4-(2-METHYL-1 H-IMIDAZOL-1 -YL)-2,2-DIPHENYLBUTANENITRILE SOLID FORM

FIELD OF THE INVENTION

The present invention relates to a solid form of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile phosphate intermediate and its use for preparing imidafenacin, and an improved process for preparing 4-(2-methyl-1-imidazolyl)-2,2- diphenylbutanamide, also known as imidafenacin, in good yield and purity using said solid form. BACKGROUND

Imidafenacin, the compound of formula (I), is an antimuscarinic agent marketed in Japan under the brand name Uritos® used to treat overactive bladder, a disease defined by the presence of urinary urgency, usually accompanied by frequency and nocturia, with or without urge incontinence. Overactive bladder dysfunction has a considerable impact on patient quality of life, although it does not affect survival.

(I)

Synthesis of 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide is first disclosed in Japanese patent JP3294961 B2 as shown in Scheme 1 . 4-bromo-2,2- diphenylbutanenitrile (II) is reacted with three equivalents of 2-methylimidazol, in dimethylformamide and in the presence of triethylamine as a base, to afford 4-(2- methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile, compound of formula (III), which is purified by column chromatography and, further, converted into its hydrochloride salt and recrystallized. Then, compound (III) is hydrolyzed with an excess of 70% sulfuric acid at 140-150 °C, followed by basification and recrystallization to provide imidafenacin (I), in an overall yield of only 25% (as calculated by data provided in docume

(III) (I)

Scheme 1 This route of document JP3294961 B2 implies several drawbacks. Firstly, purification of intermediate (III) is carried out by means of chromatographic methods, which are generally expensive, environmentally unfriendly and time consuming. Secondly, the hydrolysis of the nitrile group is carried out under strong acidic conditions and high temperature not convenient for industrial application.

Japanese document JP2003-201281 discloses a process for preparing imidafenacin as shown in Scheme 2. 4-bromo-2,2-diphenylbutanenitrile (II) is reacted, with five equivalents of 2-methylimidazol, which acts also as a base, in dimethylsufoxide to provide intermediate (III), which after an isolation step is further reacted with phosphoric acid in ethanol to provide the phosphate salt of 4-(2-methyl-1 H-imidazol-1- yl)-2,2-diphenylbutanenitrile. Hydrolysis with potassium hydroxide, followed by purification with a synthetic adsorbent provides imidafenacin (I) in a moderate overall yield

(II) (I)

Scheme 2

The use of a synthetic adsorbent is associated with problems with operativities and purification efficiencies from the viewpoint of industrial production, therefore, the process disclosed in document JP2003-201281 is not suitable for industrial application.

EP1845091 A1 discloses a process for preparing imidafenacin, according to previous document JP2003-201281 , however the purification step is carried out by either preparing the hydrochloride or the phosphate salt of imidafenacin followed by neutralization as shown in Scheme 3. Purified imidafenacin is provided in low yield, overall yield of about 31 % (as calculated by data provided in document EP1845091 A1 ). This process has several disadvantages. Firstly, EP1845091 A1 states that the penultimate intermediate, the 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate is hygroscopic, which implies handling problems. Secondly, the additional steps carried out for purification increases the cost of the final imidafenacin process and the pharmaceutical compositions containing it, which already resulted in expensive medications.

(II) (I)

HCI or

H3PO4

purified (I) HCI or Ή3ΡΟ4

Scheme 3

The intermediate phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile obtained and used in prior art processes is a solid form having needle-shaped crystals, which are difficult to filtrate. Moreover, said needle-shaped crystals are very hygroscopic and unstable and transform over time to other solid forms. In addition, the water absorbed by this solid form described in the prior art may react with the intermediate to generate further impurities.

Therefore, there is still a need to develop an improved industrially feasible process for the manufacture of imidafenacin in good purity and good yield, involving the use of stable intermediates having also improved handling characteristics. BRIEF DESCRIPTION OF THE INVENTION

The inventors have surprisingly found a new solid form of the phosphate salt of 4-(2- methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile having a plate-shaped crystal habit, referred to as Form I, that has improved handling characteristics compared to the prior art needle-shaped crystals. Particularly, the plate-shaped crystals of Form I significantly improve the rate of filtration. In addition, said plate-shaped crystals of Form I are not hygroscopic and are stable over time. Said improved stability and ease of filtration of the new solid form of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate are favorable for large scale production of imidafenacin. Thus, in one aspect the present invention relates to a solid form of the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile, referred to as Form I, characterized by:

i. a powder X-ray diffraction pattern comprising the following characteristic peaks at approximately 1 1 .0, 15.0, 17.2, 20.8 and 25.0 ± 0.2 degrees two theta, and ii. a plate-shaped crystal habit.

In another aspect, the present invention relates to a feasible process for manufacturing 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide, comprising mixing phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form with a base in a molar ratio of at least 1 :4, in the presence of a solvent and water, wherein the molar ratio between the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile and water is of at least 1 :1 , and wherein the phosphate salt of 4- (2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form, referred to as Form I, is characterized by:

i. a powder X-ray diffraction pattern comprising the following characteristic peaks at approximately 1 1 .0, 15.0, 17.2, 20.8 and 25.0 ±0.2 degrees two theta, and ii. a plate-shaped crystal habit. Surprisingly, this process provides imidafenacin in good yield and good purity.

A further aspect of the present invention provides processes for preparing the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid Form I, as defined above.

Still a further aspect of the present invention relates to the use of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid Form I as defined above to manufacture 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamide. BRIEF DESCRIPTION OF THE DRAWINGS

Figure 1 depicts needle-shaped crystals of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile phosphate as obtained in Comparative Example 1.

Figure 2 depicts plate-shaped crystals of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile phosphate as obtained in Example 1. Figure 3 depicts the X-ray powder diffraction pattern of 4-(2-methyl-1 H-imidazol-1-yl)- 2,2-diphenylbutanenitrile phosphate as obtained in Example 1. Figure 4 depicts the thermogram of differential scanning calorimetry of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile phosphate as obtained in Example 1 .

Figure 5 depicts the X-ray single crystal diffraction structure of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile phosphate as obtained in Example 1 .

DEFINITIONS

In the context of the present invention, the following terms have the meaning detailed below: The term "polar solvent" as used herein means a solvent having a dielectric constant of at least 3, said dielectric constant being the ratio of the electrical capacity of a capacitor filled with the solvent to the electrical capacity of the evacuated capacitor at 20-25 °C. The values of dielectric constant of solvents are disclosed in Vogel's Textbook of Practical Organic Chemistry 5 ^th Edition, Appendix 5. Examples of polar solvents are dichloromethane, tetrahydrofuran, ester solvents (e.g., ethyl formate, methyl acetate, ethyl acetate, ethyl malonate, etc.), ketone solvents (e.g., acetone, methyl ethyl ketone or 2-butanone, cyclohexanone, cyclopentanone, 3-pentanone, etc.), amine solvents (e.g., propyl amine, diethylamine , aniline, pyridine), alcohol solvents (e.g., methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1 -butanol, 2-butanol, 1- pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol, etc.), acid solvents (e.g., acetic acid, hexanoic acid, etc.), nitrobenzene, dimethyl sulfoxide, Ν,Ν-dimethylformamide, N,N,-dimethylacetamide, N-methyl-2-pyrrolidone, acetonitrile, and silicone solvents (e.g., silicone oils, polysiloxanes, cyclosilicones). Suitable polar solvents of the present invention are alcohols selected from methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1 -propanol, 1 -butanol, 2-butanol, 1-pentanol, 3- methyl-1 -butanol, tert-butanol, 1-octanol, benzyl alcohol and phenol.

The term "non-polar solvent" as used herein means a solvent having a dielectric constant lower than 3, said dielectric constant being the ratio of the electrical capacity of a capacitor filled with the solvent to the electrical capacity of the evacuated capacitor at 20-25 °C. Examples of non-polar solvents are aromatic hydrocarbons (e.g. toluene, o-xylene, m-xylene and p-xylene), aliphatic hydrocarbons (e.g. n-pentane, n-hexane, n- heptane, n-octane, cyclohexane, methylcyclohexane and decahydronaphthalene).

The term "purification" refers to a process for removing undesired compounds or byproducts which can be carried out on an industrial scale such as solvent extraction, filtration, slurring, washing, phase separation, evaporation, centrifugation or crystallization. In the context of the present invention purification by chromatographic methods are not considered to be capable of being carried out on an industrial scale.

As used herein, the term, "solvent extraction" refers to the process of separating components of a mixture based on their relative solubilites in two different immiscible liquids, usually water and an organic solvent. It is an extraction of a substance from one liquid into another liquid phase by using a solvent which possesses greater affinity for one component, and may therefore separate said one component from at least a second component which is less miscible in said solvent than said one component in the same solvent. The term "filtration" refers to the act of removing solid particles greater than a predetermined size from a feed comprising a mixture of solid particles and liquid. The expression "filtrate" refers to the mixture less the solid particles removed by the filtration process. It will be appreciated that this mixture may contain solid particles smaller than the predetermined particle size. The expression "filter cake" refers to residual solid material remaining on a feed side of a filtration element.

As used herein, the term "slurring" refers to any process which employs a solvent to wash or disperse a crude product. In particular, after slurring, filtration and washing may be performed.

As used herein, the term "washing" refers to the process of purifying a solid mass (e.g., crystals) by passing a liquid over and/or through the solid mass, as to remove soluble matter. The process includes passing a solvent, such as distilled water, over and/or through a precipitate obtained from filtering, decanting, or a combination thereof. For example, in one embodiment of the invention, washing includes contacting solids with solvent or solvent mixture, vigorously stirring (e.g., for two hours), and filtering. The solvent can be water, can be an aqueous solvent system, or can be an organic solvent system. Additionally, the washing can be carried out with the solvent having any suitable temperature. For example, the washing can be carried out with the solvent having a temperature between about 0 °C and about 100 °C.

The term "phase separation" refers to an extraction of one phase from a solution or mixture having at least two physically distinct regions or phases. The term "evaporation" refers to the change in state of solvent from liquid to gas and removal of that gas from the reactor. Generally gas is removed by vacuum. Various solvents may be evaporated during the synthetic route disclosed herein. As known to those skilled in the art, each solvent may have a different evaporation time and/or temperature.

The term "crystallization" refers to any method known to a person skilled in the art such as crystallization from single solvent or combination of solvents by dissolving the compound optionally at elevated temperature and precipitating the compound by cooling the solution or removing solvent from the solution or both. It further includes methods such as solvent antisolvent or precipitation.

The term "polymorphic form" or "polymorph" refers to crystalline forms of the same pure compound in which the molecules have different arrangements and/or different conformation of the molecules. As a result, the polymorphic solids have different unit cells and hence display different physical properties, including those to packing, and various thermodynamic, spectroscopic, interfacial, and mechanical properties.

The term "solvate" refers to solid molecular compounds that have incorporated the crystallizing solvent molecule in their lattice. When the solvent incorporated in the solvate is water, is called hydrate. All solvates are formed with stoichiometric or non- nonstoichiometric proportions between the compound and the solvent of crystallization. Solvates can exhibit polymorphism.

The term "solid form" includes all solid materials, polymorphs, solvates (including hydrates), amorphous solids, salts and cocrystals. The term "habit" or "shape" refers to the outer appearance of a crystal. If the environment of a growing crystal affects its external shape without changing its solid form a different habit results. These alterations are caused by the interference with the uniform approach of the crystallising molecules to the different faces of the crystal. According to the US Pharmacopeia (monograph 776), six basic crystal habits denominated equant, plates, flakes, laths, needles (acicular) and columns (columnar) are described. Many factors may affect the crystal habit such as the temperature, the level of supersaturation, the rate of cooling, the rate of agitation, the nature of the crystallizing solvent (polarity and viscosity), the presence of impurities and the water content.

The term "needle-shaped crystal habit" refers to slender particles of similar width and thickness (according to US Pharmacopeia, monograph 776). A particle is generally considered to be slender when its width is small, (preferably less than 0.2 times, more preferably less than 0.1 times) in relation to the particle's length. A particle is generally considered to have similar width and thickness when the ratio between these two measures is comprised between 0.75 and 1 .25, more preferably between 0.85 and 1.15.

The term "plate-shaped crystal habit" refers to particles having a flat shape of similar length and width but with greater thickness than a flake particle (according to US Pharmacopeia, monograph 776). A particle is generally considered to have similar width and length when the ratio between these two measures is comprised between 0.75 and 1 .25, more preferably between 0.85 and 1.15. A particle is considered to have length and width greater than its thickness when the ratio of each one of these two measures to the particle's thickness is greater than 7, preferably greater than 8.5 and more preferably greater than 10. The term "approximately" means in the context of X-ray diffraction measurements that there is an uncertainty in the measurements of the degrees 2-theta of ± 0.2 (expressed in degrees 2-theta). The term "approximately" means in the context of DSC measurements that the °C values can vary by 2 °C, preferably by 1 °C. DETAILED DESCRIPTION OF THE INVENTION Solid Form I

The inventors have realized that the prior art processes for preparing the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile, produced a different solid form having needle-shaped crystals, which were difficult to filtrate. Moreover, the needle-shaped crystals were very hygroscopic and unstable and transformed over time to other solid forms. It was observed when reproducing the prior art examples of JP2003-201281 and referential example 1 of EP1845091A1 that the 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile phosphate rapidly absorbed water up to 5-6% by weight, after remaining under ambient conditions, and transformed into a hydrate which is also hygroscopic. In addition, the water absorbed may react with the intermediate to generate further impurities. The solid form of 4-(2-methyl-1 H-imidazol- 1-yl)-2,2-diphenylbutanenitrile phosphate of the present invention, referred to as Form I, is non-hygroscopic, stable and easy to handle at industrial scale production. In fact, the solid form of the present invention does not absorb water after remaining at 30 °C ± 2 °C temperature and 50% ± 5% of relative humidity. In addition, the solid form of the present invention does not show polymorphic changes, in other words, remains polymorphically and chemically stable over a period of time, for at least 80 days at ambient conditions. Advantageously, the plate-shaped crystals of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile phosphate in solid form according to the present invention, referred as Form I, have significantly improved handling characteristics compared to the prior art needle-shaped crystals. Particularly, the plate- shaped crystals of Form I according to the present invention significantly improve the rate of filtration. Therefore, the improved stability and ease of filtration of the new solid form of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile phosphate are favorable for large scale production of imidafenacin.

One aspect of the present invention provides the phosphate salt of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form, referred to as Form I, characterized by:

i. a powder X-ray diffraction pattern comprising the following characteristic peaks at approximately 1 1 .0, 15.0, 17.2, 20.8 and 25.0 ±0.2 degrees two theta, and ii. a plate-shaped crystal habit. In one embodiment, the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile in solid form according to the present invention, referred to as Form I, is further characterized by:

i. a powder X-ray diffraction pattern comprising the following characteristic peaks at approximately 4.7, 10.0, 1 1.0, 14.7, 15.0, 16.9, 17.2, 20.8 and 25.0 ±0.2 degrees two theta, and

ii. a plate-shaped crystal habit.

In one embodiment, the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitnle in solid form according to the present invention, referred to as Form I, is further characterized by i) a powder X-ray diffraction pattern (PXRD), wherein the interplanar distance values are at approximately the values shown in detail in table 1 , and Table 1.-List of selected peaks obtained by PXRD of the phosphate salt of 4-(2-methyl- 1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form I.

Angle 2Θ (°) (±0.2) d value (A)

4.7 18.82

9.5 9.29

10.0 8.83

1 1.0 8.02

13.7 6.44

14.3 6.18

14.7 6.01

15.0 5.91

16.5 5.37

16.9 5.24

17.2 5.16

17.7 5.02

19.0 4.66

19.6 4.52

20.2 4.40

20.8 4.26

21.9 4.06

22.2 3.99

22.4 3.97 23.8 3.74

24.0 3.70

24.6 3.61

25.0 3.55

26.0 3.42 ii. a plate-shaped crystal habit.

In one embodiment, the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by i) a powder X-ray diffraction pattern (PXRD), wherein the interplanar distance values and relative intensity (in percentage) are at approximately the values shown in detail in table 2, and Table 2.- List of selected peaks obtained by PXRD of the phosphate salt of 4-(2- methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form I.

Angle 2Θ (°) (±0.2) d value (A) Rel. Int. [%]

4.7 18.82 29.4

9.5 9.29 7.5

10.0 8.83 14.7

1 1.0 8.02 25.5

13.7 6.44 5.5

14.3 6.18 9

14.7 6.01 16.2

15.0 5.91 47.1

16.5 5.37 6.1

16.9 5.24 16.9

17.2 5.16 100

17.7 5.02 9.7

19.0 4.66 25.4

19.6 4.52 25.1

20.2 4.40 30.3

20.8 4.26 54.3

21.9 4.06 13.9

22.2 3.99 6.6

22.4 3.97 7.8 23.8 3.74 5.2

24.0 3.70 19.7

24.6 3.61 19.6

25.0 3.55 29.9

26.0 3.42 1 1.2 ii. a plate-shaped crystal habit.

The term "approximately" means in this context of PXRD intensity measurements that there is an uncertainty in the measurements of the relative intensities. It is known to the person skilled in the art that the uncertainty of the relative intensities depends strongly on the measurement conditions. The relative intensity values can e.g. vary by 30%.

In addition to the previous embodiments, the phosphate salt of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by having a PXRD pattern substantially in accordance to figure 3.

In addition to the previous embodiments, the phosphate salt of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by a DSC thermogram showing an endothermic peak with an onset at approximately 176-178 °C. The term "approximately" means in the context of DSC measurements that the °C values can vary by 2 °C, preferably by 1 °C.

In addition to the previous embodiments, the phosphate salt of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by a DSC thermogram substantially in accordance to figure 4. In addition to the previous embodiments, the solid form of the phosphate salt of 4-(2- methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile of the invention, Form I, is further characterized by a monoclinic unit cell with the following dimensions:

a = 20.002(5) A

b = 6.2767(16) A

c = 17.469(5) A

a = 90° β = 1 14.0°

γ = 90°

In addition to the previous embodiments, the phosphate salt of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by a monoclinic unit cell substantially in accordance to figure 5.

In addition to the previous embodiments, the phosphate salt of 4-(2-methyl-1 H- imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by having a D90 particle size between 10 μηη and 300 μηη. Preferably, the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by having a D90 particle size between 30 μηη and 300 μηη. More preferably, the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by having a D90 particle size between 50 μηη and 300 μηη. Even more preferably, the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in solid form according to the present invention, Form I, is further characterized by having a D90 particle size between 80 μηη and 300 μηη.

Particle size parameters, D90, measured in the present invention have been obtained by means of dry particle sizing SympaTec according to the description provided in the general methods of the examples.

Preferably, the percentage of other polymorphic forms or solvates of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile present in Form I is below 20%, i.e. the solid form prepared in accordance with this invention contains less than about 20% of other polymorphic forms or solvates as measured by different analytical methods, preferably by powder X-ray diffraction (PXRD). Preferably, the percentage of other polymorphic forms or solvates present in Form I is below 10%, wherein the solid form prepared in accordance with this invention contains less than about 10% of other polymorphic forms or solvates as measured by PXRD. More preferably, the percentage of other polymorphic forms or solvates present in Form I is below 5%, wherein the solid form prepared in accordance with this invention contains less than about 5% of other polymorphic forms or solvates as measured by PXRD.

Thus, in another aspect, the present invention relates to a mixture comprising at least 80% by weight of the solid Form I of the phosphate salt of 4-(2-methyl-1 H-imidazol-1- yl)-2,2-diphenylbutanenitrile as defined herein and less than 20% by weight of other polymorphic forms or solvates of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)- 2,2-diphenylbutanenitrile, wherein the amounts by weight are expressed with respect to the total weight of the mixture. Preferably, said mixture comprises at least 90 % by weight of the solid Form I of the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile as defined herein and less than 10% by weight of other polymorphic forms or solvates of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)- 2,2-diphenylbutanenitrile, wherein the amounts by weight are expressed with respect to the total weight of the mixture. More preferably, at least 95% by weight of the solid Form I of the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile as defined herein and less than 5% by weight of other polymorphic forms or solvates of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile, wherein the amounts by weight are expressed with respect to the total weight of the mixture. Use of solid Form I of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in a process for manufacturing 4-(2-methyl-1-imidazolyl)-2,2- diphenylbutanamide.

The inventors have surprisingly found a feasible process for the manufacture of imidafenacin in good purity and good yield which involves the use of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I.

Thus, another aspect of the present invention relates to a feasible process for manufacturing 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide, comprising mixing the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form according to the present invention which has been described above, Form I, with a base, in a molar ratio between the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)- 2,2-diphenylbutanenitrile and the base of at least 1 :4, in the presence of a solvent and water, wherein the molar ratio between the phosphate salt of 4-(2-methyl-1 H-imidazol- 1-yl)-2,2-diphenylbutanenitrile and water is of at least 1 :1.

Suitable bases are alkali metal or alkaline earth metal hydroxides. Examples of alkali metal hydroxides are sodium, potassium, lithium and caesium hydroxides. Examples of alkaline earth metal hydroxides are magnesium and calcium hydroxides. Preferably, the base is alkali metal hydroxide selected from sodium, potassium hydroxide and mixtures thereof. The molar ratio between the solid form of 4-(2-methyl-1 H-imidazol-1- yl)-2,2-diphenylbutanenitrile phosphate, Form I, and the base is of at least 1 :4. Preferably, the molar ratio between the solid form of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile phosphate, Form I, and the base is of at least 1 :7, whereby the hydrolysis rate is significantly increased. A molar ratio higher than 1 :15 would still work but it would represent a higher cost from an industrial point of view. Suitable solvents used in the first aspect of the present invention may be organic solvents selected from polar solvents, non-polar solvents and mixtures thereof. Suitable polar solvents include, but are not limited to alcohols, ethers, nitrobenzene, dimethylsulfoxide and silicone solvents. Examples of alcohol solvents are methanol, ethanol, isopropanol, 1-propanol, 2-methyl-1-propanol, 1 -butanol, 2-butanol, 1- pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol and m-cresol. Suitable ethers include diethyl ether, dipropyl ether, diphenyl ether, diisopropyl ether, tert-butyl methyl ether and tetrahydrofuran. Examples of silicone solvents are silicone oils, polysiloxanes and cyclosilicones. Suitable non-polar solvents include but are not limited to aromatic hydrocarbons, aliphatic hydrocarbons and ethers such as dioxane. Examples of aromatic hydrocarbons are toluene, o-xylene, m-xylene and p-xylene. Examples of aliphatic hydrocarbons are n-pentane, n-hexane, n-heptane, n-octane, cyclohexane, methylcyclohexane and decahydronaphthalene. Preferably, the suitable solvents are polar solvents. Preferably, the polar solvents are alcohols selected from methanol, ethanol, isopropanol, 1 -propanol, 2-methyl-1- propanol, 1-butanol, 2-butanol, 1-pentanol, 3-methyl-1 -butanol, tert-butanol and 1 - octanol and mixtures thereof. More preferably, the polar solvent is methanol, ethanol, isopropanol and mixtures thereof. Preferred polar solvents are ethanol, isopropanol and mixtures thereof. The amount of solvent used to the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in solid form according to the present invention would be of at least 0.15 L per mol of the phosphate salt. Suitable amounts of solvent may be from 0.15 L per mol of the phosphate salt up to 10 L per mol of the phosphate salt according to the present invention.

The molar ratio between the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile in solid form according to the present invention which has been described above, Form I, and water is of at least 1 :1 . Ratios of the phosphate salt of 4- (2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form according to the present invention to water even up to 1 :50 can also be used. Water can be added to the reaction mixture or may be contained in commercial base or in polar solvents. Usually, commercially alkali metal or alkaline earth metal hydroxides may contain water. In addition, polar solvents may also contain certain amount of water.

The hydrolysis reaction of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in solid form according to the present invention which has been described above, Form I, with a base can be carried out from room temperature to reflux temperature of the solvent. Preferably, the reaction is carried out at reflux temperature of the solvent, between 75 °C and 95 °C, as the hydrolysis reaction rate is significantly increased.

4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide can be effectively separated and purified by employing conventional techniques known in the art such as solvent extraction, phase separation, filtration, washing, evaporation, centrifugation or crystallization. Then, the desired compound may be filtered and washed with a polar solvent selected from alcohols, water and mixtures thereof. Moreover, 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide, also known as imidafenacin, may be further purified by conventional crystallization techniques and/or by transforming it into a salt form. Suitable salts are salts of oxalic acid. Preferably, imidafenacin is purified by crystallization in polar solvents, water or mixtures thereof. Preferably, the polar solvent is an alcohol selected from methanol, ethanol, and isopropanol. Another aspect of the present invention relates to the use of the solid Form I of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile as described above to manufacture imidafenacin.

Preparation of solid Form I of the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2- diphenylbutanenitrile

Another aspect of the present invention provides a process for the preparation the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, comprising the steps of:

i. providing a slurry of a phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in a solvent,

ii. heating the slurry at a temperature from at least 75 °C and up to the reflux temperature of the solvent,

iii. optionally, seeding the mixture of step ii) with Form I of the phosphate salt of 4- (2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile,

iv. maintaining the slurry at a temperature of step ii) for at least 30 min, decreasing the temperature of the mixture of step iv) to a temperature from 25 °C to 0 °C,

isolating the solid form obtained in step v), and

optionally, washing and drying the solid form obtained in step vi).

The phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile used in step i) can be any polymorphic form, solvates (including hydrates), amorphous form or can be prepared according to prior art documents JP2003-201281 and EP1845091A1.

Suitable solvents used in step i) according to the third aspect of the present invention are selected from alcohols, esters, ethers, aromatic hydrocarbons and mixtures thereof. Suitable alcohols are isopropanol, 1 -propanol, 2-methyl-1 -propanol, 1 -butanol, 2-butanol, 1-pentanol, 3-methyl-1-butanol, tert-butanol, 1-octanol, benzyl alcohol, phenol, trifluoroethanol, glycerol, ethylene glycol, propylene glycol, m-cresol and the like. Suitable esters are ethyl acetate, isopropyl acetate, butyl acetate, isobutyl acetate, ethyl malonate and the like. Suitable ethers are dipropyl ether, diphenyl ether, isopropyl ether, 1 ,4-dioxane and the like. Suitable aromatic hydrocarbons are toluene, o-xylene, m-xylene, and p-xylene and the like. Preferably, the solvent used in step i) is selected from isopropanol, isopropyl acetate, 1 ,4-dioxane, toluene and mixtures thereof. More preferably, the solvent used in step i) is isopropanol and isopropyl acetate. The solvents used in step i) must have a water content of less than 3%, preferably less that 1 %.

The temperature used in step ii) is at least 75 °C and up to the reflux temperature of the solvent. In fact, below 75 °C the hygroscopic 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile phosphate of the prior art is obtained. Thus, the temperature of step ii) is crucial for preparing the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in solid form I free from other polymorphic forms. More preferably, the temperature used in step ii) is of at least 80 °C.

The phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, may be dried. Drying may be suitable carried out using equipment such as tray dryer, vacuum oven, air oven, fluidized bed dyer, spin flash dryer, flash dryer and the like, at atmospheric pressure or under reduced pressure. Drying may be carried out at temperatures less than about 60 °C. Preferably, the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in solid form according to the present invention, Form I, is dried at a temperature less than about 50 °C. More preferably, the phosphate salt of 4-(2- methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, is dried at 45 °C. Advantageously, the phosphate salt of 4-(2- methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, shows good drying characteristics and thermal stability.

Thus, a preferred embodiment provides a process for the preparation the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, comprising the steps of:

i. providing a slurry of a phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile in a solvent, wherein the solvent is selected from alcohols, esters, ethers, aromatic hydrocarbons and mixtures thereof, ii. heating the slurry at a temperature from at least 75 °C and up to the reflux temperature of the solvent, optionally, seeding the mixture of step ii) with Form I of the phosphate salt of 4-

(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile,

maintaining the slurry at a temperature of step ii) for at least 30 min

decreasing the temperature of the mixture of step iv) to a temperature from 25

°C to 0 °C,

isolating the solid form obtained in step v), and

optionally, washing and drying the solid form obtained in step vi).

A more preferred embodiment provides a process for the preparation the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, comprising the steps of:

i. providing a slurry of a phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2, 2- diphenylbutanenitrile in a solvent, wherein the solvent is selected from alcohols, esters, ethers, aromatic hydrocarbons and mixtures thereof, ii. heating the slurry at a temperature from at least 80 °C,

iii. optionally, seeding the mixture of step ii) with Form I of the phosphate salt of 4- (2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile,

iv. maintaining the slurry at a temperature of step ii) for at least 30 min,

v. decreasing the temperature of the mixture of step iv) to a temperature from 25 °C to 0 °C,

vi. isolating the solid form obtained in step v), and

vii. optionally, washing and drying the solid form obtained in step vi).

Another more preferred embodiment provides a process for the preparation the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, comprising the steps of:

i. providing a slurry of a phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2, 2- diphenylbutanenitrile in a solvent, wherein the solvent is selected from alcohols, esters, ethers, aromatic hydrocarbons and mixtures thereof, ii. heating the slurry at a temperature from at least 80 °C,

iii. seeding the mixture of step ii) with Form I of the phosphate salt of 4-(2-methyl-

1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile,

iv. maintaining the slurry at a temperature of step ii) for at least 30 min

v. decreasing the temperature of the mixture of step iv) to a temperature from 25 °C to 0 °C, vi. isolating the solid form obtained in step v), and

vii. optionally, washing and drying the solid form obtained in step vi).

Another more preferred embodiment provides a process for the preparation the phosphate salt of 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile in solid form according to the present invention, Form I, comprising the steps of:

i. providing a slurry of a phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2, 2- diphenylbutanenitrile in a solvent, wherein the solvent is selected from isopropanol, isopropyl acetate, 1 ,4-dioxane, toluene and mixtures thereof, ii. heating the slurry at a temperature from at least 80 °C,

iii. seeding the mixture of step ii) with Form I of the phosphate salt of 4-(2-methyl-

1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile,

iv. maintaining the slurry at a temperature of step ii) for at least 30 min

v. decreasing the temperature of the mixture of step iv) to a temperature from 25 °C to 0 °C,

vi. isolating the solid form obtained in step v), and

vii. optionally, washing and drying the solid form obtained in step vi).

The present invention also provides another process for the preparation the solid form of the phosphate salt of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile as defined herein, Form I, comprising drying the hydrate of 4-(2-methyl-1 H-imidazol-1 -yl)- 2,2-diphenylbutanenitrile phosphate at a temperature of at least 130 °C. Preferably, the temperature is of at least 140 °C. EXAMPLES

GENERAL METHODS

Optical Microscopy method wherein the microphotographs were obtained using a Canon Power Shot G5 digital camera attached to a Zeiss Stemi SV 1 1 stereomicroscope. The stereomicroscope has a variable amplification in the range between 15X and 154X and is equipped with cross coupled polarization filters (Carl Zeiss Pol 455170 and 455174) and a lambda/2 filter (Carl Zeiss Lambda 455172). For sample illumination a transmission cold light source Zeiss KL2500 LCD was used. The micrographs were taken at 154X magnification. Powder X-Ray diffraction (PXRD) pattern was acquired on a D8 Advance Series 2Theta/Theta powder diffraction system using CuKal -radiation (1 .54056 A) in transmission geometry. The system is equipped with a VANTEC-1 single photon counting PSD, a Germanium monochromator, a ninety positions auto changer sample stage, fixed divergence slits and radial soller. The sample was measured in a 1 hour scan in a range from 4° to 40° in 2Theta.

Differential Scanning Calorimetry analysis (DSC) was recorded in a Mettler Toledo DSC822e calorimeter. Experimental conditions: 40 μΙ_ aluminium crucibles; atmosphere of dry nitrogen at 50 mL/min flow rate; heating rate of 10 °C/min between 30 and 300 °C. Data collection and evaluation was done with software STARe.

Thermogravimetric analysis (TGA) was recorded in a Mettler Toledo SDTA851 e thermobalance. Experimental conditions: 40 μΙ_ aluminium crucibles; atmosphere of dry nitrogen at 80 mL/min flow rate; heating rate of 10 °C/min between 30 and 300 °C. Data collection and evaluation was done with software STARe.

Karl Fischer (KF) analyses were performed in a Metrohm KF Coulometer 831 , equipped with a generator electrode without diaphragm Metrohm 6.0345.100, using as reactive Hydranal coulomat AD.

Dynamic Vapor Sorption Analysis (DVS) experiments were performed in a Mettler Toledo TGA / DSC 1 instrument coupled with a ProUmid Modular Humidity Generator MHG32. The samples (5 - 10 mg) were weighted into 150 μΙ_ aluminium crucibles. Data collection and evaluation was done with STARe software.

X-ray Crystal Structure Determination (SCXRD), the measured crystals were prepared under inert conditions immersed in perfluoropolyether as protecting oil for manipulation. Crystal structure determinations were carried out using a Apex DUO Kappa 4-axis goniometer equipped with an APPEX 2 4K CCD area detector, a Microfocus Source E025 luS using MoKa radiation (0.71073 A), Quazar MX multilayer Optics as monochromator and an Oxford Cryosystems low temperature device Cryostream 700 plus (7 = -173 °C). Full-sphere data collection was used with ω and φ scans. Structure Solution and Refinement: Crystal structure solution was achieved using direct methods as implemented in SHELXTL4 and visualized using the program XP. Missing atoms were subsequently located from difference Fourier synthesis and added to the atom list. Least-squares refinement on F2 using all measured intensities was carried out using the program SHELXTL. All non-hydrogen atoms were refined including anisotropic displacement parameters.

Particle size distribution (PSD) was determined by laser diffraction at 2 bar dispersive pressure using a Sympatec Helos particle size analyzer equipped with an Aspiros feeder and a Rodos dry powder dispersing unit. Comparative Example 1 :

This comparative example is a reproduction of example 1 of JP2003-201281.

Preparation of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate

4-bromo-2,2-diphenylbutanenitrile (II, 100 g, 0.33 mol) and 2-methylimidazol (137 g, 1 .66 mol) were heated in DMSO (80 mL) at 100-105 °C for 7 hours. The solution was then cooled down to 20-25 °C and toluene (200 mL) and water (400 mL) were added and stirred for 30 minutes. After phase separation, the aqueous layer was extracted with toluene (100 mL). Organic layers were combined, washed twice with water (2 x 100 mL) and distilled off. The resulting brown oil was dissolved in absolute ethanol (100 mL) and a solution of orthophosphoric acid (39.1 g, 0.34 mol) in ethanol (200 mL) was added dropwise. Once the addition was finished, the reaction mixture was stirred for 1 hour at room temperature, filtered off, washed with ethanol (100 mL) and dried to provide 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate. Yield 74%. Optical microscopy: needle-shaped crystals as substantially in accordance to Figure 1. DSC (10 °C/min): Broad endothermic peak with a maximum at about 80 °C, exothermic peak with a maximum at about 130 °C and a sharp endothermic peak with a maximum at about 180°C.

TGA (10 °C/min): Weight loss of 2% below 70 °C and second weight loss of 0.7% below 100 °C, decomposition starting at 190 °C.

KF: 4.4%

PSD: D90 of 33 m

Example 1 :

Preparation of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate in solid Form I 4-bromo-2,2-diphenylbutanenitrile (II, 1.000 Kg, 3.33 mol) and 2-methylimidazol (1 .368 Kg, 16.66 mol) were heated in DMSO (0.8 L) at 100-105 °C for 7 hours. The solution was then cooled to 20-25 °C and toluene (2 L) and water (4 L) were added and stirred for 30 minutes. After phase separation, the aqueous layer was extracted with toluene (1 L). Organic layers were combined and washed twice with water (2 x 1 L). Distillation of toluene provided 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile as a brown oil (0.915 Kg), which was, then, dissolved in dry acetone (3 L) and water (0.1 L), heated to 40-45°C and seeded with 4-(2-methyl-1 H-imidazol-1 -yl)-2,2- diphenylbutanenitrile phosphate. A solution of orthophosphoric acid (0.391 Kg, 3.39 mol) in acetone (2 L) was then added dropwise, maintaining temperature at 40-45 °C. Once the addition was finished, the reaction mixture was maintained 1 hour at 40-45 °C, cooled to 20-25 °C and stirred for 1 hour. The solid was filtered, washed with acetone (1 L), suspended in 2-propanol (10 L), heated at 80 °C and 2 L of solvent were distilled. The obtained suspension was then seeded with 4-(2-methyl-1 H-imidazol-1 -yl)- 2,2-diphenylbutanenitrile phosphate solid Form I and maintained at 80 °C for 5 hours. The suspension was cooled down to 20-25°C, filtered off, washed with 2-propanol (1 L) and, finally, dried (45 °C, 0.5 torr, 12 hours).

Yield: 0.967 Kg (73%)

HPLC: 99.5 %

KF: 0.2 %

Optical microscopy: plate-shaped crystal habit as substantially in accordance to Figure 2.

PSD: D90 of 105 m

PXRD: Crystalline solid form as substantially in accordance to Figure 3.

DSC (10 °C/min): Endothermic peak with onset at 177 °C (-1 18 J/g), as substantially in accordance to Figure 4.

TGA (10 °C/min): Decomposition starting at 180 °C.

DVS: No significant weight gain up to 90% of relative humidity. At this humidity, a total increase of only 0.45% in weight was observed.

SCXRD: Crystal structure substantially in accordance to Figure 5. There are not water or solvent molecules in the crystal structure.

Example 2:

Preparation of 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate in solid Form I without seeding 4-(2-methyl-1 H-imidazol-1 -yl)-2,2-diphenylbutanenitrile phosphate (250 mg, KF: 4.4%), as prepared in Comparative Example 1 , was suspended in isopropanol at 80°C and stirred for 15 hours. Afterwards, the solid was filtered off and dried under vacuum at 40 °C for 2 hours (2 mbar).

Yield: 225 mg (90%)

Optical microscopy: plate-shaped crystals.

Example 3:

Preparation of 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide

The 4-(2-methyl-1 H-imidazol-1-yl)-2,2-diphenylbutanenitrile phosphate in solid Form I (60 g), as prepared in Example 1 , was suspended in a mixture of isopropanol (210 mL) and water (5.6 mL). Then, 90% flakes of potassium hydroxide (64.1 g) were added to the suspension and the resulting mixture was stirred at reflux temperature for 5 hours and at room temperature for 1 hour. A 3 M aqueous solution of hydrochloric acid is added to the mixture at 0-5 °C until the pH is 10.2. Then, the suspension is stirred at 0 °C for 1 hour, filtered off, washed with a 2:1 mixture of isopropanol and water and, further washed with absolute ethanol and dried to provide crude 4-(2-methyl-1 - imidazolyl)-2,2-diphenylbutanamide.

Yield: 37.1 g (80%)

HPLC: 97.6%

PXRD: Crystalline polymorphic Form I of imidafenacin, in accordance to document Journal of Pharmacy and Pharmacology, 2010, 62, 1526-1533.

Example 4:

Purification of 4-(2-methyl-1-imidazolyl)-2,2-diphenylbutanamide

Crude 4-(2-methyl-1 -imidazolyl)-2,2-diphenylbutanamide (5 g, 97.6% purity), was dissolved in ethanol (25 mL) at reflux. The solution was cooled down to 25 °C and stirred for 4 hours and, further, cooled down to 0-5 °C and stirred for 1 hour. Then, the solid obtained was filtered off, washed with cold ethanol (5 mL) and dried under an air oven at 45 °C for 24 hours.

Yield: 4.2 g (84%)

HPLC: 99.2%

DSC (10 °C/min): Endothermic peak with onset at 192 °C.

PXRD: Crystalline polymorphic Form I of imidafenacin.