Continuous manufacturing method of anticholinergic drugs

Abstract

The present invention relates to a novel method for producing anticholinergic agents / drugs such as umeclidinium bromide, tiotropium bromide, glycopyronium bromide, aclidinium bromide, and ipratropium bromide (V) in a continuous flow manner in the presence of one or more polar protic solvents. The anticholinergic drugs are in a form suitable for use by inhalation in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD).

Description

Technology Field

[0001] The present invention generally comprises 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 2,4 A novel method for preparing anticholinergics / drugs such as ]nonane bromide), glycopyronium bromide(III) (chemical name: 3-(2-cyclopentyl-2-hydroxy-2-phenylacetoxy)-1,1-dimethylpyrrolidinium bromide), aclidinium bromide(IV) (chemical name: 3(R)-(2-hydroxy-2,2-dithiene-2-ylacetoxy)-1-(3-phenoxypropyl)-1-azoniabicyclo[2.2.2]octane bromide), and 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 manner, and the anticholinergics / drugs prepared thus, and their in pharmaceuticals. This concerns usage. The anticholinergic drugs listed above are used in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD).

[0002] Background Technology

[0003] Compound (IV) of the molecular structure described above is a known anticholinergic drug with various indications and is mainly used in 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 microgram dose once daily. New compositions, combinations, dosage forms (e.g., metered-dose inhalers), and dosages using umeclidinium bromide are being developed.

[0005] WO 2005 / 104745 relates to a method for preparing umeclidinium bromide, wherein the reaction is carried out in a chlorinated solvent for a period of 16 to 24 hours:

[0006]

[0007] Non-solvent crystalline polymorphic forms of umeclidinium bromide are disclosed as active pharmaceutical ingredients (WO 2014 / 027045, US 9273001 B2), and said compounds can give rise to various crystalline solid-state forms with distinct physical properties. Preparing pure umeclidinium bromide in a single pure crystalline form with consistent levels of crystallinity and chemical purity has been a challenge in the industry due to the high sensitivity of compounds forming solvates. Eumeclidinium bromide solvates, namely methanol solvate (CZ27764 (Sanofi)), ethanol, 2-propanol, 2-methylpropan-1-ol, chlorobenzene, and p-xylene solvates (WO 2014 / 027045, US 9657011 B2), have been identified. In the batch preparation of umeclidinium bromide, 1-propanol has been used as a solvent to minimize solvate formation (WO 2014 / 027045, US 9657011 B2), thereby avoiding the resuspension of the compound in ethyl acetate, methanol, and water that was previously required (Method B of WO 2005 / 104745, Example 84). In the batch preparation of umeclidinium bromide, a thick slurry is formed, which is cooled and aged for several hours to several hours, then filtered and washed with n-propanol to obtain the product (WO 2014 / 027045, US 9657011 B2).

[0008] EP3248970 relates to solid forms of umeclidinium bromide, in particular to its non-solvent forms 1, crystalline forms A and B, and amorphous forms. Form A is prepared by crystallizing 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 a temperature higher than 180°C.

[0009] WO 2018 / 087561 relates to a method for producing high-purity umeclidinium bromide, wherein the reaction is carried out for a period of 18 to 24 hours, and the solvent is selected from cyclic ethers such as tetrahydrofuran, aromatic solvents such as toluene, ketones such as acetone, and protionic solvents such as water or combinations thereof to form a product having a single pure crystalline form having a consistent level of crystallinity and chemical purity.

[0010] Tiotropium bromide is a highly effective active pharmaceutical ingredient administered at low (microgram) therapeutic doses by inhalation. Crystalline polymorphic forms of tiotropium bromide have been reported in various published literature, including US6777423, EP14101445, EP16825442, EP1879888, EP2085396, EP1869035, and WO2011 / 01588, demonstrating that the compound can produce various solid forms with distinct physical properties.

[0011] EP2814827 describes a method for obtaining tiotropium bromide in a single pure anhydrous crystalline form by crystallization in a mixture containing methanol and acetone.

[0012] RU2453547 provides a crystalline hemi-n-propanol solvate of tiotropium bromide designated as form 12, prepared by crystallization from a solution of tiotropium bromide in n-propanol.

[0013] Against the backdrop of strict regulations, pharmaceutical companies are focusing on developing new methods to provide more efficient technologies to meet the demands of the highly competitive pharmaceutical and medical industries. Flow chemistry technologies and systems have witnessed tremendous growth in the pharmaceutical industry in recent years. The pharmaceutical sector is focusing on improving existing chemical reactions and accessing new chemicals with the help of flow chemistry.

[0014] As competition intensifies in the pharmaceutical sector, companies are focusing on rapid development, seamless discovery, and the optimization of potential drug compounds; accordingly, shortening time-to-market is some of the key drivers leading to the rapid adoption of flow chemistry.

[0015] US8865903 relates to a continuous-flow method for producing quaternary ammonium salts, such as tiotropium bromide (II), glycopyronium bromide (III), or ipratropium bromide (V), in a polar aprotic solvent selected from the group consisting of amides, nitriles, and sulfoxides, such as acetonitrile, dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and dimethyl sulfoxide, with high yield and purity. The invention states that dichloromethane is a poor solvent for the final product, and that it can precipitate in a continuous-flow reactor and block the channels. US8865903 teaches that replacing dichloromethane with methanol can increase the temperature, but the conversion rate is lower. The problem to be solved

[0016] To meet market demands, the inventors recognized the need for a more efficient method for manufacturing anticholinergic drugs. In particular, they recognized the need for a method that offers advantages over known methods for manufacturing anticholinergic agents. The inventors have now devised such a method. The advantages of the present invention include, but are not limited to, a highly efficient method having reduced reaction time of the final product, improved operability, temperature control, yield, and cost reduction, which are important for optimizing any synthesis process. In particular, significant savings can be achieved in large-scale production with only minor improvements to the reaction design.

[0017] Accordingly, the present invention discloses a method for continuous flow preparation of anticholinergic drugs such as umeclidinium bromide, tiotropium bromide, glycopyronium 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, in order to form a single pure crystalline form having high yield and excellent chemical purity. means of solving the problem

[0018] Summary of the Invention:

[0019] According to the present invention, a method for producing an anticholinergic agent is provided, which is carried out in a continuous flow manner using one or more polar proton solvents.

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

[0021] Unlike the prior art (US8865903), which describes that only polar aprotic solvents are suitable for a continuous process approach in the production of quaternary ammonium salts such as tiotropium bromide (II), glycopyronium 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, can be used in a continuous flow process to provide an efficient continuous production method for producing anticholinergic drugs with a greatly reduced reaction time without the need for additional resuspension or recrystallization steps required in the prior art production method.

[0022] The inventors of the present invention have discovered that the reaction time of the manufacturing method disclosed in the present invention is significantly shortened from 16-24 hours to 1-20 minutes. The anticholinergic obtained using the novel manufacturing method described in the present invention may be a single pure solid crystalline form having a consistent level of crystallinity and chemical purity.

[0023] The anticholinergic obtained from the manufacturing method of the present invention may preferably be formulated with at least one pharmaceutically acceptable additive, said composition suitable for inhalation. Preferably, said pharmaceutical composition comprises the anticholinergic obtained by the manufacturing method of the present invention and one or more additional active pharmaceutical ingredients. Preferably, said pharmaceutical composition may be in the form of a dry powder, a solution, or a suspension. Specific details for implementing the invention

[0024] Detailed description of the invention:

[0025] The present invention provides a method for preparing an anticholinergic drug in a continuous flow manner in the presence of one or more polar proton solvents.

[0026] The anticholinergic drugs disclosed in the present invention include, but are not limited to, umeclidinium bromide, tiotropium bromide, glycopyronium bromide, aclidinium bromide, and ipratropium bromide.

[0027] According to another aspect of the present invention, a method for preparing umeclidinium bromide is provided, comprising reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) with ((2-bromoethoxy)methyl)benzene (VII) in a continuous flow manner in one or more polar protic solvents.

[0028] Any polar protic solvent that does not form a solvate with the anticholinergic drug disclosed in this application may be used in the manufacturing method of the present invention.

[0029] One or more polar protic solvents used in the manufacturing method disclosed in the present invention include, but are not limited to, 1-propanol, water, a mixture of 1-propanol and water, or any isomer of propanol or butanol such as n-propanol and n-butanol.

[0030] Preferably, in a mixture of 1-propanol and water, the ratio of 1-propanol to water is in the range of about 30:1 to 1:1.2, preferably about 25:1.

[0031] A person skilled in the art can determine the amount of starting materials or chemicals, such as cyclic tertiary amines and alkylating agents, used in the method for preparing the anticholinergic drug disclosed in the present invention. For example, in the method for preparing umeclidinium bromide disclosed in the present invention, the concentration of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) used depends on the solubility of said compound at a specific temperature at which the reaction is performed. Preferably, a concentration of ((2-bromoethoxy)methyl)benzene (VII) in the range of about 1 to about 10 mol / L equivalents may be used in said method.

[0032] Preferably, the novel manufacturing method of the present invention does not require additional resuspending or recrystallization of the drug to obtain a non-solvent form.

[0033] The method for manufacturing an anticholinergic / drug disclosed in the present invention may include using one or more flow procedures to perform a continuous flow process.

[0034] As used herein, the term "flow procedures" refers to procedures necessary to enable the continuous execution of chemical synthesis, such as the use of specific devices and / or specific conditions. The flow procedures used herein do not include traditional batch processes. Preferably, as understood by those skilled in the art, a continuous reactor is used to transport material as a flowing stream.

[0035] The manufacturing method can be defined as continuous in that it is characterized by the continuous supply of reactants to the reactor along with the continuous formation and discharge of a product stream.

[0036] The continuous manufacturing method disclosed in the present invention is advantageous for many reasons, including but not limited to improved purity and yield of the product and reduced effluent; thus, the manufacturing method of the present invention is made more environmentally friendly.

[0037] The term "continuous flow reactor" is used to refer to a reactor capable of carrying out a chemical reaction in a continuous flow. A continuous flow reactor may also be known as a continuous tubular reactor. A continuous flow reactor may include a pipe reactor, a plug flow reactor, a tube reactor, or other commercially available continuous flow reactors, or a combination of two or more of these reactors.

[0038] In the method for preparing an anticholinergic / drug disclosed in the present invention, starting materials or chemicals such as cyclic tertiary amines and alkylating agents are preferably in the form of solutions dissolved in a suitable solvent such as the polar protic solvent disclosed in the present invention and are continuously supplied to a continuous flow reactor.

[0039] In the method for preparing umeclidinium bromide disclosed in the present invention, a solution comprising 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 solution of 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) is fed separately to a continuous flow reactor, or alternatively, the solution comprising said reactants may be pre-mixed before being introduced into the continuous flow reactor.

[0040] 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, is preferably in the range of about 120°C to about 200°C. Preferably, the reaction temperature is greater than 140°C. Preferably, the reaction temperature is in the range of about 140°C to about 180°C. Preferably, the reaction temperature is in the range of greater than 140°C to 180°C. More preferably, the reaction temperature is in the range of about 141°C to about 180°C. Most preferably, the reaction temperature is in the range of about 150°C to 180°C.

[0041] Surprisingly, in the case of the method for preparing umeclidinium bromide of the present invention, no significant impurity formation or decomposition was observed between the polar protic solvent (water or / and 1-propanol) and the alkylating agent such as ((2-bromoethoxy)methyl)benzene, despite the extreme temperature used in the method for preparing the present invention.

[0042] Surprisingly, the inventors also discovered that the use of a polar protic solvent, such as 1-propanol, water, or a mixture of 1-propanol and water, in the continuous flow method of the present invention results in reduced reaction time, excellent yield, and high purity at the extreme temperatures specified above.

[0043] The inventors of the present invention have discovered that the reaction time of the manufacturing method disclosed in the present invention is significantly shortened from 16-24 hours to 1-20 minutes. Accordingly, the reaction time of the manufacturing 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.

[0044] The flow rate can be controlled to obtain the optimal residence time of the reaction mixture in a continuous flow reactor for the purpose of completing the reaction. The flow rate of the reaction mixture through one or more continuous flow reactors can be controlled, changed, or adjusted depending on the chemical reaction being performed and the reactor model used.

[0045] The flow and pressure ranges used are characteristics of the reaction model. Those skilled in the art can determine the flow rate and pressure ranges depending on the reactor model used. For example, in the case of a custom-made stainless steel coil reactor, the flow rate is typically in the range of about 0.11 to about 0.84 mL / min, and the pressure is in the range of about 3 to about 34 bar.

[0046] Preferably, in the manufacturing 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 may be concentrated under reduced pressure. An antisolvent, preferably water, may be added to the concentrated product to form an aqueous suspension. The aqueous suspension may preferably be cooled to a temperature in the range of about 0°C to about 5°C or greater than 0°C to about 5°C, and the product in solid crystalline form is then isolated, preferably by filtration. The filtered product is washed and / or preferably dried under reduced pressure to obtain the product in a yield of up to 80%. The purity of the product obtained according to the method described in the present invention is typically in a single crystalline form of ≥98.5% by HPLC. The obtained product is preferably umeclidinium bromide.

[0047] The X-ray powder diffraction (XRPD) diffractogram, differential scanning calorimetry (DSC) thermogram, thermogravimetric analysis (TGA) thermogram, and HPLC chromatogram used to analyze the obtained product are in accordance with the art of this field.

[0048] In a particularly preferred embodiment, the manufacturing method disclosed in the present invention is useful for the production of umeclidinium bromide.

[0049] Anticholinergic agents such as umeclidinium bromide, tiotropium bromide, glycopyronium bromide, aclidinium bromide, or ipratropium bromide obtained by the manufacturing method disclosed in the present invention can be further micronized to obtain a material having a suitable particle size suitable for inhalation.

[0050] The present invention also provides an anticholinergic drug such as umeclidinium bromide, tiotropium bromide, glycopyronium bromide, aclidinium bromide, or ipratropium bromide obtained by a novel manufacturing method of the present invention. In a preferred embodiment of the present invention, the anticholinergic drug is umeclidinium bromide.

[0051] Preferably, the anticholinergic drug is in a form suitable for inhalation. The crystalline form of the anticholinergic drug obtained by the manufacturing method of the present invention may be in a non-solvent form.

[0052] The present invention also provides a pharmaceutical composition comprising the anticholinergic drug disclosed herein, preferably umeclidinium bromide obtained by the method of preparation of the present invention, and one or more pharmaceutically acceptable additives. The pharmaceutical composition is suitable for inhalation and is preferably in the form of a dry powder, solution, or suspension. The pharmaceutical composition of the present invention may further comprise one or more additional active pharmaceutical ingredients.

[0053] One or more active pharmaceutical ingredients used in the pharmaceutical composition disclosed in the present invention include, but are not limited to, vilanterol triphenatate, fluticasone furoate, or combinations thereof.

[0054] The above pharmaceutical composition may be prepared by mixing an anticholinergic drug disclosed herein, preferably umeclidinium bromide obtained by a novel manufacturing method of the present invention, and one or more pharmaceutically acceptable additives.

[0055] The pharmaceutical composition of the present invention is intended for use as a medicinal product, preferably for use in the treatment of respiratory diseases such as asthma or chronic obstructive pulmonary disease (COPD). The present invention also provides a method for treating respiratory, inflammatory, or obstructive airway diseases such as COPD and asthma in mammals such as humans, said method comprising administering a therapeutically effective amount of the pharmaceutical composition of the present invention.

[0056] The dosage and method of administration can be determined by a person skilled in the art based on ordinary knowledge.

[0057] The pharmaceutical composition may be formulated to be delivered by any suitable route, including oral, intravenous, parenteral, inhalation, nasal, topical, subcutaneous, or intramuscular.

[0058] The pharmaceutical composition of the present invention may be administered by any suitable method used for drug delivery into the respiratory tract. Accordingly, the composition of the present invention may be administered using metered dose inhalers (MDI), dry powder inhalers (DPI), nebulizers, nasal sprays, nasal drops, insufflation powders, sprays, and spray patches.

[0059] The present invention is explained by the following examples, but is not limited thereto.

[0060] Example 1

[0061] Preparation of Eumeclidinium Bromide

[0062] 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 fed into a stainless steel coil continuous flow reactor (2.1 mL) at a flow rate of 0.11 mL / min. The reactor temperature was 180°C. The reaction time was 20 minutes. The solution exiting the continuous flow reactor was collected (conversion by HPLC: 93.8%) and concentrated to a volume of 4 mL under reduced pressure. The resulting suspension was cooled to 5°C and stirred for 1 hour. The product was filtered, washed twice with methyl tert-butyl ether (MTBE), and dried under reduced pressure (white powder, 0.34 g, 80%). As a result of analyzing the product by HPLC, the purity was 98.5%.

[0063] Example 2

[0064] Preparation of Eumeclidinium Bromide

[0065] 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 fed into a stainless steel coil continuous flow reactor (2.1 mL) at a flow rate of 0.42 mL / min. The reactor temperature was 180°C. The reaction time was 5 minutes. The solution exiting the continuous flow reactor was collected (conversion by HPLC: 97.3%) and concentrated to a volume of 4 mL under reduced pressure. The resulting suspension was cooled to 5°C and stirred for 1 hour. The product was filtered, washed twice with methyl tert-butyl ether (MTBE), and dried under reduced pressure (white powder, 0.36 g, 75%). As a result of analyzing the product by HPLC, the purity was 98.9%.

[0066] Example 3

[0067] Preparation of Eumeclidinium Bromide

[0068] 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 flow rate of 0.42 mL / min. The reactor temperature was 180°C. The reaction time was 5 minutes. The solution exiting the continuous flow reactor was collected, diluted, and analyzed by HPLC, and the conversion rate was 93.2%.

[0069] Example 4

[0070] Preparation of Eumeclidinium Bromide

[0071] 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 flow rate of 0.21 mL / min. The reactor temperature was 150°C. The reaction time was 10 minutes. The solution from the continuous flow reactor was collected, diluted, and analyzed by HPLC, and the conversion rate was 88.5%.

Claims

Claim 1 A method for preparing an anticholinergic agent, carried out in a continuous flow manner using 1-propanol, water, or a mixture of 1-propanol and water as a polar protic solvent, wherein the anticholinergic agent is selected from the group consisting of umeclidinium bromide, tiotropium bromide, glycopyronium bromide, aclidinium bromide, and ipratropium bromide. Claim 2 delete Claim 3 A method of manufacturing in which the anticholinergic agent of claim 1 is umeclidinium bromide. Claim 4 A method of preparation according to claim 3, comprising reacting 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) with ((2-bromoethoxy)methyl)benzene (VII) in the presence of 1-propanol, water, or a mixture of 1-propanol and water. Claim 5 A method of manufacturing according to claim 4, wherein 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) in solution form are continuously fed into one or more continuous flow reactors. Claim 6 delete Claim 7 delete Claim 8 A method of preparation according to claim 5, wherein a solution comprising 1-azabicyclo[2.2.2]oct-4-yl(diphenyl)methanol (VI) and ((2-bromoethoxy)methyl)benzene (VII) is separately supplied to a continuous flow reactor or said solution is pre-mixed before being supplied to a continuous flow reactor. Claim 9 A manufacturing method according to claim 1, wherein the reaction temperature is 120℃ to 200℃. Claim 10 A manufacturing method according to claim 1, wherein the reaction temperature is greater than 140℃ and up to 180℃. Claim 11 A manufacturing method according to claim 1, wherein the reaction time is in the range of 1 minute to 20 minutes. Claim 12 A manufacturing method according to claim 1 that does not require additional resuspending or recrystallization of the anticholinergic agent to obtain a non-solvent form. Claim 13 A method for manufacturing according to claim 1, further comprising the step of isolating the anticholinergic agent by applying reduced pressure to form a concentrate of the solution containing the anticholinergic agent from a reactor; (ii) adding water as an antisolvent to form an aqueous suspension; (iii) cooling the aqueous suspension to a temperature of 0°C to 5°C; and (iv) isolating the product in a solid crystalline form by filtration. Claim 14 A manufacturing method according to claim 1, further comprising a step of micronizing an anticholinergic agent. Claim 15 delete Claim 16 delete Claim 17 delete Claim 18 delete Claim 19 delete Claim 20 delete Claim 21 delete Claim 22 delete

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