CN118401497A - Crystalline acetone solvate of Lei Fen nacin - Google Patents

Abstract

The present invention relates to a novel crystalline acetone solvate of refenacin and a preparation method thereof, and also relates to the use of the crystalline acetone solvate for preparing type I refenacin.

Description

Crystalline acetone solvate of revenacin

This application claims the benefit of European patent application EP21383120.9 filed on December 9, 2021.

Technical Field

The present invention relates to a novel crystalline acetone solvate of revefenacin and a preparation method thereof, and also relates to the use of the crystalline acetone solvate for preparing revefenacin crystal form I.

Background technique

Revenacin represented by the compound of formula (I) is the international common name (INN) of 1-(2-((4-(4-carbamoylpiperidin-1-ylmethyl)benzoyl)methylamino)ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate, its empirical formula is C ₃₅ H ₄₃ N ₅ O ₄ , and its molecular weight is 597.7 g/mol.

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

International Publication No. WO2005087738A1 describes the crystallization of revenacin from a mixture of water and acetonitrile for 3 days (Example 1D) and from a mixture of acetonitrile and methyl tert-butyl ether (Example 1E). The yield of revenacin obtained and the polymorphism are not disclosed.

International Publication No. WO2006099165A1 describes the preparation of Type I revinacin by crystallization of revinacin from a mixture of water and acetonitrile for 2 to 3 days (Examples 8 to 10) with a yield of about 55% (Examples 8 to 9) and a purity of 98.2% (Example 8). The document also describes the preparation of Type II revinacin by crystallization of revinacin from a mixture of acetonitrile and methyl tert-butyl ether (Example 11), although the yield and purity of the revinacin thus obtained are not disclosed.

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

International Publication No. WO2012009166A1 describes the preparation of Form III of revenacin by crystallization of revenacin in toluene with a yield of 92%.

Indian patent application IN202011029286 discloses the preparation of type I (Examples 8, 9 and 14), type II (Example 10) and amorphous (Examples 11 to 13) revenacin. Example 8 describes the crystallization of revenacin in a mixture of isopropyl acetate and n-heptane to obtain revenacin type I with a purity of 99.97%. In Example 9, revenacin is crystallized in a mixture of acetone: water (1: 1) and filtered to obtain type I revenacin with a purity of 99.9%. In Example 14, after evaporation of the solvent and grinding the residue with methyl tert-butyl ether, type I is obtained from a dichloromethane solution of revenacin with a purity of 99.5%. In Example 10, revenacin is crystallized using ethanol and methyl tert-butyl ether, filtered and dried to obtain type II revenacin with a purity of 99.8%. Examples 11, 12 and 13 describe the preparation of amorphous refenacin using acetone, dimethyl sulfoxide and methyl isobutyl ketone, respectively. The document does not mention the yields of the examples.

Chinese patent applications CN112694434, CN113121416, CN112830890 and CN110526859 disclose the use of acetonitrile and water, acetonitrile, toluene and purification by flash column chromatography to prepare revenacin with a yield of no more than 85%. These documents do not mention the polymorphism of revenacin obtained thereby.

Therefore, from what is known in the prior art, there is a need to develop a feasible and scalable process for synthesizing revifenacin, especially Form I revifenacin or its pharmaceutically acceptable salts, with high purity and industrially acceptable yield. The present invention meets this need and related needs.

Summary of the invention

The inventors have now surprisingly found that starting from a crystalline acetone solvate of refenacin, in particular from Form VI, Form I refenacin can be prepared in an advantageous process, which allows obtaining a 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), which is referred to herein as impurity-a, which is an impurity that is difficult to separate from refenacin. As shown in the examples, by forming the acetone solvate of refenacin according to the invention, the level of impurity-a) in refenacin has been reduced from 0.24% to 0.11%, maintaining a high yield (76% to 94% according to the examples of the invention), while in the comparative examples, direct purification of Form I only achieved a reduction of the impurity from 0.24% to 0.20% and a lower yield.

The provision of a novel crystalline acetone solvate of refenasin defined below is considered to be a contribution to the art due to the unpredictable behaviour of the solvate.

Therefore, a first aspect of the present invention relates to a crystalline acetone solvate of revenacin.

A second aspect of the present invention relates to a process for preparing the crystalline acetone solvate of revenacin as defined above and below, the process comprising

i) mixing revenacin with acetone or a mixture of acetone and other suitable solvents;

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

iii) isolating the crystalline acetone solvate.

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

Finally, another aspect of the present invention relates to the use of the crystalline acetone solvate defined above and below for the preparation of crystalline form V of revenacin.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the X-ray powder diffraction pattern (XRPD) of piperidin-4-yl biphenyl-2-ylcarbamate (Compound V) prepared as in Example 1.

2 shows the X-ray powder diffraction pattern (XRPD) of 1-(2-methylaminoethyl)piperidin-4-yl biphenyl-2-ylcarbamate (Compound VIII) prepared as in Example 4.

3 shows the X-ray powder diffraction pattern (XRPD) of 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate (Compound X) prepared as in Example 5.

FIG. 4 shows the X-ray powder diffraction pattern (XRPD) of the crystalline acetone solvate of Form VI revenacin prepared in Example 7.

FIG5 shows the X-ray powder diffraction pattern (XRPD) of Form I revenacin prepared in Example 11.

FIG6 shows the X-ray powder diffraction pattern (XRPD) of Form V of revenacin prepared in Example 12.

FIG. 7 shows the ¹ H-NMR (400 MHz, CDCl ₃ ) spectrum of the crystal form VI of revenacin prepared in Example 7. FIG.

Summary of the invention

Unless otherwise specified, all terms used in this application should be understood as having ordinary meanings known in the art. Other more specific definitions of certain terms used in this application are described below and are intended to be uniformly applied throughout the specification and claims.

For the purpose of the present invention, any range given includes the lower and upper limits of the range endpoints. Unless otherwise specified, the given ranges and values, such as temperature, time, etc. should be considered to be approximate.

When specifying the component ratios of the crystalline acetone solvate of the present invention, it refers to the molar ratio of the components that form the crystalline acetone solvate. The term "molar ratio" is used to indicate the stoichiometric molar amounts 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 for the molar ratio are given according to GC, TGA or ^1H NMR, these are considered to be "approximate" values due to measurement errors. It should be understood that when referring to the molar ratio, it corresponds to the molar ratio ±0.2. The variability of the results is due to the inherent sensitivity of the equipment. When values for characteristic peaks of an X-ray diffraction pattern are given, it can be said that these are "approximate" values. It should be understood that these values are the values shown in the corresponding list or table ±0.2 degrees 2θ, with Cu-K _α radiation. Measured in an X-ray diffractometer.

The term "about" or "approximately" as used herein refers to a numerical range of ±10% of a particular value. For example, the expression "about 10" or "approximately 10" includes 10±10%, ie, 9 to 11.

The term "room temperature" refers to the temperature of the environment without heating or cooling, typically 20°C to 25°C.

It is noted that, as used in this specification and the appended claims, an element without a quantifier means one or more than one unless the context clearly dictates otherwise.

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

In view of the present invention, revifenacin can be prepared by any method known in the art. Scheme 1 shows an exemplary and non-limiting method for synthesizing revifenacin, which can then be used to form the crystalline acetone solvate of revifenacin described herein. The method comprises: a) preparing 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 reaction of biphenyl-2-ylcarbamic acid 1-benzylpiperidin-4-yl ester (compound IV) with ammonium formate (HCOONH 4 ) and palladium on activated carbon (Pd/C); b) preparing 4-hydroxy-N-benzylpiperidin-4-yl ester (compound V) by reaction of biphenyl-2-isocyanate (compound II) with 4-hydroxy-N-benzylpiperidin ...-4-yl ester (compound IV) with ammonium formate (HCOONH ₄ ) and palladium on activated carbon (Pd/C); b) preparing 4-hydroxy-N-benzylpiperidin-4-yl ester (compound V) by reaction of biphenyl-2-isocyanate (compound II) with 4-hydroxy-N-benzylpiperidin-4-yl ester (compound IV) with ammonium formate ( _HCOONH ) as a reducing agent, by reductive amination of methyl-(2-oxoethyl) benzyl carbamate (compound VI) with the compound V obtained in step (a), to prepare biphenyl-2-ylcarbamic acid 1-[2-(benzylmethylamino)ethyl]piperidin-4-yl ester (compound VII); c) removing the benzoyl group of compound VII with potassium formate (HCOOK) and palladium on activated carbon (Pd/C) to obtain biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (compound VII); -yl ester (Compound VIII); d) Compound VIII is subjected to an amidation reaction with 4-formylbenzoyl chloride (Compound IX) to obtain biphenyl-2-ylcarbamic acid 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-yl ester (Compound X); e) Using sodium triacetoxyborohydride as a reducing agent, the compound X obtained in step (d) is reductively aminized with 4-piperidinecarboxamide (Compound XI) to prepare revenacin (Compound I).

In an embodiment, the crystalline acetone solvate of the present invention contains 0.2 to 1.2 moles of acetone per mole of refenacin, preferably 0.3 to 0.7 moles of acetone per mole of refenacin, and more preferably 0.5 moles of acetone per mole of refenacin.

In an embodiment, the crystalline acetone solvate of the present invention is characterized by an X-ray powder diffraction (XRPD) pattern including diffraction peaks at diffraction angles (2θ±0.2°) of 5.0°, 7.6°, 17.7°, 18.6°, 19.6°, 20.0°, and 21.0°, and is also referred to herein as Form VI.

In an embodiment, Form VI of the present invention is characterized in that the X-ray powder diffraction (XRPD) pattern includes diffraction peaks at diffraction angles (2θ±0.2°) of 5.0°, 7.6°, 17.7°, 18.6°, 19.6°, 20.0° and 21.0°, and also includes diffraction peaks at diffraction angles (2θ±0.2°) of 14.3°, 16.4°, 17.4°, 22.1° and 26.0°.

More specifically, Form VI of the present invention is characterized in that an X-ray powder diffraction (XRPD) pattern includes diffraction peaks at diffraction angles (2θ±0.2°) 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 also includes diffraction peaks at diffraction angles (2θ±0.2°) of 12.9°, 18.1°, 25.4°, 28.2° and 28.8°.

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

As mentioned above, the second aspect of the present invention relates to a method for preparing the crystalline acetone solvate of revenacin disclosed herein. In particular, the present invention provides a method for preparing the crystalline acetone solvate, which comprises

i) mixing revenacin in acetone or a mixture of acetone and other suitable solvents;

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

iii) isolating the crystalline acetone solvate.

Step i) comprises mixing refenacin with acetone, or mixing refenacin with a mixture of acetone and other suitable solvents. This mixing can be achieved by any conceivable method. Dissolving or suspending can be exemplified.

The mixing step i) is carried out at a temperature of about room temperature to about reflux temperature.

Non-limiting examples of suitable solvents that can be used alone or as a solvent mixture include water; alcohols such as methanol, ethanol, isopropanol or n-butanol; ketones such as methyl ethyl ketone or methyl isobutyl ketone; ethers such as tetrahydrofuran, diisopropyl ether, 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 N,N-dimethylformamide, acetonitrile, N,N-dimethylacetamide, N-methyl-2-pyrrolidone or dimethyl sulfoxide; hydrocarbon aliphatic solvents such as methylcyclohexane, cyclohexane, heptane or hexane; hydrocarbon aromatic solvents such as toluene or xylene.

When the other suitable solvent in step i) comprises water, the water content is equal to or lower than 15% by weight of the total solvent mixture.

Preferably, the suitable solvent used in the process of the present invention is selected from water, methanol and ethanol.

In an embodiment, the revenacin in step i) is not mixed with a solvent other than acetone.

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

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

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

The concentration of revenacin in step i) is 0.02 g/mL to 0.5 g/mL, preferably 0.07 g/mL to 0.2 g/mL.

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

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

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

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

A preferred embodiment of the present invention is a method for preparing Type VI crystalline acetone solvate, comprising

i) mixing revenacin with acetone or a mixture of acetone and other suitable solvents;

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

iii) isolating the crystalline acetone solvate.

The most preferred embodiment of the present invention is a method for preparing Type VI crystalline acetone solvate, comprising

i) mixing revenacin in acetone or a mixture of acetone and another suitable solvent selected from water, methanol and ethanol;

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

iii) isolating the crystalline acetone solvate.

The inventors unexpectedly found that the process of the present invention provides a crystalline acetone solvate of revenacin Form VI in an industrially acceptable yield and that the content of 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate (Compound X), referred to herein as impurity-a, is less than 0.20% by weight when the chromatographic purity is analyzed by HPLC method.

It is part of the present invention that the process of the present invention further comprises treating the crystalline acetone solvate disclosed herein in a mixture of acetone and water to prepare revenacin Form I. Advantageously, Form I is obtained with a lower level of impurity-a), thereby achieving good purification of impurity-a), which is difficult to purify directly from revenacin Form I.

The term "Form I of revenacin" refers to the crystalline form disclosed in International Publication No. WO2006099165A1, which is characterized by an X-ray powder diffraction (XRPD) pattern as shown in FIG. 5 .

As used herein, the term "treating" includes dissolving the crystalline acetone solvate of the present invention in a mixture of acetone and water and precipitating by cooling and/or adding an anti-solvent or anti-solvent mixture. Alternatively, treating may include slurrying the crystalline acetone solvate in a mixture of acetone and water, optionally adding an anti-solvent or anti-solvent mixture and filtering.

The treatment process according to the invention may comprise only one treatment step or more than one consecutive treatment steps.

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

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

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

Optionally, the Form I revenacin obtained according to the process of the present invention is filtered and dried. Drying can be carried out according to any conventional drying method. For example, drying is carried out under vacuum at a temperature of about room temperature to about 80°C, preferably at a temperature of about 40°C to 60°C.

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

The above-mentioned treatment of the crystalline acetone solvate Form VI of refenacin to prepare Form I is particularly useful for reducing the content of impurity-a. In particular, after treating the crystalline acetone solvate Form VI of refenacin by the above-mentioned method, the content of impurity-a in refenacin Form I is reduced to less than 0.15%.

Therefore, the above-described processing method is very advantageous and provides pure Form I revenacin.

As stated above, the use of the crystalline acetone solvate as defined above for the preparation of revenacin Form I is part of the present invention.

The use of the crystalline acetone solvate defined above and below for the preparation of form V of revenacin is also part of the present invention.

Finally, the method for preparing Form I revenacin of the present invention is also part of the present invention, and the method further comprises the step of drying Form I revenacin to prepare Form V of revenacin.

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

Form V is also part of the present invention. Form V of revenacin of the present invention is characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (2θ±0.2°) of 4.8°, 13.3°, 13.5°, 17.2°, 19.0°, 19.4° and 21.6°.

The crystal form V of revenacin of the present invention is also characterized in that the X-ray powder diffraction (XRPD) pattern includes diffraction peaks at diffraction angles (2θ±0.2°) of 4.8°, 13.3°, 13.5°, 17.2°, 19.0°, 19.4° and 21.6°, and also includes diffraction peaks at diffraction angles (2θ±0.2°) of 8.9°, 9.7°, 12.4° and 24.5°.

The crystalline form V of the present invention is also characterized in that the X-ray powder diffraction (XRPD) pattern includes diffraction peaks at diffraction angles (2θ±0.2°) 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 also includes diffraction peaks at diffraction angles (2θ±0.2°) of 10.2°, 23.0°, 23.5° and 26.6°.

In an embodiment, 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 V-form revenacin disclosed herein can be hydrated to obtain the I-form revenacin. The hydration is performed by contacting the V-form revenacin with a moist gas (usually air or nitrogen) or by slurrying the V-form revenacin in water.

The term "humidified gas" refers to a gas environment (usually air or nitrogen) with a relative humidity (RH) higher than 30%, preferably higher than 60%, more preferably higher than 90%.

The Form V of revenacin is exposed to a humidified gas at a temperature ranging from about room temperature to about 60°C, preferably in the range of room temperature to 40°C.

As mentioned above, the sixth aspect of the present invention relates to the crystalline form V of revenacin.

Example

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

X-ray Powder Diffraction (XRPD):

XRPD patterns were recorded on a Siemens D5000 diffractometer equipped with two symmetrically mounted vertical goniometers with a horizontal sample stage (Bragg-Brentano geometry), an X-ray tube, a high voltage generator (operated at 45 kV and 35 mA), and a standard scintillation detector. A nickel-filtered copper anode source was used, and the diffracted radiation was further monochromatized with a graphite crystal to avoid fluorescence effects. The diffraction patterns were recorded, including 2θ values from 2° to 50°, with a sampling rate of 0.02° per second and a step time of 1 second per step. The powder sample was pressed between two glass plates to form a thin film. The DIFFRAC Plus measurement software with EVA evaluation software (Bruker) was used to record the data and perform a preliminary analysis of the diffraction patterns. The equipment was regularly calibrated using quartz and silicon.

HPLC was used to analyze 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate (Compound X), referred to herein as impurity-a.

Chromatographic separation was performed using an Acquity BEH C18 column, 2.1×100 mm, 1.7 μm, at 35°C.

Mobile phase A: 0.1% trifluoroacetic acid in water.

Mobile phase A was prepared as follows: dilute with water and 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 was prepared by diluting with acetonitrile Ultra LC and 1 mL of trifluoroacetic acid in a 1000 mL volumetric flask.

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

The chromatograph was equipped with a UV-Vis detector (wavelength: 260 nm).

The flow rate was 0.5 mL/min.

The injection volume was 0.5 μL.

Solution

Diluent: Methanol

Test solution: 2 mg/mL revenacin sample in diluent.

0.10% impurity-a standard solution: 0.002 mg/mL impurity-a reference standard in diluent (0.10% refers to the test solution).

calculate

The quantification of impurity-a was performed as follows:

Cs: 0.10% impurity-a concentration (mg/mL)

Au: Area response of impurity-a in the test solution

Cu: Concentration of test solution (mg/mL)

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

Example 1: Preparation of piperidin-4-yl biphenyl-2-ylcarbamate (Compound V)

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

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

Example 2: Benzyl methyl-(2-oxoethyl)carbamate (Compound VI)

109.4g potassium carbonate (791 mmoles), 450mL water, 450mL tetrahydrofuran and 88.0g N-methylaminoacetaldehyde dimethyl acetal (739 mmoles) are loaded into the reactor. The resulting mixture is cooled to 0°C. 75mL benzyl chloroformate (528 mmoles) is slowly added and the mixture is allowed to warm to room temperature. The mixture is kept at room temperature until the reaction is complete. A two-phase mixture is obtained. The upper organic layer is separated, washed with 150mL HCl 1N at 25°C, and the mixture is allowed to settle. The upper organic layer is separated and mixed with 340mL water and 140mL 35% by weight HCl. The resulting mixture is stirred at 25°C for 20 hours. Then, 300mL toluene and 63.3g 25% by weight NaOH aqueous solution are added. A two-phase mixture is obtained. Layering, the organic layer is washed with 360mL 5% by weight NaHCO ₃ aqueous solution and 270mL water in turn. The organic layer was dried _{over Na2SO4} , filtered, and the solution was concentrated to dryness to give benzyl methyl-(2-oxoethyl)carbamate (Compound VI) as a light yellow oil.

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

60.0 g of piperidin-4-yl biphenyl-2-ylcarbamate (Compound V) (202 mmol) obtained in Example 1 was suspended in 240 mL of toluene. 49.1 g of benzyl methyl-(2-oxoethyl)carbamate (Compound VI (237 mmol)) obtained in Example 2 was added to the resulting suspension and 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) was slowly added, and the mixture was stirred at 25° C. for 6 hours. 180 mL of water and 153.6 g of 25 wt % NaOH were added, and the two-phase mixture was stirred at 25° C. for 1 hour. The layers were separated, and the organic layer was dried over Na ₂ SO ₄ , filtered and concentrated to give a toluene 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)

The benzene solution of biphenyl-2-yl-carbamic acid 1-[2-(benzyloxycarbonylmethylamino)ethyl]piperidin-4-yl ester (Compound VII) obtained in Example 3, 34.5g potassium formate (410 mmol), 8.0g palladium on activated carbon (5% by weight on dry basis) and 240mL isopropanol were loaded into the reactor. The reactor was fully purged with _N2 , and the mixture was stirred at 45°C for 6 hours. The palladium catalyst on activated carbon was filtered out through a diatomaceous earth pad, and the diatomaceous earth was rinsed with 80mL toluene. 280mL water and 47g 35% by weight of HCl were added to the filtered solution, and the resulting mixture was stirred at 25°C for 1 hour. The water layer was collected, toluene (320mL) and isopropanol (100mL) were added. The pH of the solution was adjusted to alkaline using a 25% by weight NaOH aqueous solution. The resulting mixture was stirred for 1 hour and separated. The organic layer was concentrated and 400mL of heptane was added at 25°C. The resulting suspension was cooled to 0°C, stirred for 30 minutes, filtered and dried in vacuo to give 53.7 g of white powdery 1-(2-methylaminoethyl)piperidin-4-ylbiphenyl-2-ylcarbamate (Compound VIII) (yield: 75%, HPLC purity: 99.8%).

Example 5: 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate (Compound X)

16.0 g of 4-carboxybenzaldehyde (Compound IX) (107 mmoles), 0.16 mL of dimethylformamide and 140 mL of toluene were added to the reactor. The resulting mixture was heated to 80°C. Keeping this temperature, 8.5 mL of thionyl chloride (117 mmoles) was added dropwise. The reaction mixture was stirred for 2 hours at this temperature. Then, the solvent was distilled under atmospheric pressure and 120 mL of heptane was added. The resulting suspension was cooled to 0°C, stirred for 1 hour and filtered. The obtained 4-formylbenzoyl chloride can be used in the next step without further purification.

23.0 g of biphenyl-2-ylcarbamic acid 1-(2-methylaminoethyl)piperidin-4-yl ester (Compound VIII) (65 mmol) obtained in Example 4, 92 mL of 2-methyltetrahydrofuran and 180 mL of 5 wt % Na ₂ CO ₃ aqueous solution were loaded into a reactor. The resulting mixture was cooled to 15° C. A solution of 4-formylbenzoyl chloride (obtained as above) in 180 mL of 2-methyltetrahydrofuran was slowly added to the mixture. The resulting reaction crude product was stirred at 30° C. for 1 hour. Layers were separated and the organic layer was washed with 140 mL of NaOH 1N. 190 mL of heptane was added to the organic layer. Then, the resulting suspension was filtered. The solid was dissolved under reflux with 400 mL of isopropanol and 150 mL of heptane, and the solution was stirred at this temperature for 30 minutes and then cooled to 10° C. The resulting suspension was stirred for 30 minutes, filtered, and dried under vacuum to give 25.0 g of 1-(2-[(4-formylbenzoyl)methylamino]ethyl)piperidin-4-ylbiphenyl-2-ylcarbamate (Compound X) as a white powder (yield: 80%, HPLC purity: 98.5%).

Example 6: Preparation of revenacin (Compound I)

20.0 g (41 mmoles) 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 mmoles) of 4-piperidinecarboxamide (Compound XI) and 360 mL of isopropanol were charged into a reactor. The resulting mixture was stirred at 60° C. for 2 hours. 270 mL of solvent was distilled off under reduced pressure, and another 270 mL of isopropanol was added. The resulting mixture was stirred at 60° C. for 4 hours and cooled to 5° C. 4.7 mL of glacial acetic acid and 17.5 g of sodium triacetoxyborohydride (82 mmoles) were added. The resulting mixture was stirred at 25° C. for 20 hours. Then, 60 mL of water was added, and the organic solvent was removed under vacuum. 150 mL of dichloromethane and 180 mL of HCl 1N were added. The mixture was stirred for 30 minutes, separated into layers, and the organic layer was discarded. 160mL of dichloromethane and 40mL of isopropanol were added to the water layer. The mixture was stirred for 30 minutes and the water layer was collected. 230mL of 2-methyltetrahydrofuran was added to the water layer, and the pH was adjusted to alkaline with 25% by weight of NaOH. The resulting mixture was stirred for 30 minutes and separated. 240mL of heptane was added to the organic layer. Then, the resulting suspension was filtered and the resulting solid was dried under vacuum. 21.3g of white solid was obtained (yield: 86%, HPLC purity: 99.3%, impurity-a: 0.24%).

Example 7: Preparation of Crystalline Acetone Solvate Form VI of Revenacin:

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

Example 8: Preparation of Crystalline Acetone Solvate Type VI of Revenacin:

2.0 g (3.4 mmol) of revenacin obtained in Example 6, 12 mL of acetone and 3 mL of ethanol were added at room temperature. The mixture was heated to reflux to obtain a solution. The solution was filtered to remove insoluble particles, cooled to 20° C. to 25° C. and stirred for at least 2 hours. The solid was filtered, washed with acetone and dried in vacuo. 1.2 g of crystalline acetone solvate type VI of revenacin (compound I) was obtained (yield 60%, HPLC purity 99.4%, impurity-a: 0.18%).

Example 9: Preparation of Crystalline Acetone Solvate Form VI of Revenacin:

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

Example 10: Preparation of crystalline acetone solvate of revenacin type VI:

6.7 g (11 mmoles) of revenacin obtained in Example 6, 40 mL of acetone and 4 mL of water were added at room temperature. The mixture was heated to reflux to obtain a solution. The solution was filtered to remove insoluble particles, cooled to 20° C. to 25° C. and stirred for at least 2 hours. The solid was filtered, washed with acetone and dried in vacuo. 4.2 g of crystalline acetone solvate type VI of revenacin (compound I) was obtained (yield 63%, HPLC purity 99.5%, impurity-a: 0.18%).

Example 11: Preparation of Crystal Form I of Revenacin:

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

Example 12: Preparation of Crystalline Form V of Revenacin:

The revenacin Form I sample obtained in Example 11 was vacuum dried at 45° C. for 8 hours to obtain revenacin Form V.

Example 13: Preparation of Crystal Form I of Revenacin:

The revenacin Form V sample obtained as in Example 12 was exposed to a nitrogen atmosphere of >90% RH at 25° C. for 8 hours. Crystalline Form I of revenacin was obtained.

Example 14: Preparation of Crystal Form I of Revenacin:

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

Comparative Example 1: Preparation of Form I of revenacin as described in Indian Patent Application IN202011029286

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

Claims (12)

1. A crystalline acetone solvate of raffinacin.

2. The crystalline acetone solvate of claim 1, containing 0.2 to 1.2 moles of acetone per mole Lei Fen of nacin, preferably 0.3 to 0.7 moles of acetone per mole Lei Fen nacin, and more preferably 0.5 moles of acetone per mole Lei Fen nacin.

3. The crystalline acetone solvate of claim 2, characterized by an X-ray powder diffraction (XRPD) pattern comprising diffraction peaks at diffraction angles (2Θ±0.2°) of 5.0 °, 7.6 °, 17.7 °, 18.6 °, 19.6 °, 20.0 ° and 21.0 °.

4. The crystalline acetone solvate of claim 3, wherein the X-ray powder diffraction (XRPD) pattern comprises diffraction peaks at diffraction angles (2Θ±0.2°) of 5.0 °, 7.6 °, 17.7 °, 18.6 °, 19.6 °, 20.0 ° and 21.0 °, and further comprises diffraction peaks at diffraction angles (2Θ±0.2°) of 14.3 °, 16.4 °, 17.4 °, 22.1 ° and 26.0 °.

5. The crystalline acetone solvate of claim 4, wherein the X-ray powder diffraction (XRPD) pattern comprises diffraction peaks at diffraction angles (2Θ±0.2°) 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 comprises diffraction peaks at diffraction angles (2Θ±0.2°) of 12.9 °, 18.1 °, 25.4 °, 28.2 ° and 28.8 °.

6. A process for preparing the crystalline acetone solvate of any one of claims 1 to 5, the process comprising

I) Lei Fen the extract is mixed with acetone or a mixture of acetone and other suitable solvents,

(Ii) Cooling the mixture prepared in step (i),

(Iii) Separating the crystalline acetone solvate.

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

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

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

10. The process for preparing form I Lei Fen of claim 9, further comprising the step of drying form I Lei Fen of the form V of Lei Fen of the form V.

11. Use of the crystalline acetone solvate according to any one of claims 1 to 5 for the preparation of Lei Fen nacin form I.

12. Use of the crystalline acetone solvate according to any one of claims 1 to 5 for the preparation of form V of Lei Fen nacin.