HK1060570B - Method for producing the anticholinergic agent tiotropium bromide - Google Patents

Description

Method for preparing anticholinergic agent tiotropium bromide

The invention relates to a method for preparing (1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta) -7- [ (hydroxy di-2-thienyl acetyl) oxygen]-9, 9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0^2，4]Novel process for nonane-bromides.

Background

The compound (1 alpha, 2 beta, 4 beta, 5 alpha, 7 beta) -7- [ (hydroxy di-2-thienyl acetyl) oxygen]-9, 9-dimethyl-3-oxa-9-azoniatricyclo [3.3.1.0^2，4]Nonane-bromides are known from european patent application EP 418716 a1 and have the following chemical structure:

this compound has important pharmacological properties and is known under the name tiotropium bromide (BA 679). Tiotropium bromide (Tiotropium) is a highly potent anticholinergic drug and therefore can be used therapeutically in the treatment of asthma or COPD (chronic obstructive pulmonary disease).

Preferably, tiotropium bromide is administered by inhalation. Suitable inhalable powders which have been filled into suitable capsules (Inhaletten) by means of corresponding powder inhalers can be used. Alternatively, it may be inhaled by means of an aerosol suitable for inhalation. These also include powdered inhalable aerosols containing, for example, HFA134a, HFA227 or mixtures thereof as propellant gas.

Due to its superior efficacy, tiotropium bromide can be used at low therapeutic doses. On the one hand, there is a particular need for pharmaceutical manufacture of the formulations to be used, and on the other hand there is a particular need to develop an industrial process which makes it possible to synthesize tiotropium bromide, which not only ensures that the product is produced in high yield, but also can be produced in good purity.

European patent application EP 418716 a1 discloses a method for the synthesis of tiotropium bromide. Which corresponds to the method illustrated in scheme 1.

Scheme 1:

in a first step, scopine (II) is reacted with bis- (2-thienyl) -hydroxyacetic acid methyl ester (III) to form scopine bis- (2-thienyl) -hydroxyacetate ester (IV), which is then quaternized to form tiotropium bromide.

Detailed Description

It was surprisingly found that tiotropium bromide with high purity can be obtained if the synthesis is carried out by a different synthesis method than described in EP 418716 a 1. This additional and surprisingly advantageous process is shown in scheme 2.

Tropine (tropinol) (V), known from the prior art, is reacted with the di- (2-thienyl) -hydroxyacetic acid derivative (VI) to form first the tropine (VII) di- (2-thienyl) -hydroxyacetic acid. The double bond of the olefin is epoxidized to convert it into the corresponding fine scopine ester (IV).

The present invention therefore relates to a process for preparing tiotropium bromide (I),

characterized in that tropine alcohol ester of the following formula (VII)

Epoxidizing to form the fine scopine ester of the formula (IV)

It is then subjected to quaternization with methyl bromide to form tiotropium bromide (I).

In the above process, a mixture of vanadium pentoxide and hydrogen peroxide is used as the epoxidizing agent for epoxidizing (VII) to form (IV).

In one aspect, in the above process, the epoxidation reaction for forming (IV) of (VII) is preferably carried out in a solvent selected from the group consisting of water, dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidone.

On the other hand, in the above method, the quaternary amination reaction for forming (I) of the (IV) is preferably carried out using methyl bromide in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone and methylenedioxide.

Based on the main importance of the tropenol esters of formula (VII) according to the invention, a further aspect of the invention generally relates to the use of the tropenol esters (VII), which may optionally be present in the form of their acid addition salts, for preparing tiotropium bromide (I). Another aspect of the invention relates to the use of the tropenol ester (VII), which may optionally be present in the form of its acid addition salts, for preparing a tropane ester of the formula (IV).

When tropinone ester (VII) is used in the form of an acid addition salt to prepare the scopine ester (IV), the acid addition salt is preferably selected from the hydrochloride, bromate, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate and hexafluorophosphate salts thereof; particularly preferred are hydrochloride and bromate salts.

Another aspect of the present invention relates to a process for the preparation of tiotropium bromide of formula (I)

The process is characterized in that in a first step, tropine of formula (V) below, optionally in the form of its acid addition salt,

with esters of the formula (VI)

(wherein R represents a group selected from the group consisting of hydroxy, methoxy, ethoxy, O-N-succinimide, O-N-phthalimide, phenoxy, nitrophenoxy, fluorophenoxy, pentafluorophenoxy, ethyleneoxy, -S-methyl, -S-ethyl and-S-phenyl) to form a tropenol ester of the formula (VII)

Then epoxidizing the mixture in a second step to form a scopine ester of the following formula (IV)

Followed by quaternization in a third step using methyl bromide to obtain the tiotropium bromide (I).

Preferably, in the above process for preparing the compound of formula (VII), tropine (V) is used in the form of an acid addition salt selected from the group consisting of its hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate salt.

On the other hand, the reaction of (V) to form (VII) is carried out in a suitable organic solvent, preferably in a solvent selected from the group consisting of toluene, benzene, N-butyl acetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidone.

On the other hand, the reaction of forming (V) into (VII) is carried out in the presence of an organic or inorganic base, preferably an inorganic base selected from organic amines, most preferably diisopropylethylamine, triethylamine, DBU or pyridine, or alkali metal or alkaline earth metal carbonates, alkoxides and hydrides selected from lithium, sodium, potassium and calcium.

On the other hand, in the compound of formula (VI), when R represents a hydroxyl group, the reaction of forming (V) into (VII) is carried out in the presence of a coupling agent preferably selected from carbonyldiimidazole, carbonylbis-1, 2, 4-triazole, dicyclohexylcarbodiimide and ethyl-dimethylaminopropylcarbodiimide.

The main importance of the tropine alcohol (V) as starting material for the preparation of tiotropium bromide (I), so a further aspect of the invention is the use of further tropine alcohol (V), which may optionally be in the form of its acid addition salt, as starting material for the preparation of tiotropium bromide (I).

To prepare the tropenol ester (VII), it is necessary to dissolve the tropinol, optionally in the form of its acid addition salt selected from the group consisting of the hydrochloride, bromate, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate and hexafluorophosphate salts, preferably in the form of its hydrochloride or bromate salts, most preferably in the form of its hydrochloride salt, in a suitable organic solvent, preferably in a solvent selected from the group consisting of toluene, benzene, N-butyl acetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidone, preferably selected from the group consisting of toluene, benzene, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidone, more preferably toluene or benzene, especially toluene. According to the invention, 0.5-3 liters (preferably 0.75-2.5 liters, most preferably between 1.25 and 1.75 liters) of organic solvent are used per mole of tropine (V) used.

In the case of the mixture thus obtained, for example using tropine in its acid addition salt form, it is necessary to add a base to form the free tropine. Suitable bases according to the invention are inorganic or organic bases, in particular organic amines. Organic amines which may be used include triethylamine, diisopropylethylamine, pyridine, dimethylaminopyridine, N-methylpyrrolidine, N-methylmorpholine or ammonia, preferably triethylamine, diisopropylethylamine, pyridine or ammonia, most preferably ammonia. At least 1 mole, preferably 1.25 to 2.5 moles, optimally 1.5 to 2 moles, of amine is added per mole of tropine alkoxide used. The amine may be added at a temperature between 0 and 60 ℃, preferably at a temperature of 15 to 50 ℃, most preferably at a temperature of 20 to 30 ℃. After the amine has been added, the resulting suspension is stirred at constant temperature for between 0.1 and 5 hours, preferably between 0.5 and 2.5 hours, optimally between 0.75 and 1.5 hours. The ammonium salt thus obtained is filtered and, if necessary, washed with the above-mentioned organic solvent. Between 0.1 and 1.5, preferably 0.3 to 1.0, liter of solvent is used per mole of tropine (V).

Part of the solvent is distilled off in vacuo at elevated temperature, preferably at a temperature of from 30 to 80 ℃ and in particular at a temperature of from 40 to 60 ℃. The distillation temperature will of course depend on the solvent chosen. Depending on the choice of the solvent. The vacuum must be adjusted to enable the distillation step to be carried out within the above temperature range. Between 0.25 and 2 liters, preferably 0.5 to 1.5 liters, of solvent can be distilled off per mole of tropine (V) used. After distilling off the above solvent amount, the reaction solution is cooled to a temperature in the range of 0 to 50 ℃, preferably 15 to 35 ℃, and then bis- (2-thienyl) hydroxyacetic acid derivative (VI) is added. According to the invention, di- (2-thienyl) hydroxyacetic acid derivatives (VI) which can be used are those in which R represents hydroxy, methoxy, ethoxy, O-N-succinimide, O-N-phthalimide, phenoxy, nitrophenoxy, fluorophenoxy, pentafluorophenoxy, ethyleneoxy, -S-methyl, -S-ethyl or-S-phenyl. Particular preference is given to the use of compounds (VI) in which R represents hydroxyl, methoxy or ethoxy, most preferably methoxy or hydroxyl. If a compound in which R is a hydroxyl group is used as the compound (VI), the reaction may be carried out in the presence of a coupling agent (e.g., carbonyldiimidazole, carbonyldi-1, 2, 4-triazole, dicyclohexylcarbodiimide or ethyl-dimethylaminopropylcarbodiimide). Between 1 and 2 moles of compound (VI) are used per mole of tropine (V) used. According to the invention, preferably 1 to 1.5 mol of (VI) are used in comparison with (V) used, and the stoichiometric amount of (VI) is optimally used. The resulting reaction mixture may be heated to form a solution, if desired. The temperature is selected in the range of 30-80 deg.C, preferably 40-60 deg.C, and most preferably about 45-55 deg.C.

The solution thus obtained is added to another solution or to a mixture of an inorganic or organic base in one of the above-mentioned solvents, preferably in the solvent used in the preparation of the mixture of (V) and (VI). Between 0.2 and 2.0 liters, preferably 0.4-1.5 liters, optimally 0.5 to 1.0 liter of solvent is used per mole of tropine (V) used to prepare a solution or a mixture containing bases. If R represents methoxy, ethoxy, vinyloxy, phenoxy, -S-methyl, -S-ethyl or-S-phenyl, the reaction can be carried out in the presence of an organic or inorganic base. The organic base used is preferably an organic amine, particularly preferably diisopropylethylamine, triethylamine, cyclic amines, for example DBU or pyridine. Suitable inorganic bases are alkali metal or alkaline earth metal carbonates, alkoxides or hydrides of lithium, sodium, potassium, calcium, such as sodium carbonate, lithium carbonate, potassium carbonate, calcium carbonate, sodium hydride, potassium hydride, calcium hydride, sodium methoxide, sodium ethoxide, potassium methoxide or potassium ethoxide. The inorganic base used is preferably the hydride or alkoxide mentioned above, preferably the hydride mentioned above, and according to the invention, sodium hydride is particularly preferably used. At least a stoichiometric amount of base is used per mole of tropine (V). Preferably 1 to 3 moles, more preferably 1.25 to 2.5 moles, optimally 1.5 to 2 moles of base are used per mole of tropine alcohol (V).

The solutions (V) and (VI) are reacted with the abovementioned base-containing solutions or the abovementioned mixtures, preferably for from 0.2 to 2.0 hours, more preferably from 0.5 to 1.5 hours, if esters in which R represents methoxy or ethoxy are used as compound (VI), it being necessary to distil off the alcohol formed at from 40 to 90 ℃, preferably from 50 to 80 ℃, most preferably from 60 to 75 ℃ and under vacuum, preferably from 150 to 500 mbar, more preferably from 200 to 350 mbar, most preferably from 250 to 300 mbar. This procedure can thus shift the reaction equilibrium towards the tropyl ester (VII). Under these reaction conditions, part of the solvent may also be distilled off. After completion of the distillation (about 5 to 10 hours), the distilled solvent may be returned to the reaction solution again, if necessary.

In any case, once distillation is complete, the solution obtained is cooled again to a temperature in the range of 40 ℃, preferably to 0-35 ℃, optimally to 10-25 ℃.

At the same temperature for 0.2 to 2 hours. Preferably 0.4-0.6 hours, hydrochloric acid is added to the mixture. The added hydrochloric acid may be in the form of an aqueous solution or a gas; among them, the addition of an aqueous solution is preferable. Preferably, concentrated hydrochloric acid (36%) in water is added. Preferably, 1 to 4 moles (more preferably 1.5-3 moles, most preferably 2.0 to 2.5 moles) of HCl are added per mole of tropine (V) used. Preferably, 0.1 to 0.4 kg (optimally 0.15 to 0.25 kg) of a 10 to 20 l (preferably 12 to 17 l) aqueous solution of 36% aqueous hydrochloric acid is added per mole of tropine (V).

All components were added and after the mixture had been stirred, the aqueous phase was separated. The aqueous phase is then washed with a suitable water-immiscible organic solvent. The preferred water-immiscible solvent is a solvent selected from the group consisting of dichloromethane and n-butyl acetate, preferably dichloromethane. If necessary, the organic phase used for the first extraction of the aqueous phase is discarded and the extraction process is repeated again.

After optionally washing with one of the above water-immiscible solvents, the aqueous phase is mixed once more with a water-immiscible solvent. The water-immiscible solvent is preferably used in an amount of 1 to 5 liters, preferably 2 to 4 liters, most preferably 2.5 to 3.5 liters, per mole of tropine (V) originally added. The mixture thus obtained is reacted with an inorganic base (preferably an alkali metal or alkaline earth metal carbonate selected from lithium, sodium, potassium, calcium, for example, sodium carbonate, lithium carbonate, potassium carbonate or calcium carbonate, with sodium carbonate being more preferred) and the pH can thus be adjusted to 7.5 to 11, preferably 8 to 10. The inorganic base is preferably added as an aqueous solution. For example, according to the invention, per mole of tropine (V) used, preferably from 0.05 to 0.4 kg, more preferably from 0.1 to 0.2 kg, of an inorganic base are added in from 0.25 l to 1.5 l, preferably from 0.5 to 1 l, most preferably from 0.7 to 0.8 l, of water.

After complete mixing of the resulting reaction mixture, the aqueous phase is separated and extracted one or more times with the water-immiscible solvent described above. A total of from 1 to 8, preferably from 2 to 6 and optimally from 3 to 5, liters of the abovementioned water-immiscible solvent are used per mole of tropine (V) originally used to extract the aqueous phase. The solvent is then removed by distillation of the combined organic phases at elevated temperature, preferably at 30-90 c, most preferably at 50-70 c. As the skilled person knows, the above temperature range depends mainly on the solvent chosen. The method of distillative removal of the solvent may also use vacuum to maintain the temperature within the temperature range defined above, if desired. In the case of a solution distilled at the highest temperature range defined above, this highest distillation temperature is of course the boiling point of the solvent.

The residue remaining after distillation is dissolved in an organic solvent. The solvent may be selected from a variety of solvents used to carry out the reaction of (V) with (VI) to form (VII) according to the present patent specification. The same solvent as in the present reaction is preferably used. From 1 to 5, preferably from 1.5 to 4, more preferably from 2 to 3, liters of solvent are used per mole of tropine (V) originally used. The solution thus obtained is heated to a temperature not exceeding the boiling temperature of the solvent, preferably to a temperature of 50-100 c, most preferably to a temperature of 80-95 c. The heated solution is allowed to cool slowly to a temperature in the range of-10 ℃ to 20 ℃, preferably 0-10 ℃. The tropanol ester (VII) is obtained as colorless crystals, which are isolated and dried. Drying is preferably carried out at a temperature of from 30 to 50 ℃ under an inert gas.

The thus obtained tropenol ester (VII) is epoxidized to form the scopine ester (IV), as described hereinafter. A suitable solvent, preferably selected from the group consisting of water, dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidone, most preferably dimethylformamide, is placed in a suitable reaction apparatus and heated to a temperature in the range of 30-70 c, preferably 40-60 c. For each mole of tropenol ester (VII) used, from 2 to 10 liters, preferably from 3 to 8 liters, more preferably from 4 to 7 liters, and most preferably from 5 to 6 liters of solvent are used. The tropine ester (VII) is added to the heated solvent described above and the resulting mixture is stirred at constant temperature until a clear solution is obtained.

The epoxidizing agent is then added portionwise to the solution at a temperature in the range from 20 to 50 ℃, preferably at a temperature in the range from 35 to 45 ℃. As epoxidizing agents, preference is given to reacting with H₂O₂Mixed vanadium pentoxide, most preferably H in combination with vanadium pentoxide₂O₂-a urea complex. Preference is given to alternating batchwise addition of H₂O₂Urea complex and vanadium pentoxide, optimally with addition of water. 0.1 to 0.5 kg, preferably 0.15 to 0.3 kg, of H are used per mole of tropenol ester (VII) used₂O₂Urea complex, 0.1-1.0 l (preferably 0.15-0.7 l; most preferably 0.2-0.4 l) of water and 0.001-0.1 kg (preferably 0.005-0.05 kg, most preferably 0.01-0.025 kg) of vanadium pentoxide. After the components have been added, the mixture is stirred at a temperature of 30-70 deg.C, preferably 40-60 deg.C, most preferably 45-55 deg.C, for 1-6 hours, preferably 1.5-4 hours, most preferably 2-3 hours.

It is then cooled to a temperature in the range of 10-30 ℃, preferably to 15-25 ℃, and the pH is adjusted to 2.5-5.5, preferably to pH3.5-4.5 with hydrochloric acid. Hydrochloric acid in the form of an aqueous solution or a gas may be further added, and an aqueous solution is preferably added. Preferably, concentrated hydrochloric acid (36%) in water is added. After complete mixing, an inorganic salt, preferably sodium bisulfite, is added. Sodium bisulfite is preferably added in the form of an aqueous solution. Per mole of tropenol ester (VII) used, preferably from 20 to 100 g (more preferably from 30 to 80 g, most preferably from 40 to 60 g) of an aqueous solution of an inorganic salt, in the range from 0.1 to 1 l (preferably from 0.3 to 0.7 l), are added (in each case per mole of compound (VII) used. Part of the solvent is distilled at a temperature of 20 to 50 deg.C (preferably 30 to 40 deg.C). About 2-8 liters (preferably 3-6 liters) of solvent are removed per mole of compound used. After cooling to about 15-25 ℃, Clarcel (C-salt (celite)) is added (about 40-100 g, preferably 60-80 g, per mole of compound (VII) used). The pH is adjusted to 1-3, preferably pH1.5-2.5, by further addition of hydrochloric acid, preferably dilute aqueous hydrochloric acid. For each mole of the compound (VII) to be used, it is preferable to use a solution of 10 to 30 g (more preferably 15 to 20 g) of 36% hydrochloric acid in 5 to 15 l (preferably 8 to 12 l) in water (for each mole of VII to be used).

The resulting solution is filtered and extracted one, two or three times with a suitable water-immiscible solvent as required. Preferably, a water-insoluble solvent selected from the group consisting of dichloromethane and n-butyl acetate is used, preferably dichloromethane. The organic phase used to extract the aqueous phase was discarded.

If necessary, after washing with any of the above-mentioned water-insoluble solvents, the aqueous phase is mixed once more with the water-insoluble solvent. Preferably, from 1 to 5 liters (more preferably from 2 to 4 liters, most preferably from 2.5 to 3.5 liters) of the water-insoluble solvent are used per mole of the tropenol ester (VII) originally used. The resulting mixture is reacted with an inorganic base (the inorganic base is preferably selected from alkali metal or alkaline earth metal carbonates of lithium, sodium, potassium or calcium, e.g. sodium carbonate, lithium carbonate, potassium carbonate or calcium carbonate, with sodium carbonate being most preferred) and the pH is adjusted to 8-11, preferably 9-10.5. The inorganic base is preferably added as an aqueous solution. For example, according to the invention, per mole of ester (VII) used, preferably from 0.25 to 2 liters, preferably from 0.75 to 1.25 liters, of an aqueous solution of from 0.05 to 0.4 kg, preferably from 0.15 to 0.3 kg, of sodium carbonate are added.

After complete mixing of the resulting reaction mixture, the aqueous phase is separated and extracted one or more times with the above-mentioned water-immiscible solvent. A total of 1-5 liters (preferably 2-4 liters) of the above water-immiscible solvent is used to extract the aqueous phase per mole of the previously used tropenol ester (VII). The solvent of the combined organic phases is then partially removed by distillation, preferably at 25 to 50 ℃ and more preferably at 30 to 40 ℃. As will be appreciated by those skilled in the art, the above temperature ranges will depend primarily on the solvent selected. If desired, vacuum may also be used for the solvent removal step of the distillation to maintain the temperature within the temperature ranges defined above. Preferably, the distillation is carried out under a low vacuum of 500-800 mbar, most preferably 600-700 mbar. About 2-6 liters (preferably 3-5 liters) of solvent are distilled off per mole of ester (VII) originally used.

Sometimes, it is necessary to remove impurities in the form of secondary amines. According to the invention, this is carried out by using organic carboxylic acid halides, preferably by acid chlorides selected from acetyl chloride, propionyl chloride or butyryl chloride. Acetyl chloride is preferably used. In general, 5 and 30 g, preferably 10 to 20 g, of carboxylic acid halide are employed per mole of ester (VII) originally used. After addition of the carboxylic acid halide at 15 to 25 ℃ the mixture is stirred at the same temperature for 15 minutes to 1.5 hours, preferably for 30 and 45 minutes.

The mixture is then brought to a temperature in the range of 10-30 ℃, preferably 15-25 ℃ and the pH is adjusted to 1-3, preferably to pH1.5-2.5, using hydrochloric acid. Hydrochloric acid in the form of aqueous solution or gas can be added; preferably in the form of an aqueous solution. Preferably, concentrated hydrochloric acid (36%) in water is added. For each mole of compound (VII) used, it is preferred to use from 0.05 to 0.5 kg (more preferably from 0.075 to 1.25 kg) of a solution of 36% hydrochloric acid in from 5 to 15 liters (preferably from 8 to 12 liters) of water per mole of VII used. The organic phase was separated and discarded.

If desired, the aqueous phase can be mixed once more with the water-insoluble solvent after washing with one of the water-immiscible solvents mentioned above. Preferably, from 1 to 5 liters, preferably from 2 to 4 liters, most preferably from 2.5 to 3.5 liters, of water-immiscible solvent are used per mole of the tropenol ester (VII) originally used. The mixture thus obtained is reacted with an inorganic base (the inorganic base is preferably selected from alkali metal or alkaline earth metal carbonates of lithium, sodium, potassium or calcium, for example sodium carbonate, lithium carbonate, potassium carbonate or calcium carbonate, with sodium carbonate being particularly preferred), and the pH is then adjusted to 8 to 11, preferably to 9 to 10.5. The inorganic base is preferably added as an aqueous solution. For example, according to the invention, per mole of ester (VII) used, preferably from 0.05 to 0.4 kg, preferably from 0.1 to 0.2 kg, of an aqueous solution of from 0.25 to 2 liters, preferably from 0.7 to 1.2 liters, of sodium carbonate are added.

After complete mixing of the reaction mixture obtained, the aqueous phase is separated and extracted once, preferably twice, with the water-immiscible solvent described above. A total of 0.5 to 2.5 liters (preferably 1 to 2 liters) of the above water-immiscible solvent is used to extract the aqueous phase per mole of the previously used tropenol ester (VII). The combined organic phases are then freed from part of the solvent, preferably by distillation at from 25 to 50 ℃ and most preferably from 30 to 40 ℃, from about 1 to 3, preferably from 1.5 to 2.5, liters of solvent per mole of ester (VII) used. Then a solvent selected from dimethylformamide, dimethylacetamide, N-methylpyrrolidone or dichloromethane, preferably dimethylformamide, is added. 1 to 5 kg (preferably 1.5 to 4 kg, most preferably 2 to 3 kg) of solvent are used per mole of ester (VII) used. The remaining amount of water-immiscible solvent previously used for extraction was distilled off from the solution under low vacuum (600-700 mbar) at a temperature of 30-40 ℃. The thus obtained scopine ester (IV) solution can be used directly in the next step without any further isolation of the intermediate compound.

To prepare tiotropium bromide (I), methyl bromide is introduced into the scopine ester solution obtained according to the above at 10-30 ℃, preferably at 15-25 ℃. Since the solution of the scopine ester (IV) used in this step was not subjected to any determination of the yield in the previous step, the following amounts refer to the amount of the tropenol ester (VII) used originally. At least 1 mole of methyl bromide is used per mole of scopine ester (IV). According to the invention, per mole of tropenol ester (VII) used, preferably from 0.1 to 0.2 kg, more preferably from 0.11 to 0.15 kg, of methyl bromide are used. After all the methyl bromide is added, the mixture is stirred at 15 to 35 ℃ for 1 to 3 days, preferably 48 to 72 hours. The dimethylformamide solvent is then distilled off in vacuo at from 30 to 60 ℃ and preferably from 45 to 55 ℃. The vacuum selected is such that the solvent is distilled off at the above-mentioned temperatures. About 0.5-2.0 liters (preferably 1.0-1.75 liters) of solvent are distilled off per mole of tropenol ester (VII) used, and then cooled to about 5-20 deg.C, preferably 10-15 deg.C. At this temperature, the mixture is stirred until the crude product has completely crystallized, and the precipitated crystals are then isolated and dried at from 30 to 50 ℃ under an inert gas, preferably nitrogen.

The product can be further purified by crystallization from methanol. About 2-8 liters, preferably 3-7 liters, optimally 4-5 liters of methanol are used per mole of tiotropium bromide (I) and the mixture thus obtained is heated under reflux until the product is dissolved. Followed by cooling to 1-15 deg.C, preferably to 3-7 deg.C, and crystallizing the product with stirring. After complete crystallization, the crystals are isolated and finally dried at from 30 to 50 ℃ under an inert gas, preferably nitrogen.

The product thus obtained can be converted into its monohydrate, if desired. To accomplish this conversion step, the following method may be used.

The solvent is mixed with tiotropium bromide in a reaction vessel of suitable size. Per mole of tiotropium bromide used, 0.4 to 1.5 kg, preferably 0.6 to 1 kg, optimally about 0.8 kg of water are used as solvent. The resulting mixture is heated with stirring, preferably above 50 c, most preferably above 60 c. The maximum temperature that can be used can be determined by the boiling point of water as the solvent. The mixture is preferably heated to a temperature in the range of 80-90 ℃. Activated carbon, which may be dry or wet with water, is added to the solution. Preferably, from 10 to 50 g (more preferably from 15 to 35 g, particularly preferably 25 g) of activated carbon are used per mole of tiotropium bromide added. If desired, the activated carbon may be added to the tiotropium bromide-containing solution in the form of a suspension in water. For suspending the activated carbon, 70 to 200 g, preferably 100 to 160 g, optimally about 135 g of water is used per mole of tiotropium bromide added. If the activated carbon is suspended in water before being added to the tiotropium bromide-containing solution, it is advantageous to wash with the same amount of water.

After the addition of the activated carbon, stirring is continued at a constant temperature for between 5 and 60 minutes, preferably between 10 and 30 minutes, and most preferably for about 15 minutes, and the resulting mixture is filtered to remove the activated carbon. The filter was then washed with water. The washing step is carried out with 140 to 400 g, preferably 200 to 320 g, optimally about 270 g of water per mole of tiotropium bromide used.

The filtrate is then slowly cooled, preferably to 20-25 ℃. The cooling is preferably carried out at a cooling rate of 1 to 10 ℃ per 10 to 30 minutes, more preferably 2 to 8 ℃ per 10 to 30 minutes, most preferably 3 to 5 ℃ per 10 to 20 minutes, and particularly preferably 3 to 5 ℃ per about 20 minutes. If desired after cooling to 20-25 deg.C, it may be further cooled to below 20 deg.C, preferably to 10-15 deg.C.

After the cooling step has been performed, the mixture is stirred for between 20 minutes and 3 hours, preferably between 40 minutes and 2 hours, most preferably about one hour to complete the crystallization reaction.

Finally, the crystals formed are isolated by filtration or suction filtration of the solvent. The crystals obtained are subjected to a washing step once more if necessary, preferably using water or acetone as a washing solvent. Per mole of tiotropium bromide used, 0.1 to 1.0 liter, preferably 0.2 to 0.5 liter, optimally about 0.3 liter of solvent may be used to wash the tiotropium bromide monohydrate crystals obtained. This washing step can be repeated if desired.

The product obtained is dried by vacuum or circulating hot air to bring the water content to 2.5-4.0%.

The following examples are provided to illustrate the synthetic procedures performed to prepare tiotropium bromide. This is to be seen as a method that can be provided by way of example only and not as a limitation on the present disclosure.

Process for the preparation of tropenol esters (VII)

Ammonia (1.8 kg) was added to 10.9 kg of tropine hydrochloride in toluene (95 l) at 25 ℃. The resulting suspension was stirred at constant temperature for about 1 hour. The ammonium hydrochloride salt formed is then filtered off and washed with toluene (26 l). A portion of the toluene (about 60 liters) was distilled off under vacuum at an external temperature of about 50 ℃. After cooling to about 25 ℃, 15.8 kg of methyl bis- (2-thienyl) glycolate were added and the resulting mixture was heated to 50 ℃ to dissolve it. Toluene (40 l) was placed in another apparatus and sodium hydride (2.7 kg) was added thereto at about 25 ℃. To this solution, the solution previously prepared from tropine and methyl glycolate was added over 1 hour at 30 ℃. After all additions, the mixture was heated at 75 ℃ for about 7 hours under reduced pressure with stirring. The methanol formed is distilled off. The remaining mixture was cooled and added to a mixture of water (958 liters) and 36% hydrochloric acid (13.2 kg). The aqueous phase was then separated and washed with dichloromethane (56 l). After further addition of dichloromethane (198 l), the mixture thus obtained is adjusted to pH 9 with a previously prepared soda solution (9.6 kg of soda in 45 l of water). The dichloromethane phase was separated and the aqueous phase was stirred with dichloromethane (262 l). The dichloromethane was evaporated at 65 ℃ until a residue. The residue was dissolved in toluene (166 liters) and heated to 95 ℃. The toluene solution was cooled to 0 ℃. The resulting crystals were isolated, washed with toluene (33 l) and dried at about 50 ℃ under a stream of nitrogen for up to 24 hours.

Yield: 18.6 kg (83%); melting point: about 160 ℃ (as determined by DSC at a heating rate of 10K/min);

preparation of scopine (IV)

260 liters of DMF was placed in a suitable reaction apparatus and heated to 50 ℃. Then 16.2 kg of tropenol ester (VII) are added and the mixture is stirred until a clear solution is obtained. After cooling to 40 ℃, hydrogen peroxide-urea complex (10.2 kg), water (13 l) and vanadium- (V) -oxide (0.7 kg) were added continuously and in portions and the contents of the apparatus were heated to about 50 ℃. After stirring for 2-3 hours at constant temperature, the mixture was cooled to about 20 ℃. The pH of the resulting reaction mixture was adjusted to about 4.0 using hydrochloric acid (36%). A pre-prepared sodium bisulfite solution (2.4 kg of 24 l aqueous solution) was added. The solvent was partially distilled off at 35 ℃ at room temperature using vacuum (about 210 l). The mixture was cooled to about 20 ℃ and Clarcel (3.2 kg) was added. The pH of the resulting mixture was adjusted to about 2.0 with dilute hydrochloric acid (36%, 0.8 kg hydrochloric acid in about 440 l aqueous solution). The resulting solution was filtered and extracted with dichloromethane (58 l). The dichloromethane phase was discarded. Dichloromethane (130 l) was added to the aqueous phase and the pH was brought to about 10.0 using a previously prepared soda solution (11.0 kg soda in 51 l water). The dichloromethane phase was separated and the aqueous phase was extracted with dichloromethane (136 liters). Dichloromethane (about 175 l) was distilled from the combined dichloromethane at 40 ℃ using a low vacuum (600-700 mbar). The contents of the apparatus were allowed to cool to 20 ℃, acetyl chloride (about 0.5 kg) was added, and the mixture was stirred at 20 ℃ for about 40 minutes. The reaction solution was moved to the second apparatus. The pH is adjusted to 2.0 at 20 ℃ with a previously prepared hydrochloric acid solution (4.7 kg of 36% hydrochloric acid in 460 l of water). The dichloromethane phase was separated and discarded. The aqueous phase was washed with dichloromethane (39 l). Dichloromethane (130 l) was then added and the pH was brought to 10.0 at 20 ℃ with a previously prepared soda solution (7.8 kg soda in 38 l water). After stirring for 15 minutes, the organic phase was separated and the aqueous phase was washed twice with dichloromethane (97 l and 65 l). The dichloromethane phases are combined and a portion of the dichloromethane (90 l) is distilled off at a temperature of 30-40 ℃ under a slight vacuum. Dimethylformamide (114 kg) was then added and the remaining dichloromethane was distilled off in vacuo at 40 ℃. The contents of the device were allowed to cool to 20 ℃.

Preparation of tiotropium bromide (I)

Methyl bromide (5.1 kg) was added to the scopine ester solution obtained according to the procedure described above at 20 ℃. The contents of the apparatus were stirred at 30 ℃ for about 2.5 days. 70 l of DMF are distilled off at 50 ℃ in vacuo. The solution was moved to a smaller device. It was washed with DMF (10 l). More DMF was distilled off at 50 ℃ in vacuo until a total of about 100 l distillate was obtained. It was allowed to cool to 15 ℃ and stirred at this temperature for a further 2 hours. The product was isolated using a suction drier and then washed with cold DMF (10 l) at 15 ℃ and cold acetone (25 l) at 15 ℃. It is dried in a nitrogen stream at a maximum temperature of 50 ℃ for not more than 36 hours.

Yield: 13.2 kg (88%); melting point: 200 ℃ to 230 ℃ depending on the purity of the crude product;

the crude product thus obtained (10.3 kg) was taken up in methanol (66 l). The mixture was refluxed to effect dissolution. The solution was allowed to cool to 7 ℃ and stirred at this temperature for 1.5 hours. The product was isolated using a suction drier, washed with cold methanol (11 liters) at 7 ℃ and dried in a nitrogen stream at about 50 ℃ for about up to 36 hours.

Yield: 9.9 kg (96%); melting point: 228 ℃ (at a heating rate of 10K/min, as determined by DSC).

The product thus obtained can be converted, if desired, into the crystalline monohydrate of tiotropium bromide. The method for performing this conversion step is as follows.

15.0 kg of tiotropium bromide was added to 25.7 kg of water in a suitable reaction vessel. The mixture was heated to 80-90 ℃ and stirred at constant temperature until a clear solution formed. Activated carbon (0.8. kg), which had been wetted with water, was suspended in 4.4 kg of water, and the mixture was added to a solution containing tiotropium bromide and washed with 4.3 kg of water. The mixture thus obtained is stirred at 80-90 ℃ for at least 15 minutes and then filtered through a heated filter into a device which has been preheated to an external temperature of 70 ℃. The filter was washed with 8.6 kg of water. The contents of the device were cooled to 20-25 ℃ at a rate of 3-5 ℃ per 20 minutes. The apparatus was further cooled to 10-15 ℃ with cold water and the crystallization reaction was completed by stirring for at least one hour. The crystals were separated using a suction dryer and the separated crystal slurry was washed with 9 liters of cold water (10-15 ℃) and cold acetone (10-15 ℃). The crystals obtained were dried at about 25 ℃ in a stream of nitrogen for about 2 hours.

Yield: 13.4 kg tiotropium bromide monohydrate (86% of theory); melting point: 230 deg.C (determined by DSC at a heating rate of 10K/min).

Claims (32)

1. Method for preparing tiotropium bromide shown in formula (I)

Characterized in that a tropenol ester of the formula (VII)

Epoxidizing to form a scopine ester of the formula (IV)

Followed by quaternization with methyl bromide to form tiotropium bromide (I).

2. The process as claimed in claim 1, characterized in that a mixture of vanadium pentoxide and hydrogen peroxide is used as epoxidizing agent for epoxidizing (VII) to form (IV).

3. The process of claim 1, wherein the epoxidation of (VII) to form (IV) is carried out in a solvent selected from the group consisting of water, dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone.

4. The process according to claim 2, wherein the epoxidation of (VII) to form (IV) is carried out in a solvent selected from the group consisting of water, dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidone.

5. The process of claim 1, wherein the quaternization of (IV) to form (I) is carried out using methyl bromide in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and methylenedioxy.

6. The process of claim 2, wherein the quaternization of (IV) to form (I) is carried out using methyl bromide in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone, and methylenedioxy.

7. The process according to claim 3, characterized in that the quaternization of the (IV) to form (I) is carried out using methyl bromide in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone and methylenedioxy.

8. The process according to claim 4, characterized in that the quaternization of the (IV) to form (I) is carried out using methyl bromide in a solvent selected from the group consisting of dimethylformamide, dimethylacetamide, N-methylpyrrolidone and methylenedioxy.

9. A process according to any one of claims 1 to 8, characterized in that the compound of formula (VII):

by tropine of formula (V) below, optionally in the form of an acid addition salt

With an ester of the formula (VI)

Wherein R is a group selected from the group consisting of hydroxy, methoxy, ethoxy, O-N-succinimide, O-N-phthalimide, phenoxy, nitrophenoxy, fluorophenoxy, pentafluorophenoxy, ethyleneoxy, -S-methyl, -S-ethyl and-S-phenyl.

10. The process according to claim 9, characterized in that the tropine (V) is used in the form of an acid addition salt selected from the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate salts thereof.

11. The process as claimed in claim 9, wherein the reaction of (V) to form (VII) is carried out in a suitable organic solvent.

12. The process as claimed in claim 10, wherein the reaction of (V) to form (VII) is carried out in a suitable organic solvent.

13. The process of claim 11, wherein said organic solvent is selected from the group consisting of toluene, benzene, N-butyl acetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF and N-methylpyrrolidone.

14. The process of claim 12, wherein the organic solvent is selected from the group consisting of toluene, benzene, N-butyl acetate, dichloromethane, THF, dioxane, dimethylacetamide, DMF, and N-methylpyrrolidone.

15. The process as claimed in claim 9, wherein the reaction for forming (V) into (VII) is carried out in the presence of an organic or inorganic base.

16. The process of claim 10, wherein the reaction for forming (V) into (VII) is carried out in the presence of an organic or inorganic base.

17. The process of claim 15, wherein the base used is an organic base.

18. The process of claim 16, wherein the base used is an organic base.

19. The process of claim 17, wherein the organic base is selected from diisopropylethylamine, triethylamine, DBU or pyridine.

20. The process of claim 18, wherein the organic base is selected from diisopropylethylamine, triethylamine, DBU or pyridine.

21. The process of claim 15, wherein the base used is an inorganic base.

22. The process of claim 16, wherein the base used is an inorganic base.

23. The process of claim 21, wherein the inorganic base is selected from the group consisting of alkali or alkaline earth metal carbonates, alkoxides, and hydrides of lithium, sodium, potassium, and calcium.

24. The process of claim 22, wherein the inorganic base is selected from the group consisting of alkali or alkaline earth metal carbonates, alkoxides, and hydrides of lithium, sodium, potassium, and calcium.

25. The process as claimed in claim 9, characterized in that, in the compound of the formula (VI), if R represents a hydroxyl group, the reaction of formation of (V) to form (VII) is carried out in the presence of a coupling agent.

26. The process as claimed in claim 10, characterized in that, in the compound of the formula (VI), if R represents a hydroxyl group, the reaction of formation of (V) to form (VII) is carried out in the presence of a coupling agent.

27. The process as claimed in claim 11, characterized in that, in the compound of the formula (VI), if R represents a hydroxyl group, the reaction of formation of (V) to form (VII) is carried out in the presence of a coupling agent.

28. The process as claimed in claim 12, characterized in that, in the compound of the formula (VI), if R represents a hydroxyl group, the reaction of formation of (V) to form (VII) is carried out in the presence of a coupling agent.

29. The method of claim 25, said coupling agent being selected from the group consisting of carbonyldiimidazole, carbonylbis-1, 2, 4-triazole, dicyclohexylcarbodiimide and ethyl-dimethylaminopropyl carbodiimide.

30. The method of claim 26, said coupling agent being selected from the group consisting of carbonyldiimidazole, carbonylbis-1, 2, 4-triazole, dicyclohexylcarbodiimide and ethyl-dimethylaminopropyl carbodiimide.

31. The method of claim 27, said coupling agent being selected from the group consisting of carbonyldiimidazole, carbonylbis-1, 2, 4-triazole, dicyclohexylcarbodiimide and ethyl-dimethylaminopropyl carbodiimide.

32. The method of claim 28, said coupling agent being selected from the group consisting of carbonyldiimidazole, carbonylbis-1, 2, 4-triazole, dicyclohexylcarbodiimide and ethyl-dimethylaminopropyl carbodiimide.