DE1801312A1 - Process for the preparation of a new aryloxyalkanoic acid and its salts - Google Patents

Description

br. Ir. Turnsiein - Dr. E. Assmann

Dr, R. Kcenigsberger

Dipl. Phys. R. Hofzbauer

Palenianwä'fe

2, iBräRhausslQfiC ^ fIIlG γ A. G. BASEL 21 1801312

4-2695 *

Process for the preparation of a new aryloxyalkanoic acid

and their salts

The present invention relates to a process for the preparation of a new arylor.yalkanoic acid and its salts with value full pharmacological properties, these compounds as new substances, pharmaceutical preparations containing them and their use.

The 2- (4-biphenylyloxy) -heptanoic acid of the formula I,

O - CH - CO - OH

and their salts with inorganic and organic bases have not yet been described. As has now been found, this acid and its salts have valuable pharmacological properties. In particular, they show hypolipemic activity in the broad sense, which can be demonstrated, for example, in the lowering of cholesterol and triglyceride levels in the blood and liver after repeated oral administration to male rats. The extraction of serum and liver lipids is carried out according to Folch, J.Bioi. Chem, 226 , 497 (1957). The triglyceride; are after Kessler and

9098 1 9/1242

Lederer, Technicon Symposia, Vol I (1965) and cholesterol according to Block et al., Technicon Symposia, Vol I (1965) with the Autoanalyzer, certainly.

The 2- (4-biphenylyloxy) -heptanoic acid and its salts are further characterized by a long and low residence time in the plasma Toxicity. They are suitable for oral and rectal administration in mammals for the treatment of hyperlipemic conditions such as hypercholesterolemia.

To produce 2- (4-biphenylyloxy) -heptanoic acid and its salts, a functional derivative of the same is hydrolyzed, if desired, releases the acid from a obtained salt and / or leads a obtained acid or, by doubling it Implementation of the salt initially obtained directly into a salt or another salt with an inorganic or organic one Base over. As functional derivatives of 2- (4-biphenylyloxy) heptanoic acid are, for example, their esters of the general formula II,

CHr ₁ "CHr," CHo-CHr ₁ "CH

ry O11 / -J UilA vjlln

O-CH -CO-O-R

(H)

in which

R is a hydrocarbon radical, in particular a lower alkyl radical, the cyclohexyl, phenyl or benzyl radical.

909819 / 12A2

There are also, for example, the nitriles, amides and lower imidoalkyl esters into consideration. The hydrolysis takes place, for example, by heating in alkanolic or aqueous-alkanolic Alkali hydroxide solutions. From the alkali · salt solutions of 2- (4-biphenylyloxy) -heptanoic acid initially obtained, either The corresponding pure alkali salt can be obtained directly by concentration or evaporation and recrystallization, or initially release the acid, then clean it e.g. by recrystallization and, if desired, again in a salt with a convert suitable inorganic or organic base. Let functional derivatives of 2- (4-biphenylyloxy) heptanoic acid It can also be used in an acidic medium, e.g. by heating in a mixture of 60-707 ° sulfuric acid or in a more aqueous alkanol Hydrochloric acid, converted into the free acid.

The esters of the general formula II as well as the corresponding nitriles, amides and lower imidoalkyl esters are for their part, new connections. To prepare the esters of the general formula II, an alkali metal salt of p-phenylphenol is used with a reactive ester with respect to the 2-hydroxy group of a 2-hydroxy-heptanoic acid ester5. the general formula III,

CH ₀ -CH ₀ -CH ₀ -CH ₀ -CHo

J L Δ Δ Z j

HO - CH - CO - O - R ₁ (HI) in which R-, has the meaning given under formula I, in

909819/1242

a suitable solvent, such as in ethanol at its boiling point or in dimethylformamide at 40-130 °, preferably 60-90 ° to. The required alkali metal salt of p-phenylphenol can be used as such or before the reaction in situ, in ethanol, e.g. by means of the corresponding alkali metal ethylate or in dimethylformamide with the help of a suitable alkali metal hydride j in particular sodium or lithium hydride, getting produced.

As reactive esters with respect to the 2-hydroxy group of compounds of the general formula III come, for example, halides, i.e. esters of 2-haloheptanoic acid, as well as Arenesulfonic acid and alkanesulfonic acid derivatives, such as 2- (4-toluenesulfonyloxy) - and 2-methanesulfonyloxy-heptanoic acid ester, into consideration. Individual such compounds, e.g. ethyl 2-bromoheptanoate, are known; others are analogous to the known compounds and / or corresponding derivatives of lower alkanoic acids can be produced. Analogous to the reactive esters of compounds of the general formula III reactive esters of 2-hydroxyheptanoic acid nitrile, e.g. the well-known 2-bromo-heptans'aurenitrile, with alkali metal salts of the p-Pheny! phenol implement. The obtained nitrile of 2- (4-biphenylyloxy) -heptanoic acid is either used directly Hydrolyzed acid or, if desired, in a manner known per se Way into the corresponding amide or a lower imidoalkyl

9038 19/1242

ester or its hydrohalide, ie converted into further starting materials suitable for hydrolysis to 2- (4-biphenylyloxy) heptanoic acid or its salts.

The nitrile and the amide of 2- (4-biphenylyloxy) -heptane. acids can also be derived from lower (4-biphenylyloxy) -n-pentylcyanoacetic acid alkyl esters, the production of which is explained below. By partial hydrolysis with an approximately equimolar amount of an aqueous or alkanolic alkali hydroxide solution, acidification and decarboxylation the desired nitrile is obtained. When boiling the said substituted alkyl cyanoacetate with excess alkanolic acid Alkali and acidification form the monoamide of the substituted malonic acid, optionally in a mixture with the free, substituted malonic acid and the desired end product 2- (4-biphenylyloxy) heptanoic acid of the formula I. By Decarboxylation gives the amide of 2- (4-biphenylyloxy) heptanoic acid or a mixture of the same with the free acid, which is the same as the pure amide in the uniform end product can be transferred.

According to a second method to set the 2 ~ (4-yloxy Biphen3 ^r) -heptans2irre and their salts prepared by mixing a functional derivative of (4-biphenylyloxy) -n-pentyl-malonic acid, especially a lower dialkyl esters, further comprising a lower Nitrilalkylester ode .: the dinitrile, heated with an inorganic or organic base until the equimolar amount of carbon dioxide is split off and, if desired, from the obtained

909819/1242

Salt of 2- (4-biphenylyloxy) -heptanoic acid releases the acid and converts the latter or the initially obtained salt into a salt or transferred to another salt with an inorganic or organic base. For example, dialkyl (4-biphenylyloxy) -n-pentylmalonic acid is boiled with excess alkanolic caustic solution, e.g. with methanolic caustic potash solution, for a few hours Reflux, the conversion of the nitrile-alkyl esters and the dinitrile becomes analogous, but under more energetic conditions, e.g. with longer reaction times and / or at a higher temperature carried out in a closed vessel.

The lower dialkyl esters, the nitrile alkyl esters and are the dinitrile of (4-biphenylyloxy) -n ~ pentyl-ioalonic acid, like this acid itself, new compounds »They can be, for example, analogous to the esters of the general. Formula III by reacting bromine or chlorine-n-pentyl-maTonic acid dialkyl esters or -cyanoacetic acid alkyl esters or bromo-pentyl-malonitrile with alkali metal salts of p-phenyl-phenol, e.g. in boiling abs. Ethanol. The bromine or chlorine compounds required for this are made, for example, by halogenation analogous to corresponding, known "compounds with a lower alkyl group, e.g. the bromo-n-butyl-malonic acid diethyl ester IJ.Am.Chem.Soc. 44, 1578-1581 (1922) 1.

909819/1242

A third process for the preparation of 2- (4-biphenylyloxy) -heptanoic acid and its salts is characterized in that the (4-biphenylyloxy) -n-pentyl-malonic acid or an acidic salt thereof with an inorganic or organic base, in particular a monoalkali metal salt thereof, heated until the equimolar amount of carbon dioxide is split off and the acid obtained when using the free dicarboxylic acid is, if desired, converted into a salt with an inorganic or organic base. For example, the dicarboxylic acid mentioned is heated to temperatures between 130-200 ° until the evolution of carbon dioxide has ended. The 2- (4-biphenylyloxy) -malonic acid is produced, for example, by hydrolysis of its lower dialkyl esters or from corresponding nitrile-alk? / L esters, ie (4-biphenylyloxy) -n-pentyl ^v -malonic acid dialkyl esters or (4-biphenylyloxy) - n-pentyl-cyanoacetic acid alkyl ester, obtained with alkanolic or aqueous-alkanolic potassium hydroxide solution or sodium hydroxide solution at moderately elevated temperatures and subsequent acidification Nitrile alkyl esters as well as, for example, dinifril, with a water-containing mineral acid, the dicarboxylic acid formed by hydrolysis under the reaction conditions directly to 2- (4-biphenylyloxy) -heptane

909819/1242

acid is decarboxylated. Used as a hydrous mineral acid for example 60 ~ 70% sulfuric acid or, in a closed vessel, concentrated hydrochloric acid, which is a organic, water-soluble or water-miscible solvent with a suitable boiling point, e.g. acetic acid, at- ' can be joined.

Another process for the preparation of 2- (4-biphenylyloxy) -heptanoic acid and its salts consists in treating an alkali metal salt of p-phenylphenol with a salt of a reactive ester with respect to the 2-hydroxy group of 2-hydroxyheptanoic acid, if desired from the obtained salt of 2- (4-biphenylyloxy) -heptanoic acid releases the acid and / or, if desired, the latter or through double conversion, the salt initially obtained directly into a salt or another salt with an inorganic or organic one Base transferred. The reaction is preferably carried out in a solvent or diluent, e.g. in a lower, optionally, water-containing alkanol, such as ethanol or butanol, or carried out in dimethylformamide at a temperature of about 80 ° to the boiling point of the reaction medium. The education the salts required as direct reaction components from the free ρ-pheny! phenol or the free acid takes place preferably in situ, e.g. by adding an alkali metal alcoholate, an alkali hydroxide or alkali metal hydride.

909819/1242

depending on the reaction medium used is an anhydrous alkanol, a water-containing alkanol or dimethylformamide. As reactive esters of 2-hydroxy-heptanoic acid come e.g. halides, arenesulfonic acid esters and alkanesulfonic acid esters in question, known examples are 2-bromoheptanoic acid and 2-chloro-heptanoic acid.

As salts of 2- (4-biphenylyloxy) heptanoic acid to be prepared if desired those whose cations are generally suitable for use as therapeutic agents in the dosages in question has no or a desired biological intrinsic effect and its solubility ensures sufficient absorption in the stomach and intestinal contents. Salts that do not meet these requirements, but, for example, can crystallize well, possibly in the course of the purification of the acid or of useful for other salts. Salts of 2- (4-biphenylyloxy) heptanoic acid which can be prepared according to the invention are particularly suitable the alkali metal salts, such as the potassium salt, the lithium salt and, above all, the sodium salt, and also alkaline earth metal salts and earth metal salts, such as the 3 calcium salt, the magnesium salt or the aluminum salt, further the ammonium salt, Salts with primary, secondary or tertiary aliphatic or isocyclic bases and secondary or tertiary heterocyclic bases, such as ethylamine, tri-

909819/1242

ethylamine, 2-aminoethanol, 2,2 ^5- iminodiethanol, 2 »dimethylaminoethanol, 2-diethylaminoethanol, ethylenediamine, benzylamine, p-aminobenzoic acid diethylaminoethyl ester, pyrrolidine, piperidine, morpholine, 1-ethyl ! piperidine, 2-piperidinoethanol, and salts with basic ion exchangers. The salts are generally prepared by combining acid and base in suitable solvents, such as, for example, methanol, optionally filtering off the precipitated salts or evaporating the salt solutions. Corresponding soluble carbonates, for example sodium or potassium carbonate or bicarbonate, can also be used instead of free bases. Furthermore, salts which are relatively sparingly soluble in the solvent used can also be prepared by double reaction of another salt of the acid with a suitable salt of the base.

2- (4-Biphenylyloxy) -heptanoic acid and its salts are as mentioned above, administered orally or rectally. The daily doses range between 50 and 500 mg for adult patients. Suitable dosage unit forms such as dragees, tablets, suppositories contain as active ingredient preferably 10-250 mg, e.g. 50 or 100 mg of the acid or a salt thereof with a pharmaceutically acceptable one inorganic or organic base.

In unit dose forms for oral use, the content of active ingredient is preferably between 10% and

909819/1242

90%. Combined to produce such unit dose forms the active ingredient e.g. with solid, powdery! Carriers, vjie lactose, sucrose, sorbitol, mannitol; Starches such as potato starch, corn starch or amylopectin, as well as laminar powder or citrus pulp powder; Cellulose derivatives or gelatine, optionally with the addition of lubricants such as magnesium or calcium stearate or polyethylene glycols Tablets or dragee cores, the latter, for example, is coated with concentrated sugar solutions, which e.g. still contain arabic gum, talc and / or titanium dioxide can, or with one in volatile organic solvents or solvent mixtures dissolved paint. Dyes can be added to these coatings, e.g. for identification different doses of active ingredients. AOs more oral Unit forms are suitable capsules made of gelatine as well as soft, closed capsules made of gelatine and a Plasticizers such as glycerin. The first contain the active ingredient preferably as granules mixed with lubricants, such as Talc or magnesium stearate, and optionally stabilizers, like NatriuTiraetabisulfit (Na ^ S ^ Ov) or ascorbic acid. In soft capsules, the active ingredient is preferably dissolved or in suitable liquids, such as liquid polyethylene glycols suspending · /, stabilizers also being added can.

90.9819 / 1242

As unit dose forms for rectal use For example, suppositories come into consideration, which consist of a combination an active ingredient with a suppository base based on natural or synthetic triglycerides (e.g. cocoa butter), polyethylene glycols or suitable higher fatty alcohols, and gelatin rectal capsules, which contain a combination of the active ingredient with polyethylene glycols.

The following regulations are intended to explain the manufacture of tablets and dragees:

a) 1000 g of 2- (4-biphenylyloxy) heptanoic acid are mixed with 550 g of lactose and 292 g of potato starch, the mixture moistened with an alcoholic solution of 8 g gelatin and granulated through a sieve. After drying, mix 60 g potato starch, 60 g talc and 10 g magnesium stearate

and 20 g of highly disperse silicon dioxide and compresses the mixture into 10,000 tablets, each weighing 200 mg and 100 mg Active ingredient content, if desired with partial notches finer adjustment of the dosage can be provided.

b) 100 g of 2- (4-biphenylyloxy) heptanoic acid are mixed well with 16 g of corn starch and 6 g of highly dispersed silicon dioxide. The mixture is mixed with a solution of 2 g of stearic acid, 6 g of ethyl cellulose and 6 g of stearin in about 70 ml of isopropyl alcohol moistened and through a sieve III (Ph.HeIv.V.)

909819/1242

granulated. The granulate is dried for about 14 hours and then passed through a H-IIIa sieve. It gets up to 16 g Corn starch, 16 g talc and 2 g magnesium stearate mixed and Pressed to form 1000 dragee cores. These are mixed with a concentrated syrup of 2 g lacca, 7.5 g gum arabic, 0.15 g of dye, 2 g of highly dispersed silicon dioxide, 25 g of talc and 53.35 g of sugar, coated and dried. The received Dragees 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:

A suppository mass is prepared from 10.0 g of 2- (4-biphenylyloxy) heptanoic acid and 163.5 g of Adeps solidus and uses it to pour 100 suppositories with 100 mg of active ingredient each. The following examples explain the preparation of 2- (4-biphenylyloxy) heptanoic acid and its salts, should However, in no way limit the scope of the invention. The temperatures are given in degrees Celsius.

909819/1242

example 1

10 g (0.031 mol) 2- (4-biphenylyloxy) -heptanoic acid-ethyl esters are mixed with 2.1 g (0.038 mol) of potassium hydroxide in 50 ml Methanol boiled under reflux for one hour. Then the solution is evaporated to a syrupy consistency and mixed them with water. This should result in a clear solution, otherwise the undissolved must be removed by washing with ether. Then the alkaline solution with 2-n. Acidified hydrochloric acid. The 2- (4-biphenylyloxy) -heptanoic acid falls first as OeI, that slowly; especially when rubbing on something It becomes methanol, crystallized, by recrystallization from methanol / water, from acetone / water or from hexane cleaned and then owns the Saip, 115-116 °.

The ester required as a starting material is as follows manufactured:

a) In one with stirrer, reflux condenser and potassium hydroxide The round-bottom flask containing the drying tube is dissolved 3.68 g (0.16 mol) of sodium in 150 ml of abs. Ethanol. Of the Sodium ethylate solution prepared in this way is 27.2 g (0.16 McI) powdered p-phenylphenol added and in the resulting Then solution of the sodium salt of p-phenylphenol 35 g (0.1475 mol) of ethyl 2-bromo-heptanoate dissolved. The reaction solution obtained is refluxed for 7 hours, during which potassium bromide separates out. The ethanol

909819/1242

is evaporated, the residue dissolved in ether and the solution as long as 0.5-n. Sodium hydroxide solution shaken out until an acidified sample of the alkaline extract is no longer cloudy. The ethereal solution is then shaken three times with 0.5-n. Sodium hydroxide solution and then with water, dry it over sodium sulfate and evaporate it. The ethyl 2- (4-biphenylyioxy) -beptane acid obtained is chromatographically pure. R _f = 0.9, Xiesel gel neutral, benzene: ethanol = 100:15.

Example 2

29.84 g (0.1 mol) of 2- (4-biphenylyloxy) heptanoic acid are dissolved in 200 ml of methanol. To the solution obtained 3.8 g (0.095 mol) of carbonaL-free sodium hydroxide are added and evaporates to dryness. The residue is extracted freed from the starting material with ether, whereupon the pure sodium salt remains, which does not melt up to 350 °.

Example 3

a) 1 g of 2- (4-biphenylyloxy) heptanoic acid nitrile (0.00358 Mol) are refluxed for 42 hours in a solution of 1 g of KOH in 35 ml of ethanol and 8 ml of Ussser. (According to this, in thin-layer chromatography, apart from the acid only to see spores on acid amide.) The reaction solution becomes with 2-n. Hydrochloric acid acidified> the ethanol in vacuo

BAD OBlSlNAL 909819/1242

evaporated and the aqueous phase extracted with ether and the ether washed twice with water. After drying with MgSO, the crude 2- (4-biphenylyloxy) -heptanoic acid is obtained from the ether phase, which is recrystallized from a benzene / gasoline mixture, melting point 115-116 °.

The 2- (4-biphenylyloxy) heptanoic acid nitrile used as the starting material is made as follows:

b) 57.0 g (0.5 mol) of ethyl cyanoacetate in 200 ml of abs. Dissolved ethanol. In order to avoid the temperature rising to over 60 °, 11.5 g (0.3 mol) of metallic sodium are only added to the solution in small portions. After about 2 hours, when the added metallic sodium has completely dissolved, 75.5 g (0.5 mol) of n-pentyl bromide are added dropwise at a temperature of 40-50 ° and the resulting mixture is then added for 2 hours Heated to reflux. ' ^: ·

After cooling to room temperature, the reaction mixture is poured onto a mixture of ice and water the separating oil taken up in ether and with water bis to the. washed neutral reaction. The ether solution obtained is dried over sodium sulfate, filtered and then.d evaporated in a rotary evaporator. Of the. Residue

9098 19/1242

Ί! ΙΙ '" ¹ Il'¹; !! ' Ijj ' ¹ ^ "ΝΙΙΙΙΙιΙϋιΊ ι' III ln |||| i, i: .. ΊΊ

is distilled in vacuo at an oil bath temperature of 140-150 °. The ethyl n-pentyl cyanoacetate boils at 117-119 ° / 12 torr.

c) In a flask equipped with a stirrer, reflux condenser and dropping funnel, 36.6 g (0.2 mol) of ethyl n-pentylcyanoacetate, 160 ml of H ₂ O, 20.5 g (0.25 mol) of sodium acetate and a spatula tip of phthalic monoperic acid are added and 32 g (0.2 mol) of bromine were added dropwise to this mixture at room temperature with thorough stirring. The reaction mixture is then heated at 60 ° for 2 1/2 hours and, after cooling, taken up with ether. The ether solution obtained is then washed successively with a dilute sodium bisulfite solution, dilute sodium bicarbonate solution and water until the reaction is neutral, dried over sodium sulfate, filtered and then evaporated in a rotary evaporator. The residue is distilled in vacuo.

The ethyl bromo-n-pentyl-cyanoacetate obtained boils at 122-124 ° / 10 torr.

d) In one with stirrer, dropping funnel and potassium hydroxide Round-bottom flasks containing the drying tube are 17.0 g (0.1 mol) of 4-hydroxybiphenyl in 350 ml of dimethylformamide dissolved at room temperature. 4.8 g (0.1 mol) of sodium hydride dispersion (50% dispersion in mineral oil) are added to this solution. added with stirring. After complete conversion to the sodium salt, 26.2 g (0.1 mol) of ethyl bromo-n-pentyl-cyanoacetate are obtained added dropwise at room temperature and the mixture

909819/1242

^{then heated to a temperature> T} on 60 ° for 1 hour while stirring on the water bath. After cooling down, the reaction mixture obtained is poured onto a mixture of ice and water, the oil which separates out is extracted with ether and washed with 1-n. Washed sodium hydroxide solution and water until neutral. The ether solution obtained is dried over sodium sulfate, filtered and then evaporated in vacuo. The residue is purified by column chromatography (silica gel (0.05-0.2 mm Merck), benzene as the solvent). After evaporation of the benzene and drying of the remaining residue, the 2- (4-biphenylyloxy) -n-pentyl-ethyl cyanoacetate obtained crystallizes out, melting point 56-59 °.

e) In a round bottom flask equipped with a magnetic stirrer 17.6 g (0.05 mol) of ethyl 2- (4-biphen.ylyloxy) -n-pentyl-cyanoacetate are obtained and 55 ml 1-n. NaOH stirred for 2 hours while warming to 80-90 ° (instead of aqueous 1N NaOH can also alcoholic 1-n. NaOH can be used). After cooling, the reaction mixture diluted with water is extracted with ether, the remaining aqueous phase is acidified with hydrochloric acid and the oil which has now separated out is taken up in ether and then washed with water. The obtained 2- (4-Bi ·· phenylyloxy) -n-pentyl-cyanoacetic acid is used as a crude product further processed.

909819/1242 ^BAD OMQfNAL

f) 12.9 g (0.04 mol) of 2- (4-biphenylyloxy) -n-pentyl-cyanoacetic acid and a trace of metallic copper powder are mixed well and carefully placed in a round bottom flask with the heated free flame. The evolution of carbon dioxide begins at a temperature of 120 °, and the temperature rises rapidly 190 ° increases. For complete decarboxylation, it is increased to 200 ° for a short time (approx. 1 min.). After cooling down, the Recrystallized residue from ethyl alcohol in the presence of animal charcoal. The obtained 2 ~ (4 ~ biphenylyloxy) -heptanoic acid nitrile melts at 68-70 °.

Example 4

a) 16 g (0.04 mol) of crude 4-biphenylyloxy-n-pentyl-malonic acid diethyl ester is refluxed for 18 hours in a solution of 5.4 g of KOH (85%) in 30 ml of methanol. After this Evaporation of the methanol in vacuo, the residue is dissolved in about 500 ml of ice water and the resulting solution with 10 ml of conc. Acidified hydrochloric acid. The precipitated colorless crystals are washed with water and dissolved in 200 ml of methanol. After filtration, the 2- (4-bipheriylyloxy) heptanoic acid is precipitated by adding water dropwise, mp 114-115 °.

The 4-biphenylyloxy-n-pentyl-malonic acid diethyl ester is made as follows:

909819/1242

b) To a solution of -1.15 g (0.05 mol) of sodium in 60 ml of abs. Ethanol is 8.5 g (0.05 mol) with the exclusion of COr 4-Hydroxy-biphenyl added. Become the solution obtained 15.45 g of bromo-n-pentyl-malonic acid dia'thyl ester are added and Heated to boiling under reflux for 7 hours. The alcohol is then evaporated off in vacuo and the residue is taken up in ether and three times with 0.5-n. Sodium hydroxide solution, and then shaken until neutral with water.

After drying, evaporation and chromatographic purification (silica gel Merck, 0.05-0.2 mm, eluent: Benzene) contains a yellow oil, n 25 - 1.5334.

Example 5

8 g of 4-biphenylyloxy-n-pentyl-malonic acid diethyl ester are in a mixture of 20 ml 5-n. Sulfuric acid and 100 ml of glacial acetic acid heated to boiling under reflux for 24 hours. After cooling, the reaction mixture is poured onto 800 ml of ice water, with the 2- (4-biphenylyloxy) -heptanoic acid precipitates in crystals. After recrystallization from a mixture of benzene / gasoline, the purified one melts Acidity at 114-115 °.

9098 19/124 2

Example 6

a) 1.5 g (0.00285 mol) of ethyl 2- (4-biphenylyloxy) -n-pentylcyanoacetate are refluxed for 21 hours in a solution of 0.8 g of KOH in 20 ml of ethanol and 2 ml of water heated to boiling. After the ethanol has evaporated off in vacuo, it is acidified with 2-n. Hydrochloric acid on, ethers out, washes the ether phase with water and dry over magnesium sulfate. After evaporation, a mixture of 2- (4-biphenylyloxy) -2-carboxy-heptanoic acid amide is obtained, 2- (4-biphenylyloxy) -heptanoic acid and · 2- (4-biphenylyloxy) -heptanoic acid amide. This mixture turns 20 Heated to the boil in xylene for minutes. After evaporation, a mixture of 2- (4-biphenylyloxy) heptanoic acid amide and is obtained the corresponding acid.

b) This mixture is refluxed for 40 hours in a solution of 1 g of KOH in 40 ml of ethanol and 5 ml of water Heated to the boil and then worked up as described for the saponification of the nitrile (Example 3a). After recrystallization from benzene / petroleum ether, the 2- (4-biphenylyloxy) heptanoic acid obtained melts at 115-116 °.

c) The mixture of 2- (4-biphenylyloxy) -2-carboxy-heptanoic acid amide shown in Example 6a), 2- (4-biphenylyloxy) heptanoic acid amide and 2- (4-biphenylyloxy) -heptanoic acid can also be acidified:

90 9819/12 42

0.6 g of the mixture obtained under 6a) are mixed in a mixture of 3 '; ral 10T / ^ yx sulfuric acid (V / V) and 17 ml of glacial acetic acid heated under reflux to a temperature of 90 ° for 6 hours. After evaporation of the acetic acid in vacuo, dilution with water and hardening, the 2- (4-biphenylyloxy) heptanoic acid is obtained after drying the ether. After recrystallizing twice from benzene / gasoline, the acid melts at 114-116 °.

Beispi el 1

To a solution of 2.3 g (0.1 mol) of sodium in 120 ml Section. Ethanol, 8.5 g (0.05 mol) of 4-hydroxy-biphenyl are added. After the added substance has completely dissolved, the mixture is cooled to 0-5 ° and at this temperature 10.45 g (0.05 Mol) 2-bromo-heptaiic acid added. The reaction mixture is heated to boiling, the alcohol evaporated, the residue dissolved in water and the solution with 2-n. Acidified hydrochloric acid. The 2- (4-biphenylyloxy) -heptanoic acid (colorless crystals) obtained melts after recrystallization from about 250 ml of 65% strength aqueous ethanol at 113-115 °.

Example 8

1 g (0.00335 mol) of 2- (4-biphenylyloxy) heptanoic acid are dissolved in 20 ml of methanol and adds them to a solution of 0.168 g (0.00254 mol) of KOH (86%) in 10 ml of methanol. The clear solution

BATH ORIGINAL 909819/12 4 2

is evaporated to dryness and the residue washed well with ether. The crystals are dissolved in hot ethyl acetate and filtered. After evaporation of the filtrate, the crystalline potassium salt of 2- (4-biphenylyloxy) -heptanoic acid is obtained. The crystals slowly decompose from 300 ° without melting, they dissolve easily in chloroform.

Example 9

0.4 g of Ca (0.01 mol) are dissolved in 40 ml of water with the exclusion of CO decomposed. 6.5 g (0.0218 mol) of 2- (4-biphenylyloxy) heptanoic acid in 150 ml of methanol are added to the suspension of Ca (OH ^ added and heated to boiling for 10 minutes. After evaporation to dryness it is rubbed with ether and washed well. The residue obtained is washed with hot methanol extracted. Colorless crystals are obtained which decompose slowly from 290 ° without melting. They are breaking up easily in chloroform.

909819 / T242

Claims (5)

Claims 1. Process for the preparation of the new 2- (4-biphenylyloxy) heptanoic acid of formula I, uHn "GHo" ufli ~ CHr »" CHo I 2 2 2 2 3 ο - gh - co - oh (ι) and their salts with inorganic and organic bases, characterized in that one is a functional derivative of the said acid is hydrolyzed, if desired from a obtained one Salt releases the acid and / or the acid obtained or, by double conversion, directly the one obtained first Salt converted into a salt or another salt with an inorganic or organic base. 2. Modification of the method according to claim 1, characterized in that a functional derivative of the (4-Biphenylyloxy) -n-pentyl-malonic acid, with an inorganic or organic base, until the equimolar amount is split off Heated carbon dioxide and, if desired, converted the acid obtained into a salt with an inorganic or organic base. 3. Modification of the method according to claim 1, characterized in that the (4-biphenylyloxy) -n-pentylmalonic acid, or an acid salt thereof with an inorganic 909819/1 242 see or organic base, until the equimolar is split off Heated amount of carbon dioxide and washed the acid obtained if necessary converted into a salt with an inorganic or organic base. 4. Modification of the method according to claim 1, characterized characterized in that one relates to an alkali metal salt of p-phenylphenol with a salt of a reactive ester converts the 2-hydroxy group of 2-hydroxyheptanoic acid, desired mostly from the obtained salt of 2- (4-biphenylyloxy) ~ heptanoic acid releases the acid and / or, if desired, the acid obtained or, by double conversion, directly converts the initially obtained salt into a salt or another salt with transferred to an inorganic or organic base. 5. 2- (4-Biphenylyloxy) -heptanoic acid and its salts with inorganic and organic bases. Fo / bm / lo.9.1968 9098 1 9/1 2.4 2