Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07D—HETEROCYCLIC COMPOUNDS
  • C07D451/00—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof
  • C07D451/02—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof
  • C07D451/04—Heterocyclic compounds containing 8-azabicyclo [3.2.1] octane, 9-azabicyclo [3.3.1] nonane, or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane or granatane alkaloids, scopolamine; Cyclic acetals thereof containing not further condensed 8-azabicyclo [3.2.1] octane or 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring systems, e.g. tropane; Cyclic acetals thereof with hetero atoms directly attached in position 3 of the 8-azabicyclo [3.2.1] octane or in position 7 of the 3-oxa-9-azatricyclo [3.3.1.0<2,4>] nonane ring system
  • C07D451/06—Oxygen atoms

Definitions

• the invention relates to a new, technically applicable manufacturing process for the preparation of tropenol, optionally in the form of its acid addition salts.
• the compound can be used as a starting compound for the preparation of pharmacologically valuable compounds.
• the compounds tiotropium bromide, ipratropium bromide or also BEA2108 may be mentioned in this context.
• These pharmacologically valuable substances are characterized by the following chemical structures:
• tropenol preferably in the form of one of its acid addition salts, in good yield and, above all, high purity.
• the present invention accordingly relates to a technical method for
• R is a radical selected from C 1 -C 4 -alkyl, C ⁇ -Cg-alkenyl and C -] - C4-alkylene-
• Phenyl which can each be substituted by hydroxy or C-
• R ' is C 1 -C 4 -alkyl and R "is a radical selected from C 1 -C 4 -alkyl and C 1 -C 4 -alkylene-phenyl, to give a compound of the formula IV
• R can have the meanings given above, and finally saponified to give the compound of the formula (I) and, if appropriate, converted into an acid addition salt by reaction with a suitable acid.
• the present invention preferably relates to an industrial process for the preparation of tropenol of the formula (I), optionally in the form of it
• Acid addition salts which is characterized in that a compound of the formula (II) in which RC ⁇ -C4-alkyl or C2-C4-alkenyl means, optionally in the form of its acid addition salts and optionally in the form of its hydrates, is used as the starting material and in which is used Formamide acetal of the formula (III) is the radicals R 'methyl or ethyl and the radicals R "are methyl, ethyl or propyl.
• the present invention particularly preferably relates to an industrial process for the preparation of tropenol of the formula (I), optionally in the form of it Acid addition salts, preferably in the form of its hydrochloride, which is characterized in that a compound of the formula (II) in which R 1-propenyl, 2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-butene -3-yl, 1-buten-4-yl, 2-buten-1-yl or 2-buten-2-yl means optionally used in the form of their acid addition salts and optionally in the form of their hydrates as the starting material and in which used in the Formamide acetal of the formula (III) the radicals R 'and R "are methyl or ethyl, preferably methyl.
• C 1 -C 4 -alkyl is understood to mean branched or unbranched alkyl groups having up to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl.
• C 1 -C 4 -alkylene-phenyl is understood to mean phenyl which is linked via a branched or unbranched alkylene bridge having up to 4 carbon atoms.
• phenyl groups can be substituted by one or more hydroxy and / or C 1 -C 4 -alkyloxy groups.
• C2-Ce alkenyl is understood to mean branched or unbranched alkenyl groups having 2 to 6 carbon atoms which have at least one double bond.
• Examples include vinyl, 1-propenyl, 2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1 -yl, 2-buten-2-yl, butadien-1 -yl, butadien-2-yl etc.
• acid addition salts are taken to mean the salts which are formed with the acids hydrochloric acid, hydrogen bromide, phosphoric acid, sulfuric acid, tetrafluoroboric acid or hexafluorophosphoric acid, preferably hydrochloric acid or hydrobromic acid.
• Production of tropenol can be done as follows.
• the compound of the formula (III) is introduced into a suitable reaction vessel. At least 1 mol of the compound (III) is usually used per mol of the compound of the formula (II) to be reacted. Preferably, between 1.01 and 5.0 mol, preferably between 1.1 and 4.0 mol, particularly preferably between 1.5 and 3.0 mol of the compound (III) are initially introduced per mol of the compound (III) to be reacted. The compound of the formula (II) is then added in portions with stirring. After the addition has ended, the mixture obtained is preferably heated to a temperature of above 40 ° C., preferably more than 50 ° C., particularly preferably more than 60 ° C. In the course of the reaction, the alcohol R'-OH is released.
• the mixture obtained is preferably heated to a temperature of above 40 ° C., preferably more than 50 ° C., and a vacuum of 100 mbar or less, preferably 60 mbar or less, particularly preferably 40 mbar or less, is applied.
• the remaining residue (crude product of the general formula (IV)) is then, with stirring, in a suitable solvent, preferably in a polar organic solvent, particularly preferably in a solvent selected from the group consisting of dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone, particularly preferably added dimethylformamide.
• a suitable solvent preferably in a polar organic solvent, particularly preferably in a solvent selected from the group consisting of dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone, particularly preferably added dimethylformamide.
• a suitable solvent preferably in a polar organic solvent, particularly preferably in a solvent selected from the group consisting of dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone, particularly preferably added dimethylformamide.
• Per mole of compound of formula (II) used for example, 0.001 to 10 L, preferably 0.01 to 5 L, particularly preferably
• the solution obtained in this way is then stirred for a period of, for example, 10 minutes to 3 hours, preferably 20 minutes to 2 hours, and heated to a temperature of more than 70 ° C., preferably more than 80 ° C., preferably more than 90 ° C. given at most 139 ° C heated acetic anhydride.
• the acetic anhydride initially introduced is particularly preferably heated to a temperature of about 120-135 ° C. According to the invention, 1 to 10 mol, preferably 2 to 8 mol, particularly preferably about 3 to 6 mol of acetic anhydride are used per mole of compound of the formula (II) originally used.
• the compound of the formula used per mole (II) preference is given to the compound of the formula used per mole (II) about 4 to 5 moles of acetic anhydride for use. CO 2 is released during this reaction.
• a further, for example, 0.0005 to 5 L, preferably 0.005 to 2.5 L, particularly preferably 0.025 to 0.5 L of the abovementioned solvent are added and the mixture obtained remains constant.
• the temperature was stirred for a further 10 minutes to, for example, 6 hours, preferably for a further 30 minutes to 3 hours, particularly preferably for a further 1 to 2 hours.
• All the liquid constituents of the reaction mixture are then removed by distillation at at least 40 ° C., preferably at least 50 ° C., particularly preferably at about 55-70 ° C. under reduced pressure, preferably at about 20 mbar less, preferably at about 10 mbar or less.
• a suitable solvent preferably in water and / or a lower alcohol, selected from the group consisting of methanol, ethanol and isopropanol, particularly preferably water, ethanol or a mixture thereof.
• a suitable solvent preferably in water and / or a lower alcohol, selected from the group consisting of methanol, ethanol and isopropanol, particularly preferably water, ethanol or a mixture thereof.
• a suitable solvent preferably in water and / or a lower alcohol, selected from the group consisting of methanol, ethanol and isopropanol, particularly preferably water, ethanol or a mixture thereof.
• 0.1 to 3 L particularly preferably about 0.5 to 2 L, of one of the abovementioned alcohols in a mixture with, for example, 0.01 to 1 L, preferably 0. 05 to 0.5 L water used as a solvent.
• a suitable base is added to the ester function of the compound of the formula (V) which is now in dissolved form.
• Preferred bases are inorganic bases selected from the group of alkali or alkaline earth carbonates, alkali or alkaline earth alcoholates and alkali or
• the hydroxides of lithium, sodium, potassium and calcium are particularly preferred, particularly preferably of sodium or calcium.
• sodium hydroxide is particularly preferably used as the base.
• the bases mentioned above can be used in pure form or, particularly preferably, in the form of aqueous concentrated solutions. If, for example, the sodium hydroxide base which is particularly preferred according to the invention is used, it is preferably added in the form of aqueous solutions with a concentration of at least 40% by weight. The use of at least stoichiometric amounts of base is required per mole of compound of the formula (II) originally used. However, the base can also be used in excess.
• the reaction mixture obtained is preferably heated to a temperature of above 50 ° C., particularly preferably above 60 ° C.
• the reaction mixture obtained after the base has been completely added, is heated to reflux with stirring for a period of about 15 minutes to 4 hours, preferably 30 minutes to 3 hours, particularly preferably 1 to 2 hours.
• the solvent is then distilled at least 40 ° C., preferably at least 50 ° C., particularly preferably at about 50-60 ° C. under reduced pressure, preferably at about 80 mbar or less, preferably at about 60 mW or less, particularly preferably at about 50 mbar or less away.
• the residue obtained is taken up in water. About 0.01 to 1, preferably about 0.1 to 1 L of water are used per mole of compound of the formula (II) originally used.
• the tropenol is extracted from this mixture using a suitable water-immiscible organic solvent, preferably using a solvent selected from the group consisting of toluene, methyl tert-butyl ether, dichloromethane, chloroform, preferably dichloromethane.
• a total of about 0.5 to 5, preferably between 0.75 and 4, liters of organic solvent are used for the extraction per mole of compound of the formula (II) used.
• the extraction is carried out according to the invention between 3 and 8, preferably 4 to 6 times. After the extraction is complete, the organic phases are combined and the organic solvent is distilled off in vacuo.
• the remaining crude product is taken up in an organic solvent, selected from the group consisting of methanol, ethanol, isopropanol, preferably isopropanol.
• an organic solvent selected from the group consisting of methanol, ethanol, isopropanol, preferably isopropanol.
• between 0.1 and 4.0 liters, preferably between about 1 and 2 liters, of the abovementioned solvent are used per mole of compound of the formula (II) originally used.
• the solution obtained is optionally filtered.
• the filtrate contains tropenol of the formula (I) in the form of its free base. If the free base is to be used in the next reaction, the solvent is distilled off under vacuum at this point. The remaining free base can then be used in the next synthesis steps without further purification.
• the free base of the tropenol is preferably converted into one of the acid addition salts.
• acid addition salts of tropenol are understood to be the salts which are selected from the group consisting of hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate or hexafluorophosphate.
• the salts hydrobromide and hydrochloride are particularly preferred, the tropenol hydrochloride being of particular importance according to the invention.
• the filtrate is cooled to a temperature in the range from -20 ° C. to 20 ° C., preferably in the range from -10 ° C. to 15 ° C.
• the suspension thus obtained is then mixed with the corresponding acid required to form the acid addition salt hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate or hexafluorophosphate.
• At least 1 mole of the respective acid is to be used per mole of compound of formula (II) originally used. If necessary, it is possible within the scope of the processes according to the invention to use the acid in excess (ie 1.1 to about 2-3 moles per mole of base (II) originally used).
• the hydrochloride of tropenol is preferably produced.
• the hydrochloric acid required for this can be added either in the form of solutions or in gaseous form. Hydrogen chloride is preferably used in gaseous form.
• One of the abovementioned acids is added to the solution of the free base of tropenol (I) until a pH of about 1 to 5, preferably of about 1.5 to 4, is reached. After the addition of the acid has ended, stirring can optionally be continued at a constant temperature for 0.5 to 2 hours. Finally, the precipitated acid addition salt of the tropenol is separated off and, if necessary, washed with a solvent selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone, preferably acetone, and dried in vacuo or under inert gas (for example nitrogen), if appropriate at elevated temperature.
• a solvent selected from the group consisting of acetone, methyl isobutyl ketone and methyl ethyl ketone, preferably acetone
• tropenol which is obtainable according to the production process according to the invention, is a valuable starting compound for the preparation of therapeutically active compounds such as, for example, tiotropium bromide, ipratropium bromide or BEA21 ⁇ 8. Because of the high purity in which tropenol is accessible according to the present invention, it is possible to provide the above-mentioned active ingredients in the specifications necessary for pharmaceutical use.
• the present invention further aims at the use of tropenol, optionally in the form of its acid addition salts, as a starting material for the preparation of therapeutically active compounds such as, for example, tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
• therapeutically active compounds such as, for example, tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
• the present invention further relates to the use of compounds of the formula (II)
• R can have the meanings given above, optionally in the form of their acid addition salts and optionally in the form of their hydrates, as starting material for the preparation of therapeutically active compounds such as, for example, tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
• the present invention preferably relates to the use of meteloidin, optionally in the form of its acid addition salts and optionally in the form of its hydrates, as a starting material for the preparation of therapeutically active compounds such as, for example, tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
• therapeutically active compounds such as, for example, tiotropium bromide, ipratropium bromide or BEA2108, preferably tiotropium bromide.
• Tropenol (I) by reaction with di- (2-thienyl) glycolic acid derivatives (VI), firstly leads to the formation of the di- (2-thienyl) glycolic acid tropenol ester (VII). This is achieved by epoxidation of the olefinic double bond in the corresponding scopine ester (VIII), from which tiotropium bromide can be obtained by reaction with methyl bromide.
• a particularly preferred aspect of the present invention relates to a method for producing tiotropium bromide
• R can have the meanings given above, optionally in the form of their acid addition salts and optionally in the form of their hydrates in a suitable solvent with a formamide acetal of the formula (III)
• R can have the meanings given above, converted and saponified to tropenol of formula (I), this optionally in the form of
• Solvent is then distilled off at about 50-60 ° C. under reduced pressure (about 40 mbar) and the remaining residue is taken up in 31 L of water. 62 L of methylene chloride are added to extract the product. After the organic phase has been separated off, the remaining aqueous phase is extracted again twice with 30 L of methylene chloride and 3 times with 21 L of methylene chloride. The organic phases obtained are combined and the solvent is removed by distillation. The remaining residue is then taken up in about 35 kg of isopropanol, treated with 1.6 kg of Clarcel, the mixture obtained is stirred and filtered. Gaseous hydrogen chloride is then passed into the solution thus obtained at an internal temperature of about -10 ° C. to + 10 ° C.
• Example 2 Preparation of tiotropium bromide a) Preparation of the tropenol ester (VII) Ammonia (1.8 kg) is introduced at 25 ° C. into 10.9 kg of tropenol hydrochloride (obtainable according to Example 1) in toluene (95 L). The suspension obtained is stirred at a constant temperature for about 1 h. The ammonium chloride formed is then filtered off and rinsed with toluene (26 L). At a jacket temperature of about 50 ° C., part of the toluene (about 60 L) is distilled off in vacuo.
• the solvent in the Vacuum partially distilled off (about 210 L). It is again cooled to about 20 ° C. and Clarcel (3.2 kg) is added. The pH is adjusted to about 2.0 with dilute hydrochloric acid (36%, 0.8 kg in about 440 L of water). The solution obtained is filtered and extracted with methylene chloride (58 L). The methylene chloride phase is discarded. The aqueous phase becomes again
• Methyl bromide (5.1 kg) is introduced at 20 ° C. into the scopine ester solution obtainable according to the previous regulation. The system contents are stirred at 30 ° C for about 2.5 days. At 50 ° C, 70 L of DMF are distilled off in vacuo. The solution is transferred to a smaller apparatus. It is rinsed with DMF (10 L). , At 50 ° C, further DMF is distilled off in vacuo until a total amount of distillate of about 100 liters has been reached. It is cooled to 15 ° C. and stirred at this temperature for 2 h. The product is isolated using a suction filter, washed with 15 ° C cold DMF (10 L) and 15 ° C cold acetone (25 L). At max. 50 ° C for max. Dried in a stream of nitrogen for 36 hours. Yield: 13.2 kg (88%); Mp: 200-230 ° C (depending on the degree of purity of the raw product);
• the crude product thus obtained (10.3 kg) is introduced into methanol (66 L). The mixture is heated to reflux to dissolve. The solution is cooled to 7 ° C and stirred for 1.5 hours at this temperature. The product is isolated using a suction filter, washed with 7 ° C cold methanol (11 L) and max. Dried 36 hours at about 50 ° C in a stream of nitrogen. Yield: 9.9 kg (96%); Mp: 228 ° C (determined by DSC at a heating rate of 10K / min).
• the product obtained in this way can be converted into the crystalline monohydrate of tiotropium bromide.
• This can be done as follows. 15.0 kg of tiotropium bromide are introduced into 25.7 kg of water in a suitable reaction vessel. The mixture is heated to 80-90 ° C and stirred at a constant temperature until a clear solution is formed. Activated carbon (0.8 kg), moist with water, is slurried in 4.4 kg of water, this mixture is added to the solution containing tiotropium bromide and rinsed with 4.3 kg of water. The mixture thus obtained is stirred at 80-90 ° C. for at least 15 minutes and then filtered through a heated filter into an apparatus preheated to a jacket temperature of 70 ° C.
• the filter is rinsed with 8.6 kg of water.
• the contents of the apparatus are cooled to 3-5 ° C per 20 minutes to a temperature of 20-25 ° C. With cold water cooling, the apparatus is cooled further to 10-15 ° C and the crystallization is completed by stirring for at least one hour.
• the crystals are isolated using a suction filter, the isolated crystal slurry is washed with 9 L of cold water (10-15 ° C) and cold acetone (10-15 ° C).
• the crystals obtained are dried at about 25 ° C. in a stream of nitrogen for about 2 hours. Yield: 13.4 kg of tiotropium bromide monohydrate (86% of theory).
• Mp . 230 ° C. (determined by DSC at a heating rate of 10K / min).

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