Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acid esters
Reexamination Certificate
2001-01-23
2002-08-27
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acid esters
C560S051000, C562S459000
Reexamination Certificate
active
06441218
ABSTRACT:
BACKGROUND OF THE INVENTION
(1) Field of the Invention
The present invention relates to a process for producing 2-substituted propionic acid having effects as anti-inflammatory agent, analgesic, antipyretic and so forth.
(2) Prior Art
As disclosed in Japanese Patent Publication No. S58-004699, compounds of 2-substituted propionic acid have effects as anti-inflammatory agent, analgesic and antipyretic. Especially, 2-[4-(2-oxocyclopentan-1-yl methyl)phenyl]propionic acid, “loxoprofen”, is commercially available as an excellent analgesic drug.
In addition to the above disclosure, as disclosed in Japanese Laid-Open Patent Publication No. S62-161740, the conventional preparation process includes the steps of (1) coupling reaction of 2-(p-halomethylphenyl)propionic acid ester with 2-cyclopentanone carboxylic acid ester in the presence of a base, and (2) decarboxylation and hydrolysis of ester with an acid.
In the above first coupling step, the hydrogen atom at &agr;-position of 2-cyclopentanone carboxylic acid ester, is taken off to give 2-(alkoxycarbonyl)-cyclopentenolate anion, which attacks the halomethyl group of 2-(p-halomethylphenyl)propionic acid ester to generate carbon-carbon bond so that the fundamental skeletal structure of loxoprofen is formed.
Although above 2-(p-halomethylphenyl)propionic acid ester is relatively inexpensive, 2-cyclopentanone carboxylic acid ester is an expensive reagent.
Furthermore, the reaction in the presence of a base, the base likely causes side reaction with halomethyl group of 2-(p-halomethylphenyl)propionic acid ester.
Proposed in PCT International Publication No. WO 97/47581 is a method that loxoprofen is produced through carbonylation of p-chloromethylstyrene in the presence of a transition metal complex catalyst. That is, the method comprises (i) carbonylation of p-chloromethylstyrene, (ii) coupling with cyclopentanone carboxylic acid ester, and (iii) decarboxylation and hydrolysis.
The above method of utilizing carbonylation is advantageous in industrial working because the structure of substituted styrene can easily be converted into the structure of substituted propionic acid ester.
However, p-chloromethylstyrene has a high polymerization activity in the presence of heat, light and pressure owing to the existence of substituted chloromethyl groups bonded to the benzene ring. Particularly in the carbonylation with a transition metal complex catalyst, p-chloromethylstyrene is liable to polymerize. This fact may be apprehended in view of the fact that commercially available p-chloromethylstyrene usually contains polymerization inhibitor and that polymerization inhibitor may be added in carbonylation as described on page 6 of the foregoing International Publication.
As described above, p-chloromethylstyrene is liable to cause self-polymerization, so that, according to the above International Publication, polymerization inhibitor is added during the carbonylation as above. In addition, it is required to use solvents as much as several times to several tens times, mostly over ten times the volume of p-chloromethylstyrene as substrate in all the examples on carbonylation.
However, the necessity for large quantity of solvent relative to the substrate substance of p-chloromethylstyrene is not advantageous in industrial practice.
In the method as described in the above International Publication, highly reactive vinyl groups are reacted to convert into other less reactive substituents in the first step among plurality of steps. This method cannot always be regarded as reasonable in industrial scale process in view of the fact that the high reactivity of vinyl group is not taken into consideration sufficiently.
Moreover, the method disclosed in the above International Publication cannot be said as inexpensive because expensive cyclopentanone carboxylic acid alkyl ester is used as a starting material. In addition, the yield is not always satisfactory either.
As mentioned above, the most suitable method for producing loxoprofen has not yet been proposed, and a more efficient method is wanted.
BRIEF SUMMARY OF THE INVENTION
It is the object of the present invention to provide a process for producing loxoprofen using adipic acid diester as one of starting materials, which is more effective as compared with conventional methods.
More particularly, a first aspect of the present invention relates to a process for producing a compound as represented by the following general formula II (hereinafter referred to as “compound II”):
wherein R′ represents an alkyl group having 4 or less carbon atoms, R″ represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and R′ and R″ can be either the same or different,
which process comprises the steps of:
to cause adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)
n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or alkaline earth metal, n represents the number corresponding to the valence of M and (OR)'s of n in number can be either the same or different,
to subject successively the above product to coupling with halomethylstyrene to obtain the compound as represented by the following general formula I (hereinafter referred to as “compound I”):
wherein R′ represents an alkyl group having 4 or less carbon atoms,
and to cause the above compound I to react with carbon monoxide and water or alcohol in the presence of a metal catalyst to obtain the above compound II.
A second aspect of the present invention relates to a process for producing 2-substituted propionic acid as represented by the following general formula III (hereinafter referred to as “compound III”):
which process comprises the steps of (1-1) to (1-3):
step (1-1) to cause adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)
n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or alkaline earth metal, n represents the number corresponding to the valence of M, and (OR)'s of n in number can be either the same or different, and successively subjecting the above product to coupling with halomethylstyrene to obtain the compound I as represented by the following general formula I:
wherein R′ represents an alkyl group having 4 or less carbon atoms,
step (1-2) to cause the above compound I to react with carbon monoxide and water or alcohol in the presence of metal catalyst to obtain a compound II as represented by the following general formula II:
wherein R′ represents an alkyl group having 4 or less carbon atoms, R″ represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and R′ and R″ can be either the same or different, and
step (1-3) to subject the above compound II to decarboxylation and hydrolysis to obtain the above compound III.
A third aspect of the present invention relates to a process for the production as described in the first or second aspect, wherein halomethylstyrene is chloromethylstyrene.
According to the above methods, the halomethyl group of halomethylstyrene is converted into a particular substituent, so that the liability for self-polymerization of vinyl group is reduced. Therefore, a large quantity of solvent is not required in carbonylation. Furthermore, it is possible to produce 2-substituted propionic acid effectively using an inexpensive starting material.
A fourth aspect of the present invention relates to a process for producing a compound II as represented by the following general formula II:
wherein R′ represents an alkyl group having 4 or less carbon atoms, R″ represents hydrogen atom or an alkyl group having 4 or less carbon atoms, and R′ and R″ can be either the same or different,
which process comprises the steps of:
causing adipic acid diester to react with alkoxide as represented by the following general formula:
M(OR)
n
wherein R represents an alkyl group having 5 or less carbon atoms, M represents alkali metal or
Suyama Kazuharu
Watanabe Saisuke
Hollander Law Firm, P.L.C.
Killos Paul J.
Nippon Petrochemicals Company Limited
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