Title of Invention	"A PROCESS FOR THE PRODUCTION OF A BENZOPYRAN-2-OL DERIVATIVE OF FORMULA(I)"
Abstract	The invention provides a process for the production of a compound of formula (I), wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of: (i) reacting a compound of formula (II), wherein OX is hydroxy or O- M+, in which M+ is a cation selected from Li+, Na+ and K+, and Y is as defined above; with trans-cinnamaldehyde (III), in the presence of a secondary amine compound; then (ii) treating the product of the preceding step with acid to afford the compound of formula (I). The above process may be used in the production of tolterodine and fesoterodine, which are useful in the treatment of overactive bladder.

Title of Invention

"A PROCESS FOR THE PRODUCTION OF A BENZOPYRAN-2-OL DERIVATIVE OF FORMULA(I)"

Abstract

The invention provides a process for the production of a compound of formula (I), wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of: (i) reacting a compound of formula (II), wherein OX is hydroxy or O- M+, in which M+ is a cation selected from Li+, Na+ and K+, and Y is as defined above; with trans-cinnamaldehyde (III), in the presence of a secondary amine compound; then (ii) treating the product of the preceding step with acid to afford the compound of formula (I). The above process may be used in the production of tolterodine and fesoterodine, which are useful in the treatment of overactive bladder.

Full Text	1 Process for the production of benzopvran-2-ol derivatives The present invention relates to an improved process for the production of intermediates useful in the preparation of tolterodine, fesoterodine and other pharmaceutically useful compounds. The invention also provides improved processes for the production of such pharmaceutically useful compounds using the intermediates. Tolterodine {2-[(lR)-3-[bis(1 -methylethyl)amino]-1 -phenylpropyl]-4-methylphenol or alternatively (+)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine}, (Formula Removed) is a muscarinic receptor antagonist for the treatment of overactive bladder including urinary incontinence. It gained its first marketing approval (as the tartrate salt) in 1997 and was launched in many markets in the following years under the trade marks DETROL and DETRUSITOL. Tolterodine tartrate was disclosed in International Patent Application WO 89/06644 (see in particular Example 22 and claim 7). WO 98/29402 discloses a process for the production of tolterodine which comprises condensing p-cresol (a) with cirmamic acid (b), followed by reduction of the resulting lactone (c) with a reducing agent, such as diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminium hydride or lithium tri-tert-butoxyaluminohydride, to give the corresponding benzopyran-2-ol compound (d). The benzopyran-2-ol compound (d) can then be converted to racemic tolterodine hydrochloride (e) by reductive amination with diisopropylamine, followed by addition of aqueous hydrochloric acid. Finally, tolterodine L-tartrate is formed by neutralisation of the hydrochloride salt (e) with NaOH/NaHCO3 and subsequent resolution using L-tartaric acid. The process is shown in Scheme 1 below. (Formula Removed) It can be seen that in the process disclosed by WO 98/29402, the benzopyran-2-ol compound (d) is prepared in two steps and involves the use of a relatively expensive reducing agent (DIBAL). WO 01/49649 describes the reductive amination of the enantiomers of compound (d) above to give tolterodine and its enantiomer. The enantiomers of compound (d) are produced by enantioselective reactions. It also relates to the same processes applied to analogous compounds, in particular the analogue of tolterodine in which the methyl group in the phenolic ring is replaced with a 5-hydroxymethyl group. US Patent Application 2003/0236438 (MacMillan et at) discloses the use of comparatively complex chiral imidazolidinone catalysts [e.g. (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one] for carrying out enantioselective 1,4-addition reactions between aniline nucleophiles and a,p-unsaturated aldehydes (this work is also described in MacMillan et al, J. Am. Chem. Soc, 2002, 124, 7894-7895). Example 2 from US Patent Application 2003/0236438 is typical of the reactions disclosed: (Formula Removed) It can be seen that the carbon atom of the aromatic ring para to the amine group bonds to the alpha-beta unsaturated aldehyde. Jurd (Journal of Heterocylic Chemistry, vol 28 (4), 1991, pp 983-986) describes the reaction of 3,4-methylenedioxyphenol, morpholine and cinnamaldehyde in methanol to produce 2-morpholinyl-4-phenylbenzopyrans. Surprisingly, it has now been found that the benzopyran-2-ol compound (d) of Scheme 1 I can be produced in a one-pot reaction starting from p-cresol (a). Analogous compounds can also be produced. Thus, according to a first aspect of the present invention, there is provided a process for the production of a compound of formula (I), (Formula Removed) wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of: (i) reacting a compound of formula (II), wherein OX is hydroxy or 0"M+, in which M+ is a cation selected from Li+, Na+ and K+, and Y is as defined above; with /trans-cinnamaldehyde (III), (Formula Removed) in the presence of a secondary amine compound; then (ii) treating the product of the preceding step with acid to afford the compound of formula (I). By "secondary amine compound" we mean an organic compound which contains at least one secondary amine group, i.e. a compound of the formula: (Formula Removed) in which R1 and R2 are not hydrogen. Preferably, Ra and Rb are each linked to the nitrogen atom by a CH2 group, for example they are independently C1-6 alkyl or together form a 4- or 5-membered alkyl chain in which one carbon atom is optionally replaced by OorN. Preferred embodiments of the first aspect of the invention are those in which: (a) OX is hydroxy; (b) Y is CHaorCH2OH; (c) the secondary amine compound is achiral; (d) the secondary amine compound contains two secondary amine groups, for example piperazine (this catalyst produces particularly high yields); (e) when the secondary amine compound contains two secondary amine groups, 0.5-1.25 mole equivalents of the secondary amine compound are used in step (i); (f) alternatively, the secondary amine compound contains one secondary amine group, and more preferably the secondary amine compound is morpholine, dibutylamine, dibenzylamine, 1,1,3,3-tetramethylguanidine, diethylamine, diisopropylamine, piperidine or an N-(C1-6 alkyl)piperazine. N-methylpiperazine is particularly preferred because it produces good yields, the initial product [see formula (VI) below] is readily hydrolysed to the corresponding lactol compound of formula (I), and the crude compound of formula (I) has an improved purity which facilitates crystallization; (g) when the secondary amine compound contains one secondary amine group, 1-5, more preferably 1-2.5 mole equivalents of the secondary amine compound are used in step(i); (h) the acid used in step (ii) is aqueous hydrochloric acid (preferably no more than 2M concentration), although the following aqueous acids at similar concentrations also provide good results: citric acid, acetic acid, oxalic acid, trifluoroacetic acid, maleic acid, fumaric acid, salicyclic acid, /trans-cinnamic acid, benzoic acid, camphor sulfonic acid and tosic acid; (i) the reaction of step (i) is carried out in an organic solvent selected from toluene, xylene, N-butyl acetate, t-amyl alcohol, dioxane and dibutyl ether, most preferably toluene (which produces particularly high yields); (j) the reaction of step (i) is carried out at a temperalure in the range 80°C to the reflux temperature of the solvent; (k) the reaction of step (i) is carried out under conditions that remove water from the reaction system (e.g. Dean-Stark conditions, in which' water produced by the reaction is condensed in a side condenser so that it does not return to the reaction mixture, and can be drained off if desired); and (1) the reaction of step (i) is carried out at or around ambient pressure (e.g. a nitrogen atmosphere of slightly elevated pressure may be used, particularly on an industrial scale). It is particularly preferred that when Y is CH2OH, the secondary amine compound is N-methyipiperazine. Preferably, the secondary amine compound contains two basic nitrogen atoms. Such compounds produce initial products [see formula (VI) below] which hydrolyse readily to compounds of formula (I). According to a second aspect of the invention, there is provided a process for the production of a compound of formula (IV), (Formula Removed) wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br, or a salt thereof, comprising: (a) producing a compound of formula (I) as defined above, using the process according to the first aspect of the invention; then (b) reductively aminating the compound of formula (I) with diisopropylamine; (c) and where desired converting the resulting compound into a salt. Preferably, in the second aspect of the invention, Y is CH3 or CH2OH. When Y is CH3, the compound of formula (IV) may be treated with L-tartaric acid in step (c), to produce tolterodine L-tartrate [i.e. R-(+)-toIterodine L-tartrate]. When the compound of formula (IV) is to be used as a pharmaceutical, the salt form produced in this second aspect of the invention is preferably pharmaceutically acceptable. However, when the compound will be processed further, this is not essential. The reductive amination of a compound of formula (I) may comprise treatment with diisopropylamine in a suitable solvent, such as methanol (which is preferred) or tert-amy1 alcohol or mixtures thereof, followed by hydrogenation in the presence of a catalyst, such as Pd/C or Pd(0H)2/C. In one embodiment, the compound of formula (IV) may be treated with an aqueous acid, such as hydrochloric acid, to afford the corresponding hydrochloride salt. The racemic compound may be converted to the corresponding (R)-enantiomer L-tartrate salt by neutralization of the hydrochloride salt in the presence of base, such as a mixture of sodium hydroxide and sodium carbonate, followed by resolution with L-tartaric acid. In one embodiment, tolterodine L-tartrate [i.e. R-(+)-tolterodine L-tartrate] is prepared. In an alternative embodiment, the (R)-enantiomer L-tart.-ate salt of the compound of formula (FV) may be prepared directly following reductive amination of the compound of formula (I) without formation of the hydrochloride salt. For example, in one embodiment the product of the reductive amination step may be treated with a solvent such as acetone and L-tartaric acid to afford the L-tartrate salt. When Y is CH3, this produces tolterodine L-tartrate [i.e. R-(+)-toIterodine L-tartrate]. According to a third aspect, the invention provides a process for the production of fesoterodine, (Formula Removed) or a pharmaceutically acceptable salt thereof, which comprises: (a) producing a compound of formula (IV), as defined above in which Y is CH2OH, using the process described above; (b) resolving the product of step (a) to obtain the (R)-enantiomer; (c) acylating the phenolic hydroxy group of the product of step (b) to produce the corresponding isobutyric acid ester; (d) and where desired or necessary, converting the resulting compound into a pharmaceutically acceptable salt. Fesoterodine, having chemical name 2-[(lR)-.3-[bis(l-methylethyl)amino]-l-phenylpropyl]-4-hydroxymethylphenyl isobutyrate or alternatively R-(+)-isobutyric acid 2-(3-diisopropylamino-l-phenyIpropyl)-4-hydroxymethylphenyl ester, is disclosed in European Patent 1077912 (see page 32 line 5 and claim 4, 3rd compound). It is indicated in the treatment of overactive bladder. In this third aspect, the resolution is preferably carried out by fractional crystallization with a chiral acid, preferably (R)-(-)-acetoxy(phenyl)acetic acid. The acylating agent is preferably isobutyryl chloride. The compound of formula (I) may exist in an open-ring form, although it is believed to exist predominantly in the closed-ring (lactol) form. Furthermore, it is believed that the process according to the first aspect of the invention produces a mixture of diastereoisomers of the lactol: (Formula Removed) (I) The R- and S-enantiomers of the chiral centre marked with an asterisk above are believed to be present in equal amounts. The production of all these tautomeric and stereoisomeric forms is embraced by the present invention. When piperazine is used in step (i) of the first aspect of the invention, the reaction proceeds via an isolable intermediate compound of formula (V), (Formula Removed) wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br. These compounds are provided according to a fourth aspect of the present invention. Preferably, Y is CH3. When N-methylpiperazine is used in step (i) of the first aspect of the invention, the reaction proceeds via an intermediate compound of formula (VI) (Formula Removed) wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br. These compounds are provided according to a fifth aspect of the present invention. Preferably, Y is CH2OH. The invention further provides a compound of formula (I), (Formula Removed) wherein Y is selected from CH2CH2OH, CH2Br and Br. The process according to the invention differs from US Patent Application 2003/0236438 (see above) in that none of the reactants are an aniline compound, and the compound of formula (II) according to the invention does not have an additional strongly activating or strongly electron-donating group present (such as methoxy in Example 2 of US Patent Application 2003/0236438). Furthermore, the amine catalysts used in the present invention are much simpler (e.g. they do not need to be chiral) and hence cheaper. The process according to the invention differs from the Jurd paper mentioned above (Journal of Heterocylic Chemistry, vol 28 (4), 1991, pp 983-986) in that none of the reactants are an aniline compound, and the compound of formula (II) according to the invention does not have an additional strongly activating or strongly electron-donating group present, such as alkoxy or hydroxy. The invention has the further advantage that, as part of a process for the production of tolterodine, in comparison with the process disclosed by WO 98/29402, a number of reaction and processing steps are eliminated, leading to a reduction in costs. Furthermore, the process avoids the use of expensive reducing agents such as diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminium hydride or lithium tri-tert-butoxyaluminohydride, which are also difficult to dispose of The invention has the further advantage that, as part of a process for the production of fesoterodine, in comparison with the processes disclosed in the prior art, a number of reaction and processing steps are eliminated, leading to a reduction in costs. Furthermore, the process avoids the use of hazardous and environmentally undesirable reagents, which are diflHcult to dispose of. The invention is illustrated by the following examples in which the following abbreviations may be used: BuOH = butanol. DEA = diethylamine DMA = dimethylacetamide DMF = dimethylformamide DMPU = l,3-dimethyI-3,4,5,6-tetrahydro-2(IH)-pyrimidone DMSO = dimethylsulphoxide EDTA = ethylenediaminetetraacetic acid ee = enantiomeric excess EtOAc = ethyl acetate EtOH = ethanol h = hour IPA = isopropyl alcohol LC-MS = liquid chromatography - mass spectrometry LOD = loss on drying MeOH = methanol min = minute n-BuOH = n-butanol p.s.i. = pounds per square inch TFA = trifluoroacetic acid THF = tetrahydrofuran tic = thin layer chromatography Example 1 Synthesis of 3.4-Dihvdro-6-methvl-4-phenvl-2H-benzopvran-2-ol (Formula Removed) p-Cresol (150g, 1.387mol) was stirred with piperazine (72g, 0.832mol, 0.6eq) in toluene (1.5L, lOml/g) and then heated at reflux under Dean & Stark conditions for at least 30 minutes to remove water giving a clear pale yellow solution. Trans-Cinnamaldehyde (262ml, 275g, 2.081 mol, 1.5eq) was then added over 2 hours whilst maintaining the reaction mixture at reflux under Dean & Stark conditions. Once the addition was complete, heating of the reaction mixture was continued at reflux under Dean & Stark conditions for a further 4 hours. The black solution was allowed to cool to 80°C and then slowly quenched over 45 minutes with a solution of 0.67M HCl(aq) (750ml, 0.601 mol, 1.3eq). The two-phase solution was then stirred vigorously for at least 12 hours at a temperature of 75-80°C. The stirring was then stopped and the mixture allowed to cool to room temperature and the phases separated. The toluene solution was then washed with IM HCl(,q) (750ml, 5ml/g), then water (3 X 750ml, 5ml/g). The 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol was not isolated but instead the toluene solution was used directly in the reductive amination step (Example 2). Example 2 Synthesis of Tolterodine L-Tartrate (Formula Removed) moist solution comprising crude 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol from Example 1 (theoretical = 333.3g in 1.5L of toluene) was diluted with methanol (750ml, 5ml/g), then diisopropylamine (583ml, 42 1g, 4.161 mol, 3eq) was added. The black solution was then hydrogenated over 20wt% Pd(OH)2/C moist (10wt%, 33g) at 621x103 Nm-2 (90 psi) and 110°C for 48 hours. A sample was removed for analysis. The reaction mixture was filtered through ArboceFTM (filter aid) to remove catalyst residues and then heated to reflux and all diisopropylamine and methanol removed by distillation and replaced with toluene resulting in a final volume of lOml/g. The black solution was then cooled to 25°C, acetone (750L, 5ml/g) was added, and then the solution heated to 55-60°C. A solution of L-Tartaric acid (312g, 2.081mol, 1.5eq) in methanol (1.05L, 7ml/g) was added over 30 minutes maintaining the temperature at 55-60°C. The resulting suspension was then allowed to cool to room temperature and stirred for 12 hours. The suspension was filtered, washed with acetone (2 X 600ml, 4ml/g), then dried in a vacuum oven at 50°C for 12 hours to give the title compound as an off white solid [159.2g, 48% (24% from p-Cresol)]. Achiral purity was 100% (no impurities detected) and chiral purity was 91.4% e.e. Example 3 Synthesis of racemic tolterodine hydrochloride (Formula Removed) To a solution of p-cresol (25 g, 0.i231 mol, 1 equiv), piperazine (11.94 g, 0.139 moi, 0.6 equiv) and toluene (250ml, 10 ml/g) at reflux under Dean & Stark conditions was added cinnamaldehyde (45.83 g, 44 ml, 0.347 mol, 1.5 equiv) over a 2 hour period and reaction mixture monitored by HPLC for the presence of p-cresol. Upon completion (2 to 3 hours), the mixture was cooled to 80°C and a solution of c.HCl (25 ml, 0.301 mol, 1.3 equiv) in water (100ml, 5 ml/g) was slowly added and heated at 80-90°C for at least 5 hours. The resulting solution was allowed to cool to room temperature and the phases separated. The toluene solution was washed with 1M HCl (125 ml, 5 ml/g), then water (3 X 125 ml). The resulting organic layer was taken into the reductive amination step (Step B) as a crude mixture. Step B. Preparation of racemic tolterodine hydrochloride To the crude solution from Step A was added methanol (125 ml, 5 ml/g cresol) and diisopropylamine (92 ml, 0.693mol, 3 equiv). The mixture was then hydrogenated over 20wt% Pd(OH)2/C wet (5.6 g, I0wt% theory of the benzopyran-2-ol) at 110 °C under 586x103 Nm-2 (85 psi) hydrogen pressure. Reaction progress was monitored by HPLC (completion usually occurs between 16 and 24h). Upon completion, the mixture was cooled, purged with nitrogen, filtered and washed with toluene (2 X 25 ml). The filtrate was then azeotroped with toluene to remove all methanol and diisopropylamine to end at a final volume corresponding to lOml/g cresol. The solution was then stirred at 50-60°C and 37% HCl (19.3 ml, 0.231 mol, 1.0 equiv c.f cresol) was added resulting in the precipitation of racemic tolterodine hydrochloride. The suspension was cooled to 25 °C and stirred for 2h, then filtered and washed with toluene (2 X 50ml). Racemic tolterodine hydrochloride was then dried under vacuum at 50°C. Yield was 52.7 g, 63% from p-cresol with achiral purity of 97%. The synthesis of tolterodine L-tartrate according to the methods of Examples 1-3 is shown in Scheme 2 below. (Formula Removed) Example 4 Influence of amine catalyst and solvent on yield of 3.4-Dihvdro-6-metbvl-4-phenvl-2H- benzopvran-2-ol The reaction of Example 1 was repeated, but varying the amine catalyst and the solvent. The temperature used was approximately lOOX or the reflux temperature of any solvent if lower (unless indicated otherwise). Dean-Stark conditions were not used unless indicated (by *). The yields are shown in the following table. (Table Removed) t denotes secondary amine compound Example 5 1.4-Bis-(6-methvl-4-phenvl-chroman-2-vn-piperazine (Formula Removed) The preparation of the title compound was carried out using the procedure of Example 1, except for the omission of a quench with aqueous acid. Instead, upon completion of the reaction the mixture was allowed to cool to ambient temperature resulting in a brown suspension. Filtration of this suspension gave a brown solid with 'H and 13C NMR providing confirmation of the structure. Melting point: 241°C. Example 6 Preparation of 6-(2-Hvdroxv-ethvl)-4-phenyl-chroman-2-ol (Formula Removed) To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (5.0 g, 36 mmol, 1 equiv), piperazine (1.87 g, 22 mmoi, 0.6 equiv) and toluene (50 ml) at reflux under N2 and Dean & Stark conditions was added cinnamaldehyde (6.4 ml, 51 mmol, 1.4 equiv) and the reaction mixture maintained at heat for 17 h. The reaction was cooled to 80°C and quenched with aqueous HCl (0.7 molar, 1.3 equiv) then stirred at heat for 18 h. The biphasic mixture was allowed to cool to ambient temperature, separated, the organic phase washed with aqueous HCl and water and the organic phase concentrated to a black residue under reduced pressure. Flash chromatography eluting with 20% EtOAc/Heptane afforded the title compound as the main constituent of an approximately 80% pure yellow oil, R/- = 0.37 (50% EtOAc/Heptane) and structure confirmed by 1H NMR and LC-MS (M+l=271). Example 7 Alternative preparation of 6-(2-hvdroxv-ethvl)-4-phenvl-chroman-2-ol using ^- methylpiperazine (Formula Removed) To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (25.0 g, 181 mmol, I equiv), N-methylpiperazine (54.4g g, 543 mmol, 3 equiv) and toluene (200 ml) at reflux under N2 and Dean & Stark conditions was added cinnamaldehyde (35.9g ml, 272 mmol, 1.5 equiv) over a period of 2 hours and the reaction mixture maintained at reflux for 17 h. The reaction was cooled to 50°C and quenched with aqueous HCl (2M, 375mL, ~4 equiv). The biphasic mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (250 mL) and the organic phase separated. The organic phase was washed with aqueous HCl (250mL), potassium bicarbonate (1M, 250mL), dried over magnesium sulphate and evaporated under reduced pressure to give a black oil (50.0g, assumed to be quantitative). Example 8 Preparation of 2-[3-(Diisopropvlamino)-1 -phenvlpropvll-4-(2-hydroxvethvl")phenol hydrochloride (Formula Removed) A mixture of 6-(2-hydroxy-ethyl)-4-phenyl-chroman-2-ol (Example 7, 30g, 111 mmol, 1 equiv), diisopropylamine (33.7g, 333 mmol, 3 eq) and palladium hydroxide on carbon [50% wet catalyst (50% by weight is water), 6g, 0.2 equiv] in toluene (120 mL) was hydrogenated at 621 x 103 Nm-2 (90 psi) hydrogen pressure at 110 "C, The reaction mixture was cooled to room temperature and filtered through arbocel and evaporated under reduced pressure. The resulting oil was dissolved in acetonitrile (200 mL) and concentrated hydrochloric acid (11.6 mL, 1.05 equiv) was added. The mixture was distilled at ambient pressure, removing approximately 100 mL of acetonitrile, and the distilled solvent replaced with fresh acetonitrile. The mixture was allowed to cool and crystallise overnight. The product was filtered and washed with a small portion of acetonitrile and dried overnight in vacuo at 50 °C to give the title compoimds as a white solid (26.7g, 68.1 mmol, 61%). Example 9 Preparation of 2-r3-(Diisopropvlamino)-1 -phenylpropvn-4-(2-hvdroxvethvl)phenol (Formula Removed) Aqueous sodium bicarbonate (165 mL) was added to a mixture of the HCl salt (Example 8, 16.5g, 42.1 mmol, 1 equiv) in ethyl acetate (165 mL) and the mixture stirred for 1 hour. The phases were separated and the organic phase washed with water (195 mL), dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as an oil containing -25% wt/wt ethyl acetate (14.6g total, 11.03g of title compound, 31 mmol, 74%). Example 10 Preparation of (R)-2-[3-(Diisopropvlamino)-1 -phenylpropvl1-4-(2-hvdroxvethvl)phenol (S)-2-phenoxvpropionic acid salt (Formula Removed) (S)-2-Phenoxypropionic acid (3.40g, 20.5 mmol, 1 equiv) was added to a solution of 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(2-hydroxyethyl)phenol (Example 9, 7.28g, 20.5 mmol, 1 equiv) in ethyl acetate. The mixture was heated at 80 °C for 2 days, upon which the mixture was cooled to room temperature, filtered and washed with ethyl acetate and dried in vacuo at 50 °C overnight to give the title compound as a white solid (3.9g, 7.48 mmol, 37% yield, 94% ee). Enantiomeric excess was determined by converting the salt to the free base with sodium hydroxide and miming normal phase chiral HPLC chromatography (Chiral Pak AS-H column, eluting with hexane (89.8%), IPA (10%), DEA (0.1%), TFA (0.1%) at 1 mL/minute). The title compound could be useful as a starting material to produce Example 5 in our co¬pending International Patent Application No PCT/IB07/000619. The corresponding hydrochloride salt to the title compound is disclosed as Example 12 in WO 98/43942. Example 11 Synthesis of 3.4-dihvdro-6-bromo-4-phenvl-2H-benzopvran-2-ol (Formula Removed) 4-Bromophenol (2.0g, 11.6mmmol) was stirred with N-methylpiperazine (3.48g, 34.8mmol, 3eq) in toluene (30mi, 15ml/g) and heated at reflux under Dean 8c Stark conditions. Once reflux was achieved, trans-cinammaldehyde (2.2g, 17.4mmol, 1.5eq) Was added over 2 hours. Once addition was complete, heating of the reaction mixture at reflux under Dean & Stark conditions was continued for 3 hours. The dark solution was cooled to 25°C and diluted with ethyl acetate (20ml, l0ml/g) and quenched with 2M HCl (30ml, 15ml/g). The phases were separated and the upper organic layer was washed with further 2M HCl (20ml, lOml/g) and IM sodium hydrogen carbonate solution (20ml, lOml/g). The organic phase was dried (MgS04), filtered and concentrated to give a dark coloured oil (4.2g, 11.6mmol, assumed to be quantitative) Example 12 Synthesis of 2-f3-(Diisopropvlamino)-l-phenvlpropvl]-4-bromophenol hydrochloride salt (Formula Removed) Crude 3,4-dihydro-6-bromo-4-phenyI-2H-benzopyran-2-ol (Example 11, 2.0g, 6.55mmol) was dissolved in toluene (20ml, lOml/g) and to this solution was added titanium tetraisopropoxide (5.84ml, 3eq) and diisopropylamine (l.Oml, l.leq). The reaction mixture was cooled to 0-5°C and sodium borohydride (0.75g, 3eq) was added portionwise over 15 minutes. Ethanol was charged dropwise over 15 minutes and stirred at 0-5°C for a further 2 hours. The reaction was quenched with water (20ml), ethyl acetate (50ml) and concentrated ammonia solution (20ml). The suspension was filtered through celite and the phases were separated. The organic layer was washed with water (50ml), dried (MgS04), filtered and concentrated to give the free base as a brown oil. This was dissolved in ethyl acetate (50ml) and 5M HCl (2ml) was added. Excess acid and water were azeotroped with fresh ethyl acetate (2x50ml) and the resulting solid was granulated in fresh ethyl acetate (20ml) for 48 hours. The solid was collected by filtration, washed with ethyl acetate (10ml) and dried at 50°C under vacuum for 4 hours. The title compound was obtained as a white solid (1.12g, 40% from 4-bromophenol). The benzyloxy analogue of the title compound is disclosed as Example 1(e) in WO 94/11337. The title compound, once resolved, could also be useful as a starting material in the production of Example 3 in our co-pending International Patent Application No PCT/IB07/000619. Example 13 Synthesis of (2-Hvdroxv-4-phenvl-3.4-dihYdro-2H-cfaromen-6-vl)methanol (Formula Removed) 4-(Hydroxymethyl)phenol (2.515kg, 20.26mol, leq) was stirred with ^-methylpiperazine (5.06kg, 50.52mol, 2.5eq) in toluene (17.74kg, 20.5L, 8.15mL/g) and then heated to reflux. /ran.s-Cinnamaldehyde (3.35kg, 25.35mol, 1.25eq) was then added over 2 hours maintaining the reaction mixture at reflux. The transfer line was washed with toluene (0.9Kg, 0.35ml/g). Once the addition was complete the reaction mixture continued to be heated at reflux for 19h. Then some toluene was distilled off, reducing the volume to approximately 18.5L. The mixture was then allowed to cool to room temperature and EtOAc was added (13.5Kg 15L, 6mL/g). The organic phase was washed with HCl 2M (46.4kg, 46.4L 18.5mL/g). The phases were separated, and ethyl acetate (27.1kg, 30L, 12ml/g) was added to dilute the organic layer. The organic phase was washed with IM HCl (17.75kg, 17.75L 7.1mL/g), 5% w/w NaHCO3 (17.5L, 7mL/g) and water (25L, lOmL/g). The phases were separated, and toluene (6.5Kg, 7.5L, 3ml/g) was added to the organic layer, and the mixture was distilled to approximately 8L. Additional toluene (7kg) was charged followed By ethyl acetate (3.9L). The mixture was heated to reflux then cooled to 22°C at l°C/minute, then stirred for 20hrs. The suspension was cooled to 2°C and granulated for 2hrs. The slurry was filtered and the cake was washed with cold toluene (2x4.3Kg, 5L). The resulting pale tan solid was dried in vacuum for 68h at 40°C, to provide 2.76Kg of product (2-hydroxy-4-phenyl-3,4-dihydro-2//-chromen-6-yl)methanol (53.4% yield) which was used in the following example without purification: 'H NMR 300MHZ d6 DMSO 5 ppm (mixture of isomers, 10:1): 1.95-2.10 (m, 2H), 2.15-2.35 (m, minor isomer), 3.25T3.35 (m, IH), 4.15-4.35 ( m, 3H), 4.80-4.95 (m, IH), 5.35-5.45 (m, minor isomer), 5.46-5.55 (m, IH), 6.51-6.54 (m, minor isomer), 6.58-6.63 (m, IH), 6.75 (d J=8.2Hz, IH), 6.98-7.40 (m, 6H). Example 14 Synthesis of 2-[3-(Diisopropvlamino)-1 -phenvlpropyll-4-(hvdroxvmethvl)phenol (Formula Removed) (2-Hydroxy-4-phenyl-3,4-dihydro-2N-chromen-6-yl)methanol (Example 13, 830 g, 3.24 mol, 1.0 eq) was stirred in methanol (4150 mL, 5.0mL/g). Diisopropylamine (1362 mL, 9.72 mol, 3.0 eq) was then added over 15 minutes via dropping funnel. The resulting solution was then stirred for one hour under nitrogen. The catalyst Pd-ESCAT 142 [(5%Pd/C paste, ca. 50% water wet) 83g, 10% w/w] was added as a slurry in methanol (2075 mL, 2.5 mL/g). The system was purged with hydrogen, then the mixture was hydrogenated at 115 psi (793 x 10^ Nm-2, 7.92 bar) at a temperature of 40°C for 20 hours. The mixture was purged with nitrogen and filtered over Arboce1TM (filter aid).. The residue pad was washed with methanol (2x1660 mL, 2x2.0 mL/g). Due to equipment limitations, the above procedure was performed two further times on 830 and 840 g scale. The three filtrates and their respective pad-washes were then combined to produce a single solution equivalent to a single 2.50 Kg scale reaction. The total volume was noted to act as the initial target volume in the following distillation procedure: • Diisopropylamine (2500 mL, 1.0 mL/g) and /-amyl alcohol (10000 mL, 4.0 mL/g) were added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to the target volume previously noted. • Diisopropylamine (2500 mL, 1.0 mL/g) and /-amyl alcohol (10000 mL, 4.0 mL/g) were added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to the target volume previously noted. • Diisopropylamine (2500 mL, 1.0 mL/g) and t-amy\ alcohol (10000 mL, 4.0 mL/g) were added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to the target volume previously noted. • t-Amyl alcohol (12500 mL, 5.0 mL/g) was added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to a volume of 12500 mL. • t-Amyl alcohol (12500 mL, 5.0 mL/g) added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to a volume of 12500 mL. /-Amyl alcohol (12500 mL, 5.0 mL/g) added to the reaction mixture to give a final volume of 25L. The t-amyl alcohol solution of crude product 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol was used in the next step with no further purification. HPLC analysis (area/area) showed 93.3% product, plus: 4.2% starting material, and other impurities at 1.4% and 0.4%. Quantitative HPLC analysis indicated the crude solution contained 2950g product (89% yield). Example 15 . Synthesis of (R)-2-r3-fDiisopropvlamino)-1 -phenvlpropvl]-4-('hvdroxvmethvl)phenol (^)- acetoxv(phenyl)acetate (Formula Removed) t-Amyl alcohol (19.2L) was added to the previous solution of 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (from Example 14) in t-amyl alcohol (25L, containing 2.95kg, 8.64mol, leq) to give a total volume of 44.2L. This solution was heated to 70°C. In a separate pot, a solution of (R)-(-)-acetoxy(phenyl)acetic acid (0.839kg, 4.32mol, O.Seq) in /-amyl alcohol (14.8L) was prepared at 50°C then cooled to room temperature once all the acid had dissolved. This solution was then added to the solution of 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyI)phenol in /-amyl alcohol over one hour. The resulting solution was then seeded with product (0.03kg, lwt%, prepared previously by a similar method but on a smaller scale). The slurry was cooled to 60'C over 2 hours and then to 25°C over another 3 hours. The mixture was stirred at 25°C for an additional 12 hours. The slurry was filtered and the cake was twice re-slurried with /-amyl alcohol (2x29.5L, 2xl0mL/g) and de-liquored well. The white solid was dried imder reduced pressure at 40°C for 12hours to provide 2.04kg (/?)-2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (37.8% yield, corrected for 14.3%w/w r-amyl alcohol (determined by LOD analysis) with 99% ee by chiral HPLC. HPLC method for ee monitoring; Column: Chiralpak AS-H Flow rate: Iml/min Mobile Phase: Heptane 92.5/ Ethanol 7.5/ Diethylamine 0.12/ Trifluoroacetic acid 0.18 Temperature: 35°C Detection: 220nm Retention times: (R)-2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol 15min (S)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol 18.4min Example 16 Synthesis of (R)-2-[3-rDiisopropvlamino)-l-phenvlpropvll-4-(hvdroxvmethvnphenol (Formula Removed) (R)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (Example 15, 1.75 kg, 3.27 mol, leq) was slurried in toluene (15.2 kg, 10 mL/g) atnd warmed to 50 °C. A 10% aq. solution of K2CO3 (1.75 kg K2CO3 dissolved in 17.5 L purified water, 10 mL/g) was charged. The mixture was stirred vigorously at 50 °C for 30 minutes. The two solution phases were separated at 50 °C. The organic phase was washed with purified water (1.75 kg, 1 mL/g) at 50 °C. The phases were separated at 50 °C and the toluene volume reduced to 3 mL/g (5.5 L) by distillation. Crystallization was performed by reducing the temperature to 62 °C and then cooling to 40 °C over 40 mins. The batch was held at 40 °C for 30 mins and then seeded using (R)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (0.01 kg, prepared previously using a similar method on a smaller scale). The batch was agitated for a further 1 hour at 40 °C and then cooled to 20 °C over 3.5 hours. The batch was granulated at 20 °C for 10 hours. The slurry was then cooled to 2 °C over 1 hour and granulated at 2 °C for 1 hour (see temperature profile below). The suspension was filtered and the cake washed with cold toluene (1.5 kg, 1 mL/g). The damp product (0.933 kg, dry estimated by % LOD analysis) was a white crystalline solid. A toluene re-slurry was then performed. Toluene (2.42 kg, 2.6 mL/g (based on dry estimate)) cooled to 3 °C and damp product was charged and agitated at 3 °C for 15 mins. The suspension was filtered and the cake washed with cold toluene (1.6 kg, 1.5 mL/g (based on dry estimate)). The damp product was dried in vacuo at 45 °C to yield (R)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (0.74 kg, 2.17 mol) in 66.7% yield as a white crystalline solid. HPLC indicates > 99.6% purity, and chiral HPLC indicates > 99% ee. Example 17 Preparation of (R)-(+)-Isobutvric acid 2-[3-(diisopropylamino)-l-phenvlpropvl]-4- (hvdroxvmethvl)phenvl ester (Formula Removed) e title compound is prepared from the compound of Example 16 using the method of US Patent 6,858,650 (see section 5, column 16). Alternatively, this reaction can be performed without the addition of an external acid-intercepting base - see US Patent 6,858,650 column 10 lines 32-40. Example 18 Preparation of (R)-(+)-Isobutvric acid 2-[3-(diisopropvlamino)-l-phenylpropvl]-4- (hvdroxvmethvl)phenvl ester hydrogen fumarate (Formula Removed) e title compound is prepared from the compound of Example 17 using the method of US Patent 6,858,650 (see section 6, column 16). Example 19 Synthesis of r2-('4-Methvlpiperazin-1 -vl)-4-phenvl-2^-chroman-6-vl]-methanol (Formula Removed) ans-Cinnamaldehyde (66.5g, 0.66mol, 1.25eq) was diluted with toluene (lOOmL, 2mL/g based on 4-(hydroxymethyl)phenol-), and was washed twice with a saturated solution of sodium hydrogen carbonate (2xl00mL) and once with water (lOOmL). This toluene solution of cinnamaldehyde was then added over 2 hours to a mixture of 4-(hydroxymethyl)phenol (50g, 0.40mol, leq) and N-methylpiperazine (I13mL, I.Omol, 2.5eq) in toluene (350mL, 7mL/g) heated to reflux under Dean-Stark conditions. Once the addition was complete the reaction mixture continued to be heated at reflux under Dean-Stark conditions for lOh. The mixture was then cooled to room temperature and a sample was evaporated to dryness under reduced pressure for analytical purposes. The dark oil contains crude [2-(4-methylpiperazin-1-yl)-4-phenyl-2N-chroman-6-yl]methanol (mixture of diastereoisomers) and impurities. EI-GC-MS (Agilent), column: ZB-5HT. Temperature program: 50°C (0.5min). 20°C/min to 320'C (2min) obtained: RT=24.4min, MW: 338. 'H NMR (DMSO) (crude mixture) 300mHz 5 (ppm): 7.40-7.00 (28H. m); 6.89 (IH, d, J=2.0 Hz); 6.81 (IH, d, J=8.3 Hz); 6.75 (IH, d, J=8.2 Hz); 6.54 (IH, d, J=1.0 Hz); 4.87 (IH, d, J=10.2 Hz); 4.45 (IH, d, J=10.0 Hz); 4.40-4.20 (3H, m); 4.36 (2H, s); 4.23 (1.8H, s); 2.86 (4H, m); 2.80-2.50 (14H, m); 2.50-2.00 (50H, m) including 2.31 (s); 2.17 (s); 2.14 (s); 2.11 (s). The synthesis of fesoterodine hydrogen fumarate according to the methods of Examples 13-18 is shown in Scheme 3 below. Scheme Removed Claims: 1. A process for the production of a compound of formula (I), (Formula Removed) wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of:- (i) reacting a compound of formula (II), (Formula Removed) wherein OX is hydroxy or O'M+, in which M+ is a cation selected from Li+, Na+ and K+, and Y is as defined above; with trans-cinnamaldehyde (III), in the presence of a secondary amine compound; then (ii) treating the product of the preceding step with acid to afford the compound of formula (I). 2. The process as claimed in claim 1, wherein OX is hydroxy. 3. The process as claimed in claim 1 or claim 2, wherein Y is CH3 or CH2OH. 4. The process as claimed in any one of claims 1 to 3, wherein the secondary amine compound is achiral. 5. The process as claimed in any one of claims 1 to 4, wherein the secondary amine compound contains two secondary amine groups. 6. The process as claimed in any one of claims 1 to 5, wherein the secondary amine compound is piperazine. 7. The process as claimed in claim 5 or claim 6, wherein 0.5-1.25 mole equivalents of the secondary amine compound are used in step (i). 8. The process as claimed in any one of claims 1 to 4, wherein the secondary amine compound contains one secondary amine group. 9. The process as claimed in any one of claims 1, 2, 3, 4 and 8, wherein the secondary amine compound is morpholine, dibutylamine, dibenzylamine, 1,1,3,3-tetramethylguanidine, diethylamine, diisopropylamine, piperidine or an N-(C\.6 alky)piperazine. 10. The process as claimed in claim 9, wherein the secondary amine compound is N-methylpiperazine. 11. The process as claimed in any one of claims 8 to 10, wherein 1-5 mole equivalents of the secondary amine compound are used in step (i). 12. The process as claimed in any one of the preceding claims, wherein the acid used in step (ii) is aqueous hydrochloric acid. 13. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out in an organic solvent selected from toluene, xylene, N-butyl acetate, t-amyl alcohol, dioxane and dibutyl ether. 14. The process as claimed in claim 13, wherein the solvent is toluene. 15. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out at a temperature in the range 80°C to the reflux temperature of the solvent. 16. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out under conditions that remove water from the reaction system. 17. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out at or around ambient pressure. 18. A process for the production of a compound of formula (IV), (Formula Removed) wherein Y is as defined in claim 1, or a salt thereof, comprising: (a) producing a compound of formula (I) as defined in claim 1, using the process claimed in any one of the preceding claims; then (b) reductively aminating the compound of formula (I) with diisopropylamine; (c) and where desired converting the resulting compound into a salt. 19. The process as claimed in claim 18, wherein Y is CH3 or CH2OH. 20. The process as claimed in claim 19, wherein Y is CH3, the compound of formula (IV) is treated with L-tartaric acid in step (c), and tolterodine L-tartrate is produced. 21. A process for the production of fesoterodine. (Formula Removed) or a pharmaceutically acceptable salt thereof, which comprises: (a) producing a compound of formula (IV), as defined in claim 18, in which Y is CH2OH, using the process of claim 18; (b) resolving the product of step (a) to obtain the (R)-enantiomer; (c) acylating the phenolic hydroxy group of the product of step (b) to produce the corresponding isobutyric acid ester; (d) and where desired or necessary, converting the resulting compound into a pharmaceutically acceptable salt. 22. The process as claimed in claim 21, wherein the secondary amine compound used to produce the compound of formula I is N-methylpiperazine. 23. A compound of formula (V), (Formula Removed) or a salt thereof, wherein Y is as defined in claim 1. A compound of formula (VI), (Formula Removed) or a salt thereof, wherein Y is as defined in claim 1. A compound of formula (VII) ,(Formula Removed) wherein Y is selected from CH2CH2OH, CH2Br and Br

Full Text

1 Process for the production of benzopvran-2-ol derivatives
The present invention relates to an improved process for the production of intermediates useful in the preparation of tolterodine, fesoterodine and other pharmaceutically useful compounds. The invention also provides improved processes for the production of such pharmaceutically useful compounds using the intermediates.
Tolterodine {2-[(lR)-3-[bis(1 -methylethyl)amino]-1 -phenylpropyl]-4-methylphenol or alternatively (+)-N,N-diisopropyl-3-(2-hydroxy-5-methylphenyl)-3-phenylpropylamine},
(Formula Removed)
is a muscarinic receptor antagonist for the treatment of overactive bladder including urinary incontinence. It gained its first marketing approval (as the tartrate salt) in 1997 and was launched in many markets in the following years under the trade marks DETROL and DETRUSITOL. Tolterodine tartrate was disclosed in International Patent Application WO 89/06644 (see in particular Example 22 and claim 7).
WO 98/29402 discloses a process for the production of tolterodine which comprises condensing p-cresol (a) with cirmamic acid (b), followed by reduction of the resulting lactone (c) with a reducing agent, such as diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminium hydride or lithium tri-tert-butoxyaluminohydride, to give the corresponding benzopyran-2-ol compound (d). The benzopyran-2-ol compound (d) can then be converted to racemic tolterodine hydrochloride (e) by reductive amination with diisopropylamine, followed by addition of aqueous hydrochloric acid. Finally, tolterodine L-tartrate is formed by neutralisation of the hydrochloride salt (e) with NaOH/NaHCO3 and subsequent resolution using L-tartaric acid. The process is shown in Scheme 1 below.
(Formula Removed)
It can be seen that in the process disclosed by WO 98/29402, the benzopyran-2-ol compound (d) is prepared in two steps and involves the use of a relatively expensive reducing agent (DIBAL).
WO 01/49649 describes the reductive amination of the enantiomers of compound (d) above to give tolterodine and its enantiomer. The enantiomers of compound (d) are produced by enantioselective reactions. It also relates to the same processes applied to analogous compounds, in particular the analogue of tolterodine in which the methyl group in the phenolic ring is replaced with a 5-hydroxymethyl group.
US Patent Application 2003/0236438 (MacMillan et at) discloses the use of comparatively complex chiral imidazolidinone catalysts [e.g. (2S,5S)-5-benzyl-2-tert-butyl-3-methylimidazolidin-4-one] for carrying out enantioselective 1,4-addition reactions between aniline nucleophiles and a,p-unsaturated aldehydes (this work is also described in MacMillan et al, J. Am. Chem. Soc, 2002, 124, 7894-7895). Example 2 from US Patent Application 2003/0236438 is typical of the reactions disclosed:

(Formula Removed)
It can be seen that the carbon atom of the aromatic ring para to the amine group bonds to the alpha-beta unsaturated aldehyde.
Jurd (Journal of Heterocylic Chemistry, vol 28 (4), 1991, pp 983-986) describes the reaction of 3,4-methylenedioxyphenol, morpholine and cinnamaldehyde in methanol to produce 2-morpholinyl-4-phenylbenzopyrans.
Surprisingly, it has now been found that the benzopyran-2-ol compound (d) of Scheme 1 I can be produced in a one-pot reaction starting from p-cresol (a). Analogous compounds can also be produced. Thus, according to a first aspect of the present invention, there is provided a process for the production of a compound of formula (I),
(Formula Removed)
wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br;
comprising the steps of:
(i) reacting a compound of formula (II),
wherein
OX is hydroxy or 0"M+, in which M+ is a cation selected from Li+, Na+ and K+, and
Y is as defined above;
with /trans-cinnamaldehyde (III),
(Formula Removed)
in the presence of a secondary amine compound; then
(ii) treating the product of the preceding step with acid to afford the compound of
formula (I).
By "secondary amine compound" we mean an organic compound which contains at least one secondary amine group, i.e. a compound of the formula:
(Formula Removed)
in which R1 and R2 are not hydrogen. Preferably, Ra and Rb are each linked to the nitrogen atom by a CH2 group, for example they are independently C1-6 alkyl or together form a 4- or 5-membered alkyl chain in which one carbon atom is optionally replaced by OorN.
Preferred embodiments of the first aspect of the invention are those in which:
(a) OX is hydroxy;
(b) Y is CHaorCH2OH;
(c) the secondary amine compound is achiral;
(d) the secondary amine compound contains two secondary amine groups, for example piperazine (this catalyst produces particularly high yields);
(e) when the secondary amine compound contains two secondary amine groups, 0.5-1.25 mole equivalents of the secondary amine compound are used in step (i);
(f) alternatively, the secondary amine compound contains one secondary amine group, and more preferably the secondary amine compound is morpholine, dibutylamine, dibenzylamine, 1,1,3,3-tetramethylguanidine, diethylamine, diisopropylamine, piperidine or an N-(C1-6 alkyl)piperazine. N-methylpiperazine is particularly preferred because it produces good yields, the initial product [see formula (VI) below] is readily hydrolysed to the corresponding lactol compound of formula (I), and the crude compound of formula (I) has an improved purity which facilitates crystallization;
(g) when the secondary amine compound contains one secondary amine group, 1-5,
more preferably 1-2.5 mole equivalents of the secondary amine compound are used in
step(i);
(h) the acid used in step (ii) is aqueous hydrochloric acid (preferably no more than
2M concentration), although the following aqueous acids at similar concentrations also
provide good results: citric acid, acetic acid, oxalic acid, trifluoroacetic acid, maleic acid,
fumaric acid, salicyclic acid, /trans-cinnamic acid, benzoic acid, camphor sulfonic acid
and tosic acid;
(i) the reaction of step (i) is carried out in an organic solvent selected from toluene,
xylene, N-butyl acetate, t-amyl alcohol, dioxane and dibutyl ether, most preferably
toluene (which produces particularly high yields);
(j) the reaction of step (i) is carried out at a temperalure in the range 80°C to the
reflux temperature of the solvent;
(k) the reaction of step (i) is carried out under conditions that remove water from the
reaction system (e.g. Dean-Stark conditions, in which' water produced by the reaction is
condensed in a side condenser so that it does not return to the reaction mixture, and can
be drained off if desired); and
(1) the reaction of step (i) is carried out at or around ambient pressure (e.g. a nitrogen
atmosphere of slightly elevated pressure may be used, particularly on an industrial scale).
It is particularly preferred that when Y is CH2OH, the secondary amine compound is N-methyipiperazine.
Preferably, the secondary amine compound contains two basic nitrogen atoms. Such compounds produce initial products [see formula (VI) below] which hydrolyse readily to compounds of formula (I).
According to a second aspect of the invention, there is provided a process for the production of a compound of formula (IV),
(Formula Removed)
wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br, or a salt thereof, comprising:
(a) producing a compound of formula (I) as defined above, using the process according to the first aspect of the invention; then
(b) reductively aminating the compound of formula (I) with diisopropylamine;
(c) and where desired converting the resulting compound into a salt.
Preferably, in the second aspect of the invention, Y is CH3 or CH2OH. When Y is CH3, the compound of formula (IV) may be treated with L-tartaric acid in step (c), to produce tolterodine L-tartrate [i.e. R-(+)-toIterodine L-tartrate]. When the compound of formula (IV) is to be used as a pharmaceutical, the salt form produced in this second aspect of the invention is preferably pharmaceutically acceptable. However, when the compound will be processed further, this is not essential.
The reductive amination of a compound of formula (I) may comprise treatment with diisopropylamine in a suitable solvent, such as methanol (which is preferred) or tert-amy1 alcohol or mixtures thereof, followed by hydrogenation in the presence of a catalyst, such as Pd/C or Pd(0H)2/C.
In one embodiment, the compound of formula (IV) may be treated with an aqueous acid, such as hydrochloric acid, to afford the corresponding hydrochloride salt. The racemic compound may be converted to the corresponding (R)-enantiomer L-tartrate salt by neutralization of the hydrochloride salt in the presence of base, such as a mixture of sodium hydroxide and sodium carbonate, followed by resolution with L-tartaric acid. In one embodiment, tolterodine L-tartrate [i.e. R-(+)-tolterodine L-tartrate] is prepared.
In an alternative embodiment, the (R)-enantiomer L-tart.-ate salt of the compound of formula (FV) may be prepared directly following reductive amination of the compound of formula (I) without formation of the hydrochloride salt. For example, in one embodiment the product of the reductive amination step may be treated with a solvent such as acetone and L-tartaric acid to afford the L-tartrate salt. When Y is CH3, this produces tolterodine L-tartrate [i.e. R-(+)-toIterodine L-tartrate].
According to a third aspect, the invention provides a process for the production of fesoterodine,
(Formula Removed)
or a pharmaceutically acceptable salt thereof, which comprises:
(a) producing a compound of formula (IV), as defined above in which Y is CH2OH, using the process described above;
(b) resolving the product of step (a) to obtain the (R)-enantiomer;
(c) acylating the phenolic hydroxy group of the product of step (b) to produce the corresponding isobutyric acid ester;
(d) and where desired or necessary, converting the resulting compound into a pharmaceutically acceptable salt.
Fesoterodine, having chemical name 2-[(lR)-.3-[bis(l-methylethyl)amino]-l-phenylpropyl]-4-hydroxymethylphenyl isobutyrate or alternatively R-(+)-isobutyric acid 2-(3-diisopropylamino-l-phenyIpropyl)-4-hydroxymethylphenyl ester, is disclosed in European Patent 1077912 (see page 32 line 5 and claim 4, 3rd compound). It is indicated in the treatment of overactive bladder.

In this third aspect, the resolution is preferably carried out by fractional crystallization with a chiral acid, preferably (R)-(-)-acetoxy(phenyl)acetic acid.
The acylating agent is preferably isobutyryl chloride.
The compound of formula (I) may exist in an open-ring form, although it is believed to exist predominantly in the closed-ring (lactol) form. Furthermore, it is believed that the process according to the first aspect of the invention produces a mixture of diastereoisomers of the lactol:
(Formula Removed)
(I) The R- and S-enantiomers of the chiral centre marked with an asterisk above are believed to be present in equal amounts. The production of all these tautomeric and stereoisomeric forms is embraced by the present invention.
When piperazine is used in step (i) of the first aspect of the invention, the reaction proceeds via an isolable intermediate compound of formula (V),
(Formula Removed)
wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br. These compounds are provided according to a fourth aspect of the present invention. Preferably, Y is CH3.
When N-methylpiperazine is used in step (i) of the first aspect of the invention, the reaction proceeds via an intermediate compound of formula (VI)
(Formula Removed)
wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br. These compounds are provided according to a fifth aspect of the present invention. Preferably, Y is CH2OH.
The invention further provides a compound of formula (I),
(Formula Removed)
wherein Y is selected from CH2CH2OH, CH2Br and Br.
The process according to the invention differs from US Patent Application 2003/0236438 (see above) in that none of the reactants are an aniline compound, and the compound of formula (II) according to the invention does not have an additional strongly activating or strongly electron-donating group present (such as methoxy in Example 2 of US Patent Application 2003/0236438). Furthermore, the amine catalysts used in the present invention are much simpler (e.g. they do not need to be chiral) and hence cheaper.
The process according to the invention differs from the Jurd paper mentioned above (Journal of Heterocylic Chemistry, vol 28 (4), 1991, pp 983-986) in that none of the reactants are an aniline compound, and the compound of formula (II) according to the invention does not have an additional strongly activating or strongly electron-donating group present, such as alkoxy or hydroxy.
The invention has the further advantage that, as part of a process for the production of tolterodine, in comparison with the process disclosed by WO 98/29402, a number of reaction and processing steps are eliminated, leading to a reduction in costs. Furthermore, the process avoids the use of expensive reducing agents such as diisobutylaluminium hydride (DIBAL), sodium bis(2-methoxyethoxy)aluminium hydride or lithium tri-tert-butoxyaluminohydride, which are also difficult to dispose of
The invention has the further advantage that, as part of a process for the production of fesoterodine, in comparison with the processes disclosed in the prior art, a number of reaction and processing steps are eliminated, leading to a reduction in costs. Furthermore, the process avoids the use of hazardous and environmentally undesirable reagents, which are diflHcult to dispose of.
The invention is illustrated by the following examples in which the following
abbreviations may be used:
BuOH = butanol.
DEA = diethylamine
DMA = dimethylacetamide
DMF = dimethylformamide
DMPU = l,3-dimethyI-3,4,5,6-tetrahydro-2(IH)-pyrimidone
DMSO = dimethylsulphoxide
EDTA = ethylenediaminetetraacetic acid
ee = enantiomeric excess
EtOAc = ethyl acetate
EtOH = ethanol
h = hour
IPA = isopropyl alcohol
LC-MS = liquid chromatography - mass spectrometry
LOD = loss on drying
MeOH = methanol
min = minute
n-BuOH = n-butanol
p.s.i. = pounds per square inch
TFA = trifluoroacetic acid
THF = tetrahydrofuran
tic = thin layer chromatography
Example 1
Synthesis of 3.4-Dihvdro-6-methvl-4-phenvl-2H-benzopvran-2-ol
(Formula Removed)

p-Cresol (150g, 1.387mol) was stirred with piperazine (72g, 0.832mol, 0.6eq) in toluene (1.5L, lOml/g) and then heated at reflux under Dean & Stark conditions for at least 30 minutes to remove water giving a clear pale yellow solution. Trans-Cinnamaldehyde (262ml, 275g, 2.081 mol, 1.5eq) was then added over 2 hours whilst maintaining the reaction mixture at reflux under Dean & Stark conditions. Once the addition was complete, heating of the reaction mixture was continued at reflux under Dean & Stark conditions for a further 4 hours. The black solution was allowed to cool to 80°C and then slowly quenched over 45 minutes with a solution of 0.67M HCl(aq) (750ml, 0.601 mol, 1.3eq). The two-phase solution was then stirred vigorously for at least 12 hours at a temperature of 75-80°C. The stirring was then stopped and the mixture allowed to cool to room temperature and the phases separated. The toluene solution was then washed with IM HCl(,q) (750ml, 5ml/g), then water (3 X 750ml, 5ml/g). The 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol was not isolated but instead the toluene solution was used directly in the reductive amination step (Example 2).
Example 2
Synthesis of Tolterodine L-Tartrate

(Formula Removed)
moist solution comprising crude 3,4-dihydro-6-methyl-4-phenyl-2H-benzopyran-2-ol from Example 1 (theoretical = 333.3g in 1.5L of toluene) was diluted with methanol (750ml, 5ml/g), then diisopropylamine (583ml, 42 1g, 4.161 mol, 3eq) was added. The

black solution was then hydrogenated over 20wt% Pd(OH)2/C moist (10wt%, 33g) at 621x103 Nm-2 (90 psi) and 110°C for 48 hours. A sample was removed for analysis.
The reaction mixture was filtered through ArboceFTM (filter aid) to remove catalyst residues and then heated to reflux and all diisopropylamine and methanol removed by distillation and replaced with toluene resulting in a final volume of lOml/g. The black solution was then cooled to 25°C, acetone (750L, 5ml/g) was added, and then the solution heated to 55-60°C. A solution of L-Tartaric acid (312g, 2.081mol, 1.5eq) in methanol (1.05L, 7ml/g) was added over 30 minutes maintaining the temperature at 55-60°C. The resulting suspension was then allowed to cool to room temperature and stirred for 12 hours. The suspension was filtered, washed with acetone (2 X 600ml, 4ml/g), then dried in a vacuum oven at 50°C for 12 hours to give the title compound as an off white solid [159.2g, 48% (24% from p-Cresol)]. Achiral purity was 100% (no impurities detected) and chiral purity was 91.4% e.e.
Example 3
Synthesis of racemic tolterodine hydrochloride
(Formula Removed)
To a solution of p-cresol (25 g, 0.i231 mol, 1 equiv), piperazine (11.94 g, 0.139 moi, 0.6 equiv) and toluene (250ml, 10 ml/g) at reflux under Dean & Stark conditions was added cinnamaldehyde (45.83 g, 44 ml, 0.347 mol, 1.5 equiv) over a 2 hour period and reaction mixture monitored by HPLC for the presence of p-cresol. Upon completion (2 to 3
hours), the mixture was cooled to 80°C and a solution of c.HCl (25 ml, 0.301 mol, 1.3 equiv) in water (100ml, 5 ml/g) was slowly added and heated at 80-90°C for at least 5 hours. The resulting solution was allowed to cool to room temperature and the phases separated. The toluene solution was washed with 1M HCl (125 ml, 5 ml/g), then water (3 X 125 ml). The resulting organic layer was taken into the reductive amination step (Step B) as a crude mixture.
Step B. Preparation of racemic tolterodine hydrochloride
To the crude solution from Step A was added methanol (125 ml, 5 ml/g cresol) and diisopropylamine (92 ml, 0.693mol, 3 equiv). The mixture was then hydrogenated over 20wt% Pd(OH)2/C wet (5.6 g, I0wt% theory of the benzopyran-2-ol) at 110 °C under 586x103 Nm-2 (85 psi) hydrogen pressure. Reaction progress was monitored by HPLC (completion usually occurs between 16 and 24h). Upon completion, the mixture was cooled, purged with nitrogen, filtered and washed with toluene (2 X 25 ml). The filtrate was then azeotroped with toluene to remove all methanol and diisopropylamine to end at a final volume corresponding to lOml/g cresol. The solution was then stirred at 50-60°C and 37% HCl (19.3 ml, 0.231 mol, 1.0 equiv c.f cresol) was added resulting in the precipitation of racemic tolterodine hydrochloride. The suspension was cooled to 25 °C and stirred for 2h, then filtered and washed with toluene (2 X 50ml). Racemic tolterodine hydrochloride was then dried under vacuum at 50°C. Yield was 52.7 g, 63% from p-cresol with achiral purity of 97%.
The synthesis of tolterodine L-tartrate according to the methods of Examples 1-3 is shown in Scheme 2 below.
(Formula Removed)
Example 4
Influence of amine catalyst and solvent on yield of 3.4-Dihvdro-6-metbvl-4-phenvl-2H-
benzopvran-2-ol
The reaction of Example 1 was repeated, but varying the amine catalyst and the solvent. The temperature used was approximately lOOX or the reflux temperature of any solvent if lower (unless indicated otherwise). Dean-Stark conditions were not used unless indicated (by *). The yields are shown in the following table.
(Table Removed)
t denotes secondary amine compound
Example 5 1.4-Bis-(6-methvl-4-phenvl-chroman-2-vn-piperazine
(Formula Removed)
The preparation of the title compound was carried out using the procedure of Example 1, except for the omission of a quench with aqueous acid. Instead, upon completion of the reaction the mixture was allowed to cool to ambient temperature resulting in a brown suspension. Filtration of this suspension gave a brown solid with 'H and 13C NMR providing confirmation of the structure. Melting point: 241°C.
Example 6
Preparation of 6-(2-Hvdroxv-ethvl)-4-phenyl-chroman-2-ol
(Formula Removed)
To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (5.0 g, 36 mmol, 1 equiv), piperazine (1.87 g, 22 mmoi, 0.6 equiv) and toluene (50 ml) at reflux under N2 and Dean & Stark conditions was added cinnamaldehyde (6.4 ml, 51 mmol, 1.4 equiv) and the reaction mixture maintained at heat for 17 h. The reaction was cooled to 80°C and quenched with aqueous HCl (0.7 molar, 1.3 equiv) then stirred at heat for 18 h. The biphasic mixture was allowed to cool to ambient temperature, separated, the organic phase washed with aqueous HCl and water and the organic phase concentrated to a black residue under reduced pressure. Flash chromatography eluting with 20% EtOAc/Heptane afforded the title compound as the main constituent of an approximately 80% pure yellow oil, R/- = 0.37 (50% EtOAc/Heptane) and structure confirmed by 1H NMR and LC-MS (M+l=271).
Example 7
Alternative preparation of 6-(2-hvdroxv-ethvl)-4-phenvl-chroman-2-ol using ^-
methylpiperazine
(Formula Removed)

To a solution of 4-hydroxyphenethyl alcohol (Tyrosol) (25.0 g, 181 mmol, I equiv), N-methylpiperazine (54.4g g, 543 mmol, 3 equiv) and toluene (200 ml) at reflux under N2 and Dean & Stark conditions was added cinnamaldehyde (35.9g ml, 272 mmol, 1.5 equiv) over a period of 2 hours and the reaction mixture maintained at reflux for 17 h. The reaction was cooled to 50°C and quenched with aqueous HCl (2M, 375mL, ~4 equiv). The biphasic mixture was allowed to cool to ambient temperature, diluted with ethyl acetate (250 mL) and the organic phase separated. The organic phase was washed with aqueous HCl (250mL), potassium bicarbonate (1M, 250mL), dried over magnesium sulphate and evaporated under reduced pressure to give a black oil (50.0g, assumed to be quantitative).
Example 8
Preparation of 2-[3-(Diisopropvlamino)-1 -phenvlpropvll-4-(2-hydroxvethvl")phenol
hydrochloride
(Formula Removed)
A mixture of 6-(2-hydroxy-ethyl)-4-phenyl-chroman-2-ol (Example 7, 30g, 111 mmol, 1 equiv), diisopropylamine (33.7g, 333 mmol, 3 eq) and palladium hydroxide on carbon [50% wet catalyst (50% by weight is water), 6g, 0.2 equiv] in toluene (120 mL) was hydrogenated at 621 x 103 Nm-2 (90 psi) hydrogen pressure at 110 "C, The reaction mixture was cooled to room temperature and filtered through arbocel and evaporated under reduced pressure. The resulting oil was dissolved in acetonitrile (200 mL) and concentrated hydrochloric acid (11.6 mL, 1.05 equiv) was added. The mixture was distilled at ambient pressure, removing approximately 100 mL of acetonitrile, and the distilled solvent replaced with fresh acetonitrile. The mixture was allowed to cool and crystallise overnight. The product was filtered and washed with a small portion of acetonitrile and dried overnight in vacuo at 50 °C to give the title compoimds as a white solid (26.7g, 68.1 mmol, 61%).
Example 9
Preparation of 2-r3-(Diisopropvlamino)-1 -phenylpropvn-4-(2-hvdroxvethvl)phenol

(Formula Removed)
Aqueous sodium bicarbonate (165 mL) was added to a mixture of the HCl salt (Example 8, 16.5g, 42.1 mmol, 1 equiv) in ethyl acetate (165 mL) and the mixture stirred for 1 hour. The phases were separated and the organic phase washed with water (195 mL), dried over magnesium sulphate and evaporated under reduced pressure to give the title compound as an oil containing -25% wt/wt ethyl acetate (14.6g total, 11.03g of title compound, 31 mmol, 74%).
Example 10
Preparation of (R)-2-[3-(Diisopropvlamino)-1 -phenylpropvl1-4-(2-hvdroxvethvl)phenol
(S)-2-phenoxvpropionic acid salt
(Formula Removed)

(S)-2-Phenoxypropionic acid (3.40g, 20.5 mmol, 1 equiv) was added to a solution of 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(2-hydroxyethyl)phenol (Example 9, 7.28g, 20.5 mmol, 1 equiv) in ethyl acetate. The mixture was heated at 80 °C for 2 days, upon which the mixture was cooled to room temperature, filtered and washed with ethyl acetate and dried in vacuo at 50 °C overnight to give the title compound as a white solid (3.9g, 7.48 mmol, 37% yield, 94% ee).
Enantiomeric excess was determined by converting the salt to the free base with sodium hydroxide and miming normal phase chiral HPLC chromatography (Chiral Pak AS-H column, eluting with hexane (89.8%), IPA (10%), DEA (0.1%), TFA (0.1%) at 1 mL/minute).
The title compound could be useful as a starting material to produce Example 5 in our co¬pending International Patent Application No PCT/IB07/000619. The corresponding hydrochloride salt to the title compound is disclosed as Example 12 in WO 98/43942.
Example 11
Synthesis of 3.4-dihvdro-6-bromo-4-phenvl-2H-benzopvran-2-ol
(Formula Removed)
4-Bromophenol (2.0g, 11.6mmmol) was stirred with N-methylpiperazine (3.48g, 34.8mmol, 3eq) in toluene (30mi, 15ml/g) and heated at reflux under Dean 8c Stark conditions. Once reflux was achieved, trans-cinammaldehyde (2.2g, 17.4mmol, 1.5eq) Was added over 2 hours. Once addition was complete, heating of the reaction mixture at reflux under Dean & Stark conditions was continued for 3 hours. The dark solution was cooled to 25°C and diluted with ethyl acetate (20ml, l0ml/g) and quenched with 2M HCl (30ml, 15ml/g). The phases were separated and the upper organic layer was washed with further 2M HCl (20ml, lOml/g) and IM sodium hydrogen carbonate solution (20ml, lOml/g). The organic phase was dried (MgS04), filtered and concentrated to give a dark coloured oil (4.2g, 11.6mmol, assumed to be quantitative)
Example 12
Synthesis of 2-f3-(Diisopropvlamino)-l-phenvlpropvl]-4-bromophenol hydrochloride salt

(Formula Removed)
Crude 3,4-dihydro-6-bromo-4-phenyI-2H-benzopyran-2-ol (Example 11, 2.0g, 6.55mmol) was dissolved in toluene (20ml, lOml/g) and to this solution was added titanium tetraisopropoxide (5.84ml, 3eq) and diisopropylamine (l.Oml, l.leq). The reaction mixture was cooled to 0-5°C and sodium borohydride (0.75g, 3eq) was added portionwise
over 15 minutes. Ethanol was charged dropwise over 15 minutes and stirred at 0-5°C for a further 2 hours. The reaction was quenched with water (20ml), ethyl acetate (50ml) and concentrated ammonia solution (20ml). The suspension was filtered through celite and the phases were separated. The organic layer was washed with water (50ml), dried (MgS04), filtered and concentrated to give the free base as a brown oil. This was dissolved in ethyl acetate (50ml) and 5M HCl (2ml) was added. Excess acid and water were azeotroped with fresh ethyl acetate (2x50ml) and the resulting solid was granulated in fresh ethyl acetate (20ml) for 48 hours. The solid was collected by filtration, washed with ethyl acetate (10ml) and dried at 50°C under vacuum for 4 hours. The title compound was obtained as a white solid (1.12g, 40% from 4-bromophenol).
The benzyloxy analogue of the title compound is disclosed as Example 1(e) in WO 94/11337. The title compound, once resolved, could also be useful as a starting material in the production of Example 3 in our co-pending International Patent Application No PCT/IB07/000619.
Example 13
Synthesis of (2-Hvdroxv-4-phenvl-3.4-dihYdro-2H-cfaromen-6-vl)methanol
(Formula Removed)
4-(Hydroxymethyl)phenol (2.515kg, 20.26mol, leq) was stirred with ^-methylpiperazine (5.06kg, 50.52mol, 2.5eq) in toluene (17.74kg, 20.5L, 8.15mL/g) and then heated to reflux. /ran.s-Cinnamaldehyde (3.35kg, 25.35mol, 1.25eq) was then added over 2 hours maintaining the reaction mixture at reflux. The transfer line was washed with toluene (0.9Kg, 0.35ml/g). Once the addition was complete the reaction mixture continued to be heated at reflux for 19h. Then some toluene was distilled off, reducing the volume to approximately 18.5L. The mixture was then allowed to cool to room temperature and EtOAc was added (13.5Kg 15L, 6mL/g). The organic phase was washed with HCl 2M
(46.4kg, 46.4L 18.5mL/g). The phases were separated, and ethyl acetate (27.1kg, 30L, 12ml/g) was added to dilute the organic layer. The organic phase was washed with IM HCl (17.75kg, 17.75L 7.1mL/g), 5% w/w NaHCO3 (17.5L, 7mL/g) and water (25L, lOmL/g). The phases were separated, and toluene (6.5Kg, 7.5L, 3ml/g) was added to the organic layer, and the mixture was distilled to approximately 8L. Additional toluene (7kg) was charged followed By ethyl acetate (3.9L). The mixture was heated to reflux then cooled to 22°C at l°C/minute, then stirred for 20hrs. The suspension was cooled to 2°C and granulated for 2hrs. The slurry was filtered and the cake was washed with cold toluene (2x4.3Kg, 5L). The resulting pale tan solid was dried in vacuum for 68h at 40°C, to provide 2.76Kg of product (2-hydroxy-4-phenyl-3,4-dihydro-2//-chromen-6-yl)methanol (53.4% yield) which was used in the following example without purification: 'H NMR 300MHZ d6 DMSO 5 ppm (mixture of isomers, 10:1): 1.95-2.10 (m, 2H), 2.15-2.35 (m, minor isomer), 3.25T3.35 (m, IH), 4.15-4.35 ( m, 3H), 4.80-4.95 (m, IH), 5.35-5.45 (m, minor isomer), 5.46-5.55 (m, IH), 6.51-6.54 (m, minor isomer), 6.58-6.63 (m, IH), 6.75 (d J=8.2Hz, IH), 6.98-7.40 (m, 6H).
Example 14
Synthesis of 2-[3-(Diisopropvlamino)-1 -phenvlpropyll-4-(hvdroxvmethvl)phenol

(Formula Removed)
(2-Hydroxy-4-phenyl-3,4-dihydro-2N-chromen-6-yl)methanol (Example 13, 830 g, 3.24 mol, 1.0 eq) was stirred in methanol (4150 mL, 5.0mL/g). Diisopropylamine (1362 mL, 9.72 mol, 3.0 eq) was then added over 15 minutes via dropping funnel. The resulting solution was then stirred for one hour under nitrogen.
The catalyst Pd-ESCAT 142 [(5%Pd/C paste, ca. 50% water wet) 83g, 10% w/w] was added as a slurry in methanol (2075 mL, 2.5 mL/g). The system was purged with
hydrogen, then the mixture was hydrogenated at 115 psi (793 x 10^ Nm-2, 7.92 bar) at a temperature of 40°C for 20 hours.
The mixture was purged with nitrogen and filtered over Arboce1TM (filter aid).. The residue pad was washed with methanol (2x1660 mL, 2x2.0 mL/g).
Due to equipment limitations, the above procedure was performed two further times on 830 and 840 g scale.
The three filtrates and their respective pad-washes were then combined to produce a single solution equivalent to a single 2.50 Kg scale reaction. The total volume was noted to act as the initial target volume in the following distillation procedure:
• Diisopropylamine (2500 mL, 1.0 mL/g) and /-amyl alcohol (10000 mL, 4.0 mL/g) were added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to the target volume previously noted.
• Diisopropylamine (2500 mL, 1.0 mL/g) and /-amyl alcohol (10000 mL, 4.0 mL/g) were added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to the target volume previously noted.
• Diisopropylamine (2500 mL, 1.0 mL/g) and t-amy\ alcohol (10000 mL, 4.0 mL/g) were added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to the target volume previously noted.
• t-Amyl alcohol (12500 mL, 5.0 mL/g) was added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to a volume of 12500 mL.
• t-Amyl alcohol (12500 mL, 5.0 mL/g) added to the reaction mixture. A vacuum distillation (100 mbar vacuum set) was then performed to distil down to a volume of 12500 mL. /-Amyl alcohol (12500 mL, 5.0 mL/g) added to the reaction mixture to give a final volume of 25L.
The t-amyl alcohol solution of crude product 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol was used in the next step with no further purification. HPLC analysis (area/area) showed 93.3% product, plus: 4.2% starting material, and other
impurities at 1.4% and 0.4%. Quantitative HPLC analysis indicated the crude solution contained 2950g product (89% yield).
Example 15 .
Synthesis of (R)-2-r3-fDiisopropvlamino)-1 -phenvlpropvl]-4-('hvdroxvmethvl)phenol (^)-
acetoxv(phenyl)acetate
(Formula Removed)
t-Amyl alcohol (19.2L) was added to the previous solution of 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (from Example 14) in t-amyl alcohol (25L, containing 2.95kg, 8.64mol, leq) to give a total volume of 44.2L. This solution was heated to 70°C. In a separate pot, a solution of (R)-(-)-acetoxy(phenyl)acetic acid (0.839kg, 4.32mol, O.Seq) in /-amyl alcohol (14.8L) was prepared at 50°C then cooled to room temperature once all the acid had dissolved. This solution was then added to the solution of 2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyI)phenol in /-amyl alcohol over one hour. The resulting solution was then seeded with product (0.03kg, lwt%, prepared previously by a similar method but on a smaller scale). The slurry was cooled to 60'C over 2 hours and then to 25°C over another 3 hours. The mixture was stirred at 25°C for an additional 12 hours. The slurry was filtered and the cake was twice re-slurried with /-amyl alcohol (2x29.5L, 2xl0mL/g) and de-liquored well. The white solid was dried imder reduced pressure at 40°C for 12hours to provide 2.04kg (/?)-2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol
(R)-acetoxy(phenyl)acetate (37.8% yield, corrected for 14.3%w/w r-amyl alcohol (determined by LOD analysis) with 99% ee by chiral HPLC.
HPLC method for ee monitoring;
Column: Chiralpak AS-H

Flow rate: Iml/min
Mobile Phase: Heptane 92.5/ Ethanol 7.5/ Diethylamine 0.12/ Trifluoroacetic acid 0.18
Temperature: 35°C
Detection: 220nm
Retention times:
(R)-2-[3-(diisopropylamino)-1 -phenylpropyl]-4-(hydroxymethyl)phenol 15min
(S)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol 18.4min
Example 16
Synthesis of (R)-2-[3-rDiisopropvlamino)-l-phenvlpropvll-4-(hvdroxvmethvnphenol

(Formula Removed)
(R)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (R)-acetoxy(phenyl)acetate (Example 15, 1.75 kg, 3.27 mol, leq) was slurried in toluene (15.2 kg, 10 mL/g) atnd warmed to 50 °C. A 10% aq. solution of K2CO3 (1.75 kg K2CO3 dissolved in 17.5 L purified water, 10 mL/g) was charged. The mixture was stirred vigorously at 50 °C for 30 minutes. The two solution phases were separated at 50 °C. The organic phase was washed with purified water (1.75 kg, 1 mL/g) at 50 °C. The phases were separated at 50 °C and the toluene volume reduced to 3 mL/g (5.5 L) by distillation. Crystallization was performed by reducing the temperature to 62 °C and then cooling to 40 °C over 40 mins. The batch was held at 40 °C for 30 mins and then seeded using (R)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (0.01 kg, prepared previously using a similar method on a smaller scale). The batch was agitated for a further 1 hour at 40 °C and then cooled to 20 °C over 3.5 hours. The batch was granulated at 20 °C for 10 hours. The slurry was then cooled to 2 °C over 1 hour and granulated at 2 °C for 1 hour (see temperature profile below). The suspension was filtered and the cake washed with cold toluene (1.5 kg, 1 mL/g). The damp product (0.933 kg, dry estimated by % LOD analysis) was a white crystalline solid.
A toluene re-slurry was then performed. Toluene (2.42 kg, 2.6 mL/g (based on dry estimate)) cooled to 3 °C and damp product was charged and agitated at 3 °C for 15 mins. The suspension was filtered and the cake washed with cold toluene (1.6 kg, 1.5 mL/g (based on dry estimate)). The damp product was dried in vacuo at 45 °C to yield (R)-2-[3-(diisopropylamino)-l-phenylpropyl]-4-(hydroxymethyl)phenol (0.74 kg, 2.17 mol) in 66.7% yield as a white crystalline solid. HPLC indicates > 99.6% purity, and chiral HPLC indicates > 99% ee.
Example 17
Preparation of (R)-(+)-Isobutvric acid 2-[3-(diisopropylamino)-l-phenvlpropvl]-4-
(hvdroxvmethvl)phenvl ester

(Formula Removed)
e title compound is prepared from the compound of Example 16 using the method of US Patent 6,858,650 (see section 5, column 16). Alternatively, this reaction can be performed without the addition of an external acid-intercepting base - see US Patent 6,858,650 column 10 lines 32-40.

Example 18
Preparation of (R)-(+)-Isobutvric acid 2-[3-(diisopropvlamino)-l-phenylpropvl]-4-
(hvdroxvmethvl)phenvl ester hydrogen fumarate
(Formula Removed)
e title compound is prepared from the compound of Example 17 using the method of US Patent 6,858,650 (see section 6, column 16).
Example 19
Synthesis of r2-('4-Methvlpiperazin-1 -vl)-4-phenvl-2^-chroman-6-vl]-methanol

(Formula Removed)
ans-Cinnamaldehyde (66.5g, 0.66mol, 1.25eq) was diluted with toluene (lOOmL, 2mL/g based on 4-(hydroxymethyl)phenol-), and was washed twice with a saturated solution of sodium hydrogen carbonate (2xl00mL) and once with water (lOOmL). This toluene solution of cinnamaldehyde was then added over 2 hours to a mixture of 4-(hydroxymethyl)phenol (50g, 0.40mol, leq) and N-methylpiperazine (I13mL, I.Omol, 2.5eq) in toluene (350mL, 7mL/g) heated to reflux under Dean-Stark conditions. Once the addition was complete the reaction mixture continued to be heated at reflux under Dean-Stark conditions for lOh. The mixture was then cooled to room temperature and a sample was evaporated to dryness under reduced pressure for analytical purposes. The dark oil contains crude [2-(4-methylpiperazin-1-yl)-4-phenyl-2N-chroman-6-yl]methanol (mixture of diastereoisomers) and impurities.
EI-GC-MS (Agilent), column: ZB-5HT. Temperature program: 50°C (0.5min). 20°C/min to 320'C (2min) obtained: RT=24.4min, MW: 338.
'H NMR (DMSO) (crude mixture) 300mHz 5 (ppm): 7.40-7.00 (28H. m); 6.89 (IH, d, J=2.0 Hz); 6.81 (IH, d, J=8.3 Hz); 6.75 (IH, d, J=8.2 Hz); 6.54 (IH, d, J=1.0 Hz); 4.87 (IH, d, J=10.2 Hz); 4.45 (IH, d, J=10.0 Hz); 4.40-4.20 (3H, m); 4.36 (2H, s); 4.23 (1.8H, s); 2.86 (4H, m); 2.80-2.50 (14H, m); 2.50-2.00 (50H, m) including 2.31 (s); 2.17 (s); 2.14 (s); 2.11 (s).
The synthesis of fesoterodine hydrogen fumarate according to the methods of Examples 13-18 is shown in Scheme 3 below.
Scheme Removed

Claims:
1. A process for the production of a compound of formula (I),
(Formula Removed)
wherein Y is selected from CH3, CH2OH, CH2CH2OH, CH2Br and Br; comprising the steps of:-
(i) reacting a compound of formula (II),
(Formula Removed)
wherein
OX is hydroxy or O'M+, in which M+ is a cation selected from Li+, Na+ and K+, and
Y is as defined above;
with trans-cinnamaldehyde (III),
in the presence of a secondary amine compound; then
(ii) treating the product of the preceding step with acid to afford the compound of
formula (I).
2. The process as claimed in claim 1, wherein OX is hydroxy.
3. The process as claimed in claim 1 or claim 2, wherein Y is CH3 or CH2OH.
4. The process as claimed in any one of claims 1 to 3, wherein the secondary amine compound is achiral.
5. The process as claimed in any one of claims 1 to 4, wherein the secondary amine compound contains two secondary amine groups.
6. The process as claimed in any one of claims 1 to 5, wherein the secondary amine compound is piperazine.
7. The process as claimed in claim 5 or claim 6, wherein 0.5-1.25 mole equivalents of the secondary amine compound are used in step (i).
8. The process as claimed in any one of claims 1 to 4, wherein the secondary amine compound contains one secondary amine group.
9. The process as claimed in any one of claims 1, 2, 3, 4 and 8, wherein the secondary amine compound is morpholine, dibutylamine, dibenzylamine, 1,1,3,3-tetramethylguanidine, diethylamine, diisopropylamine, piperidine or an N-(C\.6 alky)piperazine.
10. The process as claimed in claim 9, wherein the secondary amine compound is N-methylpiperazine.
11. The process as claimed in any one of claims 8 to 10, wherein 1-5 mole equivalents of the secondary amine compound are used in step (i).
12. The process as claimed in any one of the preceding claims, wherein the acid used in step (ii) is aqueous hydrochloric acid.
13. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out in an organic solvent selected from toluene, xylene, N-butyl acetate, t-amyl alcohol, dioxane and dibutyl ether.
14. The process as claimed in claim 13, wherein the solvent is toluene.
15. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out at a temperature in the range 80°C to the reflux temperature of the solvent.
16. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out under conditions that remove water from the reaction system.
17. The process as claimed in any one of the preceding claims, wherein the reaction of step (i) is carried out at or around ambient pressure.
18. A process for the production of a compound of formula (IV),
(Formula Removed)
wherein Y is as defined in claim 1, or a salt thereof, comprising:
(a) producing a compound of formula (I) as defined in claim 1, using the process claimed in any one of the preceding claims; then
(b) reductively aminating the compound of formula (I) with diisopropylamine;
(c) and where desired converting the resulting compound into a salt.

19. The process as claimed in claim 18, wherein Y is CH3 or CH2OH.
20. The process as claimed in claim 19, wherein Y is CH3, the compound of formula (IV) is treated with L-tartaric acid in step (c), and tolterodine L-tartrate is produced.
21. A process for the production of fesoterodine.
(Formula Removed)
or a pharmaceutically acceptable salt thereof, which comprises:
(a) producing a compound of formula (IV), as defined in claim 18, in which Y is CH2OH, using the process of claim 18;
(b) resolving the product of step (a) to obtain the (R)-enantiomer;
(c) acylating the phenolic hydroxy group of the product of step (b) to produce the corresponding isobutyric acid ester;
(d) and where desired or necessary, converting the resulting compound into a pharmaceutically acceptable salt.

22. The process as claimed in claim 21, wherein the secondary amine compound used to produce the compound of formula I is N-methylpiperazine.
23. A compound of formula (V),
(Formula Removed)
or a salt thereof, wherein Y is as defined in claim 1.
A compound of formula (VI),
(Formula Removed)

or a salt thereof, wherein Y is as defined in claim 1. A compound of formula (VII)
,(Formula Removed)

wherein Y is selected from CH2CH2OH, CH2Br and Br

Documents:

http://ipindiaonline.gov.in/patentsearch/GrantedSearch/viewdoc.aspx?id=UgrOF9rgzM4/LeKayq5DyA==&loc=+mN2fYxnTC4l0fUd8W4CAA==

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Patent Number

268687

Indian Patent Application Number

8655/DELNP/2008

PG Journal Number

38/2015

Publication Date

18-Sep-2015

Grant Date

11-Sep-2015

Date of Filing

15-Oct-2008

Name of Patentee

PFIZER LIMITED

Applicant Address

RAMSGATE ROAD, SANDWICH, KENT, CT13 9NJ, U.K

Inventors:

#	Inventor's Name	Inventor's Address
1	JENS BERTIL AHMAN,	C/O PFIZER GLOBAL RESEARCH AND DEVELOPMENT, RAMSGATE ROAD, SANDWICH, KENT, CT13 9NJ, U.K
2	BARRY RICHARD DILLON	C/O PFIZER GLOBAL RESEARCH AND DEVELOPMENT, RAMSGATE ROAD, SANDWICH, KENT, CT13 9NJ, U.K
3	ALAN JOHN PETTMAN	C/O PFIZER GLOBAL RESEARCH AND DEVELOPMENT, RAMSGATE ROAD, SANDWICH, KENT, CT13 9NJ, U.K

PCT International Classification Number

C07D 311/20

PCT International Application Number

PCT/IB2007/001379

PCT International Filing date

2007-05-21

PCT Conventions:

#	PCT Application Number	Date of Convention	Priority Country
1	60/803,068	2006-05-24	U.S.A.