Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2004-04-05
2004-12-28
Dentz, Bernard (Department: 1625)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06835839
ABSTRACT:
The present invention relates to a method for the production of biperiden.
Biperiden is a well-known central anticholinergic agent and is employed for the treatment of Parkinson's disease (Ullmanns Enzyklopädie der technischen Chemie, 4th edition, volume 21, Verlag Chemie, 1982, p. 627). It comprises a racemate of 1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,R))-1-phenyl-3-piperidinopropanol (1,S) and 1-(bicyclo[2.2.1]hept-5-en-2-yl(exo,S))-1-phenyl-3-piperidinopropanol(1,R) (Ia) and represents one of four possible pairs of enantiomers (Ia-d) of the amino alcohol 1-(bicyclo[2.2.1]hept-5-en-2-yl)-1-phenyl-3-piperidino-1-propanol (I).
DE 1 005 067 and U.S. Pat. No. 2,789,110 describe the preparation of the amino alcohol I by reacting 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with a phenylmagnesium halide. U.S. Pat. No. 2,789,110 additionally describes the preparation of the propanone II starting from 1-(bicyclo[2.2.1]hept-5-en-2-yl)-ethanone (III), paraformaldehyde and piperidine hydrochloride in a Mannich reaction, and the preparation of the ethanone III from cyclopentadiene and methyl vinyl ketone in a Diels-Alder cycloaddition.
Neither DE 1 005 067 nor U.S. Pat. No. 2,789,110 disclose whether the amino alcohol I obtained in this way is a mixture of isomers or a pure isomer.
The precursor for preparing the propanol, 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), can exist in two isomeric forms, as exo or as endo isomer (II-exo, II-endo), and only the exo form is able to afford biperiden in the abovementioned reaction with a phenylmagnesium halide.
The structural formulae of II-exo and of II-endo show for the sake of simplicity in each case only one of two possible enantiomers of the exo isomer and endo isomer, respectively. However, the designation II-exo or II-endo relates hereinafter to the pair of enantiomers of the exo or endo form.
1-(Bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III), the starting substance for synthesizing the propanone II, may also exist both as exo and as endo isomer (III-exo, III-endo) and, correspondingly, only reaction of the exo isomer leads in the subsequent steps to biperiden.
The structural formulae of III-exo and of III-endo show for the sake of simplicity in each case only one of two possible enantiomers of the exo isomer and endo isomer, respectively. However, the designation III-exo or III-endo relates hereinafter to the pair of enantiomers of the exo or endo form.
It is not possible to infer any information about the configuration of the precursors III and intermediates II employed in any of the abovementioned publications.
It is known that 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) is obtained from the cycloaddition in an exo/endo ratio of 1:4 (e.g. R. Breslow, U. Maitra, Tetrahedron Letters, 1984, 25, 1239). Since the prior art mentioned at the outset makes no statements at all about the stereochemistry of the ethanone III, it must be assumed that the ethanone III was employed in this ratio of isomers to prepare the amino alcohol I.
The preparation of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) was described in 1965 by J. G. Dinwiddie and S. P. McManus (J. Org. Chem., 1965, 30, 766). This entails exo/endo mixtures of 1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III) in which the endo content predominates being heated in methanol in the presence of sodium methanolate and isomerizing to mixtures with an exo content of about 70%. It is possible to obtain from this by fractional distillation and, where appropriate, redistillation of the distillate exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) with a purity of up to 95%.
Experiments by the applicant have shown that even on use of virtually pure exo ethanone III-exo, i.e. of an ethanone III with an exo content of at least 95%, as starting material of the Mannich reaction an exo/endo mixture of propanone II having a maximum exo/endo ratio of 4.0:1 is always obtained. This is unsatisfactory as regards obtaining pure biperiden (Ia) from reaction of the propanone II with a phenylmagnesium compound. Pure biperiden means a biperiden (Ia) with a purity of at least 99.0%, as is generally necessary for pharmaceutical applications.
It is an object of the present invention to provide a method for the production of biperiden, which provides the latter in higher yield. The meaning of biperiden is a substance of the structural formula Ia. It is particularly intended to improve the selectivity of the propanone II production in relation to the exo isomer.
We have found that this object is achieved by a method for the production of biperiden by reacting an exo/endo mixture of 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidin-1-propanone (II) with an exo/endo ratio of at least 4.5:1 with a phenylmagnesium compound, characterized in that the production of the exo/endo mixture of 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) comprises the following steps:
a) reaction of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) with a formaldehyde source and an acid addition salt of piperidine or with a formaldehyde source and piperidine in the presence of an acid in an organic solvent or in a mixture thereof with water,
b) conversion of the resulting reaction mixture into an aqueous solution and extraction of this aqueous solution with an organic solvent which has limited miscibility or is immiscible with water at a pH not exceeding 7, and
c) extraction of the raffinate obtained in b), which contains the exo/endo mixture of 1-(bicyclo[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II), at a pH of at least 7.5 with an organic solvent which has limited miscibility or is immiscible with water,
d) removal of the organic extract, purification of the organic extract by extraction with aqueous acid and subsequent removal of the solvent, resulting in 1-(bicyclo-[2.2.1]hept-5-en-2-yl)-3-piperidino-1-propanone (II) with an exo/endo ratio of at least 4.5:1.
The meaning of exo-1-(bicyclo[2.2.1]hept-5-en-2-yl)ethanone (III-exo) hereinafter is an ethanone III with an exo content of at least 96%.
The exo and endo isomers employed in the method of the invention comprise, as already described for the exo and endo ethanone III-exo and III-endo and for the exo and endo propanone II-exo and II-endo, pairs of enantiomers. In order to obtain biperiden (Ia), which is itself a racemate, racemic mixtures of enantiomers of the starting materials and of the intermediates are employed. However, the method of the invention can also be applied to pure enantiomers and to non-racemic mixtures of enantiomers.
Reaction of exo-1-(bicyclo-[2.2.1]hept-5-en-2-yl)ethanone (III-exo) with a Mannich reaction with a formaldehyde source and an acid addition salt of piperidine or with a formaldehyde source and piperidine in the presence of an acid generally takes place in a solvent suitable for Mannich reactions. Suitable solvents are, in particular, C
1
-C
4
-alkanols, e.g. methanol, ethanol, n-propanol, isopropanol, sec-butanol or isobutanol, and mixtures thereof with water. Isopropanol is preferably used.
Suitable acids are in principle the mineral acids or organic acids suitable for Mannich aminomethylation.
Hydrochoric acid or hydrogen chloride or an organic sulfonic acid of the general formula RSO
3
H is preferably used. R in this case is a monovalent organic radical, preferably C
1
-C
4
-alkyl, phenyl or C
1
-C
4
-alkyl-substituted phenyl, with methyl being particularly preferred. The reaction can take place with the acid addition salt of piperidine or else with piperidine in the presence of an acid, in which case the acid addition salt of piperidine is formed in situ.
In this case, piperidine and the appropriate acid are preferably employed in equimolar amounts. In the case where the isolated acid addition salt of piperidine is used, if the latter cannot be purchased commercially it can be prepared by reaction
Grosse Markus
Klein Peter
Thyes Marco
Vilsmaier Elmar
Weber Klaus Martin
Abbott & GmbH & Co. KG
Dentz Bernard
Wood Phillips Katz Clark & Mortimer
LandOfFree
Method for the production of biperiden II does not yet have a rating. At this time, there are no reviews or comments for this patent.
If you have personal experience with Method for the production of biperiden II, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Method for the production of biperiden II will most certainly appreciate the feedback.
Profile ID: LFUS-PAI-O-3279902