Process for the manufacture of tropenol

Details Process for the manufacture of tropenol Process for the manufacture of tropenol

2002-06-03

2003-08-26

Morris, Patricia L. (Department: 1625)

Organic compounds -- part of the class 532-570 series

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

Reexamination Certificate

active

06610849

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a production method, particularly suitable for use on an industrial scale, for producing tropenol, optionally in the form of the acid addition salts thereof.
BACKGROUND OF THE INVENTION
The compound tropenol is known from the prior art and has the following chemical structure:
The compound may be used as a starting compound for preparing pharmacologically useful compounds. For example, in this context, mention may be made of the compounds tiotropium bromide, ipratropium bromide, or BEA2108. These pharmacologically useful structures are characterized by the following chemical structures:
Because of the high potency of the abovementioned compounds, it is necessary to make them available in the purest possible form by efficient methods of synthesis. In particular the high purity requirement, which generally has to be satisfied by compounds for therapeutic use, demands the lowest possible level of contaminants in the starting compounds. When materials which contain a relatively high proportion of impurities are used as starting compounds, the purification of the end product is often difficult, as any impurities introduced initially often cannot easily be removed at later stages of the synthesis except with major losses of yield. This is particularly true when the by-products and contaminants occurring differ only slightly in structure from the main products.
Against this background the aim of the present invention is to provide a method of synthesis which enables tropenol to be produced on an industrial scale, preferably in the form of one of the acid addition salts thereof, in a good yield and, above all, in highly pure form.
DETAILED DESCRIPTION OF THE INVENTION
The objective defined above is achieved by means of the invention described hereinafter.
The present invention accordingly relates to an industrial process for preparing tropenol of formula (I)
optionally in the form of the acid addition salts thereof, characterized in that scopine esters of formula (II)
wherein:
R denotes a group selected from C
1
-C
4
-alkyl and C
1
-C
4
-alkylene-phenyl, which may be substituted in each case by hydroxy or C
1
-C
4
-alkoxy,
optionally in the form of the acid addition salts thereof and optionally in the form of the hydrates thereof, in a suitable solvent using zinc in the presence of activating metal salts, preferably activating iron or copper salts, are reduced and subsequently saponified using suitable bases to form tropenol of formula (I).
C
1
-C
4
-alkyl within the scope of the present invention denotes branched or unbranched alkyl groups with up to 4 carbon atoms. Methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl and tert-butyl may be mentioned by way of example. C
1
-C
4
-alkylene-phenyl, for the purposes of the present invention, denotes phenyl which is linked to up to 4 carbon atoms via a branched or unbranched alkylene bridge. Benzyl, phenyl-2-ethyl, phenyl-1-ethyl, phenyl-3-propyl, phenyl-2-propyl-, etc. may be mentioned by way of example. Both the C
1
-C
4
-alkyl groups and the C
1
-C
4
-alkylenephenyl groups may, unless otherwise stated, be substituted by one or more hydroxy and/or C
1
-C
4
-alkyloxy groups.
Preferably, the present invention relates to a process for preparing tropenol of formula (I), optionally in the form of the acid addition salts thereof, characterized in that scopolamine of formula (II′)
is used as the scopine derivative of formula (II), optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof.
According to the invention, the following procedure may be used to perform the process for preparing tropenol.
The solvent is preferably placed under an inert gas atmosphere, more preferably under nitrogen, in a suitable reaction vessel. Suitable solvents according to the invention include alcohols selected from among methanol, ethanol, and isopropanol or water, while it is preferable according to the invention to use water. According to the invention, between 0.25 L and 5 L, preferably between 0.5 L and 3 L, most preferably between 0.75 L and 1.5 L of solvent are used per mole of the compound of formula (II) used. Zinc, preferably in the form of zinc powder, more preferably zinc powder with an average particle size of <80 &mgr;m, most preferably <70 &mgr;m is added to the solvent with vigorous stirring. It is essential to use at least 1 mol of zinc per mole of the compound of formula (II) used. According to the invention, zinc is preferably used in an excess. Preferably, 1.2 mol to 3.5 mol, more preferably 1.5 mol to 3.0 mol of zinc are used per mole of the compound of formula (II) used. In a particularly preferred embodiment of the process according to the invention, 1.8 mol to 2.5 mol of zinc are used per mole of the compound of formula (II) used. After the zinc has been added, it may be necessary to activate it. This can be done by adding HI, HBr, or HCl, for example. Preferably, HI is used as the activating agent, preferably in the form of aqueous solutions, most preferably in the form of concentrated aqueous solutions. It may be necessary, for example, to add 0.05 mol to 0.25 mol, preferably from 0.08 mol to 0.2 mol, of activating agent per mole of the compound of formula (II) used. It may possibly be helpful to increase the temperature of the initial mixture before the activating reagent is added. The mixture is then preferably heated to a temperature of over 50° C., preferably 55° C. to 90° C., particularly preferably 60° C. to 80° C. Then the metal salts are added to the suspension of zinc in the solvent used, optionally activated by means of one of the abovementioned agents. Examples of metal salts which may be used within the scope of the present invention include salts of iron (preferably Fe(III) salts) or copper (preferably Cu(II) salts), preferably the halides thereof. FeCl
3
is preferably used as the iron salt. However, it is particularly preferred, within the scope of the process according to the invention, to use Cu(II) salts which are selected from among CuCl
2
, CuI
2
, CuBr
2
, and CuBr
2
-dimethylsulfide complex, while CuBr
2
is particularly important according to the invention. Substoichiometric amounts of the metal salt, preferably 0.01 mol to <1 mol of metal salt, are always added per mole of the compound of formula (II) used according to the invention. Preferably, 0.05 mol to 0.5 mol, most preferably 0.075 mol to 0.2 mol of metal salt are used per mole of the starting compound (II) used. The metal salt may be added to the zinc suspension in bulk or in dissolved form. According to the invention, the metal salt is preferably taken up in one of the solvents mentioned above and then added to the zinc suspension in dissolved or suspended form. It is particularly preferred when preparing the metal salt solution or suspension to use the solvent which is already being used to absorb the zinc. According to the invention, 0.5 L to 1.5 L, preferably 0.6 L to 1.0 L, of solvent are used per mole of the metal salt used to prepare the metal salt solution or suspension. This solution or suspension is then added to the initial zinc mixture with stirring.
The compound of formula (II) is then added to the zinc mixture which may be obtained by the method described hereinbefore. It may optionally be added in the form of the acid addition salts of the compound of formula (II). These acid addition salts are preferably selected according to the invention from the group comprising hydrochloride, hydrobromide, hydrogen phosphate, hydrogen sulfate, tetrafluoroborate, and hexafluorophosphate, of which the hydrochlorides or hydrobromides are particularly preferred. Any reference to acid addition salts of the compound of formula (II) also includes a reference to their hydrates, if any. When the acid addition salts mentioned above are added directly, they may be added to the initial zinc mixture in substance or in dissolved form. If the acid addition salts are added in dissolved form, it is advisable to take up the acid additio

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