WO2014012832A1 - Procédé pour la préparation de 2-(3-n,n-diisopropylamino-1-phénylpropyl)-4-hydroxyméthylphénol et de ses dérivés - Google Patents

Procédé pour la préparation de 2-(3-n,n-diisopropylamino-1-phénylpropyl)-4-hydroxyméthylphénol et de ses dérivés Download PDF

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WO2014012832A1
WO2014012832A1 PCT/EP2013/064607 EP2013064607W WO2014012832A1 WO 2014012832 A1 WO2014012832 A1 WO 2014012832A1 EP 2013064607 W EP2013064607 W EP 2013064607W WO 2014012832 A1 WO2014012832 A1 WO 2014012832A1
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trityl
compound
mixture
benzyl
hydrogen
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PCT/EP2013/064607
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Oreste Piccolo
Elios Giannini
Laura Bigini
Edoardo Gianolli
Daniele Vigo
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Cambrex Profarmaco Milano S.R.L.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/08—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions not involving the formation of amino groups, hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B55/00—Racemisation; Complete or partial inversion
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B57/00—Separation of optically-active compounds
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/02—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton by reactions involving the formation of amino groups from compounds containing hydroxy groups or etherified or esterified hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/06—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton from hydroxy amines by reactions involving the etherification or esterification of hydroxy groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C213/00—Preparation of compounds containing amino and hydroxy, amino and etherified hydroxy or amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C213/10—Separation; Purification; Stabilisation; Use of additives
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C215/00—Compounds containing amino and hydroxy groups bound to the same carbon skeleton
    • C07C215/46—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C215/48—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups
    • C07C215/54—Compounds containing amino and hydroxy groups bound to the same carbon skeleton having hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton with amino groups linked to the six-membered aromatic ring, or to the condensed ring system containing that ring, by carbon chains not further substituted by hydroxy groups linked by carbon chains having at least three carbon atoms between the amino groups and the six-membered aromatic ring or the condensed ring system containing that ring
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C217/00—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton
    • C07C217/02—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton
    • C07C217/48—Compounds containing amino and etherified hydroxy groups bound to the same carbon skeleton having etherified hydroxy groups and amino groups bound to acyclic carbon atoms of the same carbon skeleton the carbon skeleton being unsaturated and containing rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C219/00—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton
    • C07C219/26—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton
    • C07C219/28—Compounds containing amino and esterified hydroxy groups bound to the same carbon skeleton having esterified hydroxy groups bound to carbon atoms of at least one six-membered aromatic ring and amino groups bound to acyclic carbon atoms or to carbon atoms of rings other than six-membered aromatic rings of the same carbon skeleton having amino groups bound to acyclic carbon atoms of the carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/12—Preparation of carboxylic acid amides by reactions not involving the formation of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C235/00—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms
    • C07C235/02—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton
    • C07C235/32—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings
    • C07C235/34—Carboxylic acid amides, the carbon skeleton of the acid part being further substituted by oxygen atoms having carbon atoms of carboxamide groups bound to acyclic carbon atoms and singly-bound oxygen atoms bound to the same carbon skeleton the carbon skeleton containing six-membered aromatic rings having the nitrogen atoms of the carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/07—Optical isomers

Definitions

  • the process of the invention involves new amide intermediates of general formula (IIIA) and (IIIB), which by reduction provide new amide intermediates of general formula (IV A) and (IVB); the latter compounds, racemic or enantiomerically enriched, allow the production of (I) by treatment with hydrides.
  • the new intermediates are a further object of the present invention.
  • a further embodiment of the invention is a process for the preparation of Fesoterodine involving said intermediates of absolute configuration (R).
  • Fesoterodine is a pro-drug of 5-hydroxymethyl tolterodine, which is the active metabolite of Tolterodine.
  • Fesoterodine has been shown to display superior efficacy and tolerability over Tolterodine.
  • Fesoterodine fumarate was described for the first time in US6858650, which discloses the preparation of Fesoterodine by reaction of (R)-(+)-2-(3-N,N- diisopropylamino- 1 -phenylpropyl)-4-hydroxymethyl-phenol with isobutyryl chloride in the presence of triethylamine.
  • the conversion into fumarate salt is carried out by treating the product with fumaric acid in 2-butanone and cyclohexane.
  • This patent reports the melting point of Fesoterodine fumarate, either crude or recrystallized, but does not disclose the chemical and enantiomeric purity of the product.
  • US6713464 describes several 3,3-diphenylpropylamino derivatives, processes for their preparation, pharmaceutical compositions and methods for their use.
  • WO2007137799, WO2009037569 and WO2011145019 describe improvements to this synthetic scheme which, however, do not eliminate the use of critical reagents to be applied at industrial scale and tend to produce numerous wastes.
  • the process is characterized by the use of reagents that are difficult to handle at industrial level such as Diisobutylaluminium hydride (DIBAL), LiAlH 4 and expensive resolving agents such as cinchonidine.
  • DIBAL Diisobutylaluminium hydride
  • LiAlH 4 LiAlH 4
  • expensive resolving agents such as cinchonidine.
  • lactol is characterized by low yields of reaction and by the formation of many by-products and hence the process requires several purifications that make it less suitable for an industrial application.
  • WO07017544 and WO07147547 describe the way traditionally shorter, one -pot, to synthesize Tolterodine, shown in Scheme 6, which comprises the reaction between p-cresol and N,N-diisopropylcinnamylamine (DIPCA) in the presence of a strong acid:
  • the process of this invention involves new amide intermediates of general formula (IIIA) and (IIIB), which afford, after reduction, new racemic or enantiomerically enriched amide intermediates of general formula (IV A) and (IVB). These latter compounds permit the production of (I) by treatment with hydrides.
  • the new intermediates are a further object of the present invention.
  • the structures (I) and (IV A and B) include either the racemates or the possible enantiomers (R) or (S) or their mixtures, the structure (III A and B) includes the possible geometric isomers E and Z.
  • the group R is C1-C4 alkyl, phenyl, benzyl.
  • the group X represents hydrogen, benzyl, trityl, tetrahydrofuryl, tetrahydropyranyl.
  • intermediates (IIIA) and (IIIB) which may be isolated or used in solution, it is possible to produce intermediates (IV A) and (IVB), by treatment with a suitable reducing agent, in the form of racemic mixtures or enantiomerically enriched ( ) or (S) enantiomers.
  • the resolution can be carried out by selecting a suitable enantiomerically pure acid as resolving agent but, if the undesired enantiomer has to be recovered by racemization, this protective group X should be stable under basic conditions and at high temperature.
  • the phenolic group in the of resolution and racemisation processes is used unprotected even if the presence of a protective group of this OH group is not harmful.
  • the invention is also characterized in that an enantiomerically enriched molecule can be obtained, not only by the processes of resolution above described, but also through an enantioselective reduction of intermediates (IIIA) or (IIIB), that leads to enantiomerically enriched compounds (IV A) or (IVB), using suitable metal catalysts containing chiral ligands or biocatalysts as suggested by the literature. It has however to be stressed that the teachings of the prior art do not allow easily to the skilled person to envisage the catalysts and/or suitable experimental conditions to obtain an enantiomerically enriched product when the substrate is structurally complex.
  • the process of the invention is further characterized by the fact that most of the new intermediates can be isolated in solid form. This allows to overcome some of the problems left open by known processes that, on the contrary, often lead to the formation of intermediates of oily consistency, hardly isolable and purifiable, thus creating lower yield, formation of by-products and not allowing the easy isolation of API with high chemical and enantiomeric purity.
  • the process of the invention is therefore suitable for industrial scale and affords the desired product in good yield and quality.
  • Figure 1 - shows the X- ay powder diffractogram of the Fesoterodine fumarate polymorph of Example 32.
  • Figure 2 - shows the X-Ray powder diffractogram numeric pattern of the Fesoterodine fumarate polymorph of Example 32.
  • the new products were characterized by analytical and spectroscopic techniques such as, for example, HPLC, HPLC-MS, 1H-NMR, 13 C-NMR, m.p., [cc] D and IR.
  • reaction and work-up conditions can be adapted, as exemplified later, to the preparation of the novel intermediates with high yield and chemical purity.
  • a technician expert in this field can easily determine, case by case, the most appropriate conditions, in particular in function of the protective group X and of its stability at different pH conditions.
  • the Mizoroki-Heck reaction used for the preparation of novel intermediates ( ⁇ ) and (IIIB) can be performed using commercially available reagents (V) or easily prepared, such as (VI) and N, N-diisopropylcinnamide, using an unsaturated amide to aromatic halide ratio in the range from 2.5 / 1 to 0.9 / 1, preferably 1.5 / 1 - 0.9 / 1, most preferably 1.1 / 1 - 0.9 / 1.
  • the reaction is carried out in the presence of an organic medium-low polar solvent such as for example 2-methyl-tetrahydrofuran (2-Me-THF), dioxane or toluene.
  • an organic medium-low polar solvent such as for example 2-methyl-tetrahydrofuran (2-Me-THF), dioxane or toluene.
  • organic solvent to aromatic halide ratio is 2-10/1 w/w.
  • the reaction is carried out in the presence of an organic or inorganic base, and preferably in the presence of an organic sterically hindered base as, for example, ⁇ , ⁇ -dicyclohexylmethylamine.
  • the base to aromatic halide stoichiometric ratio typically ranges from 1.5 / 1 to 1/1, preferably between 1.3 / 1 and 1/1.
  • the Mizoroki-Heck reaction requires the presence of a catalyst, preferably a commercially available homogeneous catalyst based on Pd (0), e.g.
  • the most suitable phosphines for this reaction are the hindered electron rich phosphines such as, for example, t-butylphosphine, di-t-butyl(2,2-diphenyl-l-methyl-l-cyclopropyl) phosphine (c-B IDP), di(l-adamantyl)-n-butylphosphine but the technician expert in this field may choose other phosphines, in particular other hindered electron rich phosphines.
  • the aromatic halide to catalyst stoichiometric ratio should range from 100: 1 to 10000: 1, preferably 300: 1 to 5000: 1, more preferably 400: 1 to 2000: 1.
  • the obtained product (IIIA) and (IIIB) is predominantly the E isomer, which can be further purified by crystallization.
  • the pure Z isomer or a mixture containing Z and E isomers may be conveniently used for the subsequent reactions.
  • the washings should be carried out at a suitable pH and temperature, easily identified by a person skilled in the art.
  • the reduction may be effected by means of H 2 or a hydrogen donor, such as sodium hypophosphite, in the presence of a heterogeneous catalyst, preferably heterogeneous Pd catalyst, at a pressure between 0.5 and 10 bar (although higher pressures are not deleterious), in a solvent, preferably chosen among an alcohol, such as methanol, ethanol or isopropanol, or an ether, such as THF, 2-Me-THF, optionally adding a quantity of water in the range 0.5-10%, with a solvent/unsaturated amide ratio usually in the range 3/1-20/1 w/w.
  • a hydrogen donor such as sodium hypophosphite
  • a heterogeneous catalyst preferably heterogeneous Pd catalyst
  • a solvent preferably chosen among an alcohol, such as methanol, ethanol or isopropanol, or an ether, such as THF, 2-Me-THF, optionally adding a quantity of water in the range 0.5-10%, with a
  • the catalyst to unsaturated amide ratio is in the range of 1/300-1/5 w/w, preferably 1/200-1/10 w/w.
  • the hydrogenation temperature is in the range 30-100°C and preferably 40- 80°C.
  • the conversion and the yield of isolated intermediates (IV A) and (IVB) are >90%, usually >95%, while the reaction time depends on the reaction conditions.
  • a homogeneous chiral catalyst commercially available or prepared in a separate vessel and then added to the reaction mixture, may be used indifferently.
  • the known catalysts containing metals such as u, Rh, Ir, Co, Cu or Zn with suitable chiral ligands those based on Ru, Rh, Cu or Ir are particularly applicable if the chiral ligand is a phosphine.
  • the result of the reaction depends on the used catalyst, the chemical purity of the olefmic substrate and the reaction conditions.
  • Suitable solvents are ethers, alcohols, ketones, arenes, esters, and are exemplified as convenient 2-MeTHF, methyl ethyl ketone (MEK) and t.amyl alcohol. Dry solvents or solvents containing 0.1-10% w/w of water may be used.
  • aqueous hydrochloric acid, in acetonitrile at a pH in the range 0.8 - 2.5 the trityl group can be removed selectively and the Fesoterodine thus produced can be recovered with good yield and high chemical and enantiomeric purity.
  • a salt of Fesoterodine can be obtained by addition of an appropriate pharmacologically acceptable acid, in particular fumaric acid.
  • the present procedure offers the additional advantage that the fumarate salt may be obtained in a desired crystalline or amorphous form according to the experimental conditions; as concerning to the crystalline form, having a defined XRD spectral pattern, the high quality of Fesoterodine obtained with the present process makes easier the recovery of fumarate salt as solid.
  • the solid form of Fesoterodine fumarate obtained following the present invention, was characterized by X-ray Powder Diffraction (XRDP) using a Philips PW1800/10 diffractometer, equipped with software X'Pert High Score - v. 2.0a (PANalytical) and radiation Cu K .
  • XRDP X-ray Powder Diffraction
  • Philips PW1800/10 diffractometer equipped with software X'Pert High Score - v. 2.0a (PANalytical) and radiation Cu K .
  • FT-IR spectra were recorded using a Jasco FT/IR 460 plus spectrometer. Where not indicated, the spectra were recorded using the diffuse reflection method and the sample was prepared mixing about 5 mg of product with 500 mg of KBr
  • film refers to a film of product on NaCl, deposed by evaporation of a dichloromethane solution.
  • NMR spectroscopy where not indicated, data was collected using a Bruker Avance 300 MHz spectrometer and using tetramethylsilane (TSM) as reference.
  • DSC data was collected using a Mettler-Toledo DSC 822 e instrument. Standard DSC experiment: heat 40-300°C at 10 min.
  • MS spectroscopy data was collected using a Agilent 6120 quadrupole, coupled with an Agilent 1200 HPLC. The invention is further illustrated by the following examples.
  • reaction mixture is filtered through celite at 50°C and the filter is rinsed with wet 2-Me-THF (2x50 mL).
  • the filtrate is evaporated under vacuum to a volume of 70-80 mL.
  • the suspension is then heated at 50-60°C and maintained at this temperature for 15 minutes, then cooled slowly to room temperature and finally to 0-5°C, under stirring for 2-3 hours at this temperature.
  • the product is isolated by filtration, washed with cold toluene and dried under vacuum at 55°C overnight to give 49 g (0.123 mol) (c.y. 94%) of the desired product.
  • Hydrogen is introduced at first at a pressure of lObar, then reduced to lbar, carefully venting the autoclave. After repeating this procedure three times, hydrogen is introduced at 30bar and the mixture is stirred at 60°C for 16 hours, then at 60bar for additional 10 hours, obtaining ab. 80% conversion of the starting material. The mixture is filtered on charcoal and celite, then concentrated at reduced pressure and the residue diluted with IPA.
  • Hydrogen is introduced at first at a pressure of lObar, then reduced to lbar, carefully venting the autoclave. After repeating this procedure three times, hydrogen is introduced at 20bar and the mixture is stirred at 50°C for 16 hours, then at 40bar for additional 8 hours, obtaining ca. 90% conversion of the starting material. The mixture is filtered on charcoal and celite, then concentrated at reduced pressure and the residue diluted with IPA.
  • the reaction is quenched adding 30% NaOH aq (7 mL), water (14 mL) and, after 5 minutes stirring, toluene (300 mL) and water (400 mL).
  • the organic phase is evaporated to residue, taken up with toluene and evaporated to residue.
  • the residue is taken up with hexane and evaporated to residue. This residue is then triturated at room temperature with lOOmL of hexane.
  • the solid is isolated by filtration, washed with hexane and dried under vacuum to give 18.1 g of raw product.
  • the mixture is heated to 50°C for 1 h prior to be cooled to room temperature and charged with 240 mL of water and 40 mL of toluene.
  • the organic phase is discarded while the aqueous phase is washed with another portion of toluene (40 mL).
  • the aqueous phase is charged with 10% aq. Na 2 CO 3 (to basic pH), concentrated under reduced pressure, to distill off acetonitrile and extracted with methylene chloride.
  • the residue is dissolved with 30 mL of acetonitrile and concentrated HC1.
  • N,N-diisopropylcinnamamide (66.0 g, 0.285 mol), 2-bromo-4-hydroxymethyl-phenol (55.0g, 0.271 mol), N,N-dicyclohexylmethylamine (58.6 g, 0.297 mol) and 2-Me-THF (290 mL) are loaded and the mixture is heated at 70-80°C.
  • the catalyst, bis(tri-tert- butylphosphine)Pd, (130 mg, 0.25 mmol) is added and the reaction mixture is heated to about 86°C.
  • N,N-diisopropylcinnamamide 95.1 g, 0.467 mol
  • 2-bromo-4-trityloxymethyl-phenol 174.3 g, 0.391 mol
  • NN-dicyclohexylmethylamine 84.1 g, 0.431 mol
  • 2-Me-THF 785 mL
  • the mixture is heated at 70-80°C, the catalyst, bis(tri-tert- butylphosphine)Pd, (400 mg, 0.78 mmol) is added and the reaction is heated to reflux. After 2h another portion of catalyst (200 mg, 0.39 mmol) is added, the reflux is maintained for three more hours and then the reaction is cooled to room temperature.
  • a well dried 1L round bottomed flask, fitted with a mechanical stirrer, is purged with nitrogen and loaded with Compound (IVB, X Tr), prepared according to Example 25, (20 g, 33.5 mmol) and anhydrous toluene (200 mL).
  • the suspension is cooled with an ice bath and a first portion of Vitride ® (5.4 g, > 65% w/w in toluene) is added, drop-wise, at 5-10°C (exothermic reaction and H 2 evolution occur). Then the second portion of Vitride ® (39.5 g, > 65% w/w in toluene) is added, the reaction is warmed gently to 25 °C and stirred at the same temperature overnight.
  • Acetone (4.4 mL) is slowly dropped allowing the temperature to rise to 30-35°C. After 5 min 10%NaOH (200 mL) is added and the mixture is stirred for 10 min at room temperature. Then, the aqueous phase is separated and the organic phase washed, in order, with dil. NaOH (10% w/w, 100 mL) and water (3 x 100 mL). The final organic solution is evaporated under reduced pressure using a water bath (Tmax 50-60°C). The residue (ab. 18.6 g) is taken up with isopropanol (100 mL) at 60-65 °C and the suspension obtained is stirred while is cooled to room temperature. The mixture is stirred for 30min-lh and filtered to afford 16.1 g (27.6 mmol) (82%) of the product.
  • the suspension is heated at reflux temperature, for lh, cooled to room temperature (20-25°C) in lh and stirred for 30 min.
  • the product is filtered, washed with MEK (2x40 mL).
  • the product (83 g wet) is suspended in 800 mL of MEK, heated at reflux temperature, cooled to 70°C and stirred for 45 min, cooled to room temperature in lh and stirred for 30 min.
  • the product is filtered, washed with MEK (2x40 mL).
  • the product (70 g wet) is finally slurried using 660 mL of MEK and 13 mL of water.
  • the aqueous phase is discarded and the organic one is washed with water (2 x 50 mL) and evaporated under reduced pressure.
  • the oily residue obtained (26 g) is loaded in a 1-L round bottomed flask with 200 mL of acetonitrile. The solution is charged with 18 mL of water, heated at 50°C, charged with about 27 mL of aq. HC1 (6%) and stirred for 30-45 min. After cooling to room temperature, water (580 mL) is added and the suspension is stirred for about 15 min, then the solid (trityl alcohol) is filtered off and washed with water-acetonitrile mixture on filter.
  • the filtrate is neutralized adding NaHCO 3 and acetonitrile is evaporated under reduced pressure.
  • the pH is then set to about 9 with the addition of Na 2 CO (2.5-3 g...g) and methylene chloride (200 mL) is added while mixing.
  • the organic phase is separated and the aqueous one is extracted with a second portion of methylene chloride (70 mL).
  • the organic phases are merged, dried over anhydrous Na 2 CO and filtered.
  • the filtrated is concentrated under reduced pressure to a oily residue (15 g, containing 14.1 g of Fesoterodine as base).
  • Fesoterodine base (14. lg, 34.3 mmol, e.e >99%), prepared using the same procedure described in Example 32, is dissolved in 30 mL of MEK. The mixture is charged with 3.98 g (34.3 mmol) of fumaric acid and heated to 40°C to obtain a clear solution. Cyclohexane (8 mL) is dropped slowly and the mixture is allowed to cool to room temperature under stirring-and then concentrated under reduced pressure. The thick residue is charged with MEK (20 mL) and stirred at room temperature overnight.
  • the dense suspension obtained is diluted with 10 mL of MEK and cyclohexane (8 mL) is dropped in 30 min. Then, the mixture is stirred for 4 h at room temperature, cooled to 0-5°C and maintained under stirring overnight to obtain a solid product which is filtered, washed with a MEK/cyclohexane mixture (2/1) and dried under vacuum to afford Fesoterodine fumarate 15.0 g (28.4 mmol) (c.y. 83%) having e.e. > 99.9%.
  • Fesoterodine base (10.6 g, 25.7 mmol), having e.e. 96%, prepared using the same procedure described in Example 32, is dissolved in 23 mL of MEK. The mixture is charged with 2.98 g (25.7 mmol)of fumaric acid heated to 40°C to obtain a clear solution. Cyclohexane (6 mL) is dropped slowly and the mixture is allowed to cool to room temperature and maintained under stirring for 16 h before being cooled to 0-5°C. Since crystallization does not occur even after many hours at 0°C, the mixture is evaporated to dryness under reduced pressure. The thick residue is charged with MEK (15 mL) and stirred at room temperature overnight.
  • Fesoterodine base (8.0 g, 19.3 mmol) having e.e. >99%, prepared using the same procedure described in Example 32, is dissolved in 100 mL of 2-MeTHF.
  • the mixture is charged with 2.24 g (19.3 mmol) of fumaric acid and heated to 50°C to obtain a clear solution, that was allowed to cool to room temperature in about lh.
  • the product initially separated as a dispersed oil, solidifies spontaneously within 2h.
  • the mixture is then heated again to 50°C to obtain a suspension and finally is cooled to room temperature and maintained under stirring overnight.
  • the product is filtered off, washed with 2-MeTHF and dried under vacuum to give 8.0 g (15.2 mmol) (c.y. 79%) of Fesoterodine fumarate having e.e > 99.9%.

Abstract

L'invention porte sur un procédé pour la préparation de 2-(3-N,N-diisopropylamino-1-phénylpropyl)-4-hydroxyméthylphénol et de ses dérivés, en particulier le dérivé (R)-4-trityloxyméthylique, utiles comme forme intermédiaire dans la synthèse de la fésotérodine et de ses sels, en particulier pour la préparation du sel fumarate de fésotérodine.
PCT/EP2013/064607 2012-07-16 2013-07-10 Procédé pour la préparation de 2-(3-n,n-diisopropylamino-1-phénylpropyl)-4-hydroxyméthylphénol et de ses dérivés WO2014012832A1 (fr)

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ITMI2012A001232 2012-07-16
IT001232A ITMI20121232A1 (it) 2012-07-16 2012-07-16 Procedimento per la preparazione di 2-(3-n,n-diisopropilamino-1-fenilpropil)-4-idrossimetil-fenolo e suoi derivati

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