CS274444B2 - Method of 2-(4-(4-chlorobenzamide)-ethyl/phenoxy)-2-methylpropanoic acid preparation - Google Patents

Abstract

For novel prepn. of 2-(4-(2--chloro-benzamido) -ethyl-phenoxy)-2 -methyl-propionic acid (bezafibrate) of formula (I), a 4-chloro-benzoic-acid-thio ester of general formula (II), where R is a 2-mercapto-benzimid-azol-, 2-mercapto-benzaxazol- or pref. a 2-mercapto-benzo-thiazolo gp., is condensed with silylated 2-(4-(2-amino-ethyl)-phenoxy) -2-methyl-propionic-acid of formula (III). Active thio-esters of formula (II) are novel cpds.

Description

The present invention is in the field of organic chemistry and relates to a novel process for the preparation of 2- (4- [2- (4-chlorobenzamido) ethyl] phenoxy) -2-methylpropanoic acid bezafibrate - formula 1

The present invention also relates to novel intermediates useful in the above process, β as well as methods for preparing novel intermediates.

Compound of Formula I It is well known as a hypolipomic agent, which is used in modern medicine to lower blood cholesterol and lipid levels.

There is a continuing need to find a new economic process for preparing 2- (4- [2- (4-chlorobenzamido) ethyl] phenoxy) -2-methylpropanoic acid bezafibrate from the intermediate 4-chlorobenzoic acid reactive derivative, which derivative would be for transport and storage more stable and convenient than the 4-chlorobenzoyl chloride currently in use, which slowly decomposes to 4-chlorobenzoic acid on prolonged storage. At the same time, the ehora derivative should be less aggressive.

Synthesis of Compound of Formula I It is described in German Patent 2149070, which describes the reaction between 4-chlorobenzoyl chloride and 4- (2-aminoethyl) phenol to give 4- [2- (4-chlorobenzoyl) aminoethyl] phenol. This is condensed with 2-bromo-2-methylpropanoic acid β ethyl ester. The resulting ester is hydrolyzed. Syntheea of a compound of formula I is also disclosed in Austrian patent 565 167 and in English patent 2,021,575, where it is described that you are in an alkaline medium. there is a haloform reaction between 4- (2- (4-chlorobenzoyl) aminoethyl) phenol, acetone and chloroform.

The process according to the invention is carried out by reacting the active thioesters of 4-chlorobenzoic acid of the general formula II

Cl

COR (II) wherein R is 2-mercaptobenzimidazolyl, 2-mercaptobenzoxazolyl, and preferably 2-mercaptobenzothiazolyl, is condensed with the silylated form of 2- [4- (2-aminoethyl) phenoxy] -2-methylpropanoic acid of formula III

CH ₃ CH ₃ CH ₃

The condensation reaction is carried out in inert solvents, preferably methylene chloride, in a temperature range from room temperature to the boiling point of the solvent, preferably at 40 ° C.

A compound of formula III, 2- [4- (2-aminoethyl) -phenoxy] -2-ethyl-propanoic acid which is silylated with trimethylchlorailaner or preferably N, O-bie (trimethyleilyl) ecetamide (BSA), i. hexamethyldisilazansm. It is commercially available or can be prepared according to the published Yugoslavian patent application P 1086/87.

CS 274 444 B2

Compound of formula XI is a new compound * A compound of formula II can be prepared by reacting 4-chlorobenzoyl chloride of formula IV ci -

COC1

2-mercaptobenzimidazole, 2-mercaptobenzoxazole or preferably 2-mercaptobenzothiazole, all of which are commercially available.

The synthesis of the thioesters of formula II is carried out in inert organic solvents, preferably in methylene chloride, in the presence of a base, preferably triethylamine, at a temperature ranging from 0 ° C to the boiling point of the solvent, preferably at the boiling point of methylene chloride.

The novel triaatars of the formula II obtained by the reaction of 4-chlorobenzoyl chloride of the formula IV and 2-mercaptobenzimidazole, 2-mercaptobenzoxazole or 8 preferably 2-mercaptobanzothiazole in the presence of alkali, preferably triethylamine, are solid, stable, non-aggressive compounds. for transport and storage. They can be prepared from 4-chlorobenzoyl chloride at the time of its availability, whereby the obtained novel compounds of formula (II) and e are readily stored until aa are used to synthesize compounds of formula (I).

The novel compounds are highly advantageous in comparison with 8 by the unstable and aggressive 4-chlorobenzoyl chloride, which can degrade to acid by the action of moisture. They are reactive and readily reacted with silylated 2- [4- (2-arainoethyl) -phenoxy] -2-methylpropanoic acid in a dry organic solvent, preferably methylene chloride. Reaction e forms a compound of formula I (bezafibrate) in high yield and good quality *

Upon completion of the reaction, ee 2-mercaptobenzothiazole, a commercial product used in the rubber industry, can be isolated from the organic layer. The desired product is isolated from the aqueous layer.

It is also possible that upon completion of the reaction and after evaporation of the organic solvent, water is added to the residue, alkenyl is adjusted to pH 11.5 and the undissolved 2-mercaptobenzothiazole is removed. 2- (4- [2- (4-chlorobenzamido) ethyl] phenoxy) -2-methylpropanoic acid is isolated from the filtrate at eelectric point at pH 3.7.

The process of the present invention is illustrated in detail by the following non-limiting examples.

Example 1

2- (4- / 2- (4-chlorobenzamido) ethyl) -phenoxy) -2-methylpropanoic acid

2- (4- (2-Aminoethyl) phenoxy) -2-methylpropanoic acid (22.3 g, 0.1 mol) was suspended in dry methylene chloride (500 mL). While stirring at room temperature, N, bis (trimethylsilyl) acetamide (30.51 g, 0.15 mol) in triethylamine (5.9 g, 0.1 mol) was added. The reaction mixture was stirred for 30 minutes at room temperature while the silylacs were running. S-2-benzothiazolyl-4-chlorobenzothioate (30.5 g, 0.1 mol) was added and the mixture was refluxed for 8 hours. After completion of the reaction, which was monitored by thin layer chromatography, the methylene chloride was evaporated under reduced pressure, water (1100 ml) was added and the reaction mixture was stirred for 30 minutes. The pH of the reaction mixture was then adjusted to 11.5 by the addition of 25% ammonia. The reaction mixture is stirred at this pH for 30 minutes. Undissolved matter is filtered off. Aqueous hydrochloric acid (1: 1) was added to the filtrate with vigorous stirring from room temperature to pH 3.7-3.9. Stirring is continued once the pH is reached

CS 274 444 B2 next One hour. The product is filtered off, washed with water and dried in a vacuum drier at 50 ° C. There was obtained 2 - (- 4- [2- (4-chlorobenzamido) ethyl] phenoxy) -2-methylpropanoic acid (30.72 g, 85%) and m.p. 181-183 ° C. The structure of the obtained compound was confirmed by IR and NMR spectra.

The precipitate, which was filtered at pH 11.5, was dried in a vacuum drier at 40 ° C. This afforded purified 2-mercaptobenzothiazole (8.5 g, 51%) as a by-product.

Example 2

S-2-Benzothiazolyl-4-chlorobenzothioate

Suspend 2-mercaptobenzothiazole (16.7 g, 0.1 mol) in dried methylene chloride (500 mL). Triethylamine (14 mL, 0.1 mol) was added to the suspension under stirring at room temperature. After complete dissolution, 4-chlorobenzoyl chloride (17.4 g, 0.1 mol) was added dropwise with stirring. The reaction mixture was refluxed for 6 hours, then cooled to room temperature, filtered and washed with water (100 mL). After drying in an air dryer, S-2-benzothiazolyl-4-chlorobenzothioate (24.5 g, 90%) is obtained, m.p. 205-208 ° C. The structure of this compound was confirmed by both IR and NMR spectra.

Example 3

2- (4- / 2- (4-chlorobenzamido) -sthyl) -phenoxy) -2-methylpropanoic acid

2- [4- (2-Aminoethyl) -phenoxy] -2-methyl-propanoic acid (22.3 g, 0.1 mol) was suspended in dry methylene chloride (500 mL). To this suspension was added N, O-bie (trimethylsilyl) acetamide (30.51 g, 0.15 mol) with stirring at room temperature. The reaction mixture was stirred at room temperature for 30 minutes in order to allow for slylation. S-2-benzothiazolyl-4-chlorobenzothioate (30.5 g, 0.1 mol) was then added. The mixture was refluxed for six hours.

After completion of the reaction, the reaction mixture was cooled to room temperature, water (500 mL) was added and the pH was adjusted to 11.5 with stirring by adding 25% ammonia. The mixture was stirred for one hour, the organic layer was separated from the aqueous layer, the organic layer was further washed with water (300 mL), the organic layers were washed, filtered and aqueous hydrochloric acid (1 tL) was added under vigorous stirring until pH mixture does not reach

3.7 to 3.9. The precipitated product is stirred for an additional hour at room temperature, then filtered, washed with water and dried in a vacuum drier at 50 ° C. 2- (4- [2- (4-Chlorobenzoyl) -6-ethyl] -phenoxy) -2-methyl-propanoic acid (29.28 g, 81%) is obtained, m.p.

The 2-mercaptobonzothiazole is isolated from the methylene chloride layer after evaporation of the solvent, which is then purified.

Claims (2)

OBJECT OF THE INVENTION 1. A process for the preparation of 2- (4- [2- (4-chlorobenzamido) -ethyl] -phenoxy) -2-methylpropanoic acid of formula (II). Cl COHN.-CH ₂ -CH ₂ - I. ^J O-C-COOH Uh. (I), characterized in that the 4-chlorobenzoic acid active thioesters of the general formula II (n) are active, Wherein R is a 2-mercaptobenzimidazolyl group, a 2-mercaptobenzoxazolyl group, and preferably a 2-mercaptobenzothiazolyl group, is condensed with an eilylated form of 2- [4- (2-arainoethyl) phenoxy] -2-methylpropanoic acid of formula III CH - SiHN-CH 2 CH ³ CH- CHI. -OC-COOSiCHI I ³ CH-, CHCIL I .. (nr) in inert organic solvents at temperatures ranging from room temperature to the reflux temperature of the solvent · 2. The process according to claim 1, wherein the condensation is carried out in methylene chloride at a temperature of 40 [deg.] C.