CS215499B1 - 2-Phenyl-5-oxopentanoic acid derivatives and process for their preparation - Google Patents

Abstract

The subject of the invention are derivatives of 2-phenyl-5-oxopentanoic acids and a method for their preparation. The substances are prepared by alkylation of sodium salt of ethyl renyl malonate beta-chloroketones, alkaline hydrolysis of crude 2,2-disubstituted ethyl malonate and decarboxylation of the resulting crude dicarboxylic acid at elevated temperature. The substances were tested for anti-inflammatory activity and in comparative tests with the preparation Brufen, some of the substances showed significant activity in both the kaolin and adjuvant models of experimental inflammation.

Description

The invention relates to 2-phenyl-5-oxopentanoic acid derivatives of the general formula I

in which

R represents a tert-butyl or phenyl group substituted in the 4-position by a η-propoxy-, n-butoxy- or methoxy- group, a chlorine atom, a fluorine atom, or a 2- (6-methoxy) naphthyl group.

Compounds of formula I that are novel have been tested for anti-inflammatory activity in comparative tests with the known formulation of Brufen, and some have shown significant efficacy. The evaluation was performed in rats at doses of 25 and 100 mg / kg in two models of experimental inflammation (kaolin and adjuvant edema). Statistically significant anti-inflammatory activity was found with 2-phenyl-5-oxo-6,6-dimethylheptanoic acid, 2-phenyl-5-oxo-5- (4-isoproxy) phenylpentanoic acid and 2-phenyl-5-oxo-5- ( 4-chloro) phenylpentanoic acid. The first of these three acids suppresses kaolin edema at both doses, the second inhibits both model types of inflammation at 100 mg / kg and the third inhibits adjuvant edema at 25 mg / kg. The acute oral toxicity in mice expressed as LD ₅₀ for all test substances is greater than 1 g / kg.

The invention also relates to a process for the preparation of these derivatives. According to the invention, the novel 2-phenyl-5-oxopentanoic acid derivatives of the general formula I are prepared by a beta-chloroketone of the general formula II

RCOCH ₂ CH ₂ Cl (II) wherein

R denotes the same as in formula I, reacts with sodium phenylmalonate sodium to form 2,2-disubstituted ethyl malonate, which is hydrolyzed in the crude state and decarboxylated to the desired acid of formula I.

Alkylation of ethyl phenyl malonate is accomplished by preparing from sodium phenyl malonate with sodium methoxide in methanol medium the sodium salt, which, after distilling off the methanol, reacts at 100 ° C in dimethylformamide medium with the appropriate beta-chloroketone. The obtained intermediate is subjected to alkaline hydrolysis and the 2,2-disubstituted malonic acid is extracted into ether after acidification with sodium acid by acidification with mineral acid. The crude dicarboxylic acid is decarboxylated to the desired acid by heating to 130-140 ° C.

The beta-chloroketones of formula (II) are generally known or can be readily prepared by known methods. (J. Colonge: Bull. Soc. Chim. Fr. (5) 3, 2116 (1936), E. Profit et al., J. Prakt. Chem., 273, 57 (1955); RE Lutz et al. J. Org. Chem., 12, 96 (1947).

Details of the embodiment are given in the following examples. '

Example 1

Alkylation

0.87 g of sodium is dissolved in 20 ml of methanol and 8.9 g of ethyl phenyl malonate is added to the sodium methoxide solution thus prepared. The alcohol is distilled to dryness under reduced pressure, 76 ml of dimethylformamide and 5.65 g of 3-oxo-4,4-dimethylpentyl chloride are added to the residue. The mixture was maintained at 100 ° C for 8 h and at room temperature for 16 h. After the DMF was distilled to near dryness under reduced pressure, the mixture was diluted with water and extracted with ether. The combined ethereal portions were washed with water, dried and the ether distilled to dryness. 11 g of intermediate are obtained, which product is used for hydrolysis and decarboxylation without further purification.

Hydrolysis and decarboxylation

A mixture of the ligands of the crude intermediate obtained as described above, 25 ml of ethanol, 2.5 ml of water and 5.2 g of potassium hydroxide is heated to boiling for 1 h and left at room temperature for 16 h. The alcohol was distilled off under reduced pressure, the residue was diluted with water and extracted with ether. The aqueous layer was acidified with dilute hydrochloric acid, extracted with ether, the combined ethereal portions washed with water and dried. After distilling off the ether, the residue was heated at 130-140 ° C for 1.5 h until carbon dioxide evolution ceased and the crude product was recrystallized from n-hexane. 4.4 g of 2-phenyl-5-oxo-6,6-dimethyl-heptanoic acid are obtained, m.p. 86-87 ° C.

In the same manner as in Example 1, acids were prepared

2-phenyl-5-oxo-5- (4-n-propoxy) phenylpentane, m.p. 113 DEG-115 DEG C. and 2-phenyl-5-oxo-5- (4-n-butoxy) phenylpentane, m.p. Mp 130-132 ° C.

For both acids, the solvent is cyclohexane.

Example 2

From 1.06 g of sodium, 10.6 g of ethyl phenyl malonate and 9.2 g of 4-chloro-beta-chloropropiophenone, 16 g of crude intermediate are prepared in the same manner as described in Example 1, which yields the same hydrolysis and decarboxylation. g of crude acid. The crude reaction product was purified by silica gel column chromatography and the residue obtained by concentrating the chloroform eluates was recrystallized from nitromethane. 3 g of 2-phenyl-5-oxo-5- (4-chloro) phenylpentanoic acid are obtained, m.p. Mp 126-128 ° C.

In the same manner as described in Example 2, acids were prepared

2-phenyl-5-oxo-5- (4-methoxy) phenylpentane, mp 148-150 ° C (ethanol: water), 2-phenyl-5-oxo-5- (4-fluoro) phenylpentane, 1.1.133 to 134 ° C (toluene: hexane) and 2-phenyl-5-oxo-5- [2- (6-methoxy) naphthyl] pentanoate,

1.1. 196-198 ° C (nitromethane).

Claims (2)

SUBJECT What is claimed is: 1. A compound of the formula (I) EMI2.0 wherein: EMI4.0 [0005] EMI2.0 [0000] EMI2.0 [0000] R is tert-butyl or phenyl substituted in the 4-position by η-propoxy, n-butoxy or methoxy, chloro, fluoro, or 2- (6-methoxy) naphthyl. OF THE INVENTION 2. A process for the preparation of 2-phenyl-5-oxopentanoic acids of the formula I according to claim 1, characterized in that the beta-chloroketone of the formula II RCOUH ₂ CH ₂ C1 (II) in which R denotes the same as in formula I, reacted with an alkali metal salt of ethyl phenyl malonate, preferably sodium salt, whereupon the resulting 2,2-disubstituted ethyl malonate is hydrolyzed and decarboxylated.