Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
1998-06-04
2001-03-06
Kight, John (Department: 1612)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06197961
ABSTRACT:
FIELD OF THE INVENTION
The present invention relates to a novel process for preparing a salt of &ggr;-(piperidyl)butyric acid with an acid, the salt being represented by the formula (2)
wherein R is a hydrogen atom or an alkyl group, and A is an acid [hereinafter referred to as “salt of &ggr;-(piperidyl)butyric acid (2)”].
The salt of &ggr;-(piperidyl)butyric acid (2) is a compound which is useful as an intermediate for a pharmaceutical chemical by itself or in the form of a &ggr;-(piperidyl)butyric acid liberated from the acid.
BACKGROUND OF THE INVENTION
The salt of &ggr;-(piperidyl)butyric acid (2) can be prepared by hydrogenating a salt of &ggr;-(2-pyridyl)butyric acid with an acid for conversion of the pyridine ring to a piperidine ring. It is known to prepare the salt of &ggr;-(piperidyl)butyric acid (2) by hydrogenating a salt of (&ggr;-pyridyl)butyric acid with an acid using a platinum oxide as a catalyst [J. Am. Chem. Soc., 69,2461 (1947)].
However, the above-mentioned conventional process hydrogenates the salt of &ggr;-(2-pyridyl)butyric acid with an acid at a concentration of 2% in the reaction mixture, namely a much diluted salt, consequently leading to a low reactor efficiency and a low productivity. Thus the process is not practical.
The above-mentioned process poses a further problem of necessitating a large amount of platinum oxide as the catalyst. The foregoing publication teaches the use of platinum oxide in an amount of as large as 4.3% by weight in terms of Pt based on a &ggr;-(2-pyridyl)butyric acid hydrochloride.
No investigation has been heretofore made about the use of other catalysts than platinum oxide for the hydrogenation of a salt of &ggr;-(pyridyl)butyric acid with an acid. It is an object of the present invention to provide a catalyst capable of hydrogenating a salt of &ggr;-(pyridyl)butyric acid with an acid to efficiently convert the pyridine ring to a piperidine ring, providing a process for preparing a salt of &ggr;-(piperidyl)butyric acid (2) with a high productivity.
DISCLOSURE OF THE INVENTION
The present inventors conducted extensive research to overcome the foregoing prior art problems and made the following findings about the catalyst and raw materials useful in preparing a salt of &ggr;-(piperidyl)butyric acid (2). The present invention was completed based on the novel findings.
<Catalyst>
When a Rh catalyst, a Pd catalyst or a Ru catalyst is used as the catalyst in hydrogenating a salt of &ggr;-(pyridyl)butyric acid with an acid, the salt thereof being represented by the formula (1)
wherein R is a hydrogen atom or an alkyl group, and A is an acid [hereinafter referred to as “salt of &ggr;-(pyridyl)butyric acid (1)”], the salt of &ggr;-(piperidyl)butyric acid (2) can be prepared in a relatively short time with a high productivity. When these catalysts are used, unexpectedly the hydrogenation of salt of &ggr;-(pyridyl)butyric acid (1) is completed in a short time even at a very low hydrogen pressure as compared with the hydrogenation of a free &ggr;-(pyridyl)butyric acid.
<Raw Materials>
The salt of &ggr;-(pyridyl)butyric acid (1) can be prepared by carrying out the steps of:
(a) reacting a vinylpyridine compound represented by the formula (4)
wherein R is as defined above [hereinafter referred to as “vinylpyridine (4)”] with a diester of malonic acid represented by the formula (5)
wherein R
1
and R
2
are the same or different and each represents an alkyl group [hereinafter referred to as “diester of malonic acid (5)”] in the presence of a base to give a diester of 2-(pyridylethyl)malonic acid represented by the formula (6)
wherein R, R
1
and R
2
are as defined above [hereinafter referred to as “2-(pyridylethyl)malonic acid diester (6)”], and
(b) hydrolyzing and decarboxylating the 2-(pyridylethyl)malonic acid diester (6) prepared in the step (a) in an acidic aqueous solution.
When the salt of &ggr;-(piperidyl)butyric acid (2) is prepared by hydrogenation of the salt of &ggr;-(pyridyl)butyric acid (1) obtained in the steps (a) and (b), the specific impurities present in the salt of &ggr;-(pyridyl)butyric acid (1) adversely affect the reaction time for hydrogenation and the purity of the obtained salt of &ggr;-(piperidyl)butyric acid (2).
Stated more specifically, the process of preparing the salt of &ggr;-(pyridyl)butyric acid (1) produces, as a by-product, a salt of bis(pyridylethyl)acetic acid with an acid, the salt thereof being represented by the formula (3)
wherein R and A are as defined above [hereinafter referred to as “salt of bis(pyridylethyl)acetic acid (3)”].
When the salt of &ggr;-(pyridyl)butyric acid (1) containing the salt of bis(pyridylethyl)acetic acid (3) is hydrogenated, the reaction tends to involve a longer time and a high-purity salt of &ggr;-(piperidyl)butyric acid (2) is difficult to produce.
If not more than 3% by weight of the salt of bis(pyridylethyl)acetic acid (3) is present in the salt of &ggr;-(pyridyl)butyric acid (1), the hydrogenation is completed in a very short time and a high-purity salt of &ggr;-(piperidyl)butyric acid (2) can be easily produced.
SUMMARY OF THE INVENTION
According to the present invention, there is provided a process for preparing the salt of &ggr;-(piperidyl)butyric acid (2), the process comprising the step of hydrogenating the salt of &ggr;-(pyridyl)butyric acid (1) [preferably the salt of &ggr;-(pyridyl)butyric acid (1) obtained by carrying out the undermentioned steps (a) and (b) and containing not more than 3% by weight of salt of bis(pyridylethyl)acetic acid (3)] in a solvent in the presence of a catalyst, the process being characterized in that the catalyst is a Rh catalyst, a Pd catalysts or a Ru catalyst:
(a) reacting the vinylpyridine (4) with the diester of malonic acid (5) in the presence of a base to give the 2-(pyridylethyl)malonic acid diester (6), and
(b) hydrolyzing and decarboxylating the 2-(pyridylethyl)malonic acid diester (6) obtained in the step (a) in an acidic aqueous solution to give the salt of &ggr;-(pyridyl)butyric acid (1).
According to the present invention, the salt of &ggr;-(piperidyl)butyric acid (2) can be prepared in a relatively short time with a high productivity. Especially if the salt of &ggr;-(pyridyl)butyric acid (1) to be hydrogenated is one prepared in the steps (a) and (b) and containing not more than 3% by weight of salt of bis(pyridylethyl)acetic acid (3), the hydrogenation is completed in a shorter time and a high-purity salt of &ggr;-(piperidyl)butyric acid (2) can be easily prepared.
BEST MODE FOR CARRYING OUT THE INVENTION
Salt of &ggr;-(pyridyl)butyric acid (1)
The salt of &ggr;-(piperidyl)butyric acid (2) can be prepared by hydrogenation of the salt of &ggr;-(pyridyl)butyric acid (1). R in the formula (1) representing the salt of &ggr;-(pyridyl)butyric acid (1) is a hydrogen atom or an alkyl group. Preferred alkyl group is a lower alkyl group having 1 to 4 carbon atoms. A in the formula (1) is an acid. Examples of the acid are mineral acids such as hydrochloric acid and sulfuric acid, and organic acids such as p-toluenesulfonic acid and trifluoromethanesulfonic acid.
Specific examples of the salt of &ggr;-(pyridyl)butyric acid (1) are salts of &ggr;-(pyridyl)butyric acids with other acids. Useful &ggr;-(pyridyl)butyric acids include, for example, &ggr;-(2-pyridyl)butyric acid, &ggr;-(3-pyridyl)butyric acid, &ggr;-(4-pyridyl)butyric acid, &ggr;-(5-methyl-2-pyridyl)butyric acid, &ggr;-(6-methyl-2-pyridyl)butyric acid, &ggr;-(4-methyl-3-pyridyl)butyric acid, &ggr;-(2-methyl-5-pyridyl)butyric acid, &ggr;-(5-ethyl-2-pyridyl)butyric acid, etc. Examples of other acids include hydrochloric acid, sulfuric acid and like mineral acids, p-toluenesulfonic acid, trifluoro-methanesulfonic acid and like organic acids.
Preparation of salt of &ggr;-(pyridyl)butyric acid (1)
The salt of &ggr;-(pyridyl)butyric acid (1) can be prepared by conventional processes. For example, it can be prepared by hydrolysis and decarboxylation of 2-(pyridylethyl)malon
Kanno Ken
Nagaoka Masayo
Sakai Toshito
Armstrong, Westerman Hattori, McLeland & Naughton
Covington Raymond
Kight John
Koei Chemical Co. Ltd.
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