The invention concerns an improved process for the preparation of tolterodine (N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3 -phenyl propyl amine) and its salts, in particular for the preparation of the tartrate salt, and more particularly for the (+)-(R) enantiomer of tolterodine L-tartrate, starting from a novel intermediate, N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3- phenyl-2-propenamide, which can be used as pure Z or E isomer or as a mixture of Z and E isomers.

When the preparation of the enantiomer (R)-(+)-(N,N-diisopropyl-3-(2- hydroxy-5-methylphenyl)-3-phenylpropylamine) is desired by diastereomeric crystallization of a suitable compound, the present invention also concerns a process for the racemisation of the undesired (S)-(-)- (N,N-diisopropyl-3-(2- hydroxy-5-methylphenyl)-3-phenyl propylamine) enantiomer and its recycle in the process for the preparation of R-tolterodine.

Background of the invention

(R)-N,N-Diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine, known as (R)- Tolterodine, is an anti-cholinergic agent, useful in the treatment of urinary incontinence presently marketed in form of its salt with L-tartaric acid.

US 6,310, 103 discloses the corresponding enantiomer (S)-N,N- diisopropyl- 3-(2-hydroxy-5-methylphenyl)-3-phenyl propylamine ant its salts as drugs for use in the treatment of disorders of the urinary and gastrointestinal tracts.

A large number of methods for producing (N,N-diisopropyl-3-(2- hydroxy-5-methylphenyl)-3-phenyl propylamine) (I), its enantiomers and the corresponding salts have already been described. Many of them make use of starting products hardly available or dangerous reagents or the synthesis requires a high number of steps, so that the preparation is troublesome or may be not suitable on larger scale.

The preparation of (R,S)-(I) is described in US 5,382,600 where the product was recovered in numerous steps, long reaction time, and low overall yields by employing the intermediate 3,4-dihydro-6-methyl-4-phenyl-2H- benzopyran-2-one (VI). Furthermore, the use of expensive and hazardous reagents and solvents like methyl iodide, lithium aluminium hydride, and boron tribromide also renders this process unsuitable and hazardous on a commercial scale. The corresponding (R)-enantiomer, (R)-(I) was obtained by selective diastereomeric crystallization using L-(+)-tartaric acid as resolving agent in 95% ethanol and following recovering from the salt, if required. As a matter of fact, the L-tartrate salt of (R)-(I) has been directly marketed as suitable pharmaceutical form.

In the same patent, a second process is described, starting from (VI), that is transformed in a few steps into 3-[(2-methoxy-5-methylphenyl)-3- phenyl-propionic acid. The subsequent chlorination of the acidic intermediate with SOCl ₂ and the reaction with diisopropylamine yields the N,N-diisopropyl-3-(2-methoxy-5-methylphenyl)-3-phenyl-propam ide which is reduced by means of reductive agents such as LiAlH ₄ or sodium dihydro-bis- methoxyethoxy aluminate (Vitride™). The product (I) is finally obtained by deprotecting the methyl ether group with boron tribromide. It is clear that also this method is not suitable for application on industrial scale.

US 6,822, 1 19, US 7,355,077 and WO 2008/020332 disclose different methods for the preparation of (I). All of them comprise the conversion of compound (VI) into the corresponding 3-(2-(OR)-5-methylphenyl)-3-phenyl- propan- l-ol intermediate, where OR is hydroxy, methoxy or benzyloxy group, the subsequent transformation of primary alcohol function into a suitable sulphonate able to react with diisopropylamine. Finally, the compound (I) is obtained by removing the protection of phenolic OH group, isolated in the form of the corresponding hydrobromide or hydrochloride salt and purified by crystallization. Where described, the resolution is carried out by using L-tartaric acid in ethanol or in a mixture of methanol/acetonitrile. In particular, according to US 7,355,077 L-(+)-tartaric acid is used in excess (near 15% molar excess) to obtain the (I)-tartrate salt but in the subsequent recrystallization steps, needed to obtain final (R)-(I) of good quality, the enriched tolterodine must be recovered as free base and further L-(+)-tartaric acid must be added. The skilled persons easily understand that this resolution procedure is extremely work demanding.

In addition, all these processes involve a large number of steps, giving poor yields.

A further problem associated with these procedures is that dimeric impurities are generally associated with compound (I) and are difficult to remove, as reported in US 7,538,249. These impurities are formed during the reaction of the sulphonate intermediates with diisopropylamine. In order to obtain a product (I) suitable for the resolution step it is necessary to carry out an efficient purification of crude (I) which determines a decrease in the final yield.

US 5,922,914 discloses a novel intermediate, 3,4-dihydro-6-methyl-4- phenyl-2H-benzopyran-2-ol (VII), and an improved process for the preparation of (I) which involves the following steps: a) the reaction of trans-cinnamic acid with 4-methyl-phenol in acidic medium to give the above mentioned lactone (VI); b) the reduction of (VI) with diisobutyl aluminium hydride (DIBAL) to yield the corresponding benzopyran-2-ol; c) the reductive amination of the latter compound with diisopropylamine, in the presence of Pd/C catalyst in methanol. The resolution is finally carried out using ethanol or a mixture methanol/acetone with L-(+) -tartaric acid. In both cases L-(+)-tartaric acid is used in excess (near 50% molar excess) to obtain the (I)-tartrate salt without adding further tartaric acid in the recrystallization step.

This method of synthesis reduces the number of steps but it does not seem to be commercially feasible since it involves the use of the expensive and hazardous DIBAL as reducing agent.

The intermediate N,N-diisopropyl-3-(2-Hydroxy-5-methylphenyl)-3- phenyl propionamide (V) as a racemate was already described, for example, in US 6,3 10,248, US 7, 1 19,212, US 7,335,793, IN 2003CH01028, CN 101445462, but it has been obtained by means of processes different from the one object of the present invention. The reported examples of preparation of said intermediate give low yields or need processes with particular protections or multi step processes. For these reasons, said intermediate was not previously considered for the preparation of (I). In some of these patents, enantioenriched (V) was quoted as possible intermediate but no detailed description of this compound may be found.

A major problem encountered in the preparation of R-tolterodine, when a resolution process is performed, is the fact that the theoretical yield can not be higher that 50%, due to the presence of the S-isomer. Furthermore, a pharmaceutical active ingredient can not contain more than 1% of the wrong enantiomer so that the actual yield is usually much less than 50%. Therefore, S-enantiomer is an expensive by-product. A skilled person will be aware that the recover and reuse after a racemisation process is relevant for an industrial application but, to the best of our knowledge, only two patent applications address this aspect concerning the preparation of tolterodine.

547/CHE/2006 describes a process for the racemisation of (S)-tolterodine which involves the transformation of the undesired isomer into the intermediate (-)-N,N-diisopropyl-3-[2-benzyloxy-5-methylphenyl]-3- phenylpropylamine which is converted in (±)-N,N-diisopropyl-3-[2- benzyloxy-5-methylphenyl]-3-phenylpropylamine by means of a base in highly dipolar aprotic solvent. Finally, the racemic intermediate (±)-N,N-diisopropyl-3-[2-benzyloxy-5-methylphenyl]-3 -phenyl propylamine is reduced to give the (R,S) -(I). The process described in this application is however time consuming and consequently industrially disadvantageous.

CN 1626504 describes a process for preparing (R)-(I) and its tartrate which includes the recovery of S-(I) and the subsequent treatment of the (S) enantiomer with a reagent selected among organo-lithium, such as butyl lithium, or organo-magnesium compound, such as magnesium isopropyl halide, to obtain, after a proper quenching, the conversion of S-(I) into R-(I) which is finally transformed in L-(+)-tartrate-R-(I). This procedure is not a racemisation process but a stereoinversion process; moreover, the examples do not report the enantiomeric excess of S-(I) used and R-(I) obtained, so that no reliable conclusion on the efficiency and reproducibility of the process may be derived from this document.

On the basis of the prior art, there is still a need for finding improved processes for the preparation of (R)-(I) and for the recovery and reuse of the wrong enantiomer, overcoming the above problems and allowing the convenient preparation of a product with improved purity.

Description of the Invention

It has now surprisingly been found that a compound having formula (II)

(Π)

can be prepared in high yield from easily available products, by means of a simple one-step process which allows to avoid the use of hardly available starting products, reactants and reaction conditions troublesome for industrial production. Compound II can be transformed into the corresponding compound (V) as racemate or as enantioenriched compound in a nearly quantitative yield.

Compound (II), as pure Z or E isomer or as isomeric mixture of Z and E isomers, may be advantageously obtained by the Mizoroki-Heck reaction, contrary to what could be expected from the prior art, as better described later. The Z or E form, or mixtures thereof, can be obtained by modulating appropriately the reaction conditions and the related work-up because the two isomers have different solubility characteristics and a different stability with the temperature and the use of organic solvents.

Accordingly, in addition to the compound II, the invention refers also to a process for the preparation of N,N-diisopropyl-3-(2-hydroxy-5- methylphenyl)-3 -phenyl-propylamine (I) starting from said compound (II) either as pure Z or E isomer or as a mixture of Z and E isomers.

The invention also concerns a process for the preparation of the intermediate (II) by means of the Mizoroki-Heck reaction, (a detailed overview of this reaction is reported in "The Mizoroki-Heck Reaction", ed. M.Oestreich, Wiley 2009) which comprises:

1) reacting a 2-halo-4-methyl-phenol of formula (III)

(III)

wherein X is CI, Br or I

with N,N-diisopropyl-3-phenyl-2-propenamide (IV)

(IV)

in the presence of a base and of a suitable catalyst, preferably a palladium catalyst, to obtain the compound of formula (II) as a pure Z or E isomer or as a mixture of Z and E isomers, depending on the reaction and work-up conditions, the formation and/or the interconversion of both isomers being affected by the experimental conditions;

2) optional additional purification of crude compound (II), if necessary, for instance by selective crystallization, if a pure isomer is required.

As to step 1), it should be pointed out that the Mizoroki-Heck reaction, previously described on unsaturated compounds, such as unsaturated cinnamide esters (J. Org. Chem. 2007, 72, 6056-86059), and on 3-arylacrylamides (Bull. Korean Chem. Soc. 1999), has never been used on a Ν,Ν-dialkyl substituted amide. Furthermore, the excellent result observed in the present invention was unexpected because it has been reported that this type of reaction is not easily applicable on an unsaturated amide.

Starting from this novel, purified or crude isolated intermediate or from the same compound without isolating it from the reaction mixture, it is possible to carry out the synthesis of (I), by a process comprising:

i) reducing the intermediate (II) with a suitable reducing agent to obtain compound (V) as racemic mixture or enantiomerically enriched in (R) or (S) enantiomer;

(V)

ii) reducing the amide (V) to the corresponding amine (I) as racemic mixture or enantiomerically enriched in (R) or (S) enantiomer;

(I)

iii) isolating the compound (I) as a salt by adding a suitable inorganic or organic acid, preferentially tartaric acid and more preferentially enantiomerically pure L- or D- tartaric acid, using the L-enantiomer to obtain the (R)-(I) tartrate salt and the D-enantiomer to obtain the (S)-(I) tartrate salt; iv) optionally, converting the racemic or nearly racemic (R,S)-(I) L-tartrate or enantiomeric enriched (R)-(I) L-tartrate into the enantiopure (R) enantiomer as L-tartrate salt by selective crystallization.

Alternatively, step iv) is carried out on the D-tartrate salt if the enantiopure (S)-(I) enantiomer is desired. The intermediate (II) may be reduced with an almost quantitative yield in mild conditions to (R,S)-(V) using H ₂ or an hydrogen donor such as sodium hypophosphite in the presence of Pd/C as catalyst. Then, (R,S)-(V) can be converted into (I) by reduction with Vitride: the reaction product may be isolated as a salt by adding an inorganic or organic acid. The compound (I) is preferably isolated directly as racemic L-tartrate or enantiomerically enriched L-tartrate salt so avoiding, if the preparation of (R)-(I)- L-tartrate is desired, the intermediate formation of a different salt, with a clear advantage over the prior art. In fact, the quality of the isolated product (I) as tartrate is particularly suitable for the subsequent crystallization to obtain (R)-(I) in enantiomerically pure form by conventional crystallization methods.

Alternatively, the intermediate (II) can be reduced in two steps to the enantiomerically enriched form of (I) having enantiomeric excess up to 91%, if the C=C reduction occurs in the presence of a chiral catalyst; enantiomeric excess and absolute configuration depending not only on the used chiral catalyst but also on the E or Z isomer used as starting material.

This invention, characterized by the formation of novel (II) intermediate, enables the preparation of (I) as base and as salts, preferentially as the tartrate salt, in a simple, efficient and flexible way.

A further aspect of this invention is an optimized process for the resolution of tolterodine in isopropanol /water mixture using an excess of L-tartaric acid both in the resolution step and in the following recrystallization steps. The isopropanol/water ratio is preferably from 80/20 to 70/30, The L-tartaric acid/tolterodine ratio is preferably from 1.05 to 1.30.

The process for the preparation of (I) is easy to scale up industrially and gives the desired product in good yield and quality.

The present invention also provides a process for the preparation of enantioenriched (R)-I as detailed below. The mother liquors of a resolution step containing the (S) enantiomer are collected and, after distillation under vacuum, afford enantioenriched S enantiomer as free base or salt. This by-product is converted again into an equimolecular mixture of R and S enantiomer by treatment with a strong base having a pKa > 26 (as a reference for definition and estimation of the pKa values see, as for example, Acta Chem. Scand, 1995, 49, 878-887 and J.Amer. Chem.Soc, 1973, 95, 411-418) by heating at a temperature above 80°C, as shown in the following scheme:

(S)-(l) as free base or salt (R,S)-(I)

The racemic R,S mixture may be conveniently reused in the resolution step allowing an improved and more economical process.

Detailed description of the invention

The Mizoroki-Heck reaction used for the preparation of the intermediate (II) can be carried out using commercially available starting materials (III) and (IV), using a ratio (IV)/(III) which is in the range 2.5/1 to 0.9/1, preferably 1.5/1 - 1/1. It is performed in the presence of a solvent, preferentially an organic solvent with medium or low polarity such as, for example, 2-methyl-tetrahydrofuran, dioxane or toluene. Typically, the ratio between amount of solvent and (III) is 2- 10/1 w/w. Furthermore, the reaction is performed in the presence of an organic or inorganic base and, preferentially, in the presence of sterically hindered organic bases such as Ν,Ν-dicyclohexylmethylamine. The stoichiometric ratio between the base and (III) is typically in the range from about 1/1 to 1.5/1, preferentially from 1.3/1 to 1/1. The Mizoroki-Heck reaction requires the presence of a catalyst, preferentially a homogeneous Pd(0) catalyst, prepared in situ or preformed in a separate vessel and added to the reaction mixture, such as for example Pd(0)L ₂ + R ₃ P or Pd(0)(PR ₃ ) ₂ . A suitable Pd(0)L ₂ is for example Pd ₂ (dba) ₃ where dba is dibenzylideneacetone. When Pd in a different oxidation state is added to the reaction mixture, such as for example Pd(OAc), it is necessary that it is reduced in situ to obtain the active Pd(0) catalyst. The most suitable phosphines for this reaction should be the hindered electron rich phosphines such as, for example, t-butylphosphine, di-t-butyl(2,2-diphenyl-l -methyl- 1- cyclopropyl)phosphine (c-BRIDP), di(l-adamantyl)-«-butylphosphine. The stoichiometric ratio between (III) and the catalyst should be in the range from about 100: 1 to 10000: 1, preferably from 500: 1 to 5000: 1 and more preferably from 1000: 1 to 3000: 1.

The reaction temperature can affect the isomeric ratio between the E and Z isomer of (II) and can be modulated to obtain one of the two isomers in pure form or in larger excess. Temperatures lower than 100°C usually afford higher contents of E isomer, temperatures higher than 100°C afford higher amounts of Z isomer.

The purity of the E or Z isomer may be increased by simple crystallization in a suitable solvent. For example, the highly pure E isomer may be obtained by crystallization in toluene where the Z isomer is more soluble, while the highly pure Z isomer may be obtained directly from the synthesis, by fine tuning the experimental conditions.

The E or Z isomers of novel product (II) have been characterized by HPLC [Column Agilent Zorbax RX8 250x4.6 mm; Mobile phase = 1.54 g CH ₃ COONH ₄ + 500 ml water + 1,0 ml CH3COOH+ 500 ml CH ₃ CN; Flow= lml/min. wave length: 220 nm. Loop volume 10 μΕ; RT 18.2 (E isomer), 18.9 (Z isomer)], melting point (DSC): 161-164°C ((E)-isomer), 145-151°C ((Z)-isomer), 1H NMR (300 MHz, CDC1 ₃ , δ in ppm) (E isomer): 0.93 (d, 6H), 1.39 (d, 6H), 2.23 (s, 3H), 2.72 (br s, 1H), 3.35 (m, 1H), 4.27 (m, 1H), 6.25 (s, 1H), 6.78 (d, 1H), 6.86 (s, 1H), 7.02 (d, 1H), 7.30 (m, 5H); 1H NMR (300 MHz, deuterated DMSO, δ in ppm) (Z isomer): 0.89 (d, 6H), 1.18 (d, 6H), 2.16 (s, 3H), 2.72 (br s, 1H), 3.25 (m, 1H), 4.12 (m, 1H), 6.48 (s, 1H), 6.69 (d, 1H), 6.89 (s, 1H), 6.96 (d, 1H), 7.15 (m, 1H),7.25 (m, 5H), 8.95 (s, 1H).

The reduction of product (II) to (R,S)-(V) can be performed by means of H ₂ or with hydrogen donors, such as sodium hypophosphite, in the presence of wet 3%, 5% or 10% Pd/C as catalyst, using a solvent selected from the group consisting of tetrahydrofuran (THF), methyl-THF or alcohols such as methanol and ethanol, optionally adding 0.5-10% of water, and using a pressure which ranges from atmospheric pressure to 10 bar, the ratio between amount of solvent and (II) being in the range 5/1-20/1 w/w.

The ratio between the catalyst and (II) is in the range of 1/300- 1/5, preferably 1/200-1/10 w/w.

The temperature of the hydrogenation is in the range of 30-100°C and preferentially 40-80°C. The reaction time is in the range of 0.1-5 h, typically 0.5-2h. The yield of isolated (R,S)-(V) is > 90%, and usually >95%.

It is also possible to reduce directly the Mizoroki-Heck reaction mixture containing the crude, not isolated, compound (II) in order to obtain in one-pot the saturated amide (V) that may be purified, if necessary, by crystallization.

When an asymmetric reduction is performed, the enantiomeric excess of (V) is also a function of the isomeric purity of the unsaturated product (II), so that it will be proper to proceed through the isolation of the latter compound. To carry out such type of reaction, a few known catalysts suitable for asymmetric reduction of unsaturated olefins, e.g. homogeneous chiral catalyst based on Ruthenium, Rhodium, Iridium, Cobalt, Copper, Zinc with suitable chiral ligands, can be used. The outcome of this reaction is affected either by the used catalyst or by the isomeric purity and type of compound (II). For example, using a Ru catalyst with a chiral phosphine such as Segphos™ (Takasago) and working on pure Z or E isomer of (II), enantioenriched (V) is obtained with an e.e. up to 91.6% with a nearly quantitative conversion. It was observed that the absolute configuration and the e.e. of (V) may be affected by the type of isomer if the same chiral catalyst is used.

The reduction of the saturated amide (V) to (I) is carried out, as described in the literature, using VITRIDE™; according to a preferred procedure, the compound (I) may be isolated directly as (L) tartrate salt. This product has a ratio between (R)-(I) and (S)-(I) in the range of 50/50 or 90/10 and high chemical purity, greater than 97%, and for this reason it is suitable for further enrichments by crystallization, performed in alcoholic solvents or in mixture containing alcohols, following known procedures.

The resolution step may be effected using known procedures in ethanol or, preferentially, according to the present invention, in a mixture of isopropanol/water, using L-tartaric acid in suitable excess during all the precipitation and re crystallization steps, to obtain a final (R)-(I) product having the quality required by Pharmacopoeia, including the crystalline form obtainable following the procedure used by the originator.

The racemisation step is performed in organic solvent having preferentially a boiling point above 80°C, selected from ethers and aromatic hydrocarbons such as methylTHF, cyclopentyl methyl ether, xylenes, cumene, anisole, tetraline; more preferably the solvent is 2-methylTHF, cyclopentyl methyl ether, xylenes and anisole. The racemisation is performed at temperature varying from 80°C to 200°C, preferably from 80°C to 170°C, more preferably at 80- 150°C, depending on the used solvent.

The preferred base for the racemisation step is sodium amide in an amount not higher than 8 molar equivalents related to compound (I). In a preferential procedure, the racemisation is carried out on compound (I) using 0.5-6 molar equivalents of sodium amide; metal hydroxides or metal alkoxides may be used as ancillary bases.

The time required for the racemisation step is in the range of 30 minutes to 24 hours, preferably 1 to 20 hours, depending on the reaction mixture. The racemic compound thus obtained is recovered after the work-up and precipitated preferentially as L-tartrate salt and then subjected again to a fractional crystallization procedure as reported above.

The invention will be further illustrated by the following examples. Example 1

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propenamide (II)

In a vessel, under nitrogen atmosphere, N,N-diisopropylcinnamamide (278 g, 1.2 mol), 2-bromo-4-methylphenol (150 g, 0.8 mol), N,N-dicyclohexylmethylamine (204 g, 1.0 mol) and 2-methyltetrahydrofuran (1.5 L) are loaded and the temperature is adjusted to 80°C. The catalyst, bis(tri-tert-butylphosphine)Pd, (0.82 g, 2mmol) is added to the vessel and the reaction mixture is stirred until complete conversion is reached (time about 4 h). An aqueous solution of hydrochloric acid (2 w/w-%) is added until pH =1 and the mixture is cooled at 55°C. The phases separate, the water phase is discarded and the organic phase is washed again with water. The solution is then concentrated under vacuum at < 50°C to remove water by azeotropic distillation of water and 2-methyltetrahydrofuran mixture and finally treated with celite and charcoal at 50°C under stirring for 30' and filtered. The filter cake is washed with 2-methyltetrahydrofuran. The solvent is then removed under vacuum at < 50°C and the residue is charged with toluene (0.75 L) and temperature adjusted to about 80°C to obtain a homogeneous solution. Finally the mixture is slowly cooled to 0 - 5°C and the product (II) isolated by filtration and dried under vacuum (23 1 g, 85%, E/Z isomeric ratio 75/25, purity >98%).

Examples 2 and 3

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propenamide (II)

Following the procedure of example 1 but heating the toluene mixture at 105°C for 2 or 4.5h, the product (II) isolated by filtration and dried under vacuum is recovered with c.y. 85% (E/Z isomeric ratio 75/25) or with c.y. 68% (E/Z isomeric ratio 49/51).

Example 4

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propenamide (II)

Following the procedure of example 1 but isolating the product (II) directly by concentration of 2-methyl-tetrahydrofuran mixture at < 50°C, is recovered with c.y. 74% (E/Z isomeric ratio 99/1).

Example 5

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propenamide (II)

A mixture of 2-bromo-4-methylphenol (375 g, 2.0 mol), N,N-diisopropylcinnamide (695 g, 3.0 mol) and N,N- dicyclohexylmethylamine (612 g, 3.0 mol) is added to 5 litre feed vessel and mixed together under stirring. To the mixture 1 L of degassed 2-methyltetrahydrofuran (2-MeTHF) is then added. To a second feed vessel 2.5 L of degassed 2-MeTHF are charged, followed by tri-tertbutylphosphine (8.1 g, 40 mmol) and Pd ₂ (dba) ₃ (9.2 g, 10 mmol) dissolved in a small amount of degassed 2-MeTHF. After priming the continuous flow reactor system with 2-MeTHF, setting the pressure to 7 bars, the plate reactor is heated conventionally with heated oil to reaction temperature, 150- 155°C. When the reaction temperature has been reached, the bottom valves of both the feed vessels are opened and the combined flow is directed to the plate reactor. The flow rate is adjusted to correspond to a residence time in the plate reactor of 3 minutes; i.e. flow rate is set to 24 ml/min and the residence volume in the reactor is 73 ml. The temperature of the reaction mixture inside the plate reactor is measured with 3 independent thermo couples and displayed on computer screen all through the experiment. The outlet is continuously collected in two separate receiver vessels and they are discharged after completed experiment. The first vessel is in duty up the point of acceptable level of conversion and the second to collect the batch thereafter. After the usual work-up the product (II) is recovered as nearly pure Z isomer with c.y. 60%.

Examples 6-20

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propenamide (II)

The preparation of compound (II) is performed working at different reaction conditions and with different catalysts. All experiments are run with 1.5 equivalents of 2-bromo-cresol and 1.5 equivalents of base unless otherwise stated. Conversion and reaction profile is based on HPLC peak area %. (Tables 1 and 2)

Table 1

Example Pd Additives Time Temp Conv. Reaction Profile

Source Solvent (h) CO (%)

6 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P

0.02 eq Me(Cy) ₂ N

Dioxane 18 80 82 11 : 71 : 17

7 Pd(OAc) ₂ cBRIDP

0.02 eq Me(Cy) ₂ N

Toluene 24 80 100 35 : 59 : 6

8 Pd(OAc) ₂ cBRIDP

0.02 eq Me(Cy) ₂ N

Toluene 18 70 95 23 : 71 : 6

9 Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N

Dioxane 20 75 91 1 : 79 : 11

10 Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N

2-Me-THF 6 80 70 0 : 73 : 4 l l ^a Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N

Dioxane 5 80 100 1 : 95 : 4

12 ^a Pd(OAc) ₂ cBRIDP

0.01 eq Me(Cy) ₂ N

Toluene 2 80 77 3 : 94 : 3

1.5 equivalents of N,N-diisopropylcinnamide and 1.3 equivalents of base.

Table 2

Entry Pd Additives Time Temp Conv. Reaction Profile

Source Solvent (h) (°C) (%)

13 Pd(OAc) ₂ cBRIDP

0.02 eq Me(Cy) ₂ N

DMA 18 100 100 46 42 : 12

14 Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N ^a

Dioxane 18 80 89 2 87 : 11

15 Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N ^b

Dioxane 18 80 89 2 87 : 11

16 ^c Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N ^d

Dioxane 18 80 23 6 : 84 : 10

17 ^e Pd ₂ (dba) ₃ cBRIDP

0.01 eq Me(Cy) ₂ N

Dioxane 18 80 62 8 72 : 20

18 ^f Pd ₂ (dba) ₃ cBRIDP

0.02 eq Me(Cy) ₂ N

Dioxane 2 150 87 3 : 66 : 31 min (MW)

g

19 ^f Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^g

0.02 eq Me(Cy) ₂ N

Dioxane 2 80 100 0 95 : 5

20 Pd ₂ (dba) ₃ Me(Cy) ₂ N

0.02 eq Dioxane 2 150 17 26 : 23 51 min (MW)

g a2 equivalents. ^b l. l equivalents. ^c 2 equivalents 2-bromo-cresol. ^d 2 equivalents. ^e l. l equivalents of N,N-diisopropylcinnamide. ^f 1.5 equivalents of N,N-diisopropylcinnamide. ⁶ heating by using microwaves (MW)

Examples 21-28

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methyrphenyl)-3- phenyl-2-propenamide (II)

The preparation of compound (II) is performed working at different reaction conditions and with the same Pd catalyst precursor at different concentration. All experiments are run with 1.3 equivalents of base. Conversion and reaction profile is based on HPLC peak area % (Table3).

Table 3

Example Pd Additives Time Temp Conv. Reaction Profile

Source Solvent (h) (°C) (%)

21 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^b

0.02 eq Me(Cy) ₂ N 2 150 100 3 51 46

Dioxane min (MW)

22 ^c Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^d

0.01 eq Me(Cy) ₂ N 2 80 100 14 78 8

Dioxane

23 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^b

0.02 eq Me(Cy) ₂ N 2 ½ 80 100 0 : 93 : 7

2-Me-THF

24 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^b

0.02 eq Me(Cy) ₂ N 4 130 100 2 : 66 : 32

Dioxane min (MW)

25 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^d

0.01 eq Me(Cy) ₂ N 2 150 100 3 : 50 : 47

Dioxane min (MW)

26 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^d

0.01 eq Me(Cy) ₂ N 2 150 100 4 : 45 : 51

2-Me-THF min (MW)

₂₇ a, e Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^b

0.02 eq Me(Cy) ₂ N

Dioxane 2 h 80 100 0 : 88 : 51

28 ^a Pd ₂ (dba) ₃ [(CH ₃ ) ₃ C]P ^f

0.005 eq Me(Cy) ₂ N 2 150 100 3 51 46

2-Me-THF min (MW)

equivalents of N,N-diisopropylcinnamide. ^b 0.04 equivalents. equivalents of N,N-diisopropylcinnamide. ^d 0.02 equivalents. ^e 20 g scale with respect to 2-bromo-cresol. 0.01 equivalents.

Example 29

Preparation of (±)N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propanamide (R,S)-(V)

Compound (II) (168 g, 0.499 mol), 2-Me-THF (2.0 L) and water (40 mL) are loaded into a 3 L round bottomed flask, fitted with a mechanical stirrer. The flask is washed three times with nitrogen, 5% Pd/C (18 g, 50% wet) is added and the reaction mixture is stirred under hydrogen atmosphere (1 bar) at 55°C. After 2.5 hrs the HPLC showed complete conversion. The reaction is filtered, at 55 °C, trough a pad of celite and the filter is washed with wet, warm 2-MeTHF (180 mL). The filtrate is concentrated to a volume of about 350 mL under reduced pressure, toluene (720 mL) is added and 350 mL of solvent is distilled off, under reduced pressure. The mixture is cooled to 0-5 °C and stirred for lhr. Then the solid is filtered, washed with cold toluene (2 x 60 mL) and dried for 12 hrs at 55°C, at 100 mbar to afford pure (R,S)-(V) [161g, c.y. 95%].

m.p. = 176°C.

1H-NMR (300 MHz, CDC1 ₃ , δ in ppm): 1.07 (d, 3H), 1.16 (d, 3H), 1.25

(d, 3H), 1.36 (d, 3H), 2.1 1 (s, 3H), 3.1 1 (d, 2H), 3.43 (br s, 1H), 4.04 (m, 1H), 4.99 (t, 1H), 6.63 (s, 1H), 6.83 (s, 2H), 7.29 (m, 5H), 9.10 (br s, 1H).

LC-MS (pos): 340.3 [M+H] ⁺

Example 30

Preparation of (±)N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propanamide (R,S)-(V)

Compound (II) (100 g, 0.297 mol), 10%Pd/C (0.5g, 50% wet) and methanol (1.0 L) are loaded into a 2 L autoclave, fitted with a mechanical stirrer, and put under hydrogen atmosphere (5 bar). The temperature is adjusted to 70°C and the reaction mixture stirred until complete conversion is reached (lh). The catalyst is filtered off from the hot mixture, and the filter cake washed with hot methanol (200 mL). The organic phase is diluted with water (100 mL) at 60-65 °C under stirring to favor the crystallization of the product; then the mixture is cooled to 5°C, filtered and the solid washed with cold methanol /water (9/1) and dried under vacuum to afford pure (R,S)-(V) [88 g, c.y. 88%].

Example 31

Preparation of (±) N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propanamide (R,S)-(V)

Following the procedure of example 1 and treating the crude not isolated product (II) in 2-Me-THF, after a double treatment with charcoal, with 10% Pd/C and hydrogen at 5 bar at 70°C, the crude (R,S)-(V) is obtained.

Example 32

Preparation of (±) N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propanamide (R,S)-(V)

An aqueous solution of hypophosphite is prepared by mixing water (1.0 L), sodium hypophosphite (85 g) and sodium carbonate (85 g) and stirred until dissolution. A 3 L round bottomed flask, fitted with a mechanical stirrer, is loaded with compound (II) (168 g, 0.499 mol), 2-Me-THF (2.0 L) and ¼ of the prepared hypophosphite solution. The flask is washed three times with nitrogen, 5%Pd/C (18 g, 50% wet) is added and the reaction is warmed, under vigorously stirring, at 50-55°C. After 20' at this temperature, the rest of the hypophosphite solution is dropped over 1.5 hrs at 55°C. The mixture is filtered, at 55°C, trough a pad of celite and the filter is washed with wet, warm 2-Me-THF (180 mL). The aqueous phase is separated and the organic phase is washed two times with warm water (2 x 200 mL) maintaining the temperature at 50-55°C. The organic phase is treated as in previous example to afford 163 g of pure (R,S)-(V).

Examples 33-35

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propanamide (R)-(V) and (S)-(V)

To a 50-mL stainless steel autoclave equipped with a Teflon coated stirrer bar is placed [RuCl( 7-cymene)((R)-dm-segphos)]Cl (3.0 mg, 0.00296 mmol) and E-(ll) (200 mg, 0.593 mmol). The atmosphere is replaced with nitrogen gas, followed by addition of THF-MeOH (10: 1) (1. 1 mL) and THF-MeOH (10: 1) solution (0.593 M) of TFA (0. 1 mL, 0.0593 mmol). Hydrogen is initially introduced into the autoclave at a pressure of 1.0 MPa, before being reduced to 0. 1 MPa by carefully releasing the stop valve. After this procedure is repeated three times, hydrogen is introduced at 3.0 MPa and the solution is stirred at 60°C for 16h. The reaction mixture is diluted with MeOH (6.08 mL). 150 μΐ. of sample is diluted with IPA (ca 1.35 mL) and analyzed by HPLC. 94.6 area % (91.6%ee) of (S)-(V) is observed.

Working with the same amount of [RuCl(/?-cymene)((R)-dm- segphos)]Cl catalyst and (II), but using Z-isomer, in pure MeOH and in absence of TFA at 80°C for 16h, a HPLC conversion of 97 area % (87% e.e.) of (R)-(V) is observed.

Working with the same amount of [RuCl(/?-cymene)((R)-dm- segphos)]Cl catalyst and (II), but using E-isomer, in pure MeOH and in absence of TFA at 80°C for 16h, a HPLC conversion of 98 area % (74% e.e.) of (S)-(V) is observed.

Examples 36-37

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl-2-propanamide (R)-(V) and (S)-(V)

To a 100-mL stainless steel autoclave equipped with a Teflon coated stirrer bar is placed [Ru(S)-TMBTP(OCOCF ₃ ) ₂ (3.5 mg, 0.00432 mmol) and (II) as(E/Z 82/18) mixture (250 mg, 0.741 mmol). The atmosphere is replaced with nitrogen gas, followed by addition of EtOH (2.5 mL). Hydrogen is initially introduced into the autoclave at a pressure of 1.0 MPa, before being reduced to 0.1 MPa by carefully releasing the stop valve. After this procedure is repeated three times, hydrogen is introduced at 2.0 MPa and the solution is stirred at 50°C for 20h. The reaction mixture is analyzed by HPLC: 97 area % (35%ee) of (R)-(V) is observed.

Working with [Ru(R)-TMBTP(OCOCF ₃ ) ₂ (30mg) and (II) ( lg, but using pure E isomer), in pure EtOH ( 10 mL) at 50°C for 16 h, a HPLC conversion of 97 area % (41% e.e.) of (S)-(V) is observed. Example 38

Preparation of N,N-diisopropyl-3-(2-Hvdroxy-5-methylphenyl)- 3 -phenyl propylamine (R,S)-(I) as hydrochloride salt

A well dried 3 L round bottomed flask, fitted with a mechanical stirrer, is purged with nitrogen and loaded with compound (R,S)-(V) (50 g, 0.147 mol) and toluene (500 mL). The suspension is cooled with an ice bath and a first portion of Vitride™ (27 g, >65% w/w in toluene) is added, dropwise, over 30 min., at 5-10°C (exothermic reaction and H ₂ evolution occur). Then the second portion of Vitride™ (157 g, >65% w/w in toluene) is added, over 30 min, warming gently to 20-25°C. Then, the temperature is allowed to rise up to 30°C. This temperature is maintained for 3 hrs before warming the reaction to 40°C for 2h. Acetone (60 mL) is slowly dropped letting the temperature rise to 60-70°C, After 5 min 10%NaOH (150 mL) is added and the mixture is stirred for 15 min at 40-60°C, before cooling it to RT. Then, the aqueous phase is separated and the organic phase washed, in order, with dil. NaOH (5 mL 30% NaOH + 100 mL H2O), 7% aqueous NaHCO ₃ (75 mL, until the pH of the discarded aqueous phase was 8-9) and finally with water (2 x 75 mL).

The final organic solution is evaporated under reduced pressure using a water bath (Tmax 50-60°C). The residue (about 54 g) is dissolved in methyl-isobutyl-ketone (350 mL) and warmed to 50-60°C. 30% HC1 is dropped (18 mL) and 100 mL of methyl-isobutyl-ketone are distilled, under reduced pressure. Then the mixture was cooled to 20°C in lhr, stirred for 2 hrs at this temperature and filtered to afford (R,S)-(I) hydrochloride [49 g (c.y. 92%)]. Example 39

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3-phenyl propylamine (I) as L-tartrate salt

The reduction of 20 g compound (V) with Vitride™ is carried out as in the previous example but the mixture, at the end of reaction, is worked as follows. The residue, obtained after work-up and evaporation of the solvent, is dissolved in 95% ethanol (50 mL) and warmed to 60-70°C. Tartaric acid (12 g) was dissolved in ethanol (125 mL) at 60-70 mL and the solution was added to the tolterodine solution, over 15 min, keeping the temperature in the 60-70 °C range. The suspension was warmed to reflux, maintained for lhr, cooled to RT in 1 hr and stirred overnight. Than, the mixture was cooled to 0-5°C and stirred for 10 hrs. The product is collected by filtration, washed with cold 95% ethanol (2 x 25 mL) and dried under vacuum to afford high pure compound (I) as L-tartrate [19.8 g (c.y. 78%), assay: 99.4%, (R)-(I)/(S)- (I) ratio=60/40. This product may be then crystallized in EtOH 95% according to a known procedure to afford highly pure (R)-(I) [c.y 37%, e.e. 99.4%].

Example 40

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3-phenyl propylamine (I) as L-tartrate salt

The reduction of 50 g of compound (V) with Vitride™ is carried out and worked up as in the previous example to obtain crude (I) after the evaporation of solvent. The viscous residue (about 54 g) is dissolved in isopropanol (500 mL) and the solution warmed 70-75°C. At this point, L-Tartaric acid (25 g) is added and the temperature is maintained for 30 min under stirring. The suspension is cooled to RT in lhr and stirred for 2h. The product is filtered and washed with isopropanol to afford (I) as L-tartrate salt. Yield: 90%. (R)-(I)/(S)-(I) ratio=51/49. Example 41

Preparation of N,N-diisopropyl-3-(2-hvdroxy-5-methylphenyl)-3- phenyl propylamine (I) as L-tartrate salt

Working as in example 39, but using absolute ethanol, 22.9 g of compound (I) as L-tartrate were obtained [(c.y. 82%), assay: 99.4%, (R)-(I)/(S)- (I) ratio=54/46].

Example 42

Comparative examples of partial enriched N,N-diisopropyl-3-(2- Hydroxy-5-methylphenyl)- 3-phenyl propylamine (I) as L-tartrate salt.

A) starting from (R)-(I)/(S)-(I) (ratio=50/50) as HC1 salt

40.4 g of racemic (I), obtained starting from the corresponding hydrochloride (45 g, 0.124 mol), are diluted in 112 mL of EtOH 95%, heated at 60°C and added with a hot solution of 27.9 g (1.5 eq) of L-Tartaric acid in 280 mL of EtOH 95%. The mixture is maintained at 60-70°c for 30', cooled in 1 h at RT, maintained overnight at RT, and then for lOh a 0-5°C, filtered and washed with 2x 90 mL of cold EtOH to afford 46.9 g of L-tartrate salt [(R)-(I)/(S)- (I) ratio=60/40].

B) starting from (R)-(I)/(S)-(I) (ratio=51/49) as L-tartrate salt

59 g (0.124 mol) of this L-tartrate salt are diluted in 252 mL of EtOH 95%, heated at 60°C and added with a hot solution of 9.3 g (0.5 eq) of L-Tartaric acid in 140 mL of EtOH 95%. The mixture is maintained at 60-70°C for 30', cooled in 1 h at RT, maintained overnight at RT, and then for lOh a 0-5 °C, filtered and washed with 2x 90 mL of cold EtOH to afford 35.6 g of L-tartrate salt [(R)-(I)/(S)- (I) ratio=82/18].

Comparative Example 43 (crystallization according to EP 325571)

Fractional crystallization of Tolterodine hydrochloride ((R)/(S) = 50/50)

(solvent ethanol 95%)

45 g of tolterodine Hydrochloride as racemate (0.124 mol), 400 ml of methylene chloride, 220 ml of water, 8.7 ml of NaOH 30% and 4.5 g of Na ₂ CO ₃ are mixed and stirred. Two phases separate, water is removed and the organic phase is concentrated under vacuum obtaining crude tolterodine base (46 g). The residue is dissolved in 112 ml of ethanol 95% and the solution is heated to 60-70°C and added with 27.9 g of L-tartaric acid dissolved in 280 ml of ethanol 95%. The mixture is heated at 60-70°C for 1 hour, cooled to 0-5°C, and stirred for 10 hours before filtration. The isolated product is washed with cold ethanol 95% and dried under vacuum to obtain 46.9 g of (R)/(S)-tolterodine tartrate ratio 60/40.

This product is dissolved 1.90 L of ethanol 95% v/v; after distilling off

940 ml of solvent the mixture is cooled to room temperature and then to 0-5°C to obtain, after filtration, washing and drying, 25.5 g of (R)/(S)-tolterodine tartrate ratio 95/5.

After a new recrystallization in about 560 ml of ethanol 95%, using a procedure as above, 22 g of (R)/(S)-tolterodine tartrate ratio 99.6/0.4 are recovered.

The product was characterized by means of IR, DSC and XRDP, showing that the crystalline form is equivalent to the originator one [main XRDP °2Th peaks: 11.9, 14.2, 15.9 16.9, 18.4, 18.8, 20.3, 21.0, 22.0, 23.9, 24.8, 25.4, 26.3, 29.8].

Example 44

Fractional crystallization of Tolterodine L-tartrate ((R)/(S) = 61/39) (solvent mixture isopropanol/water 70/30)

30 g of (I)-L-tartrate (63 mmol), having a (R)/(S) ratio of 61/39, and 0.95 g of L-tartaric acid (6.3 mmol) are suspended in 90 ml of isopropanol/water (70/30) and the mixture is heated to reflux to obtain complete dissolution. The solution is then slowly cooled under stirring till a temperature of about 60-65°C and maintained for about lh to crystallize. Afterwards, the suspension is cooled to room temperature and maintained under stirring till the product is filtered and washed, firstly with isopropanol/water (70/30) and finally with isopropanol, to obtain 16.6 g of (I)-L-tartrate having a (R)/(S) ratio of about 95/5.

15 g of (I)-L-Tartrate (32 mmol), obtained following the previous procedure, and 0.24 g of L-tartaric Acid (1.6 mmol) are added to 68 ml of isopropanol/water (70/30) and the mixture is heated to reflux to obtain complete dissolution. The solution is then slowly cooled under stirring till a temperature of about 60-65°C and maintained for about lh to crystallize.

Afterwards, the suspension is cooled to room temperature and maintained under stirring till the product is filtered and washed, firstly with isopropanol/water (70/30) and finally with isopropanol, to obtain 12.6 g of (I)-L-tartrate having a content of (S)-(I) according to the required specifications.

The product was characterized by means of IR, DSC and XRDP showing that the crystalline form is equivalent to the originator one [main XRDP °2Th peaks: 1 1.9, 14.2, 15.9 16.9, 18.4, 18.8, 20.3, 21.0, 22.0, 23.9, 24.8, 25.4, 26.3, 29.8].

Example 45

Racemisation of (I) in xylene

Mother liquors of (I)-L-Tartrate ((R)/(S) = 25/75), obtained from the resolution step and containing about 100 g of (I)-L-tatrate (0.21 mol), are concentrated by means of distillation, under reduced pressure, to obtain a dense residue. 650 ml of water are charged and about 100 ml of solvent are distilled off.

600 ml of xylenes (b.p. 137- 142°C) and 90 g of NaOH 30% are added to the suspension and the mixture is stirred till complete dissolution. Then, the aqueous phase is separated and the organic phase washed with 100 ml of water. The organic phase is heated to reflux, under reduced pressure, to remove water by azeotropic distillation. The obtained solution is then brought to 90°C and 48 g of sodium amide (1.23 mol) are charged portionwise before heating the mixture to reflux for about 1.5 hours.

When the racemisation process is completed, according to chiral HPLC analysis using a Column that contains packing L5 1, such as for example CHIRALPACK AD, 1 ml/min of hexane / isopropanol / trifluoroacetic acid / diethylamine 400 / 40 / 1 /OA (S)-isomer R T 0.86, (R)-isomer RRT, the mixture of reaction is cooled to room temperature and 200 ml of water are charged cautiously. The phases separate, the water phase is discarded and the organic phase is washed with 7% NaHC0 _3aq (100 ml) and with water (2x70 ml). The solvent is then removed under vacuum, the residue charged with isopropanol (450 ml) and L-tartaric acid (37 g, 0.25 mol) and the mixture heated to reflux.

The suspension is maintained at 70-65°C for about 15-30 minutes, finally it is slowly cooled to 0-5°C and kept under stirring at this temperature till the product (I)-L-tartrate is isolated by filtration and dried under vacuum (79 g, 79%, (R)/(S) ratio 50/50).

Example 46

Fractional crystallization of racemic (I)-L-tartrate obtained from the treatment of the mother liquors

70 g of (I)-L-tartrate (0.15 mol) obtained in Example 45, having a (R)/(S) ratio of 50/50, and 6.7 g (0.04 mol) of L-Tartaric Acid are charged in isopropanol / water (409 ml, 70/30). The suspension is heated to reflux for about 15-30 minutes, then maintained at 60-65°C and finally cooled to room temperature and maintained under stirring till the product is isolated by filtration and dried under vacuum (36.7 g, 52%, (R)/(S) ratio 88/12).

35 g of (I)-L-tartrate (73 mmol), having a (R)/(S) ratio of 88/12, obtained as described above, and 0.9 g (6 mmol) of L-Tartaric Acid are suspended in 140 ml of isopropanol/water (70/30) and the mixture is heated to reflux to obtain complete dissolution. The solution is then slowly cooled under stirring till a temperature of about 60-65 °C and maintained for about lh to crystallize.

Afterwards, the suspension is cooled to room temperature and maintained under stirring till the product is filtered and washed to obtain 33 g of wet (I)-L-tartrate ((R)/(S) ratio 98.9/1.1).

This wet product is crystallized again, following the procedure described above, in order to obtain the final (I)-L-tartrate as a dried product (22.2 g, ((R)/(S) ratio 99.9/0.1).

Example 47

Racemisation of (I) in anisole

10 g of (I)-L-tartrate (21 mmol), having a (R)/(S) ratio of 27/73, 100 ml of xylene, 8.5 g of NaOH 30% and 80 ml of water are mixed and maintained under stirring in order to obtain complete dissolution. NaHCO ₃ is added portionwise till a pH of 8-10 then the water phase is discarded and the organic phase is washed with water (2x25 ml).

The solvent is then removed under vacuum, the residue charged with

130 ml of anisole and the mixture heated, under vacuum, to distill off about 30 ml of solvent. When the temperature reaches about 100°C, 2.1g of sodium amide (53 mmol) are added portionwise, then the mixture is heated to reflux till the racemisation process is completed.

The mixture of reaction is finally cooled to about 50°C and 30 ml of water are charged cautiously.

The phases separate, the water phase is discarded and the organic phase is washed firstly with 7% NaHC0 _3aq (20 ml) and secondly with water (2x20 ml).

The solvent is then removed under vacuum, the residue charged with isopropanol (120 ml) and L-tartaric acid (3.8 g, 25 mmol) and the mixture heated to reflux.

The suspension is finally slowly cooled to 0-5 °C and kept under stirring at this temperature till the final product (I)-L-tartrate is isolated by filtration and dried under vacuum (6.7 g, 67%, (R)/(S) ratio 50/50).

Example 48

Racemisation of (I) in 2-Me-THF

19 g of (I)-L-tartrate (40 mmol), having a (R)/(S) ratio of 28/72, 200 ml of 2-Me-THF, 17 g of NaOH 30% and 150 ml of water are mixed and maintained under stirring in order to obtain complete dissolution. NaHCO ₃ is added portionwise till a pH of 8-10 then the water phase is discarded and the organic phase is washed with water (100 ml).

The organic phase is heated to reflux, to remove water by azeotropic distillation. The obtained solution is then cooled to 60°C and 4.8 g of Sodium amide (124 mmol) are charged portionwise before heating the mixture to reflux for about 20 hours, till the racemisation process is completed.

The mixture of reaction is finally cooled to room temperature and 100 ml of water are charged cautiously. NaHCO ₃ is added portionwise till a pH of 8-10 then the water phase is discarded and the organic phase is concentrated by means of distillation, to obtain a dense residue.

The residue is charged with 120 ml of isopropanol and 7.2 g of

L-tartaric acid (48 mmol) and the mixture heated to reflux.

The suspension is then maintained at 60-65 °C for about 15-30 minutes, slowly cooled to 0-5 °C and kept under stirring at this temperature till the final product (I)-L-tartrate is isolated by filtration and dried under vacuum

(17.7 g, 93%, (R)/(S) ratio 50/50).

Example 49

Racemisation of (I)-tartrate in anisole

20 g of Tolterodine tartrate (42 mmol) having a (R)/(S) ratio of 12/88, 230 ml of anisole and 18 g of NaOH 30% are mixed and refluxed, under reduced pressure, until water is no longer distilled, then 15 ml of solvent are distilled off. 5 g of sodium amide (128 mmol) are carefully added and the reaction heated to reflux for 1.5hrs.

Once the racemisation is completed the reaction is worked up as usual to give the final product (I)-L-tartrate (17.6 g, 88%, (R)/(S) ratio 50/50).

Example 50

Racemisation of (I) in anisole

40 g of Tolterodine Tartrate (84 mmol), having a (R)/(S) ratio of 12/88, 450 ml of anisole, 300 ml of water and 34 g of 30% NaOH are well mixed until two clear phases were obtained. Then 7 g of NaHCO ₃ are added to set the pH to 9-10. The water phase is discarded and the organic phase is washed and charged with 12 g of 30% NaOH. The mixture is heated to reflux, under reduced pressure, until water is no longer distilled, then other 30 ml of solvent are distilled off. After the atmospheric pressure was restored with nitrogen, the temperature is set to 100°C and 1.64 g (42 mmol) of sodium amide are added. The mixture is heated to 135/140°C and the temperature is maintained for l,5h. After the racemisation is completed the reaction is worked up following the procedure described above and the final product (I)-L-tartrate is isolated (37 g, 92%, (R)/(S) ratio 50/50).

Example 51

Racemisation of (I)-tartrate in xylene

40 g of Tolterodine tartrate (84 mmol), having a (R)/(S) ratio of 25/75, 220 ml of xylene and 37 g of 30% NaOH are mixed and refluxed, under reduced pressure, until water is no longer distilled off. Then, the suspension is cooled to 90-100°C and 9.8 g (252 mmol) of sodium amide are carefully added and the reaction heated to reflux (135-140°C) for 1.5hrs.

The reaction is cooled under 60°C and charged with 100 ml of water; the aqueous phase is discarded and the organic phase is washed, with 7% NaHCO _3(aq) (50 ml) and water (2x50 ml). Finally, the xylene solution is concentrated to a thick residue under reduced pressure. The residue is dissolved in 200 ml of isopropanol, added with 15.1 g of L-tartaric acid (100 mmol) and heated to reflux. The obtained suspension is cooled to 60-65 °C, stirred for 15 min at this temperature and then cooled to room temperature, in about 1 hr. Finally, the mixture is stirred for 2 hrs at 0/5 °C, filtrated, washed with fresh isopropanol and finally dried under vacuum to give the final product (I)-L-tartrate (36 g, 90%, (R)/(S) ratio 50/50).