Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Patent
1995-11-16
1997-08-05
Geist, Gary
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
C07C 5968
Patent
active
056544766
DESCRIPTION:
BRIEF SUMMARY
This application is a 371 of PCT/EP94/01508, filed May 10, 1994.
BACKGROUND OF THE INVENTION
The present invention relates to a process for the preparation of gemfibrozil.
Gemfibrozil, or 2,2-dimethyl-5-(2,5-xylyloxy)-valeric acid, of formula (I): ##STR2## is a known hypolipemizing medicament widely used.
In USA, the market value of gemfibrozil in 1992 was estimated to be about 550 million dollars (SCRIP n. 1792, 5-2-93, p 7).
Therefore, it is evident the importance of methods allowing to prepare gemfibrozil in a cost-saving and industrially convenient way.
The up to now known methods do not solve satisfactorily the problem.
U.S. Pat. No. 3,674,836 discloses the reaction of a 3-(2,5-xylyloxy)propyl halide with an isobutyric acid 2-lithium derivative, to give compound (I). However, the use of lithium derivatives and anhydrous solvents involves evident drawbacks.
EP-219117 and JP-63 190 883 (Nitto Chemicals) disclose the preparation of .varies.,.varies.-dimethyl-5-valerolactone by radicalic addition of HBr to 2,2-dimethyl-4-pentenoic acid and subsequent cyclization to lactone in alkali medium. The resulting compound was used by the Applicant as an intermediate for the preparation of gemfibrozil.
Finally, U.S. Pat. No. 4,665,226 envisages the reaction of 2,5-dimethylphenol with an 5-bromo- or 5-chloro-2,2-dimetilpentanoic acid ester, in a mixed solvent system (generally toluene/dimethylsulfoxide) under reflux for a time ranging from 7 to 20 hours.
The use of high-boiling solvents, which are difficult to remove, the high temperatures and the long reaction times make such a process scarcely attracting from the industrial point of view.
SUMMARY OF THE INVENTION
Now it has been found that the reaction of 2,5-dimethylphenol with a 5-bromo- or 5-chloro-2,2-dimetilpentanoic acid ester of formula (II): ##STR3## wherein R is an alkyl, aryl, arylalkyl group and X is a halogen atom, can advantageously be carried out in the absence of solvents and in the presence of an ammonium or phosphonium quaternary salt.
DESCRIPTION OF PREFERRED EMBODIMENTS
In compounds (II), X is preferably chlorine or bromine, more preferably bromine, whereas R is preferably C.sub.1 -C.sub.6 alkyl, more preferably methyl or ethyl.
As an ammonium or phosphonium quaternary salt, tetrabutylammonium bromide is preferred.
The intermediate of formula IIa is particularly preferred ##STR4##
Compounds (II) can be prepared with known, conventional methods, for example according to the method disclosed in EP-219117 and JP-63 190 883, but operating in such conditions as to promote esterification instead of lactonization. For example, the radicalic addition of the hydrohalogen acid is followed by the reaction with alcohols in the presence of acids. The alcohols themselves can be used as reaction solvents.
The reaction of compounds (II) with 2,5-dimethylphenol is carried out preferably in the presence of acid-binding bases such as alkali or alkaline-earth metal carbonates, bicarbonates or hydroxides.
The reaction is carried out at a temperature ranging from 100.degree. to 130.degree. C., for a time from 1 to 3 hours.
The resulting gemfibrozil methyl ester is then hydrolysed with conventional methods, for example treating a methanol solution thereof with aqueous sodium hydroxide. The neutralization of the sodium salt with strong acids yields the desired compound.
The following example further illustrates the process of the invention.
EXAMPLE
A mixture of 30 kg of methyl 2,2-dimethyl-5-bromopentanoate, 50 kg of potassium carbonate, 40 kg 2,5-dimethylphenol and 3 kg of tetrabutyl ammonium bromide is heated to a temperature of 105.degree.-115.degree. C.
After that, a further 54 kg of methyl 2,2-dimethyl-5-bromopentanoate are added at such a rate as to keep temperature within the above indicated range. When the addition is over, temperature is maintained to 105.degree.-115.degree. C. for 3 hours. After cooling to 50.degree.-70.degree. C., 75 l of methanol are added, the mixture is cooled to 18.degree.-20.degree. C. and kept at this temperature for one ho
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Frare Giovanni
Piccoli Gianfranco
Tarquini Antonio
Frazier Barbara S.
Geist Gary
Recordati S.A. Chimical and Pharmaceutical Company
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