduced pressure and the residue diluted with IPA. A sample is analyzed by HPLC on a Chiralpack AD 4.6 x 250 mm (5 µm) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40: 0.4: 1; Flow = 1mL / min. Wavelength: 280 nm. Loop volume: 10 µL] observing an e.e. 55% in favor of the configuration enantiomer (S) of the product [IVA), X = Et].

Example 7

Compound preparation [(R, S) - (I), (X = H)]

2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethyl-phenol

To a suspension of 20 g (0.050 moles) of ethyl 3- (3-N, N-diisopropylamino-3-oxo-1-phenylpropyl) -4-hydroxybenzoate, prepared according to Example 4, in toluene (200 mL ) 8 mL of Vitride (65-70% w / w in toluene) is carefully added at a temperature of 5-10 ° C. Then another 60 mL of vitride is added faster at the same temperature. The mixture is then brought to 25 ° C and kept under stirring for about 20h, then it is carefully poured into a flask containing 200 mL of MeTHF, 200mL of water and 20 mL of 30% NaOH. When extinguishing is completed, the aqueous phase is eliminated and the organic phase is washed with NaHCO3 (aq) to obtain a pH value of approx. 9 and finally washed with water. The organic phase is then concentrated to residue, taken up with acetonitrile (200 mL) and 4.2 mL of 36% HCl is added to the solution. The suspension is concentrated to a small volume, taken up with 100 mL of acetonitrile and stirred at 0-5 ° C for 1.5h. The product is isolated by filtration, washing it on the buchner with cold acetonitrile. 14.4 g of the compound [(R, S) - (I), (X = H)] are obtained having a chemical purity of 95% (yield = 80%).

Example 8

Compound preparation [(R) - (I), (X = H)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol

A sample of the product obtained in example 7 has been resolved in its optical antipodes by repeating the procedure described in WO2010018484 (example 3, page 24) to obtain the compound [(R) - (I), (X = H)] , having [Î ±] D + 137 (T = 25 ° C, CH2Cl2conc. 1.0 g / 100 mL), m.p. 100-102 ° C, e.e. > 99% determined on Chiralpack IC 4.6 x 250 mm (5 µm) column [Mobile phase = 96: 4 heptane / ethanol 0.5% diethylamine; Flow = 1mL / min. Wavelength: 210 nm.].

Example 9

Compound preparation [(R, S) - (I), (X = Tr)]

2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethyl-phenol

In a flask equipped with mechanical stirring, 12.3 g of the hydrochloride of the compound [(R, S) - (I), (X = H)], in turn prepared according to example 7, (title 90% approximately), 50 mL of anhydrous DMF and 25 mL of anhydrous pyridine. 9.8 g (35.2 mmoles) of trityl chloride are added to the suspension and it is left to stir at room temperature overnight. The following day the solution obtained is heated to 60 ° C, another 1.6 g of Trityl chloride are added and it is kept at 60 ° C for 3h.

The reaction is quenched by adding 30% NaOH (12 g), water (70 ml) and 120 mL toluene. After 30 min. the reaction is diluted with 120 mL of toluene and 500 mL of water. After having buffered the aqueous phase at pH 9, with NaHCO3aq (7%), it is discarded and the organic phase is washed three times with 100 mL of water. The organic phase, after having been evaporated to residue, is resumed and re-evaporated to residue first with toluene. The final residue is then pulped at room temperature with 300 mL of hexane. The solid is isolated by filtration, washed on the filter with hexane and dried under vacuum to give 17 g of crude product. The solid obtained is then pulped at room temperature with 80 mL of isopropanol, filtered, washed with isopropanol and dried under vacuum. Thus 14.6 g of pure [(R, S) - (I), (X = Tr)] are obtained.

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, 1154, 1026, 747, 704 .

m.p. (° C): 133-137 ° C.

Example 10

Compound preparation [(R) - (I), (X = Tr)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

In a flask equipped with mechanical stirring, 10 g of [(R) (I), (X = H)], obtained according to the example 8, 40 mL of anhydrous DMF and 20 mL of anhydrous pyridine are loaded. To the solution obtained are added 3.4 g of pyridinium hydrochloride, 5.9 g of trityl chloride, it is heated to 55 ° C and maintained for 2h. Then another 5.9 g of reagent are added and it is kept at the temperature for another two hours, before cooling it to room temperature.

The reaction mixture is worked by adding 30% NaOH (7 mL), water (14 ml) and, after 5â € ™ stirring, 300 mL of toluene and 400 mL of water. After having buffered the aqueous phase at pH 9, with Na2CO3aq (10%), it is discarded and the organic phase is washed twice with 50 mL of water.

The organic phase evaporated to residue then recovered and re-evaporated to residue first with toluene and then with hexane. Finally the residue is pulped at room temperature with 100 mL of hexane. The solid is filtered and washed, washed on the filter with hexane and dried under vacuum to give 18.1 g of crude product. The solid is then pulped at 60 ° C with 90 mL of isopropanol and the suspension gradually cooled, under stirring, to 20 ° C and then kept for 1h at this temperature. The product is isolated by filtration, washed with isopropanol, and then dried under vacuum. 14.8 g of pure [(R) - (I), (X = Tr)] are thus obtained, having an 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, 1156, 1046, 1027, 899, 746, 707.

m.p. (° C): 146-147 ° C

H <1> -NMR (CDCl3, Instrument: Bruker 90 MHz, in ppm with respect to TMS): 1.2-1.4 (12H, 2, CH3); 2.6 (4H, m, CH2-CH2) 3.35 (2H, set, J = 7 Hz, CHMe2); 4.05 (2H, s, -CH2OTr); 4.60 (1H, dd, 9 and 3 Hz, CH-Ph); 6.4 (broad, phenol) 7.0-7.6 (23H, m, aromatics).

Example 11

Compound resolution [(R, S) - (I), (X = Tr)]

(S) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

0.5 g of [(R, S) - (I), (X = Tr)] prepared according to example 9 and 4 mL of t.amyl alcohol are introduced into a flask equipped with mechanical stirring. 91 mg of (R) -acetoxymandelic acid in 2.2 mL of t.amyl alcohol are added to the solution obtained by heating the mixture to 70 ° C. the mixture is then allowed to return to room temperature, the solid is filtered and washed with 2x 2mL of t.amyl alcohol. From HPLC analysis carried out on a sample released by treatment with sodium carbonate, an e.e. 20% in favor of [(S) - (I), (X = Tr)] using a Chiralpack AD 4.6 x 250 mm (5 µm) column [Mobile phase = n-hexane: isopropanol: diethylamine: TFA = 400: 40 : 0.4: 1; Flow = 1mL / min. Wavelength: 280 nm. Loop volume: 10 µL, RT (S enantiomer) = 12.1 min, RT (R enantiomer) = 10.6 min].

Example 12

Compound resolution [(R, S) - (I), (X = Tr)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

Operating as in example 11 but using 71 mg of (S) mandelic acid instead of 91 mg of (R) -acetoxy mandelic acid, a solid is obtained which is filtered and washed with 2x 2mL of t.amyl alcohol. From HPLC analysis carried out on a sample released by treatment with sodium carbonate, an e.e. 71% in favor of [(R) - (I), (X = Tr)].

Example 13

Compound resolution [(R, S) - (I), (X = Tr)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

Operating as in example 12 but using 6 mL of 2-Me-THF instead of 4 mL of t.amyl alcohol, a solid is obtained which is filtered and washed with 2x 4mL of 2-Me-THF. From HPLC analysis carried out on a sample released by treatment with sodium carbonate, an e.e. 96% in favor of [(R) - (I), (X = Tr)]

Example 14

Compound resolution [(R, S) - (I), (X = Tr)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

Operating as in example 13 but using 6 mL of toluene instead of 6 mL of 2-Me-THF, a solid is obtained which is filtered and washed with 2x 4mL of toluene. From HPLC analysis carried out on a sample released by treatment with sodium carbonate, an e.e. 24% in favor of [(R) - (I), (X = Tr)]

Example 15

Compound resolution [(R, S) - (I), (X = Tr)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

Operating as in example 12 but using 6 mL t.amyl alcohol instead of 4 mL and 85 mg of (R) -N-acetyl phenylglycine instead of 71 mg of (S) -mandelic acid, a solid is obtained which is filtered and washed with 2 x 2 mL of t.amyl alcohol. From HPLC analysis carried out on a sample released by treatment with sodium carbonate, an e.e. 60% in favor of [(R) - (I), (X = Tr)]

Example 16

Compound racemization [(R) - (I), (X = Tr)]

(R, S) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenol

3.0 g of [(R) - (I), (X = Tr)], prepared according to example 10, and 20 mL of anisole are heated to 90-100 ° C, added with 585 mg of sodium amide in portions and the mixture is heated to 125 ° C for 3h. After cooling to room temperature, water is carefully added to the mixture, then NaHCO3 aq (7%, 35 mL) and methylene chloride 40 mL are added. The organic phase is separated by decantation, dried on anhydrous Na2SO4, filtered and evaporated to a residue of 4 g. From the HPLC a yield of 77% in the desired product is calculated. The residue is then taken up with 12 mL of isopropanol, heating slightly. The solution obtained is allowed to slowly return to room temperature, then cooled to 0-5 ° C, stirred for 1h and filtered to give 2.0g of [(R, S) - (I), (X = Tr)], having an enantiomeric ratio: R / S = 50.1: 49.9.

Example 17

Compound racemization [(R) (I), (X = Tr)] and deprotection

(R, S) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol [(R, S) - (I) with X = H] as hydrochloride

OH

HCl

No.

OH Ph

8.0 g of [(R) - (I), (X = Tr)], prepared according to example 10, and 55 mL of anisole are heated to 90-100 ° C, with the addition of 909 mg of sodium amide in portions and the mixture is heated to 125 ° C for 3h. After cooling to room temperature, water is carefully added to the mixture, then NaHCO3 aq (7%, 76 mL) and methylene chloride 70 mL are added. The organic phase is separated by decantation and the aqueous phase is re-extracted with a further 70 ml of methylene chloride. The combined organic phases are dried on anhydrous Na2SO4, filtered and evaporated to obtain a residue of about 16 g. The residue is then taken up with 80 mL of acetonitrile, 8 mL of water and 7.2 mL 1.9M HCl verifying that the pH is between 2-2.5. The mixture is heated to 50 ° C for about 1 hour and then left to return to room temperature. 240 mL of water and 40 mL of toluene are added. The organic phase is separated and the aqueous phase extracted with a further 40 mL of toluene. The aqueous mixture is then basified with a 10% aqueous solution of Na2CO3, concentrated under vacuum to remove the acetonitrile and finally extracted with methylene chloride. The organic extracts thus obtained contain about 3.3 g of (R, S) - (I) with X = H. After drying and evaporation of the solvent to residue, 30 mL of acetonitrile and 36% HCl are added. It is reconcentrated to a small volume and finally the residue is taken up with 15 mL of acetonitrile. The solid is finally filtered, washed with acetonitrile and dried under vacuum to give 3.8 g (yield 73%) of (R, S) - (I) with X = H in the form of hydrochloride.

Example 18

Compound de-titylation [(R) - (I), (X = Tr)]

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethylphenol [(R) - (I), (X = H)] as hydrochloride

.

0.45 mL of 1.9 M HCl are added to a suspension of 3 g of [(R) - (I), (X = Tr)], obtained according to example 10, in 30 mL of acetonitrile and 15 mL of water. pH is 2-2.5. The mixture is then heated to 50 ° C for 1.5 h and cooled to room temperature observing complete detritylation.

80 mL of water are slowly added to the suspension that forms, stirring for 5-10 min. The solid is removed by filtration and washed with an acidic mixture of water / acetonitrile 70/30. The solution is brought to pH 9 with Na2CO3aq, evaporated under vacuum to eliminate the acetonitrile and extracted with methylene chloride (2 x 30 mL) and the organic phase is evaporated to a vacuum residue to give 1.6g of product.

The residue is taken up with 30 mL of acetonitrile acidified with 36% HCL, concentrated to a small volume and finally taken up with 15 mL of acetonitrile. The product is filtered, washed with acetonitrile and dried under vacuum to give the hydrochloride of the compound [(R) - (I), (X = H)] with high purity and e.e â ¥ 99%.

Example 19

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethylphenoxy-isobutyrate

O O

H.

No.

OR

Tr

To a solution of 2.22 g of (R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethyl-phenol [(R) - (I), X = trityl] in 20 mL of chloride of methylene 0.84 mL of triethylamine and 0.6 mL of pyridine are added and the mixture is cooled to a temperature of 10-15 ° C. After adding 0.53 mL of 2-methylpropionyl chloride, the mixture is allowed to return to room temperature and stirred for 2.5 hours. 10 mL of water and 2 mL of a 10% aqueous solution of Na2CO3 are then 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). Using as eluent initially hexane / ethyl acetate 1/1 and subsequently ethyl acetate / isopropanol 9/1. The fractions containing the desired product are combined and concentrated to the residue to give 2.3 g of product (yield 93%).

HPLC-MS (m / z): 654.5 (M + H <+>)

[Î ±] D: -11.2 (conc. 1, CH2Cl2, 25 ° C)

IR (cm <-1>): 3058, 3026, 2965, 2933, 2867, 1765, 1491, 1467, 1448, 1387, 1358, 1222, 1120, 1089, 764, 745, 702

H <1> -NMR (CDCl3, Instrument: Bruker 90 MHz, in ppm with respect to TMS): 1.05 (12H, d, 7 Hz, CH3); 1.4 (6H, 2d, 7 Hz, CH3); 2.4 (4H, m, CH2-CH2) 3.0 (3H, m, CHMe2); 4.2 (3H, bs overlapping -CH2OTr CH-Ph); 7.05 (1H, d, 9 Hz, Ar); 7.2-7.7 (22H, m, Ar).

Example 20

(R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-hydroxymethyl-phenoxyisobutyrate (II)

O O

H.

No.

OR

H.

To a solution of 2.1 g of (R) -2- (3-N, N-diisopropylamino-1-phenylpropyl) -4-trityloxymethyl-phenoxy-isobutyrate, prepared according to example 19, in 20 mL of acetonitrile 2 mL of water and 1.6 mL of 1.9M HCl are added, checking that the pH is 2-2.5. The mixture is then heated to 50 ° C for 1 hour then cooled to room temperature, diluted with 55 mL of water and filtered to remove the tritylic alcohol. The filtrate is basified and evaporated under vacuum to residue and finally extracted with methylene chloride. The organic phase is then dried over Na2SO4, filtered and evaporated again to residue to obtain 1.3 g of desired product which can be converted according to known methodology into the fumarate salt.

HPLC-MS (m / z): 412.3 (M + H <+>)

H <1> -NMR (CDCl3, Instrument: Bruker 90 MHz, in ppm with respect to TMS): 1.05 (12H, d, 7 Hz, CH3); 1.4 (6H, 2d, 7 Hz, CH3); 2.4 (4H, m, CH2-CH2) 3.0 (3H, m, CHMe2); 4.15 (1H, bt, 7 Hz, CH-Ph); 4.7 (2H, s, -CH2OH); 7.0 (1H, d, 9Hz, Ar); 7.3 (21H, m, Ar); 7.5 (1H, bs, Ar).

Example 21

Compound preparation [(VI), (X = Tr)]

2-Bromo-4-trityloxymethyl-phenol

0.3 g of pyridinium hydrochloride and then 0.5 g of trityl chloride are added to a solution of 2-Bromo-4-hydroxymethyl-phenol (0.50 g) in 4 mL of anhydrous DMF and 2 mL of anhydrous pyridine. . The mixture is heated at 50 ° C for 2h, added with a further 0.58 g of trityl chloride and kept at 50 ° C for another 2 hours and finally left to return to room temperature.

The mixture is processed similarly to example 10, obtaining 1.5 g of crude product which after crystallization with 5 mL of isopropanol gives 1 g of pure compound [(VI), (X = Tr)].

Claims (1)

CLAIMS 1. A process for the preparation of compounds of general formula (THE) OH H. No. OR X (THE) as racemates or as mixtures of (R) or (S) enantiomers in a any relative enantiomeric content where X is hydrogen, benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl, acyl (COR with R equal to C1-C4 alkyl, phenyl, benzyl) or silyl (SiTTâ € ™ Tâ € where T, Tâ € ™, Tâ € equal or different among them are C1-C4 alkyl, phenyl or benzyl), which includes: (i) the Mizoroki-Heck reaction between N, N-diisopropyl-3-phenyl-2- propenamide and an aryl bromide of formula (V) or (VI) (with Xâ ‰ H) to give an unsaturated amide of formula (IIIA) or (IIIB); (ii) the reduction reaction of the unsaturated amide of formula (IIIA) o (IIIB) to give the corresponding saturated amide of formula (IVA) or (IVB), as racemate or in enantiomerically enriched form; (iii) the saturated amide reduction reaction of formula (IVA) o (IVB), as racemate or in enantiomerically enriched form, for obtaining compound (I) with X equal to or different from hydrogen and with the meanings indicated above; and eventually; (iv) the conversion of compound (I; X = H) into compound (I; Xâ ‰ H); and eventually (v) the resolution of the racemate of compound (I) with X other than hydrogen and with the meanings indicated above. red. <cat.> <Pd cat.>, Base (I) (X = H) (V) (III A) <(IV A)> hydrides protection red. hydrides <cat.> <Pd cat.>, Base (VI) (III B) (I) (X = H) Scheme 2. A process according to claim 1 for the preparation of the compounds of formula (I) wherein X is trityl. 3. A process according to claim 1 or 2 wherein step (v) is carried out by crystallization of diastereomeric salts obtained by salification of compounds (I) in which X is different from hydrogen with an acid enantiomerically enriched in a suitable solvent. 4. A process according to claim 3 where the enantiomerically enriched acid is selected from (S) -mandelic acid and (R) -N-acetyl phenylglycine. 5. A process according to claims 3 or 4 in which the solvent is selected from those in which the solubility of the intermediate (I), with X different from hydrogen and preferably equal to trityl, is â ‰ ¥ 10% and selected between ethers, alcohols, arenes, esters and preferably between 2-Me-THF and t.amyl alcohol. 6. A process according to one of claims 3 to 5 for the preparation of the enantiomer (R) of the compound in which X is different from hydrogen and is preferably equal to trityl. 7. A process according to claim 6 wherein the enantiomer (S) of compound (I), with X different from hydrogen and preferably equal to trityl, is subjected to treatment with a strong base having a pKa â ¥ 26 to a temperature higher than 80 ° C, to obtain the corresponding product (I) as a racemate to be recycled in the process of claims 3-6. 8. A process according to claim 7, where the strong base is sodium amide or sodium hydride. 9. Process for the preparation of Fesoterodine (II) and its salts, in particular Fesoterodine fumarate, which comprises the esterification of an intermediate (I) prepared with the process of claims 1-7 with an acid derivative 2 -methylpropionic and eventual or subsequent deprotection when the intermediate (I) has Xâ ‰ H. 10. A process according to claim 9, where the intermediate (R) - (I) is used with X = trityl and the deprotection is carried out after the esterification reaction with a derivative of 2-methylpropionic acid 11. Compounds of formula (III A and B) (III A) (III B) where R is equal to C1-C4 alkyl, phenyl, benzyl and X is hydrogen, benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl, acyl (COR with R equal to C1-C4 alkyl, phenyl, benzyl) or silyl (SiTTâ € ™ Tâ € where T, Tâ € ™, Tâ € equal or different from each other are C1-C4 alkyl, phenyl or benzyl), as pure Z or E isomers or as a mixture in any possible combination of Z and E isomers. 12. Compounds of formula (IVA and B) (IV A) (IV B) where R is equal to C1-C4 alkyl, phenyl, benzyl and X is hydrogen, benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl, acyl (COR with R equal to C1-C4 alkyl, phenyl, benzyl) or silyl (SiTTâ € ™ Tâ € where T, Tâ € ™, Tâ € equal or different from each other are C1-C4 alkyl, phenyl or benzyl), as racemates or pure enantiomers (R) or (S) or as a mixture in any possible combination of enantiomers (R ) or (S). 13. Compounds of formula (I) OH H. No. OR X (THE) where X is benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl, acyl (COR with R equal to C1-C4 alkyl, phenyl, benzyl) or silyl (SiTTâ € ™ Tâ € where T, Tâ € ™, Tâ € equal or different from each other are C1-C4 alkyl, phenyl or benzyl), as racemates either pure enantiomers (R) or (S) or as a mixture in any possible combination of (R) or (S) enantiomers. 14. The compound according to claim 13 where X is trityl e preferentially where the absolute configuration is (R). 15. The compound of formula O O H. No. OR Tr e and its salts.