Organic compounds -- part of the class 532-570 series – Organic compounds – Carboxylic acids and salts thereof
Reexamination Certificate
1999-08-03
2001-07-24
Killos, Paul J. (Department: 1623)
Organic compounds -- part of the class 532-570 series
Organic compounds
Carboxylic acids and salts thereof
Reexamination Certificate
active
06265607
ABSTRACT:
BACKGROUND OF THE INVENTION
The invention relates to a novel process for the preparation of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid of the formula (I) below.
4-(4′-Chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid is an important intermediate for the synthesis of matrix metalloendoproteinase inhibitors (MMP), which are employed as active compounds for the prevention of the metastasis of malignant tumors. The compound, however, is prone to isomerization to give conjugated isomers. This reaction is induced by traces of base, strong acids and thermal stress.
On account of the importance of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid of the formula (I), a large number of procedures for the preparation of this compound exist. All known syntheses of the compound start from 4-chlorobiphenyl of the formula (II), which is reacted with AlCl
3
and itaconic anhydride of the formula (III).
J.-P. Rieu et al. (J. Pharm. Sci. 1980, 69, 49) carry out the reaction in the solvent dichloromethane. After aqueous work-up, removal of the solvent by distillation and recrystallization from an 11-fold volume of ethyl acetate, the product is obtained in a yield of only 52%.
H. Cousse et al. (Eur. J. Med. Chem. 1987, 22, 45-57) use 1,2-dichloroethane or dichloromethane as a solvent. After aqueous work-up, the organic phase is mixed with ethanol and acetone, whereupon the product precipitates, and is filtered off with suction and recrystallized. The yields indicated are, however, only 46%.
In DE-A-25 13 157 too, biphenyls and halobiphenyls are acylated with itaconic anhydride according to Friedel-Crafts in the presence of a Lewis acid catalyst. The solvent used here is the strongly toxic 1,1,2,2-tetrachloroethane. Yields for the acylation of 4-chlorobiphenyl are not indicated.
SUMMARY OF THE INVENTION
The invention was based on the object of providing a process for the preparation of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid which can be carried out industrially, which avoids the highly toxic chlorinated aliphatic hydrocarbons mentioned and affords the target product in good yields. Moreover, the process to be developed should be as free as possible of technically complicated purification procedures such as recrystallization or chromatography.
Surprisingly, it has been found that the acylation of 4-chlorobiphenyl with itaconic anhydride under catalysis with AlCl
3
in aromatic solvents leads to 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid in very good yields. In spite of the already mentioned high lability, the target product is surprisingly obtained in very high purity. It is furthermore surprising that under the conditions according to the invention no acylation of the solvent is observed.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
The present invention therefore relates to a process for the preparation of 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid of the formula (I)
by Friedel-Crafts acylation of 4-chlorobiphenyl with itaconic anhydride, which comprises carrying out the Friedel-Crafts acylation in aromatic solvents at a temperature from −20 to +80° C.
Suitable aromatic solvents are preferably those which, under the conditions according to the invention, are acylated significantly more slowly than 4-chlorobiphenyl, for example benzonitrile, nitrobenzene, bromo- and chloroaromatics. o-Dichlorobenzene, chlorobenzene and p-chlorotoluene are particularly preferred. Mixtures of these solvents can also be employed.
The starting materials 4-chlorobiphenyl and itaconic anhydride are expediently reacted in a molar ratio of 0.8:1 to 1.2:1, preferably 0.9:1 to 1.1:1.
The Friedel-Crafts catalyst employed is, for example, AlCl
3
. The amount of Friedel-Crafts catalyst is expediently 1.0 to 5 mol per mole of itaconic anhydride, preferably 2.01 to 2.7 mol per mole of itaconic anhydride.
In a preferred embodiment, 4-chlorobiphenyl and itaconic anhydride are dissolved in the solvent and this solution is added to a suspension of the Friedel-Crafts catalyst in the solvent, expediently at a temperature of −20 to +80° C., preferably at −10 to +55° C., particularly preferably at −0 to 45° C.
It is also possible to meter in a solid mixture of the reactants mentioned into initially introduced solvent. It is also possible to add the reactants separately in solid form. The addition time or dropwise-addition time can be between 1 minute and 12 hours, preferably between 0.5 and 4 hours.
The amount of solvent used (total of solvent in the recipient vessel and the solvent used for the dissolution of the reactants) can be varied within a wide range, as well as the ratio of the amounts of solvent in the recipient vessel to give the amount of solvent which is used for the dissolution of the starting materials. Total amounts of solvent between 0.5 and 20 parts by weight per part by weight of 4-chlorobiphenyl, preferably between 8 and 16, particularly preferably between 11 and 15, parts by weight per part by weight of 4-chlorobiphenyl, are expedient.
After completion of the dropwise addition or the addition, the reaction mixture is stirred for 0.5 to 24 hours, preferably 1 to 6 hours, preferably at temperatures from 0 to 55° C.
It is then hydrolyzed with water, dilute aqueous hydrochloric acid or dilute aqueous sulfuric acid.
The hydrolysis is expediently carried out by introducing the reaction mixture into water, hydrochloric acid or sulfuric acid, which are preferably 0 to 35% strength by weight, temperatures between 0 and 80° C. being preferred. The aqueous phase is separated off and the organic phase is washed one or more times with dilute hydrochloric acid or sulfuric acid (0 to 35% strength by weight). The product present suspended in the solvent is filtered off and washed one or more times with suitable solvents and dried. Suitable solvents are those which, compared with the reaction product, behave in an inert manner and have a solubility for the product of below 5%, for example o-dichlorobenzene, chlorobenzene, ethanol or ethanol-water mixtures.
In general, almost quantitative reactions to give the desired product are achieved.
It is furthermore advantageous to wash the mother liquor with a solution of a suitable complexing agent, for example a multidentate complexing agent such as ethylenediaminetetraacetic acid, it being possible for aluminum which may be contained in the product to be complexed and an isomerization of the product to give conjugated isomers to be prevented. The mother liquor can be concentrated, whereby the yield can be further increased.
The 4-(4′-chlorobiphenyl-4-yl)-4-keto-2-methylenebutyric acid thus obtained is subjected to drying. The drying of the product can be carried out at temperatures between 20° C. and 110° C. under pressures between normal pressure and 1 mbar.
REFERENCES:
patent: 4008323 (1977-02-01), Cousse et al.
patent: 4058558 (1977-11-01), Cousse et al.
patent: 5789434 (1998-08-01), Kluender et al.
patent: 2513157 (1975-10-01), None
patent: 25 13 157 (1975-10-01), None
“Snythèse structure et activitè hypocholestèrolèmiante d'une sèrie d'acides &ggr;-aryl, &ggr;-oxo butyriques substituès et dèrivès” H. Cousse, G. Mouzin, J. Rieu, A. Delhon, F. Bruniquel, F. Fauran, Eur. J. Med. Chem. 22, (1987), pp. 45-57.
“Secondary Products of Itanoxone,” J. Rieu, G. Mouzin, H. Cousse, and A. Boucherle, Journal of Pharmaceutical Sciences, vol. 69, No. 1, Jan. 1980, pp. 49-53.
Cosmo Robert
Erbes Michael
Haber Steffen
Meudt Andreas
Noerenberg Antje
Clariant GmbH
Hanf Scott E.
Killos Paul J.
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