Continuous process for preparation of anticholinergic drugs

Abstract

To provide process for the preparation of anticholinergic agents.SOLUTION: The present invention relates to a novel process for the preparation of anticholinergic agents / drugs, such as umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide, ipratropium bromide (V) in a continuous flow mode in the presence of one or more polar aprotic solvents. The anticholinergic drugs are in a form suitable for use in inhalation in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD).SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention generally relates to a compound comprising umeclidinium bromide (I) (chemical name: 4-[hydroxyl(diphenyl)methyl]-1-[2-(phenylmethyl)oxy]ethyl]-1-azoniabicyclo[2.2.2]octane bromide), tiotropium bromide (II) (chemical name: 1α,2β,4β,7β)-7-[(hydroxy-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0]oxa ... 2,4 ]nonanebromide(1α,2β,4β,7β)-7-[(hydroxy-di-2-thienylacetyl)oxy]-9,9-dimethyl-3-oxa-9-azonia-tricyclo[3.3.1.0 2,4]nonane bromide, glycopyrronium bromide), glycopyrronium bromide (III) (chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide), acridinium bromide (IV) (chemical name: 3(R)-(2-hydroxy-2,2-dithien-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide The present invention relates to a novel process for the preparation of anticholinergic agents / drugs such as benzodiazepine (V) bromide (chemical name: [8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]oct-3-yl]-3-hydroxy-2-phenyl-propanoate), ipratropium bromide (V) (chemical name: [8-methyl-8-(1-methylethyl)-8-azoniabicyclo[3.2.1]oct-3-yl]-3-hydroxy-2-phenyl-propanoate) in a continuous flow mode, to the agents so prepared and to their use in medecine. The above anticholinergic drugs are used in the treatment of respiratory diseases such as asthma and chronic obstructive pulmonary disease (COPD).

[0002] [ka] [Background technology]

[0003] The compound of molecular structure (IV) shown above is known and is an anticholinergic drug of various uses, primarily for the treatment of chronic obstructive pulmonary disease (COPD) and asthma.

[0004] Umeclidinium bromide is a highly effective active pharmaceutical ingredient used to prepare pharmaceutical compositions administered as a dry powder for oral inhalation at a dose of 1 microgram per day. New compositions, combinations, administration forms (e.g., metered dose inhalers), and dosages using umeclidinium bromide are being developed.

[0005] WO2005 / 104745 relates to a process for the preparation of umeclidinium bromide, the reaction being carried out in a chlorinated solvent for between 16 and 24 hours.

[0006] [ka] Unsolvated crystalline polymorphic forms of umeclidinium bromide have been disclosed as an active pharmaceutical ingredient indicating that the compound can occur in various crystalline solid states with different physical properties (WO2014 / 027045, US9273001 B2). The preparation of a single pure crystalline form of pure umeclidinium bromide with a consistent level of crystallinity and chemical purity has been a challenge in the industry due to the compound's susceptibility to form solvates. Umeclidinium bromide solvates, namely methanol solvate (CZ27764 (Sanofi)), ethanol, 2-propanol, 2-methylpropan-1-ol, chlorobenzene, and p-xylene solvates (WO2014 / 027045, US9657011 B2), have been identified. In batch preparations of umeclidinium bromide, 1-propanol was used as the solvent to minimize solvate formation (WO2014 / 027045, US9657011 B2) and avoided the previously required resuspension of the compound in ethyl acetate, methanol, and water (Example 84, Method B, WO2005 / 104745). In batch preparations of umeclidinium bromide, a thick slurry was formed which was cooled and aged for several hours, then filtered and washed with n-proposal to yield the product (WO2014 / 027045, US9657011 B2).

[0007] EP3248970 relates to solid forms of umeclidinium bromide, in particular its nonsolvated form 1, crystalline forms A and B, and amorphous form. Form A is prepared by crystallization from a solution of umeclidinium bromide in a mixture of methanol and water in a volume ratio of 1:1 to 2:1. Form B is obtained from form A at temperatures above 180°C.

[0008] WO2018 / 087561 relates to a method for the preparation of high purity umeclidinium bromide, wherein the reaction is carried out for between 18 and 24 hours and the solvent is selected from cyclic ethers such as tetrahydrofuran, aromatic solvents, ketones such as toluene, acetone, protic solvents such as water, or combinations thereof to form a single pure crystalline form of the product with a consistent level of crystallinity and chemical purity.

[0009] Tiotropium bromide is a highly effective pharmaceutical ingredient administered in low (microgram) therapeutic doses by inhalation. Crystalline polymorphism of tiotropium bromide has been reported in various publications, including US6777423, EP14101445, EP16825442, EP1879888, EP2085396, EP1869035, and WO2011 / 01588, showing that the compound can occur in various solid forms with different physical properties.

[0010] EP 2814827 describes a process by which tiotropium bromide is obtained in a single pure anhydrous crystalline form by crystallization in a mixture containing methanol and acetone.

[0011] RU 2453547 provides a crystalline hemi-n-propanol solvate of tiotropium bromide, designated Form 12, which was prepared by crystallization from a solution of tiotropium bromide in n-propanol.

[0012] Against the backdrop of stringent regulations, pharmaceutical companies are focusing on developing new ways to deliver more efficient technologies to meet the demands of the competitive pharmaceutical and healthcare industry. Flow chemistry techniques and systems have seen tremendous growth in the pharmaceutical industry in recent years. The pharmaceutical industry is focused on improving existing chemical reactions and accessing new chemical entities with the help of flow chemistry.

[0013] Amid increasing competition in the pharmaceutical industry, companies are focusing on rapid development, seamless discovery, and optimization of potential drug compounds, thereby reducing time to market, are some of the key drivers leading to the rapid adoption of flow chemistry.

[0014] US8865903 relates to a continuous flow process for the preparation of quaternary ammonium salts such as tiotropium (II) bromide, glycopyrronium (III) bromide or ipratropium (V) bromide in high yield and purity in polar aprotic solvents selected from the group consisting of amides, nitriles and sulphoxides such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, dimethylsulfoxide. The invention explains that dichloromethane is a poor solvent for the final product and may precipitate in the continuous flow reactor and block the channels. US8865903 shows that the temperature can be increased by replacing dichloromethane with methanol, but the conversion is rather low. Summary of the Invention [Problem to be solved by the invention]

[0015] To meet market demand, the present inventors have recognized that a need exists for more efficient methods for preparing anticholinergic drugs, particularly methods that offer advantages over known methods for the preparation of anticholinergic drugs.

[0016] The present inventors have contemplated just such a method. The advantages of the present invention include, but are not limited to, a highly efficient method with reduced reaction time, improved operability, temperature control, yield, and reduced cost of the final product, which is important for optimizing the synthetic method. Notably, even small improvements in reaction design can lead to significant savings in large-scale production.

[0017] Thus, the present invention discloses a continuous flow process for the preparation of anticholinergic drugs such as umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide or ipratropium bromide in one or more polar protic solvents, preferably 1-propanol, water or a mixture of 1-propanol and water, to form a single pure crystalline form with good yield and excellent chemical purity.

[0018] The present invention provides a process for the preparation of anticholinergic drugs in a continuous flow mode in the presence of one or more polar protic solvents. [Means for solving the problem]

[0019] According to the present invention, there is provided a process for preparing an anticholinergic drug, the process being carried out in a continuous flow mode using one or more polar protic solvents.

[0020] According to the present invention, there is provided a process for preparing one or more anticholinergic drugs, such as umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide or ipratropium bromide, in one or more polar protic solvents, such as 1-propanol, water or a mixture of 1-propanol and water, in a continuous flow mode.

[0021] Contrary to the state of the art (US8865903) which describes only polar aprotic solvents which the inventors found to be suitable for a continuous process approach in the preparation of quaternary ammonium salts such as tiotropium bromide (II), glycopyrronium bromide (III) or ipratropium bromide (V), the inventors of the present invention have surprisingly discovered that one or more polar protic solvents such as 1-propanol, water or a mixture of 1-propanol and water are used in an efficient continuous flow mode process for the preparation of anticholinergic drugs in very short reaction times and without the need for additional resuspension or recrystallization steps required in conventional methods.

[0022] The inventors of the present invention have found that the reaction time of the method disclosed in the present invention is drastically reduced from 16-24 hours to 1-20 minutes. The anticholinergic drug obtained using the novel method described in the present invention can be in a single pure solid crystalline form with consistent levels of crystallinity and chemical purity.

[0023] The anticholinergic drug obtained from the method of the present invention can be preferably formulated with at least one pharma- ceutically acceptable excipient, and the composition is suitable for inhalation.Preferably, the pharmaceutical composition comprises the anticholinergic drug obtained by the method of the present invention and one or more additional active pharmaceutical ingredients.Preferably, the pharmaceutical composition can be in the form of dry powder, solution or suspension.

[0024] [Detailed Description of the Invention] The present invention provides a process for the preparation of anticholinergic drugs in a continuous flow mode in the presence of one or more polar protic solvents.

[0025] Anticholinergic agents disclosed in the present invention include, but are not limited to, umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide and ipratropium bromide.

[0026] According to another aspect of the present invention, there is provided a process for the preparation of umeclidinium bromide by reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) with ((2-bromoethoxy)methyl)benzene (VII) in one or more polar protic solvents in a continuous flow mode.

[0027] Any polar protic solvent that does not form solvates with the anticholinergics disclosed in this application may be used in the methods of the present invention.

[0028] The one or more polar protic solvents used in the methods disclosed herein include, but are not limited to, 1-propanol, water, a mixture of 1-propanol and water, or any isomer of propanol or butanol, e.g., n-propanol, n-butanol, etc.

[0029] Preferably, the ratio of 1-propanol to water in the mixture of 1-propanol and water ranges from about 30:1 to 1:1.2, preferably about 25:1.

[0030] Those skilled in the art can determine the amount of starting material or chemicals, such as cyclic tertiary amine, alkylating agent, etc., used in the method of preparing anticholinergic drugs disclosed in the present invention. For example, the concentration of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) used in the process of preparing umeclidinium bromide disclosed in the present invention depends on the solubility of the compound at the specific temperature at which the reaction is carried out. Preferably, a concentration ranging from about 1 to about 10 mole / L equivalent of ((2-bromoethoxy)methyl)benzene (VII) is used in this method.

[0031] Preferably, the novel methods of the present invention do not require further resuspension or recrystallization of the drug to obtain the unsolvated form.

[0032] The methods for the preparation of anticholinergic agents / drugs disclosed in the present invention may include using one or more flow procedures to carry out a continuous flow mode process.

[0033] The term "flow procedure" as used herein refers to the use of specific equipment and / or specific conditions necessary to allow the continuous execution of those procedures, e.g., chemical synthesis. As used herein, flow procedure does not include traditional batch processes. Preferably, a continuous reactor is used to carry the materials as a flowing stream, as will be understood by those skilled in the art.

[0034] The process may be defined as continuous in that it is characterized by the continuous feeding of reactants to a reactor and the continuous formation and discharge of a product stream.

[0035] The continuous process disclosed in this invention can be advantageous for a number of reasons, including, but not limited to, improved product purity and yield, and reduced effluents, making current processes more environmentally friendly.

[0036] The term "continuous flow reactor" is used to refer to those reactors that allow chemical reactions to occur in a continuous flow. Continuous flow reactors are also known as continuous tubular reactors. Continuous flow reactors can include pipe reactors, plug flow reactors, tube reactors or another commercially available continuous flow reactor, or a combination of two or more such reactors.

[0037] In the process for preparation of anticholinergic drugs / drugs disclosed in this invention, the starting materials or chemicals such as, for example, cyclic tertiary amines, alkylating agents, etc. are preferably in the form of a solution in a suitable solvent such as, for example, a polar protic solvent as disclosed in this invention, which are continuously fed to a continuous flow reactor.

[0038] In the process of preparing umeclidinium bromide disclosed in the present invention, a solution containing 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) is preferably prepared in a polar protic solvent such as 1-propanol, water, or a mixture of 1-propanol and water. The solutions of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) are introduced separately into the continuous flow reactor or, alternatively, the solutions containing the reactants can be premixed before being introduced into the continuous flow reactor.

[0039] The temperature at which the reaction is carried out in a polar protic solvent such as 1-propanol, water, or a mixture of 1-propanol and water preferably ranges from about 120° C. to about 200° C. Preferably, the reaction temperature is greater than 140° C. Preferably, the reaction temperature ranges from about 140° C. to about 180° C. Preferably, the reaction temperature ranges from greater than 140° C. to 180° C. More preferably, the reaction temperature ranges from about 141° C. to about 180° C. Most preferably, the reaction temperature ranges from about 150° C. to 180° C.

[0040] Surprisingly, despite the extreme temperatures used in the process of the present invention, no significant impurity formation or decomposition was observed in the case of the process for the preparation of umeclidinium bromide of the present invention between polar protic solvents (water and / or 1-propanol) and alkylating agents such as ((2-bromoethoxy)methyl)benzene.

[0041] Surprisingly, the inventors have also found that the use of polar protic solvents such as 1-propanol, water, or mixtures of 1-propanol and water in the continuous flow mode process of the invention results in short reaction times, good yields and high purity, even at the extreme temperatures mentioned above.

[0042] The inventors of the present invention have found that the reaction time of the method disclosed in the present invention is extremely shortened from 16-24 hours to 1-20 minutes. As a result, the reaction time of the method of the present invention is preferably in the range of about 1 minute to about 20 minutes, preferably in the range of about 2 minutes to about 20 minutes, more preferably in the range of about 5 minutes to about 20 minutes, and most preferably in the range of about 5 minutes to about 10 minutes.

[0043] The flow rate may be adjusted to obtain an optimal residence time of the reaction mixture in the continuous flow reactor in order to drive the reaction to completion. The flow rate of the reaction mixture through one or more continuous flow reactors may be controlled, altered, or adjusted depending on the chemical reaction being carried out and the reactor model being used.

[0044] The range of flow rates and pressures used is characterized by the reactor model. A skilled person can determine the flow rate and pressure range depending on the reactor model being used. For example, for a custom-built stainless steel coil reactor, the flow rate typically ranges from about 0.11 to about 0.84 mL / min and the pressure ranges from about 3 to about 34 bar.

[0045] Preferably, in the method disclosed in the present invention, the product is isolated by removing the solvent from the reaction mixture. The reaction mixture obtained from the reactor should be concentrated under reduced pressure. An anti-solvent, preferably water, should be added to the concentrated product to form an aqueous suspension. The aqueous suspension is preferably cooled to a temperature ranging from about 0°C to about 5°C, or from above 0°C to about 5°C, after which the solid crystalline form of the product is isolated, preferably by filtration. The filtered product should be washed and / or dried, preferably under reduced pressure, so that the product can be obtained in a yield of up to 80%. The purity of the product obtained by following the procedure described in the present invention is typically ≧98.5% in single crystalline form by HPLC. The product obtained is preferably umeclidinium bromide.

[0046] The X-ray powder diffraction (XRPD) diffractograms, differential scanning calorimetry (DSC) thermograms, thermogravimetric analysis (TGA) thermograms and HPLC chromatograms used for the analysis of the obtained products are in accordance with the state of the art.

[0047] In a particularly preferred embodiment, the methods disclosed in the present invention are useful for the preparation of umeclidinium bromide.

[0048] The anticholinergic drugs such as umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide or ipratropium bromide obtained by the methods disclosed in the present invention may be further micronized to provide a material with an appropriate particle size suitable for inhalation.

[0049] The present invention also provides an anticholinergic drug, such as umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide or ipratropium bromide, obtainable by the novel process of the present invention. In a preferred embodiment of the present invention, the anticholinergic drug is umeclidinium bromide.

[0050] Preferably, the anticholinergic is in a form suitable for inhalation.The crystalline form of the anticholinergic obtained by the process of the invention may be in a non-solvated form.

[0051] The present invention also provides a pharmaceutical composition comprising an anticholinergic drug as disclosed herein, preferably umeclidinium bromide obtained by the method of the present invention, and at least one pharma- ceutical acceptable excipient.The pharmaceutical composition is preferably suitable for inhalation in the form of dry powder, solution or suspension.The pharmaceutical composition of the present invention may further comprise one or more additional active pharmaceutical ingredients.

[0052] The one or more active pharmaceutical ingredients used in the pharmaceutical compositions disclosed herein include, but are not limited to, Vilanterol trifenatate, Fluticasone furoate, or a combination thereof.

[0053] The pharmaceutical composition may be prepared by mixing an anticholinergic agent disclosed herein, preferably umeclidinium bromide obtained by the novel process of the present invention, and one or more pharma- ceutical acceptable excipients.

[0054] The pharmaceutical composition of the invention is for use as a medicament, preferably for use in treating a respiratory disease such as asthma or chronic obstructive pulmonary disease (COPD). The invention further provides a method of treatment in a mammal, such as a human, for treating a respiratory, inflammatory or obstructive airways disease, such as COPD and asthma, comprising administration of a therapeutically effective amount of a pharmaceutical composition of the invention. The dosage and method of administration can be determined by a person skilled in the art based on general knowledge.

[0055] Pharmaceutical compositions may be formulated to be delivered by any suitable route, including oral, intravenous, parenteral, inhalation, intranasal, topical, subcutaneous, or intramuscular. The pharmaceutical compositions of the present invention may be administered by any suitable method used to deliver drugs to the respiratory tract. Thus, the compositions of the present invention may be administered using metered dose inhalers (MDIs), dry powder inhalers (DPIs), nebulizers, nasal sprays, nasal drops, insufflation powders, sprays and spray patches.

[0056] The invention will now be illustrated, without being limited, by the following examples.

[0057] Example 1 (Preparation of Umeclidinium Bromide) A solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.3 g, 1.0 mmol) and ((2-bromoethoxy)methyl)benzene (0.24 mL, 1.5 mmol) in 1-propanol (30 mL) was injected into a stainless steel coil continuous flow reactor (2.1 mL) at a rate of 0.11 mL / min. The reactor temperature was 180 °C. The reaction time was 20 min. The solution coming out of the continuous flow reactor was collected (HPLC conversion: 93.8%) and concentrated under reduced pressure to a volume of 4 mL. The resulting suspension was cooled to 5 °C and stirred for 1 h. The product was filtered, washed twice with methyl tert-butyl ether (MTBE) and dried under reduced pressure (white powder, 0.34 g, 80%). The product was analyzed by HPLC and had a purity of 98.5%.

[0058] Example 2 (Preparation of Umeclidinium Bromide) A solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.34 g, 1.2 mmol) and ((2-bromoethoxy)methyl)benzene (0.27 mL, 1.7 mmol) in 1-propanol (10 mL) was injected into a stainless steel coil continuous flow reactor (2.1 mL) at a rate of 0.42 mL / min. The temperature of the reactor was 180 °C. The reaction time was 5 min. The solution coming out of the continuous flow reactor was collected (HPLC conversion: 97.3%) and concentrated under reduced pressure to a volume of 4 mL. The resulting suspension was cooled to 5 °C and stirred for 1 h. The product was filtered, washed twice with methyl tert-butyl ether (MTBE) and dried under reduced pressure (white powder, 0.36 g, 75%). The product was analyzed by HPLC and had a purity of 98.9%.

[0059] Example 3 (Preparation of Umeclidinium Bromide) A solution containing 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.3 g, 1.0 mmol) and ((2-bromoethoxy)methyl)benzene (0.24 mL, 1.5 mmol) in 1-propanol (30 mL) was injected into a stainless steel coil continuous flow reactor (2.1 mL) at a rate of 0.42 mL / min. The reactor temperature was 180 °C. The reaction time was 5 min. The solution exiting the continuous flow reactor was collected, diluted, and analyzed by HPLC, giving a conversion of 93.2%.

[0060] Example 4 (Preparation of Umeclidinium Bromide) A solution containing 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (0.3 g, 1.0 mmol) and ((2-bromoethoxy)methyl)benzene (0.24 mL, 1.5 mmol) in 1-propanol (30 mL) was injected into a stainless steel coil continuous flow reactor (2.1 mL) at a rate of 0.21 mL / min. The reactor temperature was 150 °C. The reaction time was 10 min. The solution exiting the continuous flow reactor was collected, diluted, and analyzed by HPLC, giving a conversion of 88.5%.

[0061] The invention described in the present specification is further described below. [Note] (1) A method for preparing an anticholinergic drug which is a tertiary amine precursor of a quaternary amine salt or a quaternary amine salt, characterized in that the method is carried out in a continuous flow mode using a solvent consisting exclusively of one or more polar protic solvents. (2) 2. The method for preparing an anticholinergic drug according to claim 1, characterized in that the anticholinergic drug is selected from the group consisting of umeclidinium bromide, tiotropium bromide, glycopyrronium bromide, aclidinium bromide and ipratropium bromide. (3) 3. The method for preparing an anticholinergic drug according to claim 1 or 2, wherein the anticholinergic drug is umeclidinium bromide. (4) 3. A process for the preparation of an anticholinergic drug according to claim 3, comprising the reaction of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) with ((2-bromoethoxy)methyl)benzene (VII) in the presence of one or more polar protic solvents. (5) 5. A method for preparing an anticholinergic drug according to claim 4, characterized in that 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) in solution are continuously fed into one or more continuous flow reactors. (6) 6. A method for preparing an anticholinergic drug according to any one of claims 1 to 5, characterized in that the solvent is 1-propanol, water or a mixture of 1-propanol and water. (7) 7. The method for preparing an anticholinergic drug according to claim 6, wherein the ratio of 1-propanol to water in the mixture is in the range of 30:1 to 1:1.2, or 25:1. (8) 8. A method for preparing an anticholinergic drug according to any one of claims 5 to 7, characterized in that the solutions comprising 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) in one or more polar protic solvents are fed individually to the continuous flow reactor or a plurality of the solutions are premixed before being fed to the continuous flow reactor. (9) 9. A method for preparing an anticholinergic drug according to any one of claims 1 to 8, characterized in that the method is carried out at a reaction temperature in the range of 120°C to 200°C, or in the range of 140°C to 200°C. (10) 10. A process for the preparation of an anticholinergic drug according to any one of claims 1 to 9, characterized in that the process is carried out at a reaction temperature in the range of 140°C to 180°C, or in the range of 150°C to 180°C. (11) 11. A method for preparing an anticholinergic drug according to any one of 1 to 10, characterized in that the method is carried out with a reaction time ranging from 1 minute to 20 minutes, or from 5 minutes to 10 minutes. (12) (i) forming a concentrate of the solution comprising the anticholinergic drug from the one or more continuous flow reactors; (ii) adding water to obtain an aqueous suspension; (iii) cooling to a temperature of 0°C to 5°C; and (iv) isolating said anticholinergic drug in solid crystalline form, 6. The method for preparing an anticholinergic drug according to claim 5, further comprising isolating the anticholinergic drug. (13) 13. A method for preparing an anticholinergic drug according to any one of 1 to 12, further comprising micronizing the anticholinergic drug. (14) 13. The method for preparing an anticholinergic drug according to claim 12, wherein a concentrate of the solution containing the anticholinergic drug is formed from the one or more continuous flow reactors by reducing pressure. (15) 13. The method for preparing an anticholinergic drug according to claim 12, characterized in that the anticholinergic drug is isolated by filtration.

Claims

[Claim 1] A process for the preparation of an anticholinergic drug, characterized in that the process is carried out in continuous flow mode using a solvent consisting exclusively of one or more polar protic solvents.

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