DE2030003A1 - alpha (p chloro) phenoxy isobutter acid square brackets on 2 (p chloro) 'phenoxy 2 methyl square brackets on propyl ester and process for the production of the same - Google Patents

Description

BOEHRINGERMAMHEIMGMBH 1698 ^ ^U

oc- (p-chloro) -phenoxy-130'-butyric acid- [2 '- (p-chloro) -phenoxy-2'-methyl] - ■ propyl ester and process for making the same

The present invention relates to a- (p-chloro) -phenoxy-isobutyric acid- [2 ^l - (p-chloro) phenoxy-2 ^l -methylpropyl ester, a process for the preparation of this compound and its use for the preparation of medicaments with antiatherosclerotic action. The structure of this new ester is represented by the formula I.

The compound shows remarkable pharmacological properties, in particular, it has an unusual effect even in small doses severe reduction in serum triglycerides. In addition, their use in animal experiments led to a considerable lowering of the cholesterol level, without undesirable side effects occurring. Both the

Lowering of the serum triglycerides, as well as the lowering of the cholesterol exceeds that of the starting compounds for the

partially an analogous effect is known, considerable. The compounds according to the invention are therefore effective medicaments against atherosolerosis.

The preparation of the compound I can be carried out in a manner known per se take place that one «- (p-chloro) -phenoxy-isobutyric acid or a derivative.'der formula II

o-C-COX

^CH 3 (II)

in which X is a reactive radical

109852/1921

with 2- (p-chloro) -phenoxy-2-diethyl-propanol- (l) or a compound of formula III

? ^H 3

O-C-CH _{9 -Y}

^CH 5 (in)

converts, in which Y is a reactive radical

As reactive derivatives of the formula II, which are used for reaction with 2- (p-chloro) -phenoxy-2-methyl-propanol, or the corresponding alcoholate are suitable, those compounds in particular are of interest in which X denotes halogen, an azide, acyloxy, or alkoxy group.

The free a- (p-chloro) -phenoxy-isobutyric acid or its salts are preferably reacted with compounds III in which Y represents a reactive inorganic or organic acid radical. As an acid residue e.g. halides and sulfonic acid residues are well suited.

The reaction is preferably carried out in inert solvents, such as benzene, chloroform, higher-boiling ethers, etc _.; optionally at elevated temperature. To increase the yield, the by-product (water, alcohol) formed is preferably continuously removed from the reaction medium by distillation or, if an acid is formed, bound by adding a weak base. The bases used are preferably tertiary amines, such as pyridine or triethylamine, which can also be used as the reaction medium.

The method according to the invention is illustrated by the following example explained in more detail.

- 5 109852/1921

B e i a p ie 1

To a suspension of 21.47 S (Ojl mole) cc (p-chloro) -phenoxyisobuttersäure in 50 ^m l of abs. 0.7 ml of absolute dimethylformamide and 13.1 g (0.1 mol) of thionyl chloride are added to chloroform and the mixture is kept at reflux temperature for 30 minutes. Thereafter, chloroform and excess thionyl chloride are distilled off (towards the end of the distillation under vacuum) and the dry residue is taken up in 30 ml of absolute eyridine. The pyridine solution is then added dropwise with stirring to a solution of 20.1 g (0.1 mol) of 2- (p-chloro) -phenoxy-2-methyl-propanol- (l) in 30 ml of absolute pyridine, a precipitate separating out . During the dropwise addition, the mixture is kept at about 25 ° C., then stirred for two hours at room temperature and the reaction mixture is then poured into cold water. After acidification with dilute hydrochloric acid, the mixture is extracted with ether, the ether phase is washed successively with dilute hydrochloric acid, with aqueous sodium carbonate solution and with water, dried (sodium sulfate) and the ether is then evaporated off. The ester crystallizes out by adding some methanol. After recrystallization from isopropanol g (6Q ° / o ä. Th.) To obtain 27.0 colorless crystals of mp. 51-52 ⁰ C (bp. 187-188 ° C at 0.15 torr). The structure of the obtained α- (p-chloro) -phenoxy-isobutyric acid- [2 ^l - (p-chloro) -phenoxy-2-methyl] -propyester is confirmed by spectra and elemental analysis. The preparation of 2- (p-chloro) -phenoxy-2-niethyl-propanol is carried out by reducing the cx- (p-chloro) -phenoxy-isobutyric acid ethyl ester with lithium aluminum hydride:

A solution of 24.27 g (0.1 mol) of a- (p-chloro) -phenoxy-isobutyric acid ethyl ester in 50 ml of abs. Ether becomes very slowly and with cooling to a suspension of 4g lithium aluminum hydride in 200 ml abs. Ether added dropwise. The mixture is then kept at boiling temperature for 2 hours, then decomposed by adding saturated sodium chloride solution and filtered. After the ether has been distilled off, the crude alcohol is obtained in a practically quantitative yield. After distillation, 17.4 (87 # d. Th.) Of colorless liquid, bp. I45-I46 ⁰ at 13 Torr
109-111 ° at 0.4 torr

20th

D = ^X

109852/1921

Claims (5)

Claims - (p-chloro) -phenoxy-isobutyric acid- [2 «- (p-chloro) -phenoxy-2-methyl] '» propyl ester of formula I CH. CH ₂ ι 3, 3 η - <\ Ci- / Vo-C-COOCH ₂ CO- / yci CH PTT (ι) 2) Process for the preparation of the compound of the formula I, characterized in that cc- (p-chloro) phenoxyisobutyric acid or a derivative of the formula II o-c-cox CH, (II) in which X is a reactive radical, ι with 2- (p-chloro) -phenoxy-2-methyl-propanol- (I) or a compound of the formula III CH3 Cl- / \ -0-C-CH _o -Y \ / ι 2 ^CH 3 (III) in which Y represents a reactive radical . 109852/1921 ■ - s-- 2Ö30003 3) Method according to claim 2, characterized in that as By-product water or alcohol is continuously separated by distillation » 4) Method according to claim 2, characterized in that as By-product resulting acid binds by adding a weak base. 5) Use of the compound of the formula I for the production of medicaments with antiatherosclerotic effect. 109852/1921