HK1080847B - Stable hydrate of a muscarinic receptor antagonist - Google Patents

Description

Stable hydrates of muscarinic receptor antagonists

The present invention relates to stable solid hydrates of the muscarinic receptor antagonist (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide, also known as darifenacin (VII):

in addition, the invention also relates to a pharmaceutical composition containing the hydrate and application of the hydrate in medicines. Such pharmaceutical compositions are particularly relevant in the following situations: treatment of conditions requiring muscarinic receptor antagonists such as irritable bowel syndrome, diverticulosis, esophageal achalasia, chronic obstructive airways disease, overactive bladder including symptoms of urinary incontinence, urgency and frequency, urinary incontinence, neurogenic urgency or pollakiuria, treatment of bladder dysfunction, urinary leakage (urinary leak), painful or difficult urination resulting from neurogenic, spastic or hypertonic bladder, dysfunctional bladder syndrome, gastrointestinal disorders including gastrointestinal hyperactivity, and laxative effects on intestinal smooth muscle cells.

European patent 0388054 describes a family of 3-substituted pyrrolidine derivatives as muscarinic receptor antagonists, including darifenacin and its pharmaceutically acceptable salts. Such pharmaceutically acceptable salts include acid addition salts, particularly the hydrochloride, hydrobromide, hydrofluoride, sulphate or bisulphate, phosphate or hydrogenphosphate, acetate, besylate, citrate, fumarate, gluconate, lactate, maleate, mesylate, succinate and tartrate salts.

The hydrobromide salt of darifenacin is the preferred compound for medical use. The salts are prepared from the corresponding anhydrous free base. However, a problem associated with the free base is that it is very unstable and has a shelf life of only 1 month. In addition, the free base in a form sufficiently pure for pharmaceutical use may be difficult to prepare.

Surprisingly, it has been found that this problem can be solved by synthesizing a hydrate of darifenacin for conversion to the hydrobromide salt instead of using the free base to prepare the hydrobromide salt. The solid hydrate has been found to remain stable for well over 1 year. Furthermore, a purity level suitable for pharmaceutical use can be achieved. The conversion of the solid hydrate to a pharmaceutically acceptable hydrobromide salt can be achieved via an easy conversion process.

Accordingly, the present invention provides stable solid hydrates of darifenacin. X-ray crystallography has shown that the hydrate of the invention can be isolated as a compound having a darifenacin to water stoichiometric ratio of 1: 0.6 to 1: 1.

More specifically, the present invention provides compounds of formula (IX):

in a preferred embodiment, the compounds of formula (IX) are characterized by an infrared spectrum using a single reflection ATR (attenuated Total reflection) at the following v_max(cm^-1) Shows a significant absorption band: 3625. 3516, 3440, 2948, 2806, 1699, 1622, 1597, 1578, 1488, 1471, 1445, 1378, 1353, 1325, 1312, 1280, 1242, 1196, 1152, 1119, 1102, 1086, 1024, 981, 939, 925, 900.

The compounds of formula (IX) can also be characterized by an X-ray powder diffraction pattern obtained using copper radiation (λ ═ 0.15405nm) which shows the main peaks at the following 2 θ angles: 8.39, 10.519, 13.272, 13.693, 15.908, 16.289, 16.855, 19.637, 21.135, 21.55, 21.722, 23.006 and 26.284 degrees.

Furthermore, it can be characterized by a Differential Scanning Calorimetry (DSC) curve, which shows a steep endothermic peak at a scanning rate of 20 deg.C/min at 101 deg.C.

Infrared spectroscopy was performed using a Nicolet Avatar 360FT-IR spectrophotometer.

The samples were examined using a single reflectance ATR (attenuated total reflectance) with a spectrophotometer scanning spectrum range of 650cm^-1To 4000cm^-1。

PXRD data were obtained using a SIEMENS D5000X-ray powder diffractometer equipped with an automatic sample conversion device, a theta-theta goniometer, an automatic beam divergence slit, a secondary monochromator (secondary monochromator), and a scintillation counter. Samples were prepared for analysis by compacting the powder onto a silicon wafer sample set. Each sample was spun while using copper K-alpha₁X-ray (wavelength: 1.5406 angstroms) radiation, and the X-ray tube was operated at 40kV/40 mA.

The analysis was performed using a goniometer operating in a step and scan mode, where the mode was set to 0.02 ° per step in the 2 θ range of 2 ° -45 °, counting 5 seconds.

DSC was performed using a PerkinElmer DSC-7 instrument equipped with an automatic sample changer. About 3mg of sample was accurately weighed, placed in a 50 microliter aluminum pan, and crimped with a perforated lid. The sample was heated at a rate of 20 deg.C/min within the range of 40 deg.C to 250 deg.C under a nitrogen purge.

The invention also provides a pharmaceutical composition comprising a hydrate of the invention as described above, together with a pharmaceutically acceptable excipient, diluent or carrier.

In addition, the present invention provides the use of a hydrate of the invention as described above or a pharmaceutical composition comprising a hydrate of the invention as described above as a medicament.

Still further, the present invention provides the use of a hydrate of the invention as described above or a pharmaceutical composition comprising a hydrate of the invention as described above for the manufacture of a medicament for the therapeutic or prophylactic treatment of a medical condition for which a muscarinic receptor antagonist is indicated. Such conditions are irritable bowel syndrome, diverticular disease, esophageal achalasia, chronic obstructive airway disease, overactive bladder including symptoms of urinary incontinence, urgency and frequency, urinary incontinence, neurogenic or pollakiuria, treatment of bladder dysfunction, urinary leakage, painful or difficult urination resulting from neurogenic, spastic or hypertonic bladders, dysfunctional bladder syndrome, gastrointestinal disorders including gastrointestinal hyperactivity and the relaxing effect on smooth muscle cells of the intestine.

The present invention also provides a method of treating a mammal to treat or prevent a medical condition for which a muscarinic receptor antagonist is indicated, which comprises administering to said mammal an effective amount of a hydrate of the invention as described above or a pharmaceutical composition comprising a hydrate of the invention as described above.

The invention also includes all suitable isotopic variations of the hydrates of the present invention as described above. The "isotopic variation of a hydrate of the present invention" as recited above is defined as wherein at least one atom is replaced by an atom having the same atomic number but an atomic mass different from the atomic mass usually found in nature. Examples of isotopes that can be incorporated into hydrates of the invention as described above include isotopes of hydrogen, carbon, nitrogen and oxygen, each as²H、³H、¹³C、¹⁴C、¹⁵N、¹⁷O and¹⁸and O. Certain isotopic variations of the hydrates of the present invention as set forth above, for example, those having a radioactive isotope such as incorporated therein³H or¹⁴C, useful in drug and/or substrate tissue distribution studies. Tritium, i.e.³H and carbon-14, i.e.¹⁴The C isotopes are particularly preferred for their ease of preparation and detection. Furthermore, with isotopes such as deuterium, i.e.²H substitution may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosage requirements, and thus may be preferred in certain circumstances. Isotopic variations of a hydrate of the present invention as described above can generally be prepared by conventional procedures, e.g., by exemplary methods or by the preparative methods described in the examples and preparations for subsequent use of an appropriate isotopic variation of an appropriate reagent.

The hydrates of the present invention as described above may be administered alone, but will generally be administered in admixture with a suitable pharmaceutical excipient, diluent or carrier selected with regard to the intended route of use and standard pharmaceutical practice. For example, the hydrates of the present invention as described above may be administered orally, buccally or sublingually in the form of tablets, capsules, multiparticulates (multiparticulates), gels, films, ovules (ovules), elixirs, solutions or suspensions, which may contain flavouring or colouring agents, for immediate-, delayed-, modified-, sustained-or controlled-release administration. The hydrates of the present invention as described above may also be applied as fast dispersing or fast dissolving dosage forms or in the form of high energy dispersions or as coated particles. Suitable formulations of the hydrates of the present invention as described above may be in coated or uncoated form as required.

These solid pharmaceutical compositions, e.g. tablets, may contain excipients such as microcrystalline cellulose, lactose, sodium citrate, calcium carbonate, dibasic calcium phosphate and glycine; disintegrants such as starch (preferably corn, potato or tapioca starch), starch glycollate, croscarmellose sodium and certain complex silicates; and granulation binders such as polyvinylpyrrolidone, Hydroxypropylmethylcellulose (HPMC), Hydroxypropylcellulose (HPC), sucrose, gelatin, and gum arabic. Additionally, lubricating agents such as magnesium stearate, stearic acid, glyceryl behenate and talc may be included.

Solid compositions of a similar type may also be used as fillers in gelatin or HPMC capsules. In this regard, preferred excipients include lactose (lactose), starch, cellulose, lactose (milk sugar) or high molecular weight polyethylene glycols. For aqueous suspensions and/or elixirs, the hydrates of the invention as described above may be combined with various sweetening or flavouring agents, colouring matter or dyes, with emulsifying and/or suspending agents, with diluents such as water, ethanol, propylene glycol and glycerin, and combinations thereof.

The hydrates of the present invention as described above may also be administered parenterally, for example intravenously, intraarterially, intraperitoneally, intrathecally, intraventricularly, intraurethrally, intrasternally, intracranially, intramuscularly or subcutaneously, or they may be administered by infusion or needleless injection techniques. For such parenteral administration, they are best used in the form of sterile aqueous solutions which may contain other substances, such as sufficient glucose salts to make the solution isotonic with blood. The aqueous solution should be suitably buffered (preferably to a pH of 3 to 9) as necessary. The preparation of suitable parenteral formulations under sterile conditions can be readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.

For oral and parenteral administration to human patients, the daily dosage level of the hydrate of the invention as described above is typically 1.5 to 30mg (administered in one or divided doses). The physician in any event will determine the actual dosage which will be most suitable for any individual patient and that dosage will vary with the age, weight and response of the particular patient. The above dosages are exemplary of the average case. There are, of course, individual instances where higher or lower dosage ranges should be employed and such are included within the scope of this invention.

The hydrates of the present invention as described above may also be administered intranasally or by inhalation and are conveniently delivered in the form of a dry powder inhaler or in the form of an aerosol spray presentation from a pressurised container, pump, spray, atomiser or nebuliser, optionally with the use of a suitable propellant, e.g. dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, hydrofluoroalkanes such as 1, 1, 1, 2-tetrafluoroethane (HFA 134A)^TM) Or 1, 1, 1, 2, 3, 3, 3-heptafluoropropane (HFA227 EA)^TM) Carbon dioxide, or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount of the drug. The pressurised container, pump, spray, atomiser or nebuliser may contain a solution or suspension of the active compound, for example using a mixture of ethanol and propellant as the solvent, which may additionally contain a lubricant, for example sorbitan trioleate. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a hydrate of the invention as described above and a suitable powder base such as lactose or starch.

The aerosol or dry powder formulation is preferably arranged to contain from 0.2mg to 3.0mg of a hydrate of the invention as described above per metered dose or "puff" for delivery to a patient. The total daily dose of the aerosol formulation is from 0.5mg to 10.0mg of the hydrate of the present invention as described above, which can be administered in a single dose, or more usually, in divided doses throughout the day.

Alternatively, the hydrates of the present invention as described above may be administered in the form of suppositories or pessaries, or may be administered topically in the form of gels, hydrogels, lotions, solutions, creams, ointments or dusting powders. The hydrates of the present invention as described above may also be applied transdermally or transdermally, for example, by the use of a skin patch. They may also be administered by pulmonary or rectal routes.

Alternatively, hydrates of the present invention as described above may be topically or transdermally applied to the skin, mucous membranes, for example, as gels, hydrogels, lotions, solutions, creams, ointments, dusting powders, dressings (dressing), foams, films, skin patches (such as, but not limited to, reservoirs, scaffolds, adhesive inclusion drugs (drug-in-adhesive), multi-layer pressed (multi-layer) polymer systems), wafers, implants, sponges, fibers, bandages, microemulsions, and combinations thereof. For these applications, the hydrates of the present invention as described above may be suspended or dissolved, for example, in a mixture of one or more of the following: mineral oil, liquid paraffin, white petrolatum, propylene glycol, polyoxyethylene polyoxypropylene complex, emulsifying wax, glycerin, silicone fluid, fixed oils including synthetic mono-or diglycerides, and fatty acids and fatty acid esters including oleic acid, water, sorbitan monostearate, polyethylene glycol, liquid paraffin, polysorbate 60, cetyl esters wax (cetyl ester wax), palmityl alcohol (cetearyl alcohol), 2-octyldodecanol, benzyl alcohol, alcohols such as ethanol. Alternatively, penetration enhancers may also be used, such as, but not limited to, those disclosed in the following documents: finnin and Morgan, Journal of pharm. sciences, 10 months 1999, "transdermal penetration enhancers: application, limitations and potential ". The following substances may also be used: polymers, carbohydrates, proteins, phospholipids in nanoparticle form (such as niosomes or liposomes) or suspended or dissolved. In addition, they can be delivered using iontophoresis, electroporation, sonophoresis (sonophoresis), and needle-free injection.

The hydrates of the present invention as described above may also be used in combination with cyclodextrins. Cyclodextrins are known to form inclusion and non-inclusion complexes with drug molecules. The formation of drug-cyclodextrin complexes can alter the solubility, dissolution rate, bioavailability, and/or stability properties of the drug molecule. Drug-cyclodextrin complexes are generally useful in most dosage forms and routes of administration. As an alternative to direct complexation with the drug, cyclodextrins may be used as an auxiliary additive, e.g. as a carrier, diluent or solubiliser. alphA-, betA-and gammA-cyclodextrins are most commonly used, and suitable examples are described in WO-A-91/11172, WO-A-94/02518 and WO-A-98/55148.

The compounds of the invention can be prepared as follows:

scheme 1

Surprisingly, it has been found that darifenacin can be obtained in pharmaceutically pure form from a solution of darifenacin, which is subjected to a resin treatment and then converted to the hydrate via a toluene solvate (see steps a and B in scheme 1). Darifenacin toluene solvate can be converted directly to the hydrobromide salt, but this conversion does not allow the manufacturer flexibility in terms of schedule, since toluene solvate is unstable during medium to long term storage. This additional burden on the manufacturing process can be overcome by converting the darifenacin toluene solvate to darifenacin hydrate, which is stable for a long period of time, and thus, can be converted to darifenacin hydrobromide when needed, without fear of a quality decline of compound (IX) during this time.

The present invention therefore further provides a process for providing a hydrate of the invention as described above in pharmaceutically pure form by resin treatment of darifenacin, followed by conversion to a toluene solvate, followed by conversion of the toluene solvate to the hydrate. A solution of darifenacin in a suitable organic solvent or water-organic solvent mixture is mixed with the resin and the resulting mixture is stirred between ambient and reflux temperatures. Subsequently, the darifenacin solution was separated from the resin by filtration. Preferably the resin is a quaternary ammonium hydroxide resin. The resin treatment may be carried out in batch mode or in continuous process mode. The hydrate can be further refined to obtain the acid addition salt of darifenacin. Preferably the acid addition salt is the hydrobromide salt.

Furthermore, the present invention also provides a novel intermediate in the form of darifenacin toluene solvate, useful for providing the hydrate of the present invention as described above. It is understood that other solvates of darifenacin, such as ethyl acetate solvate, may be used in place of toluene solvate.

X-ray crystallography has shown that: compound (VIII) has a 1: 1 stoichiometric ratio, i.e., 1 molecule of darifenacin and 1 molecule of toluene in the asymmetric unit.

The compounds of the formula (VIII) are characterized by an infrared spectrum using a single reflection ATR (attenuated Total reflection) at the following v_max(cm^-1) Shows a significant absorption band: 3463. 3342, 3299, 3285, 3022, 2925, 2825, 1673, 1614, 1490, 1440, 1384, 1333, 1319, 1243, 1195, 1152, 1130, 1115, 1102, 1028, 1003, 980, 939, 926, 907.

The compound can also be characterized by an X-ray powder diffraction pattern obtained using copper radiation (λ ═ 0.15405nm) showing the main peaks at the following 2 θ angles: 12.572, 12.754, 15.978, 17.419, 18.537, 18.889, 20.78, 21.562, 22.437, 22.736, 23.767, 24.075, 24.266, 25.35, 25.762, 27.214, and 29.716 degrees.

The compounds are further characterized by their Differential Scanning Calorimetry (DSC) curve, which shows a steep endothermic peak at 92 ℃ at a scanning rate of 20 ℃/min.

The following examples illustrate the preparation of the compounds disclosed in scheme 1:

example 1:

(S) -2, 2-Diphenyl-2- (3-pyrrolidinyl) acetonitrile hydrobromide (II)

A mixture of (S) -2, 2-diphenyl-2- (1-toluenesulfonyl-3-pyrrolidinyl) acetonitrile (I) [ see European patent publication 0388054] (83.8kg, 201.2mol), 48% aqueous hydrobromic acid (419L, 5L/kg of Compound 1) and phenol (16.8kg, 0.2kg/kg of Compound I) was heated under reflux for 3 hours. The mixture was cooled and extracted with dichloromethane (1 × 560kg, 1 × 523 kg). The extracts were combined and washed with aqueous sodium chloride (15kg in 150kg water). The organic layer was concentrated and replaced with ethyl acetate essentially to a total volume of about 440L. Hexane (276kg) was added at 40 ℃ and the product was collected by filtration at 0-5 ℃. (S) -2, 2-diphenyl-2- (3-pyrrolidinyl) acetonitrile hydrobromide was washed with cold ethyl acetate and dried under vacuum at 60 ℃. Yield: 52.8kg (76%).

ν＝3441，2940，2745，2455，2246，1972，1886，1806，1596，1585，1561，1494，1450，1392，1289，1255，1217，1159，1104，1070，1034，1002，967，917，899，833，766，750，702，664，645，546，496，472cm^-1。

¹HMR(300MHz，CDCl₃): δ ═ 2.12(2H, m), 3.15(1H, m), 2.96(3H, m), 3.76(1H, quintuple, J8 Hz), 7.25-7.41(6H, m), 7.47(4H, t, J8 Hz), 9.23(1H, br.s), 9.43(1H, br).

LRMS (electrospray, positive ion): m/z [ MH⁺]263。

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝-55.9°

Example 2

(S) -3- (Cyanodiphenylmethyl) -1- [2- (2, 3-dihydrobenzofuran-5-yl) acetyl ] pyrrolidine (IV)

To a cooled (0-5 ℃) slurry of 2- (2, 3-dihydrobenzofuran-5-yl) acetic acid (III) (9.85kg, 55.3mol) in ethyl acetate (115L) was added carbonyldiimidazole (8.97kg, 55.3 mol). The reaction was stirred at 5-10 ℃ for 1 hour, then (S) -2, 2-diphenyl-2- (3-pyrrolidinyl) acetonitrile hydrobromide (II) (17.25kg, 50.2mol) was added. The reaction was allowed to warm to 20-25 ℃ and stirred for an additional 3 hours. The reaction mixture was washed with 2N aqueous hydrochloric acid (42L) followed by aqueous sodium bicarbonate (2.1kg in 42L water). The ethyl acetate solution was concentrated and substantially replaced with toluene to give a total volume of product in toluene of about 43L. The yield of (S) -3- (cyanodiphenylmethyl) -1- [2- (2, 3-dihydrobenzofuran-5-yl) acetyl ] pyrrolidine was assumed to be 100% (21.2kg) and was used directly for the preparation of compound V.

ν＝3448，3059，3026，2973，2948，2878，2236，1959，1890，1811，1719，1643，1600，1491，1449，1421，1362，1336，1297，1241，1219，1198，1159，1125，1102，1034，1002，983，944，917，892，836，804，764，752，701，667，646，618，576，550，469，424，405cm^-1。

For this compound, there are two structural configurations that produce some resonant "doublet-up" signal.¹HMR(300MHz，CDCl₃)：δ＝1.85-2.20(2H，m)，3.16&3.18(2H，t，J 9Hz)，3.20-3.85(7H，m)，4.54&4.55(2H，t，J 9Hz)，6.68&6.70(1H，d，J 9Hz)，6.83&6.94(1H，d，J 9Hz)，7.05&7.12(1H，s)，7.22-7.48(10H，m)。

LRMS (electrospray, positive ion): m/z [ MH⁺]423。

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝+85.9°

Example 3

(S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetonitrile (V)

To a toluene solution of (S) -3- (cyanodiphenylmethyl) -1- [2- (2, 3-dihydrobenzofuran-5-yl) acetyl ] pyrrolidine (IV) (7.43kg of active ingredient, 17.59mol) and a cooled (0 ℃) mixture of sodium borohydride (0.87kg, 23mol) in tetrahydrofuran (29.7L) was added boron trifluoride tetrahydrofuran complex (4.31kg, 30.81mol) at a rate to maintain the reaction temperature below 10 ℃. The reaction was warmed to ambient temperature and stirred for an additional 4 hours. Aqueous piperazine solution was added and the mixture was heated to reflux for 8 hours. The aqueous layer was separated and washed with 1% aqueous sodium chloride (22.3L) at 40 ℃. The organic layer was concentrated at atmospheric pressure and replaced with isopropanol substantially to a total volume of about 30L. The product crystallized on cooling and was collected by filtration at 0-5 ℃. (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetonitrile (V) was washed with cold isopropanol and dried under vacuum at 50 ℃. Yield: 6.34kg (88%).

ν＝3441，3088，3056，3032，2947，2924，2884，2856，2790，2744，2237，1955，1883，1809，1614，1596，1489，1448，1385，1353，1338，1322，1290，1245，1216，1195，1148，1130，1101，1076，1033，1016，1003，980，944，921，891，847，819，799，764，750，701，674，658，646，573，563，540，504，491，427，403cm^-1。

¹HMR(300MHz，CDCl₃)：1.86(1H，m)，2.10(1H，m)，2.38(1H，t，J 9Hz)，2.52(1H，q，J 8Hz)，2.59-2.75(4H，m)，2.84(1H，m)，3.02(1H，dt，J 4&9Hz)，3.16(2H，t，J 9Hz)，3.47(1H，m)，4.53(2H，t，J 9Hz)，6.67(1H，d，J 8Hz)，6.90(1H，d，J 8Hz)，7.00(1H，s)，7.23-7.40，(6H，m)，7.46(4H，t，J 8Hz)。

LRMS (electrospray, positive ion): m/z [ MH⁺]409。

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝+31.8°

Example 4

(S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetonitrile hydrobromide (VI)

To a slurry of (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetonitrile (V) (30.0g, 0.073mol) in methanol (150mL) was added 48% aqueous hydrobromic acid (13.6g, 0.081mol), maintaining the temperature below 40 ℃. The mixture was heated to reflux for 1 hour. The batch was cooled to 0 ℃ and the product collected by filtration, washed with methanol (60mL) and dried under vacuum at 50 ℃ to give (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetonitrile hydrobromide (VI) (33.5g, 93%).

ν＝3440，3059，3002，2931，2893，2856，2653，2624，2548，2496，2471，2239，1960，1888，1812，1615，1599，1493，1450，1394，1363，1332，1294，1242，1159，1129，1106，1088，1073，1035，1003，981，941，889，830，766，751，725，703，666，645，582，548，534，500，476，423cm^-1。

¹HMR(300MHz，CDCl₃)：2.08(1H，m)，2.46(1H，m)，2.75(1H，q，J10Hz)，2.69-3.33(7H，m)，3.70(1H，m)，3.83(1H，m)，4.09(1H，m)，4.54(2H，t，J 9Hz)，6.69(1H，d，J 8Hz)，6.92(1H，d，J 8Hz)，7.06(1H，s)，7.27-7.50(10H，m)，12.08(1H，br)。

LRMS (electrospray, positive ion): m/z [ MH⁺]409。

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝+90.0°

Example 5

(S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide toluene solvate (VIII)

The method comprises the following steps: a slurry of potassium hydroxide (48.7g, 0.87mol) in 2-methylbutan-2-ol (175mL) was heated at 50-60 ℃. After 1 hour, (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] was added]-3-pyrrolidinyl } -2, 2-diphenylacetonitrile hydrobromide (VI) (25.0g, 0.051mol), and the resulting mixture was heated under reflux for 20 hours. The reaction mixture was cooled to ambient temperature and water (125mL) was added, maintaining the temperature below 30 ℃. The mixture was stirred for 15 minutes, then allowed to stand and the organic phase separated. The organic phase was washed with aqueous sodium chloride (125mL of a 5 wt% solution) to give (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl]-a solution of 3-pyrrolidinyl } -2, 2-diphenylacetamide (VII) in 2-methylbutan-2-ol. The solution was placed in Amberlite^®The resin (37.5g) was heated to reflux in the presence of heat for 22 hours and then cooled to ambient temperature. Filtration to remove Amberlite^®The resin was washed with 2-methylbutan-2-ol (25 mL). The combined 2-methylbutan-2-ol phases were concentrated and replaced with toluene essentially to a final volume of about 140 mL. The toluene solution was cooled to 0 ℃ during which crystallization occurred. (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] ethyl is collected by filtration]-3-pyrrolidinyl } -2, 2-diphenylAcetamide toluene solvate (VIII), washed with cold toluene (25mL) and dried under vacuum at 35 ℃. Yield (22.2g, 84%).

The method 2 comprises the following steps: a slurry of potassium hydroxide (40g, 0.71mol) in 2-methylbutan-2-ol (140mL) was heated at 50-60 ℃. After 1 hour, (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] was added]-3-pyrrolidinyl } -2, 2-diphenylacetonitrile (V) (20g, 0.049mol) and heating the resulting mixture to reflux for about 20 hours. The reaction mixture was cooled and water (100mL) was added, maintaining the temperature below 34 ℃. The mixture was stirred for 30 minutes and the organic phase was separated. The organic phase was washed with aqueous sodium chloride (100mL of 5 wt% solution) to give a solution of the product in 2-methylbutan-2-ol. The solution was placed in Amberlite^®The resin (30g) was heated to reflux for 9 hours and then cooled to ambient temperature. Filtration to remove Amberlite^®The resin was washed with 2-methylbutan-2-ol (20 mL). The combined 2-methylbutan-2-ol phases were concentrated and replaced with toluene essentially to a final volume of about 80 mL. The toluene solution was cooled to 0 ℃ during which crystallization occurred. (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] ethyl is collected by filtration]-3-pyrrolidinyl } -2, 2-diphenylacetamide toluene solvate (VIII), washed with cold toluene (70mL) and dried under vacuum at 35 ℃. Yield (17.2g, 68%).

ν＝3463，3342，3299，3285，3022，2925，2825，1673，1614，1490，1440，1384，1333，1319，1243，1195，1152，1130，1115，1102，1028，1003，980，939，926，907cm^-1。

¹HMR(300MHz，d⁶-DMSO): δ 1.57(1H, m); 1.93(2H, m); 2.3-2.5(6H, m); 2, 82(1H, t, J9); 3.11(2H, t, J9); 3.62(1H, m); 4.47(2H, t, J9); 6.62(1H, d, J8); 6.82(1H, d, J8); 6.99(1H, s); 7.08(2H, m); 7.2-7.4(10H, m). A signal corresponding to toluene in a molar ratio of 1 was observed at 2.3 and was located in (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl]Below the aromatic region of-3-pyrrolidinyl } -2, 2-diphenylacetamide.

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝-119.0°

Example 6

(S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide hydrate (IX)

A solution of (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide toluene solvate (VIII) (16g, 0.031mol) in acetonitrile (320mL) was concentrated at ambient temperature under reduced pressure. The resulting foam was dissolved in acetonitrile (48mL) and water (1.1mL) was added dropwise thereto at ambient temperature. The solution was stirred at ambient temperature until crystallization occurred and stirred overnight. (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide hydrate (IX) was collected by filtration and dried under vacuum at ambient temperature. Yield (10.4g, 76%).

ν＝3625，3516，3440，2948，2806，1699，1622，1597，1578，1488，1471，1445，1378，1353，1325，1312，1280，1242，1196，1152，1119，1102，1086，1024，981，939，925，900cm^-1。

¹HMR(300MHz，d⁶-DMSO)：δ＝1.57(1H，m)，1.93(2H，m)，2.3-2.5(6H，m)，2，82(1H，t，J 9)，3.11(2H，t，J 9)，3.62(1H，m)，4.46(2H，t，J 9)，6.62(1H，d，J 8)，6.81(1H，d，J 8)，6.99(1H，s)，7.07(2H，m)，7.2-7.4(10H，m)。

Karl Fischer water content: 2.7% by weight

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝-120.7°

Example 7

(S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide hydrobromide (X)

The method comprises the following steps: a solution of (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide toluene solvate (VIII) (30.4g, 0.059mol) in butan-2-one (213mL) was warmed to 33 ℃ to give a solution, which was then cooled to 15 ℃. Then 48% aqueous hydrobromic acid (9.9g, 0.059mol) was added and the mixture was stirred at 15 ℃ for 1 hour and at 0 ℃ for 2 hours. (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide hydrobromide (X) was collected by filtration, washed with butan-2-one (65mL) and dried under vacuum at 50 ℃ for 18 h. Yield (24.6g, 83%).

The method 2 comprises the following steps: to a solution of (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide hydrate (IX) (3.60g, 0.0081mol) in butan-2-one (30mL) was added 48% aqueous hydrobromic acid (1.36g, 0.0081 mol). The mixture was stirred at 20 ℃ for 1 hour and at 0 ℃ for 1 hour. (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide hydrobromide (X) was collected by filtration, washed with butan-2-one (10mL) and dried under vacuum at 50 ℃ for 18 h. Yield (3.90g, 95%). m.p. 232 ℃.

ν＝3468，3211，3052，2995，2870，2693，2586，1668，1585，1492，1442，1243，983，850cm^-1。

¹HMR(300MHz，CDCl₃)：δ＝2.10-2.23(1H，m)，2.81-2.99(2H，m)，3.00-3.15(4H，m)，3.15(2H，t)，3.18-3.29(1H，m)，3.48(1H，t)，3.69(1H，s)，3.80-3.95(1H，m)，4.52(2H，t)，5.58(1H，bs)，5.62(1H，bs)，6.63(1H，d)，6.84(1H，d)，7.01(1H，s)，7.19-7.40(10H，m)，11.48(1H，bs)。

Optical rotation: [ alpha ] to]₃₆₅ ²⁵＝+46.0°

Claims (21)

1. A stable solid hydrate of darifenacin, having a stoichiometric ratio of darifenacin to water of from 1: 0.6 to 1: 1.

2. A hydrate according to claim 1, having the following formula (IX):

3. according to claimThe hydrate of claim 1 or 2, characterized by an infrared spectrum using single reflection ATR (attenuated total reflection) at the following ν_max(cm^-1) Shows a significant absorption band: 3625. 3516, 3440, 2948, 2806, 1699, 1622, 1597, 1578, 1488, 1471, 1445, 1378, 1353, 1325, 1312, 1280, 1242, 1196, 1152, 1119, 1102, 1086, 1024, 981, 939, 925, 900.

4. A hydrate according to claim 1 or 2, characterised by an X-ray powder diffraction pattern obtained using copper radiation (λ ═ 0.15405nm) which shows the main peaks at the following 2 Θ angles: 8.39, 10.519, 13.272, 13.693, 15.908, 16.289, 16.855, 19.637, 21.135, 21.55, 21.722, 23.006 and 26.284 degrees.

5. A hydrate according to claim 1 or 2, characterized by a Differential Scanning Calorimetry (DSC) curve which shows a steep endothermic peak at a scanning rate of 20 ℃/min at 101 ℃.

6. A pharmaceutical composition comprising a hydrate according to any preceding claim and a pharmaceutically acceptable excipient, diluent or carrier.

7. Use of a hydrate according to any one of claims 1 to 5 in the manufacture of a medicament for the therapeutic or prophylactic treatment of a medical condition for which a muscarinic receptor antagonist is indicated.

8. Use according to claim 7, wherein the medical condition is selected from irritable bowel syndrome, diverticulosis, esophageal achalasia, chronic obstructive airway disease, overactive bladder, urinary incontinence, neurogenic or pollakiuria, treatment of bladder dysfunction, urinary leakage, pain or difficulty in urination caused by neurogenic, spastic or hypertonic bladders, dysfunctional bladder syndrome, gastrointestinal disorders and relaxation effects on smooth muscle cells of the intestine.

9. Use according to claim 8, for the preparation of a medicament for the therapeutic or prophylactic treatment of the symptoms of urinary incontinence, urgency and frequency of overactive bladder.

10. Use according to claim 8 for the preparation of a medicament for the therapeutic or prophylactic treatment of gastrointestinal hyperactivity.

11. Use according to any one of claims 7 to 10, wherein the medicament is suitable for topical transdermal administration.

12. Use according to any one of claims 7 to 10, wherein the medicament is suitable for buccal administration.

13. A solvate of darifenacin of formula (VIII):

14. the solvate according to claim 13 characterized by an infrared spectrum using single reflection ATR (attenuated total reflection) at the following ν_max(cm^-1) Shows a significant absorption band: 3463. 3342, 3299, 3285, 3022, 2925, 2825, 1673, 1614, 1490, 1440, 1384, 1333, 1319, 1243, 1195, 1152, 1130, 1115, 1102, 1028, 1003, 980, 939, 926, 907.

15. A solvate according to claim 13 or claim 14 characterised by an X-ray powder diffraction pattern obtained using copper radiation (λ ═ 0.15405nm) which shows the main peaks at the following 2 Θ angles: 12.572, 12.754, 15.978, 17.419, 18.537, 18.889, 20.78, 21.562, 22.437, 22.736, 23.767, 24.075, 24.266, 25.35, 25.762, 27.214, and 29.716 degrees.

16. The solvate according to claim 13 or 14, characterized by a Differential Scanning Calorimetry (DSC) curve which shows a steep endothermic peak at a scanning rate of 20 ℃/min at 92 ℃.

17. The solvate according to claim 15, characterized by a Differential Scanning Calorimetry (DSC) curve which shows a sharp endothermic peak at a scan rate of 20 ℃/min at 92 ℃.

18. A process for providing a solvate of formula (VIII) according to claim 13, comprising subjecting (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide to ion exchange resin treatment, followed by mixing with toluene.

19. A process for providing a hydrate as defined in any one of claims 1 to 5 in pharmaceutically pure form, which comprises subjecting (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide to an ion exchange resin treatment, followed by conversion to a toluene solvate, and converting this solvate to the hydrate.

20. A process for providing a darifenacin acid addition salt, comprising converting the hydrate prepared by the process of claim 19 into an acid addition salt of (S) -2- {1- [2- (2, 3-dihydrobenzofuran-5-yl) ethyl ] -3-pyrrolidinyl } -2, 2-diphenylacetamide.

21. The method according to claim 20, wherein said acid addition salt is the hydrobromide salt.