DE2014479A1 - Process for the preparation of new, substituted aryloxyacetic acids and their salts - Google Patents

Description

J. R. GEIGY A. G. 4,000 BASEL 2.1

Dr. F. Zumetein Sr. - Dr. E. Assmann Dr. R. Koenigeberger - Dipl. Phys. R. Holzbauer

Dr. F. Zumstein jun. Patent attorney

8 Munich 2, Brauhausstrasse 4 / III

4-3018 *

Process for the preparation of new, substituted aryloxyacetic acids and their salts

The present invention relates to processes for the preparation of new, substituted aryloxyacetic acids and their Salts with valuable pharmacological properties, these compounds as new substances, pharmaceutical preparations containing them

Substituted aryloxyacetic acids of the general formula I

0 - CH - CO - OE

in which . ■

R is an alkyl group having 3 to 10 carbon atoms or the Benzyl group means

as well as their alkali and alkaline earth salts are not yet known become"

As has now been found, these 3 possess new substances valuable pharmacological properties. They show in particular Hypolipäifjische effectiveness in the broad sense, the aich. e.g. to de /

009841/193 3

201U79

Lowering of the serum cholesterol level with repeated oral egg Administration to male rats can be detected. The determination of serum cholesterol is carried out according to Richterich and Lauber, Klin.Wochenenschrift 40, 1252 (1962). For example First, an orbital blood sample is taken under carbon dioxide-oxygen - Anesthesia performed and the serum gholesterol determined and then the substance to be tested is administered per os on four consecutive days in daily doses of 10 mg / kg. On the fifth day, 16 hours after the last drug administration, the second blood sample and determination of the serum cholesterol takes place.

The new, substituted aryloxyacetic acids of the general formula I as well as their alkali and alkaline earth salts stand out due to a long and low residence time in plasma Toxicity. They are suitable for oral and rectal administration to mammals for the treatment of hyperlipeal conditions, such as hypercholesterolemia.

In the compounds of general Forael I, R is as Alkyl group with 3 to 10 carbon atoms e.g. the propyl, Butyl, isobutyl, pentyl, isopentyl, neopentyl, kexyl, Isohexyl-, 3r3-Diiüethylbutyl-, Hep tyl-, Cctyl-, ITonyl- or Decyl group.

To produce the new compounds of the general Formula I and the alkali and Erdaikalisalze of these

009841/1933 BATH ORIGINAL

2ÜU479

Formula falling free carboxylic acids one sets an alkali metal alkali des p- (1,2,3,4-tetrahydro-1-naphthyl) phenol with a Salt with respect to the carboxyl group of a reactive ester with respect to the 2-hydroxy group of a compound of the general Formula II,

HO - CH - CO- OK (II)

in which R has the meaning given under formula I, inter alia, ' If desired, make one of the previously obtained salt Carboxylic acid of the general formula I releases the latter and leads if desired, the free carboxylic acid or by double Implementation, directly converting the initially obtained courtship into one or into another alkali or alkaline earth salt,

The p- (1,2,3,4 ^ -Tetrahydro-naphthyl) -phenol and its preparation have been described several times in the literature. In the case of the reactive esters with regard to the 2-hydroxy. groups of a compounds of the general formula II are, for example, halides ", ie 2-Kalogen-alkanoic acids yen the 2-Haloöor; -valeric acid up to the 2-Kalogen-dödeoansäu-re.n, further a.o." Jlalogen-hycirosiir.tsä-areri sovie \ i: r. Corresponding arylsulfonyloxy and kethrinsalfonyloxy derivatives, such as, for example, 2-arylsulfonyl- 'oxyalkanoic acids and 2-ethane, sulfonic, - loxya, VkcLr ^ acids. For the procedure according to the procedure, r-, 3. Alkali salts, such as sodium or potassium salts, of the aforementioned acids,

0 0 9 8-14 / 11'9
BATH ORIGINAL

201U79

Similar compounds, e.g. numerous 2-bromoalkanoic acids, are known and others can be prepared analogously to the known compounds. The reaction is preferably carried out in a solvent or diluent, for example in a lower, optionally water-containing one Alkanol, such as ethanol, or in a hydroxyl group-free one; Solvents such as dimethylformamide, dimethylacetamide or hexamethylphosphoric acid triamide, at temperatures between approx. 50-150 or up to the boiling point of the solvent used or, if necessary, also carried out above it in a closed vessel. The formation of the required as a reaction component Alkali salt of p- (1,2,3,4-tetrahydro-I-naphthyl) -phenol like also: required salts of free carboxylic acids, e.g. of 2-haloalkanoic acids, preferably takes place in situ, e.g. by adding an alkali metal alcoholate or an alkali metal hydride or amides, depending on the reaction medium, an anhydrous alkanol, a water-containing alkanol or dimethylformamide or ^ Another hydroxyl group-free solvent is used.

According to a second process, the carboxylic acids of the general formula I and other alkali and alkaline earth salts are obtained by hydrolyzing a functional derivative of such a carboxylic acid, if desired3 liberating the carboxylic acid from a salt obtained and, if desired, this or directly the salt initially obtained in a or . converted into another alkali or alkaline earth salt. As functional derivatives of carboxylic acids of the general formula I, for example, are suitable

009841/1933
BAOORIGINAL

2Q1U79

their lower alkyl esters, other esters such as cyclohexyl, Phenyl and benzyl esters, as well as nitriles, amides and lower imido alkyl esters. The hydrolysis takes place, for example, by heating in alkanolic or aqueous-alkanolic alkali hydroxide solutions to temperatures between approx. 50 and the boiling point of the reaction medium used.

. From the alkali salt solutions initially obtained

of, acids of the general formula I can either be obtained by inputting | close or evaporation and recrystallization directly the corresponding extract pure alkali salts or first release the acids, then clean e.g. by recrystallization and, if desired, in alkaline earth salts or again in alkali salts Conversion, Functional derivatives of carboxylic acids of general Formula I can also be used in an acidic medium, e.g. by boiling, in 60-70% sulfuric acid or in a mixture of conc. hydrochloric acid .and. Glacial acetic acid, hydrolyze to the free carboxylic acids, I.

The lower alkyl esters which can be used as starting materials are obtained, for example, analogously to the first-mentioned process for the preparation of the free carboxylic acids of the general formula I, in which the lower alkyl esters of the acids in question, ζ, B, instead of salts, are used in these processes. 2-Halogenalkansäurealkylestar o4er a-Haloganhydrocinnamatesäurealkylester, uses .. Other esters are produced in the same way. Eb enf''il? UQ. Analog; can.man.under van ^ -halagenalkaraiitrilen odor aH 009841/113: 3 " ^:

" ⁶ " 201U79

nitriles produce the nitriles of the acids required as end products. Nitriles which can be used for hydrolysis are e.g. also from substituted [p- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxy] -cyanoacetic acid alkyl esters by partial hydrolysis with the equimolar amounts of aqueous-alkanolic Alkali, release of the resulting substituted cyanoacetic acids and decarboxylation available by heating. Instead of the mentioned nitriles directly to the desired end materials To hydrolyze free carboxylic acids or their alkali salts, they can also first be partially converted to the corresponding Hydrolyze amides or by the successive action of hydrogen chloride and a lower alkanol in corresponding, lower imidoalkyl esters or their hydrochlorides, i.e. in further functional derivatives of the carboxylic acids of the general Convert formula I, which are suitable for hydrolysis to the latter.

Instead of uniform lower alkyl esters, amides or nitriles of carboxylic acids of the general formula I, mixtures of the same with the carboxylic acids desired as end products can also be used for the hydrolysis according to the process, as they are used under appropriate reaction conditions in the hydrolysis of the substituted [ p- ( _{1,2 f} 3,4-tetrahydro-. 1-naphthyl) -phenoxy] -malonic acid dialkyl ester and decarboxylation of the crude hydrolysis products are obtained.

0 09841/1933

BAOOBIOtNAL

According to a third process, the carboxylic acids of the general formula I and their salts are prepared by adding a substituted malonic ester of the general formula III,

(III)

in which ^,

Rj represents a lower alkyl group and R has the meaning given under formula I, heated in a hydrolyzing medium until one of the Is hydrolyzed ester groups and is present instead of the other hydrogen. I.

0098AT / 1933

- 8 - 201U79

According to one embodiment of the process, the compounds of the general formula III are boiled in the presence of an aqueous one Mineral acid under reflux and leads the acid of the general formula I obtained, if desired, into an alkali or Alkaline earth salt over. The mineral acids used are, for example, 60-70% sulfuric acid or concentrated hydrochloric acid, the latter with glacial acetic acid, if necessary.

According to a further embodiment of the process, the compounds of the general formula III are boiled in aqueous, alkaline medium and, if desired, sets the acid of general formula I from the directly obtained salt free. For this embodiment, the reaction medium used is preferably excess alkanolic alkali lye, e.g. methanolic potassium hydroxide solution.

In a third embodiment of the process, compounds of the general formula III are first boiled in an alkaline medium and then leads the mixture of hydrolysis products obtained initially by heating in an acidic medium Medium in uniform acids of the general formula I over. Included, Possible reaction media are the same as in the aforementioned embodiments.

009RA1 / 1933

- 9 - 20U479

In the starting materials of the general formula III, R ^ as a lower alkyl group can in particular denote the methyl or the alkyl group. However, the corresponding propyl or butyl esters can also be used. To carry out the reaction according to the invention, it is generally sufficient to reflux the compounds of the general formula III for a few hours in the media mentioned. Here can
if necessary, work can be carried out under pressure in a closed vessel to achieve higher temperatures.

The substituted [ρ- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy] -malonic acid dialkyl esters encompassed by the general formula III are in turn new compounds. she
can, for example, analogously to the first-mentioned process for the preparation of the carboxylic acids of the general formula I by reacting according to the definition for R
substituted bromo- or chloromalonic acid dialkyl esters

009 841/193 3

with alkali metal salts of p- (1,2,3 »4-tetrahydro-l-naphthyl) phenol, for example in abs. Ethanol at Si ed et erap era door or among the others in the first process for the production the reaction conditions given for the compounds of general formula I. Of those for the said reaction The bromine or chlorine compounds required are some, e.g. the bromobutyl malonic acid diethyl ester [J.Am.Chem.Soc. 4ji, 1578-1581 (1922)], known and others obtainable by halogenation analogously to the known compounds.

A fourth process for the preparation of the carboxylic acids of the general formula I and their alkali and alkaline earth metal salts consists in using a dicarboxylic acid of the general formula IV,

- CO - OH

(IV)

in which R has the meaning given under formula I, or an acidic alkali metal or alkaline earth metal salt thereof up to the point of cleavage the equimolar amount of carbon dioxide is heated and the at

0098A 1/1933

COPY
BATH ORIGINAL

The use of a free dicarboxylic acid resulting free monocarboxylic ¹ -efiure if desired, converted into an alkali or alkaline earth-r. For example, you heat a dicarboxylic acid of the general; Mean formula IV or an acidic salt of such at temperatures between 130-200, until the carbon dioxide development has ended. If necessary, the decarboxylation is promoted by adding catalysts, such as, for example, copper powder, or of organic bases, such as, for example, quinoline. The dicarboxylic acids of general formula IV are obtained, for example, by hydrolysis of their lower alkyl esters falling under general formula III with alkanolic or aqueous-alkanoic caustic potash or sodium hydroxide solution at moderately elevated temperatures and subsequent acidification.

Instead of pure dicarboxylic acids or Dicarbonsa'ureraonoalkentern the general formula TV can be used according to the invention Decarboxylation also raw hydrolysis products from under the general formula III falling dicarbonic acid dialkyl esters use ', in addition to the compound of the general formula IV already a certain amount created during hydrolysis and work-up Proportion of the desired enintoff in general Formula I included.

As an alkali and alkaline earth salt to be produced if required of the carboxylic acids of the general formula I come, for example, their üatriu-v .-, - potassium, lithium, Miigncsiu. ^ - and CaiciumsaD'ze in question. The Herntellun / j "diener SaI ^ e takes place

00 98 A1 / T9 * 3
/ GOPY

ORIGINAL

" ¹² " 2Q1U79

for example by combining acid and base in one suitable solvents such as methanol, ethanol, acetone-water, optionally filtering off one directly or after adding a second liquid of precipitated salt or evaporation of the salt solution. Furthermore, salts can be found in the solvent used are relatively sparingly soluble, also by double reaction of another salt of the acid with the base or a suitable one make fc salt of the same.

pie carboxylic acids of the general formula I and their alkali and alkaline earth salts are, as mentioned above, orally or administered rectally. The daily doses range between 1-10 mg / kg warm-blooded animals, preferably 4-10 mg / kg warm-blooded animals. Suitable dose Uniform form, such as dragees, tablets, suppositories as an active ingredient preferably 10-250 mg, e.g. 50 or 100 mg of one Carboxylic acid of the general formula I or an alkali or alkaline earth metal salt of such.

H In unit dosage forms for oral use

the content of active ingredient preferably between 10? » and 9Of ». For the production of such unit dose formers. if the active ingredient is combined, for example, with solid, powdery carriers, such as lactose, sucrose, sorbitol, iannitol; Starches such as potato starch, corn starch or amylopectin, also laminaria powder or citruo pulp powder; Cellulose derivatives or gelatin, optionally with the addition of lubricants, such as magnesium or calcium stearate or polyethylene glycols, to tablets or to dragee cores. The latter covers

009841/1933

BADORKLÖNAti '

for example, with concentrated sugar solutions, which, for example, may also contain gum arabic, talc and / or titanium dioxide, or with a lacquer dissolved in volatile organic solvents or solvent mixtures. Dyes can be added to these coatings, for example to identify different doses of active ingredient. Other suitable oral dosage unit forms are push-fit capsules made of gelatin and soft, closed capsules made of gelatin and a plasticizer such as glycerine. The first contain the active ingredient preferably as granules mixed with lubricants, such as talc or magnesium stearate, and optionally stabilizers, such as sodium metabisulphite (Na ₀ S ₀ O ₁ -) or ascorbic acid. In soft capsules, the active ingredient is preferably in suitable liquids, such as liquid polyethylene glycols, dissolved or suspended, and stabilizers can also be added. ·

As unit dosage forms for rectal use

For example, suppositories come into consideration, which consist of a combination · "' tion of an active ingredient with a suppository base on the Based on natural or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatin rectal capoein, which is a combination of the active ingredient with polyethylene glycols »

The following regulations are intended to facilitate the manufacture of Explain tablets and dragees in more detail:

009841/1933 BATH

20U479

a) 1000 g of 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] heptanoic acid v.-earth mixed with 550 g of lactose and 292 g of potato starch, the mixture with an alcoholic solution of 8 g of gelatin moistened and granulated through a sieve. After drying, mix 60 g of potato starch, 60 g of talc and 10 g of magnesium tearat and 20 g of highly disperse silicon dioxide and press the mixture into 10,000 tablets, each weighing 200 mg and ICO mg Active ingredient content, if desired with partial notches for the finer Adjustment of the dosage can be provided.

b) 100 g of 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] heptanoic acid are made with 16 g! -! Silica mixed well. The mixture is mixed with a solution of 2 g stearic acid, 6 g ethyl cellulose and 6 g stearin in approx. 70 ml of isopropyl alcohol moistened and granulated through a sieve III (Ph. HeIv. V). The granulate is dried for about 14 hours and then beaten through sieve II-IHa. Then it becomes 16 g Corn starch, 16 g talc and 2 g magnesium stearate mixed and added 1000 tablet cores pressed. These will be focused with a Syrup of 2 g of lacca, 7.5 g of gum arabic, 0.15 g of coloring, 2 g of fumed silica, 25 g of talc and 53/35 g of sugar oversaturated and dried. The coated tablets each weigh 260 mg and each contain 100 mg of active ingredient.

c) The following instructions are intended to explain the production of suppositories in more detail:

009841/1933 BADO9K5WAL ■■

One prepares a Suppositorieninasse of 10.0 g of 2- [p- (l, 2, 514-tetrahydro-1-naphthyl) phenoxy] -heptanoic acid and 163.5 g Adeps solidus and poured into 100 suppositories each with 100 mg of active ingredient.

The following examples explain the preparation of the compounds of general formula I and salts thereof in more detail, but are not intended to restrict the scope of the invention in any way. The temperatures are given in degrees Celsius. When naming the compounds shown, the alkyl radicals that deviate from the normal, unbranched chain are identified by information v? Ie secondary, tertiary or iso- alkyl . If this information is missing, the normal, unbranched remainder is always meant.

0098A1 / 1933

bad oäfäitfÄEö ms

201U79

example 1

4.48 g (0.02 mol) of p- (1,2,3,4-tetrahydro-1-naphthylphenol) are added to a solution of 0.46 in a round bottom flask equipped with a reflux condenser, dropping funnel, potassium hydroxide drying tube, stirrer and gas inlet tube g (0.02 mol) of sodium in 35 ml of absolute ethanol under nitrogen. An ethanolic solution of the sodium salt of 2-bromoheptanoic acid prepared in the same way is added dropwise to the resulting solution of the substituted sodium phenolate with stirring [from 4.2 g ( 0.02 mol) 2-bromo-heptanoic acid, 0.46 g (0.02 mol) sodium, 80 ml absolute ethanol] and refluxed for 8 hours, then the reaction mixture is freed from solvent in vacuo and taken up in water. The oil which precipitates out after acidification of the aqueous solution with concentrated hydrochloric acid is taken up in ether. The aqueous phase is extracted repeatedly with ether, the combined ethereal solutions are dried after washing with water over magnesium sulfate and the solvent is evaporated off in vacuo - [p- (l, 2, 3,4-Tetrahydro-1-naphthyl) -phenoxy] -heptanoic acid, which is in the form of oil and is mainly still contaminated with p- (1,2,3,4-tetrahydro-1-naphthyl) -phenyl, is column chromatography [silica gel 0.05-0.2 mm Merck, solvent benzene-glacial acetic acid (90:10)]. The solid residue obtained after evaporation of the pure fractions is recrystallized twice from pentane, 2.25 g (32 % of theory) of 2-ίp- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] - heptanoic acid with a melting point of 77-81 °.

009841/1933 BAD ORIQtNAL

In an analogous manner, starting from 4.48 g (0.02 mol) of p- (1,2,3,4-tetrahydro-1-naphthyl) ^ phenol were obtained:

a) with 3.62 g (0.02 mol) of 2-bromo-valeric acid the 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] valeric acid of melting point 125 ° -127 ° (from ether / pentane);

b) with 5.58 g (0.02 mol) of 2-bromo-dodecanoic acid the 2- [p- (1,2,3,4-tetrahydror-1-naphthyl)> phenoxy] ^

■ ι

dodecanoic acid with a melting point of 83-85 ° (from ether / pentane);

c) with 4.58 g (0.02 mol) of a-bromo-hydrocinnamic acid the

hydrocinnamic acid with a melting point of 146; 148 ° (from ether / pentane);

d) with 4.20 g (0.02 mol) of 2-brpm ^ isoheptanoic acid, 2- [ p- (1,2,3,4-tetrahydro-1-naphthyl) - ^ phenoxy] isoheptanoic acid with a melting point of 107> 109 ° (from ether / pentane), |

0098417 1933

201U79

At game l 2

a) In a round bottom flask equipped with a stirrer, reflux condenser with calcium chloride drying tube and dropping funnel, 40 ml Section. Given ethanol and 0.945 g (0.041 mol) of "atrium" for production of sodium ethanolate. To the solution obtained a solution of 9.2 g (0.041 mol) of p- (l, 2,3 »4-tetra ~ hydro-1-naphthyl) phenol is then added and then added 12.6 g (0.041 mol) of 2-Bro.Ti-dodecaiiGäure-EthyleGter were slowly added dropwise. After the end of the dropwise addition, the reaction mixture becomes boiled under reflux for another 3 hours. Then it is in a vacuum evaporated and the residue partitioned between water and ether. The ether phase is washed with water to pH = 7, over Sodium sulfate dried and evaporated. The residue is in High vacuum fractionated. The 2- [p- (1,2,3,4-tetrahydro-l-r: aphthyl) -phenoxyj-dodecanoic acid ethyl ester distilled at 194-196 / 0.005 torr. (Bath temperature 245-250 °). Yield 11.6g, 62.7> 6 der Theory.

b) The whole amount of the ester obtained above becomes added to a solution of 3.36 g of potassium hydroxide in 120 al of methanol and refluxed for an hour. The mixture is evaporated in vacuo, the residue is taken up in va3ser and this solution with conc. Acidified hydrochloric acid. That also divorced Oil is dissolved in ether, the ethereal solution with water washed and dried with sodium sulfate. After evaporation

009841/1933

BADORfQINAL

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a partially crystallizing oil is obtained in vacuo. Crystallization from ether-pentane gives 2- [p- (1,2,3,4-tetrahyclro-1-naphthyl) phenoxy] clodecaric acid from 3mp. 83-85. Yield 9, £ 'g, 84.4 # d. Th.

Analogous to a) and b), but without purifying the analogous to a) esters produced are obtained (yield can over both stages);

from 4.2. β (0.019 mol) p- (l, 2,3; 4-tetrahydro-i-naphthyl) -phenol ■ and-Λ, 65 β (0.0? col) 2-brroni-heptanoic acid ~ ethyl ester 2.9 g ( 41.355 theory) of 2- [p- _(t l 2,3,4-Tetrahyurü-l-naphthyl) -phenoxy3 - heptansiiurc, SINP. 77-81 ° (from fentan);

from 4.49 β (0.02 I-iol) p- (1,2,3,4-tetrahydro-1-naphthyl5-phenol and 4.74 β (0.02 hol) 2-bromo-isoheptanoic acid-ethyl3ter J. ₁ A g (43, 4 ^ ά .. Th.) 2- [p- (1,2 ₁ 3,4-Tetrahydrp-1-naphthyl) -phenoxy] -isoheptanic acid, Sap. 107-109 ° (from ether Pentane); (j

from 11.21 Q "(0.05 Hol) p- (l ₎ 2,3 * 4-Tetrahy, Iro-1-naphthyl) -phenol and 10.45 β (0.05 mol)" 2-3rom-valeriar .5liure-Uthylester 4.6 g (28.4 ^ of theory) 2-iP- (1,2,3,4-Tetrahydrc-1-: - iaphthyl) -henoxy] -valeric acid, m.p. 125-127 ° (from Aether-rentar.);

from 9.0 g (0.04 mol) of P- (1,2,3,4> -tetrahydro-1-naphthyl) -phei: ol and 11.3 B (0.044 mol) of a-broni-hydroci: ~ tP acid ethyl ester 1.1 g (6.7> i d.Th.) a- [p- (l, 2,3,4-tetrahydro-l-naphthyl) -phenozy] -hydro?, in} t acid vos.Snp . 146-145 ° (from ether-pentane).

0Q9841 / 1933 BAt

- i. \ J -

201U79

Example 3

3.33 g (0.01 mole) 2- [p- (1,2,3,4-tetrahydro-inaphthyl) phenoxy] heptanoic acid nitrile are in a solution of 3.5g potassium hydroxide in 100 ml of ethanol and 25 ml of water Boiled under reflux for 40 hours. Then the solution is with. 2-n. Hydrochloric acid acidified, the ethanol evaporated in vacuo and the remaining aqueous phase extracted with ether. The extract is washed twice with water, with magnesium sulfate dried and the ether evaporated in vacuo. The so obtained crude 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] heptanoic acid is recrystallized from ether / pentane. M.p. 77-81 °.

The 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] heptanoic acid nitrile used as the starting material can be represented as follows:

In a round bottom flask equipped with a stirrer, reflux condenser and ^ KOH drying tube, 70 ml of abs. Submitted dimethylformamide and added 1.44 g (0.03 mol) of sodium hydride dispersion 50% in mineral oil, and 6.73 g (0.03 mol) of p- (1,2,3,4-tetrahydro-1-naphthyl) phenol. After slight warming and evolution of gas, the mixture is stirred for 2 hours at room temperature. 5.7 g (0.03 mol) of 2-eromheptanoic acid nitrile are added dropwise to the resulting solution and the mixture is then stirred at 90 ° for 4 hours. The reaction mixture is poured onto ice, acidified with KCl to pH - 1 and extracted with ether. The ether phase is washed with water to pH = 7, dried over sodium sulfate and evaporated .

009841/1933

BÄD0RK3INAL

. 20U479

The oily residue is chromatographed over 250 g "Merck" silica gel 0.05 0.2 tnm in benzene. The pure fractions contain 5.4 g of 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy]

24 ° heptanoic acid nitrile = 54% of theory. n _ß : 1.553-

Example 4 I.

A solution of 3.51 g (0.01 mol) of 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxyl-heptanoic acid amide and 1.5 g of potassium hydroxide in a mixture of 120 ml of methanol and 12 ml of water is refluxed for 20 hours and then evaporated to dryness. The residue is suspended in water with 2-n. Hydrochloric acid acidified and with Aether extracted. The extract is washed with water, dried with magnesium sulfate and the ether is evaporated off in vacuo. The obtained 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) - | phenoxy] -heptanoic acid melts out after recrystallization Ether-pentane at 77-81 °.

The 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy) -heptane-mureamide used as starting material can be obtained according to the following rule:

009 84 1/1933

BÄD0RH3INAI.

20U479

In a round bottom flask with a reflux condenser, potassium hydroxide Drying tube and gas inlet tube are added (4.48 g (0.02 mol) of p- (1,2,3,4-tetrahydro-1-naphthyl) phenol to a Solution of 0.46 g (0.02 mol) sodium in 35 ml abs. Ethanol under nitrogen. To the solution of the phenolate thus obtained a solution of 7.02 g (0.02 mol) of 2-chloro-heptanoic acid amide (Vandewijzer, Bl.Soc.Chim.BeIg. 45 [1936], 252, 255) in 80 ml of abs. Ethanol and reflux for 8 hours. Then the reaction mixture is in vacuo freed from the solvent and taken up with water. That crude amide is taken up with chloroform. The chloroform solution is three times with 0.5-n. Soda lye shaken out, then dried with magnesium sulfate and the chloroform is distilled off. The residue is recrystallized from ethanol. 5.60 g (79% of theory) of pure amide with a melting point of 130-132 ° are obtained.

0098A 1/1 93 3

BAO / .QBtGINAL '

201U79

Example 5

In a round bottom flask equipped with a reflux condenser and stirrer, 0.8 g (1.5 mol) of 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy 1-2- • decylmalonic acid diethyl ester were added in a mixture from 2 ml 5-n. Sulfuric acid and 10 ml of glacial acetic acid are boiled under reflux for 24 hours * After cooling, the reaction mixture is poured onto KO ml of ice water, a milky, cloudy emulsion being formed. Extract with benzene, wash the benzene solution with water and dry it over sodium sulfate. Wrong after evaporation; 0.6 g of crude 2- (p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] dodecate acid remain as a yellow oil which crystallizes from hexane. After recrystallizing twice from He:; the pure acid is in the form of white crystals with a melting point of 83-85 ° ^C. Yield 0.47 g, 12.2% of theory.

In an analogous way the following are obtained:

from 0.68 g (1.5 m mol) of 2- [p- (1,2,3 ^ 4-tetrahydro-l-naphthol i thyl) phenoxy 1-2-pentyl-malonic acid diethyl ester 0.3A g (65% of theory ) 2-Ip- (1,2,3,4-tetxahydro-1-naphthyl) -phenoxy] -heptanoic acid of m.p. 77- ^r (from ether / pentane);

from 0.64 g (1.5 m mol) of 2-Ip- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxyl-2-propyl-malon :: uredi :: thylester 0.33 g (68% of theory) 2 - Ip- (1,2,3,4-Tetra * nydro-l-naphthyl) -phenoxyl-valeric acid from Snip. 125 "127 ^ί (from ether / pentane).

0098 41/1

20-479

The representation of the substituted diethyl malonate used as the starting material is shown below for the 2- (p- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy] -2-pentyl-malonic acid diethyl ester described. The other starting materials can be obtained analogously.

In a round bottom flask with a reflux condenser, dropping funnel, Potassium hydroxide drying tube, stirrer and gas inlet tube one adds 2.24 g (0.01 mol) of p- (1,2,3,4-tetrahydro-1 naphthyl) phenol to a solution of 0.23 g (0.01 mol) Sodium in 50 ml abs. Ethanol under nitrogen. In the solution of the substituted sodium phenolate thus obtained 3.09 g (0.01 mol) of 2-bromo-2-pentylmalonic acid diethyl ester are added dropwise with stirring and reflux for 10 hours. The reaction mixture is evaporated in vacuo and distributed the residue between water and ether. After washing with water and drying with magnesium sulfate, the Ether solution, which gives 4.4 g of a yellowish oil. This oil is purified by column chromatography [Silica gel 0.05-0.2 mm Merck, solvent benzene-ethanol (95: 5)] · The fractions containing the desired ester are combined and evaporated. IJjch drying in a high vacuum receives 2.8 g (61.9% of theory) of pure 2-fp- (1,2,3,4-tetrahydro-l-naphthyl) -phenoxy] -2-pentyl-malonic acid-

2 (D

20 ° diethyl ester, a yellowish gel; n _n : 1.5246.

009841/1933
BATH

'20Ί-Α4 "7

Analogously one obtains:

from 2.24 g (0.01 mol) p- (1,2,3,4-tetrahydro-lnaphthyl) -phenol and 2.81 g (Q, oil Hol) 2-bromo-2-pr, opylmalonic acid diethyl ester 1.1 g, 26 , 0 % of theory, 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy] -2-propyl-malon-

20 °
acid diethyl ester; n _D : 1.5348;

from 2.24 g (0.01 mol) of p- (1,2,3,4-tetrahydro-lnaphthyl) -phenol and 3.8 g (0.01 mol) of 2-bromo-2-decylmalonic acid diethyl ester 3.2 g, 61.2% of theory, 2- Ip- (1,2,3,4-Tetrahydror.l-naphthyl) -phenoxy] -2-decyl-

20 °
malonic acid diethyl ester, n ~: 1.5190.

009841/1933
BATH

. 26th

201U79

Example 6

2.8 g (0.0062 mol) of 2- | p- (1,2,3,4-tetrahydro-inaphthyl) -phenoxy] -2-phenyl-rnalonic acid diethyl ester are dissolved in a solution of 2.8 g of potassium hydroxide in 50 ml of methanol 6 Boiled under reflux for hours. After the solvent has evaporated in vacuo, the residue is dissolved in 100 ml of water and washed with ether. The aqueous solution is then concentrated to 50 ml, acidified by adding 50 ml of concentrated hydrochloric acid and the precipitate which has precipitated out is brought into solution by adding ethanol. The clear solution is refluxed for 5 hours and then the ethanol is distilled off, the roae 2-fp- (1,2,3,4-Te traiiydr o-i-naph thy 1) -phenoxy] -hep tans'- '.ure crystalline deposited. Yield 1.55 g (Jb% of theory). Mp. 77-ol ° (from ether / pentane).

The following were obtained in an analogous manner:

from 2.0 g (0.00472 mol) 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] -2-propyl-r.alone '; acid diethyl ester 1.21 g (80.5 % of theory) 2- [p- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxy] -valeric acid from Snp. 125-127 ° (from ether / pentane);

from 2.0 g (O, OO3ö2 mol) 2- [p- (1,2,3,4-tetrahydro-1-naphthy]) -phenoxy] -2-decyl-rnalonic acid dietl / yl ester 1.20 g (74.3 % of theory) 2- [p- (L, 2,3,4-tetrahydro-1-naphthylyl) -phericucy] -dodecanoic acid from Si'ip. 83-85 °.

009841/1933

BATH

201U79

Example 7

3.96 g (O, Ol mol) of 2- [p- (l, 2,3,4-tetrahydro-lnaphfchyl) -phenoxy-2-pentyl-inalons'äure ^c are heated for 20 minutes under stirring to 140th The crude 2-Ip- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy-1-heptanoic acid obtained in this way is purified by column chromatography [silica gel 0.05 0.2 mm Merck, solvent benzene-glacial acetic acid (h5: 15)]. The fractions containing the desired acid are combined and evaporated in vacuo. F; after I twice

Recrystallization from Pentaη gives 3.45 g (87 % of theory) of pure 2-Ip- (1,2,3,4- ^r retrahydro-l-iiaphthyI) -phenoxy] -hcp "tanic acid from Srap. 77-Fl ^c .

Analogously one obtains from:

3.96 g (0.01 mol) of 2-lp- (1,2,3,4-tetrahydro-inaphthyl) pheno>; y] -2-isopentyl-iT! Alonic acid 3.20 g (81 % of theory) 2- [ p- (1,2,3,4-Tetralwdro-1-naphthy1) -phenoxy] -isoheptane-acid of melting point 107-109 (from ether / pentane); '

3.68 g (0.01 mol) 2-lp- (1,2,3,4-tetrahydro-l-naphthyl) phenoxy] -: N-propyl-ir _: alonsate 2.75 g (85% of theory) 2- Ip- (1,2 , 3j4-Tetrahydro-1-naphth; hyl; -ur.enoxy] -valeric acid of m.p. 3 25-127 ° (from ether / pentane);

. 009 8 417.lij3.3

201U79

4.66 g (0.01 mol) 2-Ip- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxy J-2-gecyl-malonic acid 3,9Og (84 % of theory) 2- [ρ- (1, 2,3,4-tetrahydro-1-naphthyl) phenoxy J-dodecanoic acid with a melting point of 83 ° -85 ° (from ether / pentane);

4.16 g (0.01 mol) 2- [p- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxy] -2-benzyl-malonic acid 3.7Og (89 % of theory) α- [ρ- (1,2,3,4-Tetrahydro-l-naphthyl) -phenoxy] -hydrocinnamic acid of m.p. 146-148 ° (from ether / pentane).

The representation of the starting materials is subsequently for 2- (p- (1,2,3,4-tetrahydro-1-naphthyl) -phenoxy] -2-pentyl-malonic acid described in detail. The other substituted malonic acids are represented analogously will.

2.24 g (0.01 mol) of p- (1,2,3,4-tetrahydro-1-naphthyl) are added to a round bottom flask with reflux condenser, dropping funnel, KaliuT.hydro :: id drying tube, stirrer and gas inlet pipe . -phenol 2u a solution of 0.23 g (0.01 mol) llatriurr. in 50 ml abs. Ethanol 'under nitrogen. 3.09 g (0.01 mol) of 2-Brctri-2-pentyl-inalons-diethyl ester are added dropwise with stirring to the solution of the substituted sodium phenolate obtained in this way, and the mixture is refluxed for 10 hours. The reaction mixture is evaporated in vacuo and the residue is distributed

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"Γ ¹ 29 - ■ :.. '.

201U79

between water and ether. After washing with water and drying with magnesium sulphate, the ethereal solution is evaporated to give 4.4 g of a yellowish oil. This ¹ oil is purified by column chromatography (silica gel 0.05-0.2 mm Merck, solvent benzene-ethane oil. (95: 5)]. The fractions containing the desired ester are combined and evaporated. After drying in a high vacuum, 2.8 g (61.9% of the Theory) pure 2- [p- (1,2., 3,4-tetrahydro-1-naphthy1) phenoxy] -2-pentyl-

20 ° ι

dlethyl malonate, a yellowish oil; n _D : 1.5246.

2.8 g (0.0062 mol) of 2- [p- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxy, 1-4 -pentyl-malonic acid diethyl ester are in a solution of 2.8 g of potassium hydroxide in 50 ml of methanol and boiled 5 ml of water under reflux for 6 hours. After evaporation of the solvent in vacuo, the residue becomes dissolved in water and washed with ether. The aqueous phase is acidified with concentrated hydrochloric acid and i extracted. After the ethereal solution has been dried over magnesium sulphate, it is evaporated in vacuo and the resulting solution crude 2- [p- (1,2,3,4-tetrahydro-1- naphthyl) -phenoxy] -2-pentyl-malonic acid used for decarboxylation without further purification.

009841/1933 BAD © Μ «

- rj -

Example 8

1.05 g (0.0025 mol) of 2- [ρ- (1,2,3,4-tetrahydro-lnaphthyl) -phenoxy] -dodecanoic acid are dissolved in 20 ml of methanol. 0.1 g (0.0025 hol) of carbonate-free sodium hydroxide is added to this solution and evaporated to dryness. The oily residue is triturated with ether, the crude sodium hydroxide salt being obtained in solid form. It is sucked off and washed intensively with ether. This gives 0.95 g (86.0 % of theory) of pure ITatriur salt which is slightly hygroscopic and decomposes between 260 ° -320 ° with a gradual brown color.

Analogously one obtains:

from 0.85 g (0.0024 mol) 2- [p- (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] heptanoic acid 0.87 g (96.5 % of theory) pure sodium salt of the 2- [ _P - (1,2,3,4-tetrahydro-1-naphthyl) phenoxy] heptanoic acid of m.p. 308-311 °.

009841/1933

201U79

Example 9

30 rag (0.75 tnmol) of calcium are decomposed in 5 ml of water under nitrogen. 52B mg (1.5 tri-iol) 2- [p- (1, 2/3, A-tetrahydro-1-naplrthyl) -phenoxy] -heptanoic acid in 50 ml of methanol are added to the calcium hydroxide suspension thus obtained Heated under reflux for 15 minutes, then the solvent is reduced to approx. 10 ml in vacuo concentrated, the calcium salt which crystallizes out is filtered off and treated with 60? .- ige: v. Check for methanol. > After drying in a high vacuum, 510 mg (91.6 % of theory) of pure calcium salt of 2- [p- (1,2,3,4-tetrahydro-l-naphthyl) phenoxy] heptanoic acid, which is between 26% 2oO ^c melts with decomposition.

009841/1933
BATH

Claims (7)

Claims ../ Process for the production of new, substituted Iryloxyessigsäumn of the general formula I, R.
I.
0 - CH - CO - OK (D in which R is an alkyl group having 3 to 10 carbon atoms or the benzyl group means and their alkali and bradalkali salts, characterized in that the3 man. an alkali metal salt of p- (1,2,3,4-? -etrahydro-lnaphthyl) -phenol with a salt with respect to the carboxyl group, a reactive ester with respect to the 2-hydroxy group a compound of the general formula II, R.
HO - CH - CO - OH (II) in which R has the meaning given under formula I, converts, desired casen from the initially obtained salt of a Carboxylic acid of the general formula I releases the latter and If necessary, the free carboxylic acid or, by double 009841/1933 - 33 -. 201 U79 Put directly the salt initially obtained in or in a different alkali or alkaline earth salt transferred. 2. Modification of the method according to claim 1, characterized characterized in that one is a functional derivative of a carboxylic acid the general formula I given in claim 1, in which R has the meaning defined there, hydrolyzes, if desired liberates the carboxylic acid from a salt obtained and, if desired, this or directly the first er f held salt converted into or into another alkali or alkaline earth salt. · -. 3. Modification of the procedure according to claim. .1 -, - thereby characterized in that a substituted malonic ester of the general formula III O - C - COOR ₁ COOR ₁ in which . R, a lower alkyl group and R as defined in claim 1 has given meaning, in a hydrolyzing medium, heated until one of the esters * groups is hydrolyzed and instead of the other hydrogen is present. 009841/1933 4. Modification of the procedure gCiiJifjn claim 1, dadur characterized that nan is a dicarboxylic acid of general Formula 17, R.
0 - C - CO - OH CO - Oil (IV) in chalice Ii d: ie has the meaning given in claim 1, or an acidic alkali metal or alkaline earth metal salt thereof up to the point of cleavage the tiqui.TiOlaren "tight carbon dioxide is heated and the at Use of a free dicarboric acid obtained free conocarboxylic acid gev.i-hiBchtor.fall in an alkaline or alkaline earth caught. 5 »Substituted aryloxyacetic acids in the claim given iillgena formula I, in which R the given there Has meaning, as well as their alkali and alkaline earth salts. ~ * 35 " 20UA79 6. 2- [p- (l _f 2 _l 3,4-tetrahydro-1-naphthyl) phenoxy] -. heptanoic acid and its alkali and alkaline earth salts. _v . , 7. Pharmaceutical preparations for the treatment of hyperlipemic conditions, characterized by a content of at least one substituted arylcxycr has the meaning defined there, and / or an:;: Alkali or Srdalkalialn of such, in combination with an: inert carrier materials and, if necessary, further additives. J. R. G E I G Y Λ. Gi 00 9 8-1 / 19? 3