MX2007000595A - Method for producing tiotropium salts and silicon derivatives as intermediates - Google Patents

Abstract

The invention relates to a novel method for producing tiotropium salts of general formula (1) via the corresponding silyl compound, wherein X-can have the meanings cited in the claims and in the description.

Description

PROCEDURE FOR THE PRODUCTION OF TIOTROPY SALTS AND SILICON DERIVATIVES AS INTERMEDIATE PRODUCTS The invention relates to a new process for the preparation of tiotropium salts of the general formula 1 wherein "X" may have the meanings indicated in the claims and in the description Background of the Invention Anticholinergics can be used in numerous diseases in a therapeutically convenient manner Here, for example, asthma or COPD therapy should be emphasized. (Chronic Obstructive Pulmonary Disease) For the therapy of these diseases, for example, anticholinergics having a basic structure of scoppine, tropenol or also tropine are proposed, for example, in WO 02/03289. of the art, tiotropium bromide is especially disclosed as a very potent anticholinergic, and tiotropium bromide is known, for example, from EP 418 716 A1.

In addition to the synthetic processes disclosed in the prior art described for preparing scopinic esters, a method for preparing scopinic esters is disclosed in WO 03/057694 in particular. The object of the present invention is to provide an improved technical synthesis method that allows a simpler synthetic access to the compounds of the general formula 1 in an improved manner compared to the state of the art.

Detailed Description of the Invention The present invention relates to a process for the preparation of tiotropium salts of the formula 1 wherein X ~ can mean a simple negative charge anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate, characterized in that a compound of the formula 2 is reacted wherein X "may have the meanings mentioned above, in a step with a compound generated in situ of the formula 3 ^ wherein R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl, -O-C (= NR ') -NHR ", -0-S02-phenyl, -0-S02-phenyl-methyl, -O-SO2-R '-O-CO-C (methyl) 3, -O-CO-phenyl-N02, chloro, bromo, -N3 and -O- (P = 0) R '' ', wherein R' C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; R "C1-C4 alkyl, C3-C6 cycloalkyl, alkylene Ci-C4-N (Ci-C4 alkyl) 2; R '' 'C 1 -C 4 alkyl, -O-C 1 -C 4 alkyl, phenyl u - 0-phenyl R1 and R2, can mean, the same or different, methyl, ethyl, propyl, butyl or phenyl, wherein the phenyl may be optionally substituted with one or more C1-C4 alkyl radicals, in an appropriate solvent by addition of an appropriate base to a compound of formula 4 wherein the groups X ~, R1 and R2 may have the meanings mentioned above, and the compound of the formula _ is converted without isolation by reaction with an appropriate acid or an appropriate de-silylation reagent with separation of the silyl group in the compound of the formula 1. Preferably, the present invention relates to a process for the preparation of tiotropium salts of the formula 1, wherein X "can be a simple negative charge anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate, preferably chloride, bromide or methanesulfonate, with special preference bromide. A particularly preferred process according to the invention is characterized in that the reaction is carried out with a compound generated in situ of formula 3, wherein R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl, -0-C (= NR ') -NHR ", -0-S02-phenyl-methyl, -0-C0-C (methyl) 3, and chloro, wherein R' methyl, ethyl or cyclohexyl; R" methyl, ethyl, cyclohexyl, C2-C3 alkylene (methyl) 2 or C2-C3-N alkylene (ethyl) 2, and R1 and R2, the same or different, methyl, ethyl, propyl or butyl A process of particular preference according to the invention characterized in that the reaction is carried out with a compound generated in situ of the formula 3, wherein R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl, -0-C (= N-cyclohexyl) -NH -cyclohexyl, -0-C (= N-ethyl) -NH-CH2-CH2-CH2-NMe2 and -0-CO-C (methyl) 3, preferably N-imidazolyl or N-triazolyl, with special preference N- imidazolyl and R1 and R2, same or different, methyl, ethyl, propyl or butyl, preferably methyl or ethyl, with special preference methyl; R2 methyl or ethyl, preferably methyl. By alkyl groups and by alkyl groups of Whose component are other radicals, they are referred to as branched and unbranched alkyl groups with 1 to 4 carbon atoms. By way of example, methyl, ethyl, propyl, butyl are mentioned. Unless otherwise mentioned, in the above-mentioned definitions propyl, butyl, all possible isomeric forms are included. By way of example, the name propyl comprises the two isomeric radicals n-propyl and iso-propyl, the butyl designation comprising n-butyl, iso-butyl, sec-butyl and tert-butyl. By alkylene bridge or alkylene group, unless otherwise indicated, branched and unbranched alkyl groups having 1 to 4 carbon atoms, for example, methylene, ethylene, propylene, butylene bridges, are designated. Methylene, ethylene, propylene and butylene bridges are especially preferred. Unless otherwise indicated, all the possible isomeric forms are included by the definitions mentioned above ethylene, propylene, butylene. The definitions phenylmethyl and phenyl-NC > 2 are for phenyl rings that are substituted with methyl or NO2. In this case all possible isomers are included (ortho, meta or para), attributing a singular importance to substitution for or meta. As cycloalkyl groups, cycloalkyl radicals of With 3-6 carbon atoms are designated, for example, cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl. To carry out this procedure, one can proceed as described below. In the first place, the compound of the formula 3_ is generated in situ in an appropriate solvent. The term "in situ" refers, in this case, to obtaining the compound of formula 3 without it being subsequently isolated. The preparation of formula 3 is carried out by reacting dithienylglycolic acid, preferably alkaline salts of dithienylglycolic acid, with special preference of sodium dithienylglycolate with a coupling reagent selected from the group consisting of carbonyldiimidazole, carbonyldi-1,2, -triazole , dicyclohexylcarbodiimide, ethyl dimethylaminopropylcarbodiimide, toluenesulfonyl chloride, pivaloyl chloride, nitrobenzoic acid anhydride, oxalyl chloride, phosgene, sulfonyl chloride and phosphorus chlorides, preferably carbonyldiimidazole, carbonyldi-1,2,4-triazole, dicyclohexylcarbodiimide, ethyl dimethylaminopropylcarbodiimide, with special preference carbonyldiimidazole in an appropriate solvent, preferably in an organic solvent polar aprotic, with special preference in a solvent selected from the group consisting of acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, dioxane and sulfolane, preferably tetrahydrofuran, dimethylformamide or N-methylpyrrolidone at a temperature of - 20 ° C-60 ° C, preferably -10 ° C-45CC, with special preference of -10 ° C-25 ° C and subsequent addition of a silyl compound of the formula 5.

I 5, in which the radicals R 1 and R 2 can have the meanings mentioned above and L is a leaving group selected, preferably, from the group consisting of halide, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate, with special preference methanesulfonate, trifluoromethanesulfonate, bromine or chlorine, more preferably bromine or chlorine, attributing to the chlorine singular importance according to the invention. The silyl compound _5 can be added to the mixture of dithienylglycolic acid or dithienylglycolic acid salt with a coupling reagent in the aforementioned solvent, optionally in the presence of a base such as, for example, pyridine, imidazole or N-alkylamine, or you can also arrange first together with the dithienylglycolic acid or the dithienylglycolic acid salt in the aforementioned solvent, optionally in the presence of a base such as, for example, pyridine, imidazole or N-alkylamine, and then mixing with the aforementioned coupling reagent. Preferably, the three components mentioned above are added for the formation of the compound of formula 3 in stoichiometric amounts, but optionally the reaction can also be carried out in the presence of one of the three components in excess (for example 1.1 to 1.5 equivalents) ). By mole of the in situ generated compound of the formula 3, 0.2 to 1.5 liters, preferably 0.3 to 1 liter of the solvent mentioned are used in this place. After adding the three components, the obtained solution is mixed to form the compound of the general formula 3_ at the aforementioned temperature for about 5 minutes to 2 hours, preferably for 10 minutes to 1 hour, with special preference for 20-40 minutes , for example by agitation. The compound of the formula 2 is then added to the solution obtained in this manner. This addition can be carried out by adding a solution or suspension of the compound of the formula 2 to one or more of the solvents. above mentioned or by addition, preferably in portions, of the compound of the formula 2_ in substance. When the compound of the formula i2 is added dissolved or suspended in one or more solvents, the use of the same solvent as used for the in situ preparation of the compound of the formula 3 is offered. The amount, in which the compound of formula 2 is added, is determined according to the amount of compound generated in situ of formula 3_. If, for the formation of the compound of formula 3, the three components dithienylglycolic acid or dithienylglycolic acid salt, coupling reagent and compound of the formula 5 are used in stoichiometric amounts, the compound of the formula _3 is in the molar amount for the three components, dithienylglycolic acid or dithienylglycolic acid salt, coupling reagent and compound of the formula _5 were selected. If the three components dithienylglycolic acid or dithienylglycolic acid salt, coupling reagent and compound of the formula 5 ^ are not applied in stoichiometric amounts for the formation of the compound of the formula 3_, the compound of the formula 3_ is in the molar amount of the component having a lower proportion of the three starting compounds dithienylglycolic acid or dithienylglycolic acid salt, coupling reagent and compound of the formula 5.

The molar ratio of the compound of the formula 2 to the in situ-generated compound of the formula _3 varies preferably in a range from 2: 1 to 1: 5, preferably 1.5: 1 to 1: 3, with special preference 1: 1 to 1: 2, attributing singular importance to a ratio of 1: 1 to 1: 1.5 according to the invention. After adding the compound of the formula 3_, the reaction mixture obtained is combined with a base taken in an appropriate solvent. The solvents mentioned above are used as solvents according to the invention. Preferably, in this place that solvent is used which is also used for the formation of the compound of the formula 3_. As a base, organic or inorganic bases can be used. As the organic bases, alkali metal imidazolides are preferably used, which can be generated, for example, in situ from alkali metals and imidazole or the alkali metal hydrides and imidazole. Suitable alkali metal imidazolides are preferably lithium, sodium or potassium imidazolides, with sodium or lithium imidazolide being preferred according to the invention. It is preferred to use in particular the alkali alcoholates of sterically hindered alcohols (for example, potassium tertiary butylate). Other preferred bases are selected according to the invention from the group consisting of lithium diisopropylamide (LDA), lithium hexamethyldisilazane or sodium (LiHMDS or NaH DS). As an inorganic base, they are taken into account with Preference is given to lithium, sodium or potassium hydrides. It is preferred to use in particular sodium hydride as the inorganic base. By mole of the compound used of the formula 2, 0.5-2 moles, with special preference 1-1.5 moles of base are preferably used. In the context of the process according to the invention, in most cases it is sufficient, however, when only 1-1.1 moles of base are added per mole of the compound of the formula 2 used. To prepare the basic solution or suspension, preferably 0.2 to 1.5 liters, preferably 0.3 to 1 liter of the solvent mentioned, are used per mole of base. The addition of the base is preferably carried out at a temperature of -20-60 ° C, preferably 0-45 ° C, especially preferably 0-25 ° C. After adding the base, the obtained mixture is stirred to form the compound of formula j for about 10 minutes to 6 hours, preferably for 30 minutes to 3 hours, particularly preferably for 45 minutes to 1.5 hours at constant temperature. To release the compound of the formula _1 from the in situ generated compound of the formula, the addition of an appropriate H-X acid is preferably carried out at a temperature below 10 ° C, with particular preference at about 0 ° C. Preferably, the selection of the acid is In this case, it is determined according to the anion X "in the desired end product of the general formula 1. Optionally, in the context of the present invention, addition of an appropriate de-silylation reagent which is selected can be carried out together with the HX acid. preferably from the group of ammonium fluorides, with particular preference tetrabutylammonium fluoride, tetraethylammonium fluoride, benzyltrimethylammonium fluoride, tetrahexylammonium fluoride, tetraoctylammonium fluoride or hydrofluoric acid in free or complex form, such as, for example, pyridinium fluoride, triethylamine-HF complex As an alternative to the use of one of the aforementioned acids, the release of the compound of formula 1 can also be carried out exclusively by means of the above-mentioned desilylation reagents. the present invention are preferably synthesized those compounds of the general formula _1 in where X "is bromide, the following procedure is described for the preparation of the preferred tiotropium bromide according to the invention. It is clear to the skilled person that a corresponding procedure can be employed by selecting the appropriate reagent HX or YF, where Y can be a cation such as a proton or a metal cation or ammonium, alkylammonium, tetraalkylammonium or pyridinium or a complex such as, for example, aluminum trifluoride-HF or other fluoride donor such as, for example, diethylaminosulphuric trifluoride (DAST), analogously also for preparing those compounds wherein X "is not bromide To prepare compounds of formula 1 with X" = bromide (= tiotropium bromide) they have at constant temperature, with respect to the compound used of formula 2, preferably 0.2 to 20 mol, preferably 0.5 to 15 mol, with special preference 1 to 14 mol of hydrobromic acid. The hydrogen bromide used can be added in this case in gaseous form or in the form of preferably saturated solutions. According to the invention, the addition of hydrogen bromide is preferably carried out in dissolved form in glacial acetic acid or water. In this case, a 33% solution of hydrogen bromide in glacial acetic acid or with special preference as 62% aqueous hydrobromic acid is used with particular preference. The addition of the acid is preferably carried out so slowly that the temperature of the reaction mixture does not exceed 20 ° C. Once the addition is finished, stirring is continued at a constant temperature, possibly also under cooling with ice (between 0.5 and 6 hours). In order to produce, as indicated in the examples, it is possible to proceed in particular according to methods known per se. By way of example, the reaction mixture is combined with a protic solvent, preferably with a alcohol, with special preference with methanol or ethanol or isopropanol. According to the invention, preferably 0.5 to 20 liters, particularly preferably 0.7 to 13 liters of alcohol, are added per mole of compound used of formula 2 and the mixture obtained is stirred at a temperature of 0-60 ° C, preferably from 10-45 ° C, with special preference of 15-25 ° C for a period of about 0.5-6 hours, preferably 0.5-5 hours, with special preference 0.5-4 hours. The solution obtained is then mixed with a non-polar organic solvent, preferably with a solvent selected from the group consisting of a ketone (such as, for example, acetone or methyl ethyl ketone), an alcohol (such as, for example, methanol, ethanol, propanol, isopropanol, butanol or amyl alcohol), toluene, ethyl acetate, n-butyl acetate, dichloromethane, diethyl ether, methyl tert-butyl ether, tetrahydrofuran and dioxane, with special preference isopropanol, toluene or acetone. After mixing well, the crystallized product is separated and washed with the aforementioned solvent. To separate water-soluble impurities, the crude product can be treated with water or with aqueous solutions of bromide, for example sodium or potassium bromide solution. Another purification of the compounds thus obtained of formula 1 can be carried out, if necessary, by chromatography on silica gel or by means of recrystallization from suitable solvents such as, for example, lower alcohols such as, for example, methanol, ethanol or isopropanol, optionally under pre-treatment with activated carbon. Due to its importance as intermediates of the process according to the invention for the preparation of the compounds of the formula 1, the present invention also relates to the compound of the formula wherein R, R1 and R2 can have the meanings mentioned above, as such. Due to its importance as intermediates of the process according to the invention for the preparation of the compounds of the formula 1, the present invention also relates to the compound of the formula where X ", R1 and R2 can have the meanings mentioned above, as such. In addition, the present invention relates to the use of the compounds of the formula 3_ mentioned above for the preparation of compounds of the formula 1. Furthermore, the present invention relates to the use of the compounds of the formula 4_ mentioned above for the preparation of compounds of the formula 1. The following examples serve to illustrate the synthesis procedures performed by way of example. They should be understood only as possible ways of proceeding, represented by way of example, without limiting the invention to its content.

Synthesis Example 1: In a mixture of 13.1 g (50 mmol) of sodium dithienylglycolate and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of N-methylpyrrolidone (NMP) are poured dropwise at 20 ° C 5.43 g ( 50 mmole) of chlorotrimethylsilane. After stirring for 30 min, they are added dropwise 9. 38 g (37.5 mmol) of scopine methobromide and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of NMP at 20 ° C and stirred for 1 h at 20 ° C. After cooling to 0 ° C, they are added dropwise 50 ml of a 33% solution of hydrogen bromide in glacial acetic acid, not exceeding the temperature of 20 ° C. Then add 50 ml of methanol and stir for 1 h at 20 ° C. The reaction mixture is extracted twice with 200 ml of toluene at a time and after separating the toluene phase it is crystallized with 150 ml of isopropanol at 0 ° C. The crude product is filtered, washed with 30 ml of cold isopropanol and dried in vacuo. Yield 15.0 g (85%, based on scopoin metobromide).

Synthesis Example 2: In a mixture of 13.1 g (50 mmoles) of sodium dithienylglycolate and 8.1 g (50 mmoles) of carbonyldiimidazole in 25 ml of dimethylacetamide, 5.43 g (50 mmoles) of chlorotrimethylsilane are added dropwise at 20 ° C. . After stirring for 30 min, they are added dropwise 9. 38 g (37.5 mmol) of scopic metobromide and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 30 ml of dimethylacetamide at 20 ° C and stirred for 1 h at 20 ° C. After cooling to -4 ° C, they are added dropwise 50 ml of a 33% solution of hydrogen bromide in glacial acetic acid, not exceeding the temperature of 20 ° C. Then add 50 ml of methanol and stir for 3 h at 20 ° C. The reaction mixture is extracted with 500 ml of toluene and after separating the toluene phase it is crystallized with 150 ml of isopropanol at 0 ° C. The crude product is filtered, washed with 30 ml of cold isopropanol and dried in vacuo. Yield 14.1 g (80%, based on scopoin metobromide).

Synthesis Example 3: In a solution of 13.1 g (50 mmol) of sodium dithienylglycolate and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of dimethylformamide (DMF), 5.43 g (50 mmol) are added dropwise at 20 ° C. ) of chlorotrimethylsilane. After stirring for 30 min, they are added dropwise 12. 5 g (50 mmol) of scopic metobromide and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of dimethylformamide at 20 ° C and it is stirred for 1 hour at 20 ° C. After cooling down to -5 ° C, they are added dropwise 50 ml of a 33% solution of hydrogen bromide in glacial acetic acid, not exceeding the temperature of 20 ° C. Then add 20 ml of methanol and stir for 1 hour at 20 ° C. The reaction mixture is extracted twice with 200 ml of toluene at a time and after separating the toluene phase crystallizes with 150 ml of isopropanol at 5 ° C. The crude product is filtered and recrystallized from 120 ml of methanol by adding 5 g of activated carbon. After cooling to 0 ° C, the obtained tiotropium bromide is filtered, washed with 5 ml of cold methanol and dried in vacuo. Yield 15.0 g (64% relative to the methobromide of scopina).

Synthesis: In a solution of 13.1 g (50 mmoles) of sodium dithienylglycolate and 8.1 g (50 mmoles) of carbonyldiimidazole in 25 ml of dimethylformamide, 5.43 g (50 mmoles) of chlorotrimethylsilane are added dropwise at 20 ° C. . After stirring for 30 min, 12.5 g (50 mmol) of scopoin methobromide are added and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) are added dropwise. ) in 15 ml of DF at 20 ° C and stirred for 1 hour at 20 ° C. After cooling down to -5 ° C, 50 ml of a 33% solution of hydrogen bromide in glacial acetic acid are added dropwise, the temperature not exceeding 20 ° C. Then add 20 ml of methanol and stir for 1 hour at 20 ° C. The reaction mixture is extracted twice with 200 ml of toluene at a time and after separating the toluene phase crystallizes with 150 ml of isopropanol at 5 ° C. The crude product is filtered and recrystallized from 120 ml of methanol by adding 5 g of activated carbon. After cooling to 0 ° C, the obtained tiotropium bromide is filtered, washed with 5 ml of cold methanol and dried in vacuo. The crystals obtained in this way are dissolved in 20 ml of water at 90 ° C and the monohydrate of tiotropium bromide crystallizes by cooling to 15 ° C. The product is filter, wash with 7 ml of water and 8 ml of acetone and filter dry. Yield 9.8 g (40% relative to scopoin methobromide).

Example of Synthesis 5; In a mixture of 13.1 g (50 mmol) of sodium dithienylglycolate and 8.1 g (50 mmol) of carbonyldiimidazole in 25 ml of dimethylformamide, 5.43 g (50 mmol) of chlorotrimethylsilane are poured dropwise at 20 ° C. After stirring for 30 min, they are added dropwise 12. 5 g (50 mmol) of scopine methobromide and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of dimethylformamide at 20 ° C and stirred for 1 hour at 20 ° C. After cooling to 0 ° C, 5 ml of a 33% solution of hydrogen bromide in glacial acetic acid are added dropwise., not exceeding 10 ° C. Then 120 ml of 1 M tetrabutylammonium fluoride in THF (0.12 mol) are added and stirred for 1 h at room temperature. The reaction mixture is mixed with 800 ml of dichloromethane and stirred for 1 h at room temperature. The crystallized crude product is filtered and recrystallized from 120 ml of methanol by adding 5 g of activated carbon. After cooling to 0 ° C, the obtained tiotropium bromide is filtered, washed with cold methanol and dried in vacuo. Yield 9.5 g (44% respect to scopoina methobrorauro). Synthesis Example 6: In a solution of 13.1 g (50 mmol) of sodium dithienylglycolate in 25 ml of dimethylformamide, 5.43 g (50 mmol) of chlorotrimethylsilane are poured dropwise at 20 ° C. After stirring for 30 min, at room temperature 8.1 g (50 mmol) of carbonyldiimidazole are added in portions and the mixture is stirred for a further 10 min. Then 10 g (40 mmol) of scopolamine methobromide are added and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of water are poured dropwise. dimethylformamide at 20 ° C and stirred for 1 hour at 20 ° C. After cooling down to -5 ° C, 50 ml of a 33% solution of hydrogen bromide in glacial acetic acid are added dropwise, the temperature not exceeding 20 ° C. Then add 20 ml of methanol and stir for 30 min at room temperature. The reaction mixture is extracted twice with 200 ml of toluene at a time and crystallized from 150 ml of isopropanol by cooling to 5 ° C. The crystallized crude product is filtered and recrystallized from 120 ml of methanol by adding 5 g of activated carbon. After cooling to 0 ° C, the obtained tiotropium bromide is filtered, washed with cold methanol and dried in vacuo. The product is dissolved in 24 ml of water at 90 ° C and the tiotropium bromide monohydrate crystallizes by cooling to 15 ° C. The product is filtered and washed with 6.5 ml of water and 10.5 ml of acetone and dried. Yield 8.1 g (42% relative to scopoin methobromide).

Example 7: In a solution of 13.1 g (50 mmol) of sodium dithienylglycolate in 25 ml of dimethylformamide, 5.43 g (50 mmol) of chlorotrimethylsilane are poured dropwise at 20 ° C. After stirring for 30 min, at room temperature 8.1 g (50 mmol) of carbonyldiimidazole are added in portions and the mixture is stirred for a further 10 min. Then 10 g (40 mmol) of scopolamine methobromide are added and a solution of 2.59 g (38 mmol) of imidazole and 1.52 g (38 mmol) of sodium hydride (60%) in 15 ml of water are poured dropwise. dimethylformamide at 20 ° C and stirred for 1 hour at 20 ° C. After cooling to 10 ° C, 6 ml of a 33% solution of hydrogen bromide in glacial acetic acid are added dropwise, not exceeding the temperature of 20 ° C. Then 120 ml of 1 M tetrabutylammonium fluoride in THF (0.12 mol) are added and stirred for 30 min at room temperature. The reaction mixture is mixed with 800 ml of dichloromethane and stirred for 15 min at room temperature. The crystallized crude product is filtered and recrystallized from 120 ml of methanol by adding 2 g of activated carbon. After cooling to 0 ° C, the obtained tiotropium bromide is filtered, washed with cold methanol and dried in vacuo. The product dissolves in 18 ml of water at 90 ° C and tiotropium bromide monohydrate crystallizes by cooling to 15 ° C. The product is filtered and washed with 5 ml of water and 8 ml of acetone and dried. Yield 6.5 g (34% relative to scopoin methobromide).

Synthesis 8: In a solution of 13.1 g (50 mmol) of sodium dithienylglycolate in 25 ml of tetrahydrofuran, 5.43 g (50 mmol) of chlorotrimethylsilane are poured dropwise at 20-30 ° C. After stirring for 60 min, 8.1 g (50 mmol) of carbonyldiimidazole are added and after another 30 min, 10.01 g (40 mmol) of scopolamine methobromide are added and stirring is continued for 30 min. Then a solution of 2.60 g (38 mmol) of imidazole and 1.65 g (38 mmol) of sodium hydride (55%) in 25 ml of dimethylformamide at 20 ° C are added dropwise and the mixture is stirred for 1 hour at 20 ° C. ° C. After cooling to 0 ° C, 20 ml of 62% hydrobromic acid are poured dropwise, the temperature not exceeding 20 ° C. After stirring for 40 min, the reaction mixture is stirred at 20 ° C in 350 ml of isopropanol and cooled to 10 ° C. The crude product is filtered, washed with 50 ml of cold isopropanol and dried in vacuo. Yield 18.9 g of reddish-brown crystals, CCD equals comparison.

The crude product is dissolved with 2.2 g of activated carbon in 100 ml of refluxing methanol and filtered. The solution is then concentrated to 30 ml and cooled to 3 ° C. The crystals are filtered, washed with 5 ml of cold methanol and dried. Yield 12.1 g of whitish beige crystals, CCD equals comparison. The crystals obtained in this way are dissolved with 1.2 g of activated carbon in 28 ml of water at 80 ° C and filtered. After cooling to 15 ° C, the crystallized tiotropium bromide monohydrate is filtered and dried. Yield 9.4 g (48% with respect to the scopolamine metobromide used).

Synthesis Example 9: In a solution of 39.3 g (150 mmol) of sodium dithienylglycolate in 117 ml of tetrahydrofuran, 17.9 g (165 mmol) of chlorotrimethylsilane are poured dropwise at 0 ° C. After stirring for 60 min at 10-20 ° C, it is cooled to 0 ° C, and a solution of 24.3 g (150 mmol) of carbonyldiimidazole in 105 ml of dimethylformamide is poured dropwise. After stirring for another 30 min, 30.3 g (121 mmol) of scopolamine methobromide are added and stirring is continued for 60 min at 10-20 ° C. The mixture is cooled to 10 [deg.] C. and a solution of 16.8 g (150 mmol) of potassium tert-butylate is poured in 90 ml of tetrahydrofuran at 10-20 ° C and stirred for 60 min at 20 ° C. After cooling down to 0 ° C, 60 ml of 62% hydrobromic acid are poured dropwise, the temperature not exceeding 20 ° C. After stirring for 40 min, the reaction mixture is stirred at 20 ° C in 1150 ml of isopropanol and cooled to 10 ° C. The crude product is filtered, washed with 70 ml of cold isopropanol and dried in vacuo. Yield 61.5 g of reddish-brown crystals, CCD equals comparison. The crude product is dissolved with 6.15 g of activated carbon in 615 ml of refluxing methanol and filtered. Then 570 ml of methanol are distilled, and the solution is cooled to 10 ° C. The crystals are filtered, washed with 35 ml of cold methanol and dried. Yield 40.9 g of whitish beige crystals, CCD equals comparison. The crystals obtained in this way are dissolved with 2.2 g of activated carbon in 94 ml of water at 80 ° C and filtered, then washed with 24 ml of water. After cooling to 15 ° C, the crystallized tiotropium bromide monohydrate is filtered, washed with 25 ml of water and 35 ml of acetone and dried. Yield 28.6 g (48% with respect to the scopolamine metobromide used).

Claims (8)

1. CLAIMS 1) Procedure for the preparation of tiotropium salts of the formula wherein "X" means a simple negative charge anion, preferably an anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate, characterized in that a compound of the formula 2 is reacted wherein X "may have the meanings mentioned above, in a step with a compound generated in situ of the formula 3 ^ wherein R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl, -0-C (= NR ') -NHR ", -0-S02-phenyl, -0-S02-phenyl-methyl, -0-S02-R ', -0-CO-C (methyl) 3, -0-CO-phenyl-N02 / chloro, bromo, -N3 and -0- (P = 0) R' '', wherein they mean R 'C 1 -C 4 alkyl or C 3 -C 6 cycloalkyl; R "C 1 -C 4 alkyl, C 3 -C 6 cycloalkyl, C 1 -C 4 alkylene (C 1 -C 4 alkyl) 2 R '' 'C 1 -C 4 alkyl, -0-C 1 -C 4 alkyl, phenyl u-0-phenyl R1 and R2 may mean, the same or different, methyl, ethyl, propyl, butyl or phenyl, wherein the phenyl may optionally be substituted with one or more C1-C4 alkyl radicals, in an appropriate solvent per addition of an appropriate base to a compound of the formula _ wherein the groups X ", R1 and R2 can have the meanings mentioned above, and the compound of the formula is converted without isolation by reaction with an appropriate acid or an appropriate de-silylation reagent with separation of the silyl group in the Formula 1.
2. 2) Procedure for the preparation of salts of tiotropium of formula 1 according to claim 1, characterized in that X "can be a simple negative charge anion selected from the group consisting of chloride, bromide, iodide, methanesulfonate or trifluoromethanesulfonate, preferably chloride, bromide or methanesulfonate, with special preference bromine
3. 3) Process for the preparation of tiotropium salts of the formula _ 1 according to claim 1 or 2, characterized in that the reaction is carried out with a compound generated in situ of the formula 3, in which R is a selected radical of the group consisting of N-imidazolyl, N-triazolyl, -0-C (= NR ') -NHR ", -0-S02-phenyl-methyl, -0-C0-C (methyl) 3 and chloro, wherein R 'is methyl, ethyl or cyclohexyl, R "methyl, ethyl, cyclohexyl, C2-C3-N alkylene (methyl) 2 or C2-C3-N alkylene (ethyl) 2, and R1 and R2, the same or different , methyl, ethyl, propyl or butyl
4. 4) Process for the preparation of tiotropium salts of the Formula 1 according to claim 1, 2 or 3, characterized in that the reaction is carried out with a compound generated in situ of the formula 3_, wherein R is a radical selected from the group consisting of N-imidazolyl, N-triazolyl, -0-C (= N-cyclohexyl) -NH-cyclohexyl, -0-C (= N-ethyl) -NH-CH2-CH2-CH2-NMe2 and -0-CO-C (methyl) 3, preferably N-imidazolyl or N-triazolyl, with special preference N-imidazolyl and R1 and R2, same or different, methyl, ethyl, propyl or butyl, preferably methyl or ethyl, with special preference methyl; R2 methyl or ethyl, preferably methyl.
5. 5) Process for the preparation of tiotropium salts of the formula 1 according to one of claims 1 to 4, characterized in that the compound of the formula 3 ^ is generated in situ in an appropriate solvent by reaction of dithienylglycolic acid or alkaline salts of dithienylglycolic acid with a coupling reagent selected from the group consisting of carbonyldiimidazole, carbonyldi-1,2,4-triazole, dicyclohexylcarbodiimide, ethyl dimethylaminopropylcarbodiimide, toluenesulfonyl chloride, pivaloyl chloride, nitrobenzoic acid anhydride, oxalyl chloride, phosgene, sulfonyl chloride and phosphorus chlorides, and subsequent addition of a silyl compound of the formula _5 wherein the radicals R1 and R2 can have the meanings mentioned above and L is a leaving group which is preferably selected from the group consisting of halide, methanesulfonate, trifluoromethanesulfonate and para-toluenesulfonate.
6. 6) Process for the preparation of tiotropium salts of the formula 1 in accordance with the claim 5, characterized in that the solvent is selected from the group consisting of acetonitrile, nitromethane, formamide, dimethylformamide, N-methylpyrrolidinone, dimethyl sulfoxide, dimethylacetamide, tetrahydrofuran, dioxane and sulfolane.
7. 7) Compound of formula 3 characterized in that R, R1 and R2 can have the meanings mentioned in claims 1 to 5.
8. 8) Compound of formula 4 characterized in that X ", R1 and R2 may have the meanings mentioned in claims 1 to 5.