HK1068613B - Technical synthesis method for producing tropenol - Google Patents

Description

Industrial synthesis process for the preparation of dephenols

The invention relates to a novel process for the preparation of Tropenol (Tropenol) which is used industrially, optionally in the form of its acid addition salts.

Background

The compound, namely, the terpineol, is disclosed by the prior art and has the following chemical structure:

the compounds are useful as starting compounds for the preparation of effective pharmaceutical compounds. Examples of compounds relevant for this are tiotropium bromide (tiotropium bromide), ipratropium bromide or BEA 2108. The effective structural characteristics of these drugs are the following chemical structural formulas:

tiotropium bromide ipratropium bromide BEA2108

Since these compounds have high activity, it is required to prepare the compounds in high purity as much as possible by an efficient synthesis method. In particular, the compounds generally used in therapy must meet the high purity requirements that the content of impurities in the starting compounds be as low as possible. If the substances used as starting compounds contain higher impurities, purification of the end product is often rendered difficult, since the initially incorporated impurities are still present in the subsequent synthesis steps and lead to a reduction in the yield on isolation. This occurs in particular when the differences between the structure of the by-products or impurities formed and the respective main products are small.

Against this background, the object of the present invention was to provide a process for the preparation of dephenols which can be produced industrially, preferably in the form of their acid addition salts, in high yields and, in particular, in high product purities.

Detailed description of the invention

The above object of the present invention is achieved by the following description.

The invention relates to a method for the industrial preparation of a tropenol of formula (1), optionally in the form of its acid addition salts, characterized in that: the scopine esters of formula (II), optionally their acid addition salts and their hydrates, are reduced by zinc in the presence of an activated metal salt, preferably an activated iron or copper salt, in a suitable solvent, followed by saponification under the action of a suitable base to form the dephenols of formula (1).

In the formula (II): r represents C₁-C₄-alkyl and C₁-C₄A radical of alkylene-phenyl, each of which may be substituted by hydroxy or C₁-C₄-alkoxy substitution.

C in the invention₁-C₄Alkyl means having not more than 4Branched or straight chain alkyl groups of carbon atoms. Such as methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl. C in the invention₁-C₄-alkylene-phenyl means that the phenyl group is linked to up to 4 carbon atoms through a branched or straight chain alkylene bridge. Such as benzyl, phenyl-2-ethyl, phenyl-1-ethyl, phenyl-3-propyl, phenyl-2-propyl, and the like. Whether or not it is C₁-C₄-alkyl, or C₁-C₄Alkylene-phenyl which may, unless otherwise stated, be substituted by one or more hydroxy groups and/or C₁-C₄-alkoxy substitution.

Preferably the present invention relates to a process for the preparation of the tropenol of formula (1), optionally in the form of its acid addition salts, characterized in that a scopolamine of formula (II'), optionally its acid addition salts as well as its hydrates, is used as the tropane derivative of formula (II).

According to the present invention, the process of the present invention can be carried out as follows to produce a dephenolate. The solvent is preferably placed in a suitable reactor under an inert atmosphere, particularly preferably under nitrogen. Solvents suitable for use in the present invention are alcohols selected from methanol, ethanol and isopropanol, or water, with water being preferred according to the invention. According to the invention, the amount of solvent used per mole of compound of formula (II) is 0.25 to 5 liters, preferably 0.5 to 3 liters, especially 0.75 to 1.5 liters. To this solvent is added zinc, preferably zinc powder, more preferably zinc powder having an average particle size of < 80 microns, especially < 70 microns, with vigorous stirring. At least 1 mole of zinc is required per mole of compound of formula (II). An excess of zinc is preferably used according to the invention. Zinc is preferably used in an amount of from 1.2 to 3.5 mol, particularly preferably from 1.5 to 3.0 mol, per mol of compound of the formula (II). In a particularly preferred embodiment of the process according to the invention, from 1.8 to 2.5 mol of zinc are used per mole of compound of the formula (II). After the zinc addition is complete, they must be activated. The activation process can be achieved by adding, for example, HI, HBr or HCl. Preferably HI is used, most preferably HIIt is an aqueous solution thereof, particularly a concentrated aqueous solution, as an activating agent for activation. For example, from 0.05 to 0.25 mol, preferably from 0.08 to 0.2 mol, of activator must be added per mole of compound of the formula (II). It is advantageous to increase the temperature of the initial mixture before adding the activator. The mixture is then heated at a temperature of more than 50 ℃, preferably from 55 to 90 ℃, particularly preferably from 60 to 80 ℃. The metal salt is then added to the suspension of zinc in the solvent used, if appropriate activated by one of the abovementioned formulations. Examples of metal salts which can be used within the scope of the present invention are iron salts (preferably Fe- (III) -salts) or copper salts (preferably Cu- (II) -salts), preferably halides thereof. The preferred iron salt used is FeCl₃. However, particular preference is given to using Cu- (II) -salts selected from CuCl in the process of the invention₂、CuI₂、CuBr₂And CuBr₂Dimethyl sulfide complex, and in the present invention, CuBr is preferably selected₂. According to the invention, a stoichiometric amount of metal salt can be added per mole of compound of the formula (II), preferably in an amount of from 0.01 to < 1 mole. The metal salt is preferably used in an amount of 0.05 to 0.5 mol, preferably 0.075 to 0.2 mol, per mol of starting compound (II). The metal salt can be added to the zinc suspension as a substance or in dissolved form. According to the invention, the metal salt is preferably placed in one of the solvents mentioned above and then added to the zinc suspension in dissolved or suspended form. It is particularly preferred to use solvents which have been used for uptake of zinc to prepare the metal salt solution or suspension. According to the invention, from 0.5 to 1.5, preferably from 0.6 to 1.0, liter of solvent is used per mole of metal salt to prepare the metal salt solution or suspension. This solution or suspension is then added to the zinc mixture described above with stirring.

The compound of formula (II) is then added to the zinc mixture prepared as described above. If desired, the addition can also be carried out in the form of an acid addition salt of the formula (II). The acid addition salts used according to the invention are preferably selected from the group consisting of hydrochloride, hydrogen bromide, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate and hexafluorophosphate salts, with hydrochloride and hydrogen bromide salts being particularly preferred. As regards the acid addition salts of the compounds of formula (II), they include the hydrate forms thereof, if any. When the above acid addition salts are added directly, they may be added to the original zinc mixture in substance or in dissolved form. If the acid addition salt is added in dissolved form, it is advisable to place the acid addition salt of the compound of formula (II) in one of the solvents mentioned above. Preferably, the solution is prepared using those solvents which have been used in the preparation of zinc suspensions. According to the invention, 0.5 to 1.5 liters, preferably 0.6 to 1.0 liter, of solvent are used per mole of acid addition salt of formula (II).

Alternatively, the compound of formula (II) in free base form can be initially converted in a suitable solvent to a dissolved acid addition salt with the aid of the corresponding acid in a separate test apparatus, and this solution is subsequently added to the zinc mixture described above. In this case, the above-mentioned solvent may be used as the solvent. It is advantageous to use some of the solvents already used for the preparation of the zinc suspensions described above. According to the invention, preferably from 0.5 to 1.5, preferably from 0.6 to 1.0, liter of solvent are used per mole of free base of the formula (II). The resulting suspension is then combined with the corresponding acid required to form the acid addition salt, i.e., the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate or hexafluorophosphate salt. At least 1 mole of the acid concerned is added per mole of the free base of formula (II). However, in the process of the present invention, it is of course also possible to use an excess of acid (i.e. from 1.1 to about 2 moles of acid per mole of base (II)). The hydrochloride or hydrogen bromide of compound (II) is preferably used according to the invention. The hydrochloric acid can be added either in the form of an aqueous solution or in gaseous form, preferably in the form of an aqueous solution. Preferably, concentrated hydrochloric acid (36%) is added dissolved in water. If hydrogen bromide is used, which is particularly preferred in the context of the present invention, it can likewise be added in aqueous solution or in gaseous form, preference being given to aqueous solution. Concentrated hydrogen bromide (62%) is preferably added dissolved in water. The pH is adjusted to 3.5-5.5, preferably 4.5-5, by adding one of the above-mentioned acids to a suspension of the free base of formula (II) in the relevant solvent.

The solution of the acid addition salt of formula (II) described above and optionally obtained in different ways is added to the zinc suspension. If necessary, the addition process may be carried out, for example, under elevated temperature conditions. It is reasonable to perform such a temperature increase if the mixture has been heated before the addition of the activator. If the addition is carried out at elevated temperature, temperatures of above 50 ℃, preferably from 55 to 90 ℃ and particularly preferably from 60 to 80 ℃ are suitable according to the invention.

After the end of the addition, the reaction mixture is stirred at a temperature of from 50 to 100 deg.C, preferably from 60 to 95 deg.C, particularly preferably from about 70 to 85 deg.C. Depending on the solvent selected, the maximum temperature mentioned in the above temperature range naturally becomes lower if the solvent used is boiling at a temperature lower than the above maximum temperature. Stirring was continued at constant temperature until the reaction was complete (0.5-4 hours). The progress of the reaction can be controlled by, for example, thin layer chromatography.

After the reaction is complete, the reaction mixture is mixed with a suitable base to saponify the ester functionality. The bases are preferably inorganic bases selected from the group consisting of alkali metal-or alkaline earth metal carbonates, alkali metal-or alkaline earth metal alcoholates and alkali metal-or alkaline earth metal hydroxides. Here, particular preference is given to using the hydroxides of lithium, sodium, potassium and calcium, preferably the hydroxides of sodium or potassium. According to the invention, the use of sodium hydroxide as base is particularly preferred. The above-mentioned bases can be used as pure alkali or preferably as concentrated solutions in water. For example, if the base used according to the invention is sodium hydroxide, which is particularly preferred, it is preferred to add an aqueous alkali solution having a concentration of at least 40% by weight. The use of at least a stoichiometric amount of base per mole of the starting compound of formula (II) is required. Of course, an excess of base may also be used. The addition of the base can be carried out at a temperature of from 0 to 50 ℃, preferably from 10 to 40 ℃, particularly preferably from 20 to 30 ℃ or can be carried out immediately after the addition of the base. Stirring is continued at this temperature until the reaction is complete (12-24 hours depending on the amount added). When the amounts added are small (for example on a kilogram scale), the saponification can be carried out at elevated temperatures (50-100 ℃ C., preferably 55-90 ℃ C., particularly preferably 60-80 ℃ C.). This reduces the reaction time to about 15 minutes to 10 hours, preferably 0.5 to 3 hours. The progress of the reaction can be controlled, for example, by thin layer chromatography.

After the reaction is complete, the temperature is adjusted to 0-50 c, preferably 15-45 c, with stirring, and the zinc salt is removed by filtration. The residue of the filter is washed with a solvent for reaction as necessary. For extraction, the combined filtrates are extracted with an organic solvent that is immiscible to slightly miscible with the solvent of choice for the reaction. The organic solvent is preferably selected from methyl-tert-butyl ether, dichloromethane and chloroform, preferably dichloromethane is used. According to the invention, extraction is carried out using from 0.5 to 5, preferably from 0.75 to 4, liters of organic solvent per mole of compound of formula (II). The extraction is carried out 3 to 8 times, preferably 4 to 6 times, according to the invention. After the extraction was complete, the organic phases were combined and the organic solvent was distilled under vacuum.

The remaining crude product is dissolved in an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, preferably isopropanol. According to the invention, 0.1 to 2.0 l, preferably 0.3 to 1.0 l, of the abovementioned solvent are used per mole of the starting compound of the formula (II). The solution obtained is separated from the precipitated solid (metal salt of acid RCOOH, wherein R has the previously mentioned meaning) by filtration. The filtrate contains the dephenolate of formula (I) in its free base form. If the free base is used in the next reaction, the solvent is distilled off in vacuo at this point. The remaining free base was used in the next step without further purification. However, according to the present invention, it is preferred to convert the free base of the tropenol into an acid addition salt. In the context of the present invention, the term "acid addition salt of dephenolic acid" is intended to mean a salt selected from the group consisting of hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate and hexafluorophosphate. Particularly preferred salts here are hydrogen bromide and the hydrochloride, particularly interesting according to the invention is the hydrochloride of the terpineol. To prepare the acid addition salts, the filtrate is cooled to-10-20 deg.C, preferably-5-15 deg.C. The corresponding acid required for the formation of the acid addition salt, i.e. the hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulphate, tetrafluoroborate or hexafluorophosphate salt, is then added to the suspension thus formed. At least 1 mole of the acid concerned is used per mole of the original free base of formula (II). An excess of acid (i.e., 1.1 to about 2-3 moles of acid per mole of the original base (II)) may be used within the scope of the process of the present invention. The hydrochloride of the pinitol is preferably prepared according to the invention. The hydrochloric acid required for this purpose can be in solution or in gaseous form. The hydrochloride salt in gaseous form is preferably added to the above-mentioned solvent in a separate reactor until saturation. It is particularly preferred to use a solvent for preparing the dephenolized filtrate in order to prepare this HCl solution. One of the above acids is added to the solution of the free base of the tropenol (I) until a pH of from 1.5 to 6.5, preferably from 2 to 6, is reached. After the addition of the acid is completed, it is preferable to further stir at a constant temperature for 0.5 to 2 hours. Finally, the precipitated acid addition salt of the tropenol is isolated and optionally washed with a solvent selected from acetone, methyl isobutyl ketone and methyl ethyl ketone, preferably acetone, and dried in vacuo.

As mentioned above, the dephenols prepared by the process of the present invention are effective starting compounds for the preparation of therapeutically active compounds such as tiotropium bromide, ipratropium bromide or BEA 2108. Due to the high purity of the dephenols obtained according to the invention, the active substances mentioned above can be prepared as required for pharmaceutical applications.

Accordingly, the object of the present invention is the use of dephenols, if desired in the form of their acid addition salts, as starting materials for the preparation of therapeutically active compounds such as tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.

Furthermore, the invention relates to the use of compounds of formula (II), optionally in the form of their acid addition salts and in the form of their hydrates, as starting materials for the preparation of therapeutically active compounds such as tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.

In the formula: r represents C₁-C₄-alkyl and C₁-C₄A radical of alkylene-phenyl, each of which may be substituted by hydroxy or C₁-C₄-alkoxy substitution.

The invention preferably relates to the use of scopolamine, optionally in the form of its acid addition salts and in the form of its hydrates, as starting material for the preparation of therapeutically active compounds such as tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.

The process shown in reaction scheme 1 can be used to prepare tiotropium bromide from dephenolate.

Reaction route 1:

the dephenols (I) prepared according to the invention are first reacted with the bis- (2-thienyl) -glycolic acid derivative (III) to form the bis- (2-thienyl) -glycolic acid-dephenolate (IV). The ester is converted to the corresponding tropyl ester (V) by oxidation of the double bond of the olefin, and the tiotropium bromide is obtained by reaction of the tropyl ester with methyl bromide.

A particularly preferred aspect of the present invention therefore relates to a process for the preparation of tiotropium bromide,

the method is characterized in that: in a first step, the tropyl ester of formula (II), optionally an acid addition salt thereof, is converted into the tropenol of formula (I) by reduction with zinc in a suitable solvent in the presence of an activated metal salt, preferably an activated iron or copper salt, with saponification with a suitable base,

in the formula (II): r represents C₁-C₄-alkyl and C₁-C₄A radical of alkylene-phenyl, each of which may be substituted by hydroxy or C₁-C₄-alkoxy substitution.

If desired in a second reaction stage with esters of the formula (III)

To obtain dephenolate ester of formula (IV)

In a third step oxidation is carried out to form the tropyl ester of formula (V)

And quaternised with methyl bromide in the fourth step to give tiotropium bromide.

The following examples are intended to illustrate in detail the synthetic method for the preparation of tiotropium bromide. These examples are merely illustrative and are not intended to limit the scope of the present invention.

Example 1:

preparation of dephenolate (I) in the form of the hydrochloride salt (kilogram grade)

3l of water are introduced into a reactor flushed with nitrogen, 390 g of zinc powder (< 63 μm) are added with vigorous stirring and 66 ml of 57% aqueous hydrogen iodide are added as activator. The mixture was stirred at room temperature for about 5 minutes. 67.2 g of Cu (II) -bromide in 260 ml of water were then slowly added. To this mixture 910.2 g of a solution of scopolamine in about 2.6 l of water was slowly added and the pH was adjusted to 4.5-5 with 227 ml of 62% aqueous hydrogen bromide. After the addition was complete, the mixture was heated to a temperature of 75-80 ℃ and stirred at this temperature for about 2 hours. After the reaction was complete (controlled by DC), cool to about 65 ℃. 480 ml of 45% aqueous solution of caustic soda were added and the mixture was stirred at a temperature of 65-70 c until complete saponification (about 1 hour). After cooling to about 40 ℃, the zinc salt was filtered off and washed with about 200 ml of water. The filtrate was extracted several times with dichloromethane (3-5 times 2-4 liters of dichloromethane each), the organic phases were combined and the solvent was distilled off under reduced pressure. The remaining residue (371 g crude product) was taken up in 1.5 l isopropanol and the precipitated solid (deacid-metal salt) was filtered off. The filtrate was cooled to-10-10 ℃ and 120 g of HCl dissolved in 780 ml of isopropanol were slowly added with vigorous stirring. The pH was adjusted to 2.5-4 and after addition was complete, stirring was continued for an additional 1 hour at about-5 ℃. Finally the suspension is filtered and the filter residue is washed again with about 600 ml of acetone and then dried under vacuum at a temperature of about 60 ℃.

Yield: 408.1 g of dephenolhydrochloride (77.4%, calculated as scopolamine used)

Example 2:

preparation of dephenolic alcohol (I) in its hydrochloride form (technical Scale)

130l of water are introduced into a reactor flushed with nitrogen, and 21.5kg of zinc powder (< 63 μm) are added with vigorous stirring. The mixture is heated to a temperature of 65-75 ℃. To the mixture was added 6.2kg of 57% aqueous hydrogen iodide solution. A solution of 3.7kg of Cu (II) -bromide in 20-25 l of water is then added. The mixture was stirred for a further 5 minutes if necessary, followed by the addition of a solution of 65.8kg of scopolamine hydrobromide-trihydrate in 140 liters of water and 145 liters of water. The resulting mixture was heated to 75-85 ℃ and stirred for 2-2.5 hours. After the reaction was complete (controlled by DC), 35.5kg of 45% aqueous caustic soda solution was added. The mixture is heated to 20-30 ℃ and the precipitate is further stirred for 20-24 hours. After the reaction was complete (controlled by DC), the contents of the entire reactor were filtered and the remaining residue was washed with about 30 liters of water. The filtrate was mixed with 75kg of sodium chloride at a constant temperature. 150L of methylene chloride was added thereto to conduct extraction. The organic phase was separated and the aqueous phase was extracted 4 times with the same amount of dichloromethane. The combined organic phases were distilled to remove the solvent. To the remaining residue was added about 100 liters of isopropanol and the temperature was adjusted to 0-10 ℃. A solution of 5.5kg of hydrogen chloride in 38 liters of isopropanol is then added to adjust the pH to about 2.5-5.5. The precipitated dephenolhydrochloride salt is separated off and washed with 30l of acetone. After drying, 21.3kg of product were obtained (yield: 81%, based on the scopolamine hydrobromide used).

Example 3: preparation of tiotropium bromide

a) Preparation of terpineol ester (IV)

Ammonia (1.8kg) was fed at 25 ℃ into a solution of 10.9kg of dephenolhydrochloride (obtained according to example 1) in toluene (95L). The obtained suspension was stirred at constant temperature for about 1 hour. The ammonium chloride formed was then filtered and washed again with toluene (26L). A portion of the toluene (about 60L) was distilled off in vacuo at a jacket temperature of about 50 ℃. After cooling, 15.8kg of methyl di- (2-thienyl) glycolate was added at about 25 ℃ and the resulting mixture was heated to 50 ℃ to effect dissolution. Toluene (40L) was charged to another reactor, and sodium hydride (2.7kg) was added to the reactor at about 25 ℃. To this solution was added a solution of dephenolic and methyl glycolate formed beforehand at 30 ℃ over 1 hour. After the addition was complete, the mixture was heated to 75 ℃ while stirring under reduced pressure for 7 hours. Methanol is thus formed by distillation. The remaining mixture was cooled and added to a mixture of water (958L) and 36% hydrochloric acid (13.2 kg). The aqueous phase was separated and washed with dichloromethane (56L). After further addition of dichloromethane (198L), the mixture thus obtained is adjusted with a prepared soda solution (9.6kg soda in 45L water) to a pH of 9. The dichloromethane phase was separated and the aqueous phase was stirred (ausgeruhrt) with dichloromethane (262L). The dichloromethane phase was evaporated to residue at 65 ℃. The residue was taken up in toluene (166L) and heated to 95 ℃. The toluene solution was cooled to 0 ℃. The crystals formed were separated, washed with toluene (33L) and dried in a stream of nitrogen at about 50 ℃ for up to 24 hours.

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

b) preparation of scopine ester (V)

In a suitable reactor 260L DMF was added and heated to 50 ℃. Then 16.2kg of dephenolate ester (IV) was added and the mixture was stirred until the solution became clear. After cooling to 40 ℃, hydrogen peroxide-urea complex (10.2kg), water (13L) and vanadium (V) oxide (0.7kg) were added in portions in order, heating the contents of the reactor to about 50 ℃. After stirring at constant temperature for 2-3 hours, it was cooled to about 20 ℃. The reaction mixture obtained was adjusted to about ph4.0 with hydrochloric acid (36%). A sodium hydrogen sulfate solution (2.4kg in 24L water) prepared in advance was added. The solvent (about 210L) was distilled in partial vacuum at an internal temperature of 35 ℃. It was again cooled to about 20 ℃ and mixed with Clarcel (3.2 kg). The pH was adjusted to about 2.0 with dilute hydrochloric acid (36%, 0.8kg in about 440L water). The resulting solution was filtered and extracted with dichloromethane (58L). The dichloromethane phase was discarded. Methylene chloride (130L) was added to the aqueous phase and the pH was adjusted to about 10.0 with a pre-prepared soda solution (11.0kg in 51L water). The dichloromethane phase was separated and the aqueous phase was extracted with dichloromethane (136L). Methylene chloride (about 175L) was distilled off from the combined methylene chloride phases at 40 ℃ under a weak vacuum (600 and 700 mbar). The contents of the reactor were cooled to 20 ℃. Acetyl chloride (about 0.5kg) was added and the mixture was stirred at 20 ℃ for about 40 minutes. The reaction solution was transferred to the second reactor. The pH was adjusted to 2.0 with a ready solution of hydrochloric acid (4.7kg of hydrochloric acid 36% in 460L of water) at 20 ℃. The dichloromethane phase was separated and removed. The aqueous phase was washed with dichloromethane (39L). Dichloromethane (130L) was then added and the pH adjusted to 10.0 at 20 ℃ with a pre-prepared soda solution (7.8kg soda in 38L water). After stirring for 15 minutes, the organic phase was separated and the aqueous phase was washed 2 times with dichloromethane (97L and 65L). The dichloromethane phases were combined and a portion of the dichloromethane (about 90L) was distilled under a mild vacuum at a temperature of 30-40 ℃. Dimethylformamide (114kg) was then added and the remaining dichloromethane was distilled under vacuum at 40 ℃. The contents of the reactor were cooled to 20 ℃.

c) Preparation of tiotropium bromide

To the scopine ester solution prepared according to the above procedure was delivered methyl bromide (5.1kg) at 20 ℃. The contents of the reactor were stirred at 30 ℃ for about 2.5 days. 70L of DMF was distilled off under vacuum at 50 ℃. The solution was transferred to a smaller reactor. Wash again with DMF (10L). The DMF added was distilled off in vacuo at 50 ℃ until the total distillation reached about 100L. Cooled to 15 ℃ and stirred at this temperature for a further 2 hours. The product was isolated by suction filter dryer and washed with cooled DMF (10L) at 15 ℃ and cooled acetone (25L) at 15 ℃. Drying is carried out for up to 36 hours at a maximum of 50 ℃ in a nitrogen stream.

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

the crude product thus obtained (10.3kg) was added to methanol (66L). The mixture was heated to reflux until dissolved. The solution was cooled to 7 ℃ and stirred at this temperature for 1.5 hours. The product was isolated by means of a suction filter dryer, washed with cooled methanol (11L) at 7 ℃ and dried in a stream of nitrogen at about 50 ℃ for up to 36 hours.

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

The product thus obtained may, if desired, be converted into crystalline monohydrate of tiotropium bromide. The procedure was as follows. In a suitable reactor containing 25.7kg of water, 15.0kg of tiotropium bromide were added. The mixture was heated to 80-90 ℃ and stirred at the same temperature until the solution was clear. Activated carbon moistened with water (0.8kg) was suspended in 4.4kg of water, and the mixture was added to a solution containing tiotropium bromide and washed with 4.3kg of water. The mixture thus obtained was stirred at 80-90 ℃ for at least 15 minutes, followed by filtration through a heated filter into a reactor preheated to an external temperature of 70 ℃. The filter was rinsed with 8.6kg of water. The contents of the apparatus are cooled to a temperature of 20-25 c at a rate of 3-5 c every 20 minutes. The reactor was cooled again to 10-15 ℃ with cold water and the crystallization was completed by stirring for at least 1 hour. The crystals were separated by suction filter drier and the separated crystal slurry was washed with 9L of cold water (10-15 ℃ C.) and cooled acetone (10-15 ℃ C.). The crystals thus obtained were dried at a temperature of about 25 ℃ for about 2 hours in a nitrogen stream.

Yield: 13.4kg tiotropium bromide monohydrate (86% of theory)

Melting point: 230 deg.C (measured by DSC at a heating rate of 10K/min).

Claims (8)

1. A process for the preparation of dephenols of formula (1), optionally in the form of their acid addition salts, characterized in that: reduction of the tropyl ester of formula (II), optionally in the form of its acid addition salts and in the form of its hydrates, by zinc in the presence of an activated iron or copper salt in water, followed by saponification with a suitable base to give the tropenol of formula (1),

in the formula: r represents C₁-C₄-alkyl and C₁-C₄A radical of alkylene-phenyl, each of which may be substituted by hydroxy or C₁-C₄-alkoxy substitution.

2. A method according to claim 1, characterized in that: the use of scopolamine of formula (II'), optionally in the form of an acid addition salt and in the form of a hydrate, as scopine ester of formula (II)

3. A method according to claim 1, characterized in that: in a first step, zinc is added to water, in a second step, if necessary after activation with a suitable activator, a metal salt is added, in a third step, a compound of formula (II), if necessary in the form of its acid addition salt and/or of its hydrate, in a fourth step, the ester function is saponified with the aid of a suitable base, and then the compound of formula (I), if necessary in the form of its acid addition salt, is isolated.

4. A method according to claim 2, characterized in that: in a first step, zinc is added to water, in a second step, if necessary after activation with a suitable activator, a metal salt is added, in a third step, a compound of formula (II), if necessary in the form of its acid addition salt and/or of its hydrate, in a fourth step, the ester function is saponified with the aid of a suitable base, and then the compound of formula (I), if necessary in the form of its acid addition salt, is isolated.

5. The method of claim 1, 2, 3 or 4, wherein: the metal salt adopts Fe- (III) or Cu- (II) salt.

6. The method according to claim 5, characterized in that: the metal salt adopts Fe- (III) or Cu- (II) halide.

7. The method according to claim 5, characterized in that: the salt is selected from FeCl₃、CuCl₂、CuI₂、CuBr₂And CuBr₂-a dimethyl sulphur complex.

8. The method of claim 7, wherein: the salt is CuBr₂。