WO2023104920A1

WO2023104920A1 - Crystalline acetone solvate of revefenacin

Info

Publication number: WO2023104920A1
Application number: PCT/EP2022/084860
Authority: WO
Inventors: Joana Raquel FERREIRA DA COSTA; David FONT GIMBERNAT
Original assignee: Medichem, S.A.
Priority date: 2021-12-09
Filing date: 2022-12-07
Publication date: 2023-06-15

Abstract

The present invention relates to a novel crystalline acetone solvate of revefenacin and a process for its preparation. It also relates to its use for the preparation of Form I revefenacin.

Description

Crystalline acetone solvate of revefenacin

This application claims the benefit of European Patent Application EP21383120.9 filed 9 December 2021.

TECHNICAL FIELD

The present invention relates to a novel crystalline acetone solvate of revefenacin and a process for its preparation. It also relates to its use for the preparation of crystalline Form I of revefenacin.

BACKGROUND ART

Revefenacin, represented by the compound of formula (I), is the international commonly accepted name (INN) for biphenyl-2-ylcarbamic acid 1-(2-((4-(4-carbamoylpiperidin-1- ylmethyl)benzoyl)methylamino)ethyl)piperidin-4-yl ester, and has an empirical formula of C35H43N5O4 and a molecular weight of 597.7 g/mol.

Revefenacin is a biphenyl carbamate tertiary amine agent that belongs to the family of the long-acting muscarinic antagonists. Revefenacin is marketed in the United States under the name Yupelri™ as an oral inhalation solution for the maintenance treatment of patients with chronic obstructive pulmonary disease (COPD).

International Publication No. W02005087738A1 describes the crystallization of revefenacin from a mixture of water and acetonitrile for 3 days (example 1 D) and from a mixture of acetonitrile and methyl tert-butyl ether (example 1 E). Neither the yield nor the polymorphism of revefenacin thus obtained is disclosed.

International Publication No. W02006099165A1 describes the preparation of Form I of revefenacin by crystallization of revefenacin for 2-3 days from a mixture of water and acetonitrile (examples 8-10) with a yield of about 55% (examples 8-9) and with a purity of 98.2% (example 8). This document also describes the preparation of Form II of revefenacin by crystallization of revefenacin from a mixture of acetonitrile and methyl tert-butyl ether (example 11) although neither the yield nor the purity of revefenacin thus obtained is disclosed.

International Publication No. WO2011008809 describes the preparation of Form III of revefenacin from revefenacin (example 1) and from its diphosphate salt (example 2) in the presence of acetonitrile and isopropyl acetate, respectively, with a yield below 81 %. Example 3 describes the recrystallization of Form III of revefenacin with toluene in 92.7% yield. This document also describes the crystallization of Form IV of revefenacin from revefenacin using acetonitrile with a purity of 99.6% and a yield of 88%.

International Publication No. W02012009166A1 describes the preparation of Form III of revefenacin by crystallization of revefenacin in toluene in a yield of 92%.

Indian Patent Application I N202011029286 discloses the preparation of Form I (examples 8, 9 and 14), Form II (example 10) and the amorphous form of revefenacin (example 11- 13). Example 8 describes the crystallization of revefenacin in a mixture of isopropyl acetate and n-heptane to obtain Form I of revefenacin with a purity of 99.97%. In example 9, revefenacin was crystallized in a mixture of acetone: water (1 :1) and filtered to obtain Form

I of revefenacin with a purity of 99.9%. In example 14, Form I is obtained from a dichloromethane solution of revefenacin after evaporation of the solvent and trituration of the residue using methyl tert-butyl ether, with a purity of 99.5%. In example 10, revefenacin was crystallized using ethanol and methyl tert-butyl ether, filtered and dried to obtain Form

II of revefenacin with a purity of 99.8%. Examples 11 , 12 and 13 describe the preparation of revefenacin in amorphous form by using acetone, dimethyl sulfoxide, and methyl isobutyl ketone, respectively. This document is silent on the yield of the examples.

Chinese Patent Applications CN112694434, CN113121416, CN112830890 and CN 110526859 disclose the preparation of revefenacin using acetonitrile and water, acetonitrile, toluene and by purifying by column flash chromatography in a yield not higher than 85%. These documents are silent on the polymorphism of revefenacin thus obtained.

Therefore, from what is known in the prior art, there is a need in developing a feasible and scalable process for the synthesis of revefenacin, in particular for Form I of revefenacin, or a pharmaceutically acceptable salt thereof, in high purity and industrially acceptable yields. The present invention fulfils this and related needs. SUMMARY OF THE INVENTION

The inventors have now surprisingly found that starting from the novel crystalline acetone solvate of revefenacin, in particular from Form VI, the Form I of revefenacin can be prepared in an advantageous process that allows the obtention of the product with a lower content of related substances, in particular, the process allows reducing the content of the impurity biphenyl-2-ylcarbamic acid 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-yl ester (compound X) herein referred as impurity-a, which is an impurity difficult to be separated from the revefenacin. As shown in the Examples, the level of impurity a) in revefenacin has been reduced from 0.24% to 0.11% through the formation of the acetone solvate of revefenacin of the present invention, maintaining high yields (76-94% according to the examples of the present invention) while in the comparative example the direct purification of crystalline Form I only achieved a reduction of the impurity from 0.24% to 0.20% and with lower yields.

Due to the unpredictable behaviour of solvates, the provision of the new crystalline acetone solvate of revefenacin defined herein below is considered a contribution to the art.

Thus, a first aspect of the invention relates to a crystalline acetone solvate of revefenacin.

A second aspect of the invention relates to a process for preparing the crystalline acetone solvate of revefenacin as defined herein above and below which comprises i) combining revefenacin in acetone or a mixture of acetone and an additional suitable solvent; ii) cooling the mixture prepared in step (i); and iii) isolating the crystalline acetone solvate.

Another aspect of the invention relates to the use of the crystalline acetone solvate as defined herein above and below for the preparation of Form I of revefenacin.

Finally, another aspect of the present invention relates to the use of the crystalline acetone solvate as defined herein above and below for the preparation of crystalline Form V of revefenacin.

BRIEF DESCRIPTION OF THE DRAWINGS Fig. 1 shows the X-Ray Powder Diffractogram (XRPD) plot of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (compound V) prepared as in Example 1.

Fig. 2 shows the X-Ray Powder Diffractogram (XRPD) plot of biphenyl-2-ylcarbamic acid 1- (2-methylaminoethyl) piperidin-4-yl ester (compound VIII) prepared as in Example 4.

Fig. 3 shows the X-Ray Powder Diffractogram (XRPD) plot of biphenyl-2-ylcarbamic acid 1- (2-[(4-formylbenzoyl)methylamino]ethyl) piperidin-4-yl ester (compound X) prepared as in Example 5.

Fig. 4 shows the X-Ray Powder Diffractogram (XRPD) plot of crystalline acetone solvate Form VI of revefenacin prepared as in Example 7.

Fig. 5 shows the X-Ray Powder Diffractogram (XRPD) plot of revefenacin Form I prepared as in Example 11.

Fig. 6 shows the X-Ray Powder Diffractogram (XRPD) plot of crystalline Form V of revefenacin prepared as in Example 12.

Fig. 7 shows the ¹H-NMR (400 MHz, CDCh) spectrum of crystalline Form VI of revefenacin prepared as in Example 7.

DETAILED DESCRIPTION OF THE INVENTION

All terms as used herein in this application, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in the present application are as set forth below and are intended to apply uniformly through-out the specification and claims.

For the purposes of the present invention, any ranges given include both the lower and the upper end-points of the range. Ranges and values given, such as temperatures, times, and the like, should be considered approximate, unless specifically stated.

When a ratio of components of the crystalline acetone solvate of the present invention is specified, it refers to the molar ratio of the components that form the crystalline acetone solvate. The term “molar ratio” has been used to express the stoichiometric amount in moles of each of the components of the solvate. The molar ratio can be determined by GC (gas chromatography), ¹H NMR (Proton nuclear magnetic resonance), thermogravimetric analysis (TGA) or single crystal X-ray diffraction (SCXRD). When values of molar ratio are given according to GC, TGA or ¹H NMR it is said that these are “approximate” values due to the measurement error. It should be understood that when a molar ratio is mentioned, it corresponds to a molar ratio ± 0.2. The variability of the results is due to the inherent sensibility of the equipment.

When values of characteristic peaks of an X-ray diffractogram are given, it is said that these are “approximate” values. It should be understood that the values are the ones shown in the corresponding lists or tables ± 0.2 degrees 2 theta measured in an X-ray diffractometer with Cu-Ka radiation A= 1 .54056 A.

The term "about" or “around” as used herein refers to a range of values ± 10% of a specified value. For example, the expression "about 10" or “around 10” includes ± 10% of 10, i.e. from 9 to 11 .

The term “room temperature” refers to a temperature of the environment, without heating or cooling, and is generally from 20 °C to 25 °C.

It is noted that, as used in this specification and the appended claims, the singular forms ”a”, “an”, and “the” include plural referents unless the context clearly dictates otherwise.

As mentioned above, the first aspect of the invention relates to a crystalline acetone solvate of revefenacin.

Revefenacin can be prepared by any method known in the art in view of the present invention. An exemplary and non-limiting process for synthesizing revefenacin, which can subsequently be used to form a crystalline acetone solvate of revefenacin as described herein, is shown in Scheme 1 . This process comprises: a) the preparation of biphenyl-2- ylcarbamic acid piperidin-4-yl ester (compound V) by reaction of biphenyl-2-isocyanate (compound II) with 4-hydroxy-N-benzylpiperidine (compound III) and subsequent debenzylation of biphenyl-2-ylcarbamic acid 1-benzylpiperidin-4-yl ester (compound IV) with ammonium formate (HCOONH4) and palladium on activated carbon (Pd/C); b) the preparation of biphenyl-2-ylcarbamic acid 1-[2-(benzylmethylamino)ethyl]piperidin-4-yl ester (compound VII) by reductive amination of methyl-(2-oxoethyl)carbamic acid benzyl ester (compound VI) with the compound V obtained in step (a) using sodium triacetoxyborohydride (NaBH(OAc)3) as reducing agent; c) removal of benzoyl group of compound VII using potassium formate (HCOOK) and palladium on activated carbon (Pd/C) to obtain biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (compound VIII); d) the amidation reaction between compound VIII and 4-formylbenzoyl chloride (compound IX) to obtain biphenyl-2-ylcarbamic acid 1-(2-[(4- formylbenzoyl)methylamino]ethyl)piperidin-4-yl ester (compound X); e) preparation of revefenacin (compound I) by reductive amination of the compound X obtained in step (d) with 4-piperidinecarboxamide (compound XI) using sodium triacetoxyborohydride as reducing agent.

Scheme 1

In an embodiment, the crystalline acetone solvate of the present invention, contains 0.2 to 1 .2 moles of acetone per mol of revefenacin, preferably 0.3 to 0.7 moles of acetone per mol of revefenacin, and more preferably 0.5 moles of acetone per mol of revefenacin.

In an embodiment, the crystalline acetone solvate of the present invention is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 5.0, 7.6, 17.7, 18.6, 19.6, 20.0 and 21.0 and is herein also named crystalline Form VI. In an embodiment, the crystalline Form VI of the present invention is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 5.0, 7.6, 17.7, 18.6, 19.6, 20.0 and 21.0 and further comprising diffraction peaks at diffraction angles (20±O.2°) of 14.3, 16.4, 17.4, 22.1 and 26.0. More specifically, the crystalline Form VI of the present invention is characterized by an X- ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 5.0, 7.6, 14.3, 16.4, 17.4, 17.7, 18.6, 19.6, 20.0, 21.0, 22.1 and 26.0, and further comprising diffraction peaks at diffraction angles (20±O.2°) of 12.9, 18.1 , 25.4, 28.2 and 28.8.

In an embodiment, the crystalline Form VI of the present invention is characterized by an X-ray powder diffraction (XRPD) pattern as shown in Fig. 4.

As mentioned about, a second aspect of the invention relates to a process for preparing the crystalline acetone solvate of revefenacin as herein disclosed. Particularly, the present invention provides a process for preparing the crystalline acetone solvate which comprises i) combining revefenacin in acetone or a mixture of acetone and an additional suitable solvent; ii) cooling the mixture prepared in step (i); and iii) isolating the crystalline acetone solvate.

Step i) involves combining revefenacin and acetone or combining revefenacin and a mixture of acetone and an additional suitable solvent. This combination can be accomplished by any conceivable method. Dissolving or suspending can be mentioned by way of example.

The combining step i) is performed at a temperature from about room temperature to about reflux temperature.

Non-limiting examples of suitable solvents, which can be used alone or as a mixture of solvents, include water; alcohols such as methanol, ethanol, isopropanol or n-butanol; ketones such as methyl ethyl ketone or methyl isobutyl ketone; ethers such as tetra hydrofuran, diisopropylether, 2-methyltetrahydrofuran, cyclopentyl methyl ether or methyl tert-butyl ether; esters such as ethyl acetate, methyl acetate, isopropyl acetate, n- propyl acetate or n-butyl acetate, halogenated solvents such as dichloromethane, or chloroform; polar aprotic solvents such as /V,/V-dimethylformamide, acetonitrile, /V,/V- dimethylacetamide, /V-methyl-2-pyrrolidone or dimethylsulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene or xylene.

When the additional suitable solvent in step i) comprises water, the water content is equal to or lower than 15 wt % of the total solvent mixture. Preferably, the suitable solvent used in the process of the present invention is selected from the group consisting of water, methanol and ethanol.

In an embodiment, revefenacin in the step i) is combined with no solvent other than acetone.

In an embodiment, revefenacin in the step i) is combined in a mixture of acetone and water.

In an embodiment, revefenacin in the step i) is combined in a mixture of acetone and methanol.

In an embodiment, revefenacin in the step i) is combined in a mixture of acetone and ethanol.

The concentration of revefenacin in step i) is comprised between 0.02 and 0.5 g/mL, preferably between 0.07 and 0.2 g/mL.

Step ii) involves the step of cooling the mixture prepared in step i). The cooling step ii) is performed at a temperature in the range of about -20°C to room temperature, preferably about 0°C to room temperature.

Suitable seeding may be possible either during the step i) of combining revefenacin with acetone or a mixture of acetone and a suitable solvent and/or during the step ii) of cooling. In an embodiment, no seeding is performed in the process of the invention.

Step iii) involves isolating the crystalline acetone solvate. The crystalline acetone solvate of the present invention is isolated by means of conventional techniques, such as filtration, centrifugation or solvent evaporation. Preferably, the crystalline acetone solvate is isolated by filtration.

Optionally, the isolated crystalline acetone solvate can be subjected to one or more suitable washing stages and/or drying by any suitable method.

A preferred embodiment of the invention, is a process for preparing the crystalline acetone solvate Form VI which comprises i) combining revefenacin in acetone or a mixture of acetone and an additional suitable solvent; ii) cooling the mixture prepared in step (i); and iii) isolating the crystalline acetone solvate. A most preferred embodiment of the invention, is a process for preparing the crystalline acetone solvate Form VI which comprises i) combining revefenacin in acetone or a mixture of acetone and an additional suitable solvent selected from the group consisting of water, methanol, and ethanol; ii) cooling the mixture prepared in step (i); and iii) isolating the crystalline acetone solvate.

The inventors have surprisingly found that the process of the invention provides the crystalline acetone solvate of revefenacin Form VI with an industrially acceptable yield and with less than 0.20% by weight of biphenyl-2-ylcarbamic acid 1-(2-[(4- formylbenzoyl)methylamino]ethyl)piperidin-4-yl ester (compound X) herein referred as Impurity-a when analyzed by an HPLC method for chromatographic purity.

Impurity-a

It is part of the invention the process of the present invention that further comprises the treatment of the crystalline acetone solvate as herein disclosed in a mixture of acetone and water to prepare Form I of revefenacin. Advantageously, Form I is obtained with a lower level of impurity a), thus achieving a good purification from impurity a) which is difficult to be purified directly from revefenacin Form I. The term "Form I of revefenacin” refers to the crystalline form as disclosed in the International Publication No. W02006099165A1 and characterized by an X-ray powder diffraction (XRPD) pattern as shown in Fig. 5.

The term of “treatment” as used herein comprises dissolving the crystalline acetone solvate of the present invention in a mixture of acetone and water and precipitating by cooling and/or by adding an anti-solvent or a mixture of anti-solvents. Alternatively, the treatment may comprises slurring the crystalline acetone solvate in a mixture of acetone and water, optionally adding an anti-solvent or a mixture of anti-solvents, and filtering.

The process of treatment according to the present invention can include only one treatment step or more than one consecutive treatment steps.

The dissolving step is performed by contacting the crystalline acetone solvate of the present invention in a mixture of acetone and water and heating the mixture at a temperature higher than 35°C, and preferably at reflux temperature.

In an embodiment of the present invention, the treatment of the crystalline acetone solvate as herein disclosed is in a mixture of acetone and water, wherein the water content is higher than 15 wt %.

The cooling step is performed at a temperature in the range of from about -20°C to room temperature, preferably from about 0 °C to room temperature.

Optionally, revefenacin Form I obtained according to the process of this invention is filtered and dried. Drying may be performed according to any usual drying method. For example, drying is performed under vacuum at a temperature from about room temperature to about 80°C, preferably at a temperature from about 40°C to 60°C.

In an embodiment of the present invention, the crystalline acetone solvate Form VI of revefenacin as herein disclosed is treated in a mixture of acetone and water to prepare Form I.

The above described treatment of the crystalline acetone solvate Form VI of revefenacin to prepare Form I is particularly useful for the reduction of the content of Impurity-a. Particularly, after treating the crystalline acetone solvate Form VI of revefenacin by the above described process, the content of impurity-a in revefenacin Form I is reduced to less than 0.15%. Hence, the above treatment process is highly advantageous and provides pure revefenacin Form I.

As mentioned above, it is part of the invention the use of the crystalline acetone solvate as defined herein above for the preparation of Form I of revefenacin.

It is also part of the present invention the use of the crystalline acetone solvate as defined herein above and below for the preparation of crystalline Form V of revefenacin.

Finally, it is also part of the invention the process of the present invention to prepare revefenacin Form I that further comprises the step of drying Form I of revefenacin to prepare crystalline Form V of revefenacin.

Drying may be performed according to any usual drying method. For example, drying is performed under vacuum at a temperature from about room temperature to about 80°C, preferably at a temperature from about 40°C to 60°C.

Crystalline Form V is also part of the present invention. The crystalline Form V of revefenacin of the present invention is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 4.8, 13.3, 13.5, 17.2, 19.0, 19.4 and 21.6.

The crystalline Form V of revefenacin of the present invention is also characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 4.8, 13.3, 13.5, 17.2, 19.0, 19.4 and 21.6 and further comprising diffraction peaks at diffraction angles (20±O.2°) of 8.9, 9.7, 12.4 and 24.5.

The crystalline Form V of the present invention is also characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 4.8, 8.9, 9.7, 12.4, 13.3, 13.5, 17.2, 19.0, 19.4, 21.6 and 24.5 and further comprising diffraction peaks at diffraction angles (20±O.2°) of 10.2, 23.0, 23.5 and 26.6.

In an embodiment, the crystalline Form V of the present invention is characterized by an X- ray powder diffraction (XRPD) pattern as shown in Fig. 6.

In an embodiment of the present invention, the Form V of revefenacin as herein disclosed may be hydrated to obtain Form I of revefenacin. Hydration is performed by exposing revefenacin Form V with a humidified gas (typically air or nitrogen) or by slurring the Form V of revefenacin in water.

The term “humidified gas” refers to a gas atmosphere (typically air or nitrogen) with a relative humidity (RH) higher than 30%, preferably higher than 60% and more preferably higher than 90%.

Exposing revefenacin Form V to humidified gas is performed at a temperature from about room temperature to about 60°C, preferably at temperature range from room temperature to 40°C.

As mentioned above, the sixth aspect of the invention relates to the crystalline Form V of revefenacin.

Examples

Hereinafter, the present invention is described in more detail and specifically with reference to the Examples, which however are not intended to limit the present invention.

X-Ray Powder Diffraction (XRPD):

The XRPD pattern was recorded on a Siemens D5000 diffractometer equipped with two symmetrically mounted vertical goniometers (Bragg-Brentano geometry) with horizontal sample stages, an X-ray tube, a high voltage generator (working at 45 kV and 35 mA) and standard scintillation detectors. Ni-filtered Cu-anode source was used, and diffracted radiation was further monochromatized with a graphite crystal to avoid fluorescence effects [( (K_a) = 1 .54056 A], The diffraction pattern was recorded including values of 20 that range from 2 to 50° with a sampling rate of 0.02° per second and a step time of 1 second per step. The powdered sample was pressed between two glass plates, forming a film. DIFFRAC Plus measurement software with EVA evaluation software (Bruker) was used to record the data and for a primary analysis of the diffraction pattern. The equipment was periodically calibrated using quartz and silicon.

HPLC used for analyzing biphenyl-2-ylcarbamic acid 1-(2-[(4- formylbenzoyl)methylamino]ethyl)piperidin-4-yl ester (compound X) herein referred as impurity-a.

The chromatographic separation was carried out using an Acquity BEH C18, 2.1 x 100 mm, 1 .7 pm at 35°C. Mobile phase A: 0.1 % trifluoroacetic acid solution in water.

Mobile phase A is prepared as follows: Dilute with water, 1 mL of trifluoroacetic acid in a 1000 mL volumetric flask.

Mobile phase B: 0.1 % trifluoroacetic acid in acetonitrile Ultra LC.

Mobile phase B is prepared as follows: Dilute with acetonitrile Ultra LC, 1 mL of trifluoroacetic acid in a 1000 mL volumetric flask.

The chromatograph was programmed as follows: initial 2 min isocratic 80% mobile phase A; 2-25 min linear gradient to 70% mobile phase A; 25-40 min isocratic 60% mobile phase A.

The chromatograph was equipped with equipped with an UV-Visible detector (wavelength: 260 nm).

The flow rate was 0.5 mL/min.

The Injection volume was 0.5 pL.

Solutions

Diluent: methanol

Test solution: 2 mg/mL of revefenacin sample in diluent.

Standard solution of impurity-a at 0.10%: 0.002 mg/mL of impurity-a reference standard in diluent (0.10% referred to test solution).

Calculation

The quantification of the impurity-a is performed as follows:

Cs: Concentration in mg/mL of impurity-a 0.10%

Au: Area response of impurity-a in test solution

Cu: Concentration in mg/mL of test solution

As: Peak area response of compound X in standard solution of impurity-a at 0.10%

Example 1 : Preparation of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (compound V)

40.0 g of biphenyl-2-isocyanate (205 mmol) (compound II) were added to a solution of 39.9 g of 4-hydroxy-N-benzylpiperidine (209 mmol) (compound III) in 220 mL of heptane at 60 °C. The resulting mixture was stirred at 60 °C for 10 hours. Then, the resulting suspension was cooled down to 25 °C and then filtered. The solid was dissolved with ethanol at reflux, stirred for 30 minutes at this temperature, cooled down to 0 °C and filtered to yield 68.8 g of biphenyl-2-ylcarbamic acid 1-benzylpiperidin-4-yl ester (compound IV) as a white crystalline powder.

60.0 g of biphenyl-2-ylcarbamic acid 1-benzylpiperidin-4-yl ester (compound IV) (155 mmol) obtained above, 29.4 g of ammonium formate and 4.5 g of palladium on activated carbon (5 wt% dry basis), 330 mL of methanol and 45 mL of 6M aqueous HCI were charged in a reactor. The reactor was well purged with N2 and the mixture was stirred at 45 °C for 8 hours. Palladium on activated carbon catalyst was filtered off through a Celite pad and the Celite was rinsed with 48 mL of methanol. 140 mL of 10 wt% aqueous NaOH were added over the filtered solution and the resulting mixture was cooled down to 15 °C. Then, the resulting suspension was filtered. The solid was dissolved with 150 mL of isopropanol and 18 mL of water at reflux, stirred 1 hour at this temperature. The solution was then cooled down to 15 °C, filtered and washed with isopropanol to yield 38.50 g of biphenyl-2- ylcarbamic acid piperidin-4-yl ester (compound V) as a white crystalline powder (yield: 84%, HPLC purity: 99.8%).

Example 2: Methyl-(2-oxoethyl)carbamic acid benzyl ester (compound VI)

109.4 g of potassium carbonate (791 mmol), 450 mL of water, 450 mL of tetra hydrofuran and 88.0 g of N-methylaminoacetaldehyde dimethyl acetal (739 mmol) were charged in a reactor. The resulting mixture was cooled down to 0 °C. 75 mL of benzyl chloroformate (528 mmol) were slowly added and the mixture was allowed to warm to room temperature. The mixture was maintained at room temperature until completion of the reaction. A biphasic mixture was obtained. The upper organic layer was separated, washed with 150 mL of HCI 1 N at 25 °C and the mixture was allowed to settle. The upper organic layer was separated and mixed with 340 mL of water and 140 mL of HCI 35 wt%. The resulting mixture was stirred at 25 °C for 20 hours. Then, 300 mL of toluene and 63.3 g of NaOH 25 wt% aqueous solution were added. A biphasic mixture was obtained. Layers were separated, and the organic layer was washed successively with 360 mL of 5 wt% aqueous NaHCCh and 270 mL of water. The organic layer was dried over Na2SO4, filtered, and the solution was concentrated to dryness to afford methyl-(2-oxoethyl)carbamic acid benzyl ester (compound VI) as a pale-yellow oil.

Example 3: Biphenyl-2-yl-carbamic acid 1-[2-(benzyloxycarbonylmethylamino) ethyl]piperidin-4-yl ester (compound VII)

60.0 g of biphenyl-2-ylcarbamic acid piperidin-4-yl ester (compound V) (202 mmol) as obtained in example 1 was suspended in 240 mL of toluene. To the resulting suspension was added 49.1 g of methyl-(2-oxoethyl)carbamic acid benzyl ester (compound VI (237 mmol), as obtained in example 2, dissolved in 165 mL of toluene.

The resulting mixture was stirred at 25 °C for 2 hours. Then, 77.2 g of sodium triacetoxyborohydride (364 mmol) were slowly added and the mixture was stirred for 6 hours at 25 °C. 180 mL of water and 153.6 g of NaOH 25 wt% were added, and the biphasic mixture was stirred at 25 °C for 1 hour. Layers were separated and the organic layer was dried over Na2SO4, filtered, and concentrated to afford a toluenic solution of biphenyl-2-yl- carbamic acid 1-[2-(benzyloxycarbonylmethylamino) ethyl]piperidin-4-yl ester (compound VII) in toluene.

Example 4: Biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl) piperidin-4-yl ester (compound VIII)

Biphenyl-2-yl-carbamic acid 1-[2-(benzyloxycarbonylmethylamino) ethyl]piperidin-4-yl ester (compound VII) toluenic solution obtained in Example 3, 34.5 g of potassium formate (410 mmol), 8.0 g of palladium on activated carbon (5 wt% dry basis) and 240 mL of isopropanol were charged in a reactor. The reactor was well purged with N2 and the mixture was stirred at 45 °C for 6 hours. Palladium on activated carbon catalyst was filtered off through a Celite pad and the Celite was rinsed with 80 mL of toluene. 280 mL of water and 47 g of HCI 35 wt% were added over the filtered solution and the resulting mixture was stirred for 1 hour at 25 °C. The aqueous layer was collected, and toluene (320 mL) and isopropanol (100 mL) were added. The pH of the solution was adjusted to basic using NaOH 25 wt% aqueous solution. The resulting mixture was stirred for 1 hour and the layers were separated. The organic layer was concentrated, and 400 mL of heptane were added at 25 °C. The resulting suspension was cooled down to 0 °C, stirred 30 minutes, filtered, and dried under vacuum to yield 53.7 g of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl) piperidin-4-yl ester (compound VIII) as a white powder (yield: 75 %, HPLC purity: 99.8%).

Example 5: Biphenyl-2-ylcarbamic acid 1-(2-[(4-formylbenzoyl)methylamino]ethyl) piperidin-4-yl ester (compound X)

16.0 g of 4-carboxybenzaldeyde (compound IX) (107 mmol), 0.16 mL of dimethylformamide and 140 mL of toluene were added to the reactor. The resulting mixture was heated at 80 °C. 8.5 mL of thionyl chloride (117 mmol) were added dropwise maintaining this temperature. The reaction mixture was stirred at this temperature for 2 hours. Then, solvent was distilled under atmospheric pressure and 120 mL of heptane were added. The resulting suspension was cooled down to 0 °C, stirred 1 hour and filtered. The obtained 4- formylbenzoyl chloride was used in next step without further purification. 23.0 g of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (compound VIII) (65 mmol) as obtained in Example 4, 92 mL of 2-methyltetrahydrofuran and 180 mL of 5 wt% aqueous Na2COs were charged in a reactor. The resulting mixture was cooled down to 15 °C. A solution of 4-formylbenzoyl chloride (as obtained above) in 180 mL of 2- methyltetrahydrofuran, was slowly added over this mixture. The resulting reaction crude was stirred 1 hour at 30 °C. Layers were separated and the organic layer was washed with 140 mL of NaOH 1 N. 190 mL of heptane were added to the organic layer. Then, the resulting suspension was filtered. The solid was dissolved with 400 mL of isopropanol and 150 mL of heptane at reflux, the solution was stirred for 30 minutes at this temperature and then cooled down to 10 °C. The resulting suspension was stirred 30 minutes, filtered, and dried under vacuum to yield 25.0 g of biphenyl-2-ylcarbamic acid 1-(2-[(4- formylbenzoyl)methylamino]ethyl)piperidin-4-yl ester (compound X) as a white powder (yield: 80 %, HPLC purity: 98.5%).

Example 6: Preparation of revefenacin (compound I)

20.0 g (41 mmol) of biphenyl-2-ylcarbamic acid 1-(2-[(4-formylbenzoyl)methylamino]ethyl) piperidin-4-yl ester (compound X) obtained in example 5, 10.6 g (82 mmol) of 4- piperidinecarboxamide (compound XI) and 360 mL of isopropanol were charged in a reactor. The resulting mixture was stirred at 60 °C for 2 hours. 270 mL of solvent were distilled off under reduced pressure and additional 270 mL of isopropanol were added. The resulting mixture was stirred for 4 hours at 60°C and cooled down to 5° C. 4.7 mL of glacial acetic acid and 17.5 g of sodium triacetoxyborohydride (82 mmol) were added. The resulting mixture was stirred for 20 hours at 25 °C. Then, 60 mL of water were added, and organic solvent was removed under vacuum. 150 mL of dichloromethane and 180 mL of HCI 1 N were added. The mixture was stirred 30 minutes, layers were separated, and the organic layer was discarded. 160 mL of dichloromethane and 40 mL of isopropanol were added to the aqueous layer. The mixture was stirred 30 minutes and the aqueous layer was collected. 230 mL of 2-methyltetrahydrofuran was added to the aqueous layer and pH was adjusted to basic using NaOH 25 wt%. The resulting mixture was stirred for 30 minutes, and layers were separated. 240 mL of heptane were added to the organic layer. Then, the resulting suspension was filtered an the obtained solid was dried under vacuum. 21.3 g of white solid were obtained (yield: 86 %, HPLC purity: 99.3%, impurity-a: 0.24%).

Example 7: Preparation of crystalline acetone solvate Form VI of revefenacin:

12.0 g (20 mmol) of revefenacin obtained as in example 6 and 70 mL of acetone were charged at room temperature. The mixture was stirred at least 2 hours at room temperature. The resulting suspension was then cooled to 0-5 °C and stirred for 1 hour. The solid was collected by filtration and dried under vacuum. 11.3 g of crystalline acetone solvate Form VI of revefenacin (compound I) were obtained (yield: 94%, HPLC purity: 99.5 %, impurity- a: 0.16%).

Example 8: Preparation of crystalline acetone solvate Form VI of revefenacin:

2.0 g (3.4 mmol) of revefenacin obtained as in example 6, 12 mL of acetone and 3 mL of ethanol were charged at room temperature. The mixture was heated to reflux, and a solution was obtained. The solution was filtered to remove insoluble particles and cooled down to 20-25 °C and stirred for at least 2 hours. The solid was filtered, washed with acetone and dried under vacuum. 1 .2 g of crystalline acetone solvate Form VI of revefenacin (compound I) were obtained (yield 60 %, HPLC purity 99.4%, impurity-a: 0.18%).

Example 9: Preparation of crystalline acetone solvate Form VI of revefenacin:

2.0 g (3.4 mmol) of revefenacin obtained as in example 6, 15 mL of acetone and 2 mL of methanol were charged at room temperature. The mixture was heated to reflux, and a solution was obtained. The solution was filtered to remove insoluble particles and cooled down to 20-25 °C and stirred for at least 2 hours. The solid was filtered, washed with acetone and dried under vacuum. 1.1 g of crystalline acetone solvate Form VI of revefenacin (compound I) were obtained (yield 55 %, HPLC purity 99.3%, impurity-a: 0.19%).

Example 10: Preparation of crystalline acetone solvate Form VI of revefenacin:

6.7 g (11 mmol) of revefenacin obtained as in example 6, 40 mL of acetone and 4 mL of water were charged at room temperature. The mixture was heated to reflux, and a solution was obtained. The solution was filtered to remove insoluble particles and cooled down to 20-25 °C and stirred for at least 2 hours. The solid was filtered, washed with acetone and dried under vacuum. 4.2 g of crystalline acetone solvate Form VI of revefenacin (compound I) were obtained (yield 63 %, HPLC purity 99.5%, impurity-a: 0.18%).

Example 11 : Preparation of crystalline Form I of revefenacin:

10.0 g (16.7 mmol) of crystalline acetone solvate Form VI of revefenacin obtained as in example 7, 36 mL of acetone and 8 mL of water were charged at room temperature. The mixture was heated to reflux, and a solution was obtained. The solution was filtered to remove insoluble particles and cooled down to 0-5 °C and stirred for at least 3 hours. The solid was filtered, washed with acetone and dried under vacuum at 30-35°C. 7.3 g of revefenacin (compound I) crystalline Form I were obtained (yield 81 %, HPLC purity 99.6%, impurity-a: 0.11 %).

Example 12: Preparation of crystalline Form V of revefenacin:

A sample of Form I of revefenacin obtained as in example 11 was dried under vacuum for 8 hours at 45 °C. Crystalline Form V of revefenacin was obtained.

Example 13: Preparation of crystalline Form I of revefenacin:

A sample of revefenacin Form V obtained as in example 12 was exposed for 8 hours at 25 °C to >90%RH nitrogen atmosphere. Crystalline Form I of revefenacin was obtained.

Example 14: Preparation of crystalline Form I of revefenacin:

A sample of crystalline acetone solvate Form VI of revefenacin obtained as in example 7 was dried under vacuum for 4 hours at 45 °C (drying step). The obtained solid was exposed to >90%RH nitrogen atmosphere for 4 hours at 25 °C (hydration step). The drying/hydration cycle was repeated 3 more times. Crystalline Form I of revefenacin was obtained.

Comparative example 1 : Preparation of crystalline Form I of revefenacin as described in Indian Patent Application IN202011029286

5.0 g (8.4 mmol) of revefenacin obtained as in example 6, 37 mL of acetone and 37 mL of water (acetone:water 1 :1) were charged at room temperature. The mixture was stirred 3 hours at room temperature and then the solution was cooled down to 5-10 °C and stirred 3 additional hours. The solid was filtered and dried under vacuum. 3.7 g of crystalline revefenacin Form I (compound I) were obtained (yield 74 %, HPLC purity 99.4%, impurity- a: 0.20%).

Claims

1 . A crystalline acetone solvate of revefenacin.

2. The crystalline acetone solvate according to claim 1 , containing 0.2 to 1.2 moles of acetone per mol of revefenacin, preferably 0.3 to 0.7 moles of acetone per mol of revefenacin, and more preferably 0.5 moles of acetone per mol of revefenacin.

3. The crystalline acetone solvate according to claim 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 5.0, 7.6, 17.7, 18.6, 19.6, 20.0, and 21.0.

4. The crystalline acetone solvate according to claim 3, characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 5.0, 7.6, 17.7, 18.6, 19.6, 20.0 and 21.0 and further comprising diffraction peaks at diffraction angles (20±O.2°) of 14.3, 16.4, 17.4, 22.1 , and 26.0.

5. The crystalline acetone solvate according to claim 4, characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (20±O.2°) of 5.0, 7.6, 14.3, 16.4, 17.4, 17.7, 18.6, 19.6, 20.0, 21.0, 22.1 , and 26.0 and further comprising diffraction peaks at diffraction angles (20±O.2°) of 12.9, 18.1 , 25.4, 28.2, and 28.8.

6. A process for preparing the crystalline acetone solvate according to anyone of claims 1 to 5 which comprises i) combining revefenacin in acetone or a mixture of acetone and an additional suitable solvent,

(ii) cooling the mixture prepared in step (i)

(iii) isolating the crystalline acetone solvate.

7. The process for preparing the crystalline acetone solvate according to claim 6, wherein the additional suitable solvent in step i) comprises water, and the water content is equal to or lower than 15 wt % of the total solvent mixture.

8. The process for preparing the crystalline acetone solvate according to claim 6, wherein the suitable solvent is methanol or ethanol.

9. The process for preparing the crystalline acetone solvate according to any of claims 6 to 8, further comprising treating crystalline acetone solvate obtained in step iii) in a mixture of acetone and water wherein the water content is higher than 15 wt %. yielding to Form I of revefenacin.

10. The process for preparing Form I of revefenacin according to claim 9, further comprising the step of drying Form I of revefenacin to prepare crystalline Form V of revefenacin.

11. Use of the crystalline acetone solvate according to anyone of claims 1 to 5 for the preparation of Form I of revefenacin.

12. Use of the crystalline acetone solvate according to anyone of claims 1 to 5 for the preparation of crystalline Form V of revefenacin.