Industrial process for preparing tropenol

Details Industrial process for preparing tropenol Industrial process for preparing tropenol

2003-05-29

2004-06-08

Huang, Evelyn Mei (Department: 1625)

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

Organic compounds

Heterocyclic carbon compounds containing a hetero ring...

C546S127000, C546S131000, C546S091000

Reexamination Certificate

active

06747153

ABSTRACT:

FIELD OF THE INVENTION
The invention relates to a new industrially useable process for preparing tropenol, optionally in the form of the acid addition salts thereof.
BACKGROUND TO 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 valuable compounds. For example, 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:
Because of the high degree of efficacy of the above compounds they have to be made available in as pure form as possible using efficient methods of synthesis. The stringent purity requirements, in particular, with which compounds intended for therapeutic use generally have to comply, demand the lowest possible levels of contaminant in the starting compounds. If materials which contain relatively high levels of impurities are used as starting compounds, purification of the end product is often difficult as any impurities introduced at the beginning often cannot easily be removed at later stages of synthesis or only at the expense of substantial losses of yield. This is particularly the case when the by-products or impurities present only differ slightly structurally from the main products in question.
Against this background the problem of the present invention is to provide a method of synthesis which allows industrial production of tropenol, preferably in the form of one of the acid addition salts thereof, in a good yield and particularly with a high degree of purity.
DETAILED DESCRIPTION OF THE INVENTION
The problem defined above is solved by 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 a compound of formula (II)
wherein
R denotes a group selected from C
1
-C
4
-alkyl, C
2
-C
6
-alkenyl and C
1
-C
4
-alkylene-phenyl, each of which may be substituted by hydroxy or C
1
-C
4
-alkoxy,
optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof in a suitable solvent, is reacted with a formamide-acetal of formula (III)
 wherein
R′ denotes C
1
-C
4
-alkyl and R″ denotes a group selected from C
1
-C
4
-alkyl and C
1
-C
4
-alkylene-phenyl, to obtain a compound of formula IV
 wherein the groups R, R′ and R″ may have the meanings given above, this is then converted by decarboxylation into an ester of formula (V)
 wherein R may have the meanings given above, and lastly this ester is saponified to obtain the compound of formula (I) which is optionally converted into an acid addition salt by reaction with a suitable acid.
Preferably, the present invention relates to an industrial process for preparing tropenol of formula (I), optionally in the form of the acid addition salts thereof, which is characterized in that a compound of formula (II) wherein R denotes C
1
-C
4
-alkyl or C
2
-C
4
-alkenyl is used as starting material, optionally in the form of the acid addition salts thereof and optionally in the form of the hydrates thereof, and wherein, in the formamide-acetal of formula (III) used, the groups R′ denote methyl or ethyl and the groups R″ represent methyl, ethyl or propyl.
Most preferably, the present invention relates to an industrial process for preparing tropenol of formula (I), optionally in the form of the acid addition salts thereof, preferably in the form of its hydrochloride, which is characterized in that a compound of formula (II) wherein R denotes 1-propenyl, 2-propenyl, 1-buten-1-yl, 1-buten-2-yl, 1-buten-3-yl, 1-buten-4-yl, 2-buten-1-yl or 2-buten-2-yl is used as starting material, optionally in the form of the acid addition salts thereof as well as optionally in the form of the hydrates thereof and wherein in the formamide-acetal of formula (III) used the groups R′ and R″ represent methyl or ethyl, preferably methyl.
Most preferably, the compound of formula (II) used is the compound wherein R denotes 2-buten-2-yl. This compound is also known by the name meteloidin in the prior art.
The term C
1
-C
4
-alkyl within the scope of the present invention denotes branched or unbranched alkyl groups with up to 4 carbon atoms. Examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl and tert-butyl. The term C
1
-C
4
-alkylene-phenyl within the scope of the present invention denotes phenyl which is linked via a branched or unbranched alkylene bridge having up to 4 carbon atoms. Examples include benzyl, phenyl-2-ethyl, phenyl-1-ethyl, phenyl-3-propyl, phenyl-2-propyl- etc. Both the C
1
-C
4
-alkyl groups and also the C
1
-C
4
-alkylene-phenyl groups may, unless otherwise specified, be substituted by one or more hydroxy and/or C
1
-C
4
-alkyloxy groups.
By C
2
-C
6
-alkenyl are meant within the scope of the present invention branched or unbranched alkenyl groups with 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.
Unless otherwise stated, within the scope of the present invention the term acid addition salts refers to the salts formed with the acids hydrochloric acid, hydrobromic acid, phosphoric acid, sulphuric acid, tetrafluoroboric acid or hexafluorophosphoric acid, preferably hydrochloric acid or hydrobromic acid.
According to the invention, the following procedure may be followed for performing the process for preparing tropenol according to the invention.
The compound of formula (III) is placed in a suitable reaction vessel.
Usually at least 1 mol of the compound (III) is used per mol of the compound of formula (II) to be reacted. Preferably, between 1.01 and 5.0 mol, preferably between 1.1 and 4.0 mol, most preferably between 1.5 and 3.0 mol of the compound (III) are put in per mol of the compound (III) to be reacted. Then the compound of formula (II) is added batchwise with stirring. After the addition has ended the mixture obtained is heated preferably to a temperature of above 40° C., preferably more than 50° C., most preferably more than 60° C. In the course of the reaction the alcohol R′—OH is released. It is preferably removed from the reaction equilibrium by distillation. This distillation may optionally be carried out under reduced pressure. If the compound of formula (III) used is the compound wherein R′ denotes methyl, the temperature is preferably adjusted to a range from about 55-90° C., more preferably from about 60-85° C. After the reaction has ended the compound of formula (III) which was optionally used in excess is removed by distillation under reduced pressure. To do this the mixture obtained is preferably heated to a temperature of above 40° C., preferably above 50° C., and a vacuum of 100 mbar or less, preferably 60 mbar or less, most preferably 40 mbar or less is applied.
The residue remaining (crude product of general formula (IV)) is then taken up with stirring in a suitable solvent, preferably in a polar organic solvent, most preferably in a solvent selected from the group consisting of dimethylformamide, acetonitrile, dimethylacetamide and N-methylpyrrolidinone, most preferably dimethylformamide. For example 0.001 to 10 L, preferably 0.01 to 5 L, most preferably 0.05 to 1 L of solvent may be used per mol of the compound of formula (II) used in order to prepare this solution. Preferably at this point about 0.07 to 0.5 L of solvent are used per mol of the compound of formula (II) originally put in.
The solution thus obtained is then added, over a period of for example 10 minutes to 3 hours, preferably 20 minutes to 2 hours, to stirred acetic anhydride heated to a temperature of more than 70° C., preferably more than 80° C., preferably more than 90° C.

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