NO742802L - - Google Patents

Description

"Analogy method for the preparation of

pharmacologically active biphenyl derivatives"

The invention relates to analog methods for the production of pharmacologically active biphenyl derivatives with the general formula I:

where

R-^ means a chlorine or fluorine atom, and

B means a hydroxy group, an alkoxy or aralkyl group or an amino group, and if B means a hydroxy group, physiologically compatible salts thereof with inorganic or organic bases.

The compounds especially have an antiphlogistic effect.

The analogue method for the preparation of compounds of the general formula I is distinctive in that:

1) For the preparation of compounds with the general formula I where B means a hydroxy group, a compound with the general formula II is reacted:

where

is as stated at the outset and

X is a hydroxy group, a halogen atom or an arbitrary acyloxy residue with a 1,1-dihalogenethylene in sulfuric acid, and the intermediate is hydrolyzed by the addition of water. Preferably, 1,1-dichloroethylene is used in sulfuric acid which preferably contains boron trifluoride.

2) For the preparation of compounds of the general formula I where B has the meanings given above, by reduction of compounds of the general formula III:

where

and B is as stated above and

A means the group

The reduction is carried out, for example, with catalytically activated hydrogen. Noble metal oxides such as platinum oxide serve as catalysts, for example, but also metal catalysts from the range of Raney metals such as e.g. Raney nickel or Raney cobalt. The reduction takes place in a solvent, for example in a carbinol such as e.g. methanol or ethanol, at temperatures between 0 and 100°C and at a hydrogen pressure between 1 and 100 atm, preferably at 2 to 10 atm.

The reduction can also take place by the above-mentioned compounds being treated with hydrogen iodide, possibly in the presence of small amounts of red phosphorus and possibly in the presence of a polar solvent such as e.g. glacial acetic acid, at elevated temperatures. This gives compounds of the general formula I, where B is a hydroxy group.

The reduction can also be carried out with nascent hydrogen, thus for example by the action of hydrogen which has been released by the action of magnesium on a carbinol, e.g. on methanol.

3) For the preparation of a compound of the general formula I where B means a hydroxy or alkoxy group, a compound of the general formula III is reduced, where A means the group:

The reduction can, for example, be carried out with catalytically activated hydrogen. Noble metal oxides such as platinum oxide, palladium on barium sulphate or charcoal serve as catalysts, but also metal catalysts such as e.g. Raney nickel or Raney cobalt. The reduction takes place in a solvent, for example in a carbinol such as methanol or ethanol, at temperatures between 0 and 100°C, preferably 20 to 80°C, and at a hydrogen pressure between 1 and 100 atm., preferably 2 to 10 atm. In particular, the reduction with palladium on barium sulphate or charcoal in the presence of glacial acetic acid and a catalytic amount of a mineral acid such as e.g. perchloric acid proved beneficial.

The reduction can also be carried out with hydrogen iodide, possibly in the presence of a small amount of red phosphorus and possibly in the presence of a polar solvent such as e.g. glacial acetic acid, at elevated temperatures, whereby the free acids are deposited.

4) To prepare a compound of the general formula I where B means a hydroxy group, a compound of the general formula IIa is reacted:

where

has the meanings given above, andHal means a halogen atom, preferably a chlorine, bromine or iodine atom, with an alkali salt or an alkoxymagnesium salt of a malonic acid ester, and the malonic acid ester obtained has the general formula IV:

where

R^ has the initially stated meanings and the residues

Rg means lower alkyl residues, saponified to the free acid and then decarboxylated to an acid of the general formula I with the release of one mole of carbon dioxide.

As an alkali salt of the malonic acid ester, preferably the dimethyl or diethyl ester, the sodium or potassium salt is used in particular, but instead of the alkali salt a magnesium salt, for example the ethoxymagnesium salt, can also be used.

The reaction of a halide of the formula IIa with a salt of the malonic acid ester preferably takes place in a solvent, for example in a lower alkanol, especially in ethanol or methanol corresponding to the ester used. However, it is also advantageous to use carboxylic acid esters, for example diethyl carbonate as a solvent, to avoid alcoholysis. If an alkali alcoholate is used in the preparation of the alkali salt of the malonic acid ester, the alcohol obtained is suitably distilled off before it is reacted with the halide of formula IIa.

The reaction temperature lies between room temperature and the boiling point of the solvent used and depends in particular on the halide used with formula Ila. If Hal is a bromine atom, the reaction can be carried out at room temperature, however, if Hal is a chlorine atom it must usually be heated, preferably to the boiling point of the solvent.

The alkali halide formed by the reaction is then separated by filtration. The formed malonic acid ester of formula IV can be saponified and decarboxylated without isolation, but can of course first be isolated and purified by distillation. The esters of formula IV, where Rj. means lower alkyl residues, as well as the corresponding, well-crystallising malonic acid where R^ means hydrogen,

are new compounds which are important intermediates for the production of•therapeutically valuable biphenyl derivatives.

The saponification of the malonic acid ester preferably takes place alkaline. By adding alkaline lye to a solution of it.

purified esters of formula IV or to the reaction mixture obtained and upon slight heating, the alkali salt of the free malonic acid is formed, from which the corresponding [1-(4-biphenylyl)-1-ethyl]-malonic acid is liberated by the addition of a stronger acid. The decarboxylation of these malonic acids then takes place by heating to a temperature of approx. 10 to 20° above the melting point, preferably to 200°C and" is finished after a short time. However, the decarboxylation can also take place at lower temperatures or by heating to 130-140°C in a higher boiling solvent such as dimethylformamide, o-dichlorobenzene, xylene, diethylene glycol dimethyl ether, etc.

The obtained acids of the general formula I can then,

if desired, by known methods transferred into esters or amides.

Compounds of the general formula I where the residue B

means an alkoxy group, can, however, also be prepared directly by decarbaloxylation of compounds of the general formula IV where the residue R1 is as indicated above and R1 means an alkyl residue. A compound of the general formula IV is thereby heated in aqueous dimethylsulfoxide, dimethylformamide, dimethylacetamide or

,similar aprotic solvents in the presence of sodium chloride to temperatures between 130 and 190°C. Instead of sodium chloride, other alkali halides can also be used, e.g. potassium fluoride or sodium chloride, as well as sodium cyanide or sodium phosphate.

5) Compounds of the general formula I where the residue B

is a hydroxyl group can be prepared by saponification of 3-(4-biphenylyl)-butyronitriles with the general formula V:

where the rest

R1 has the meanings given above.

The saponification takes place in the presence of a base or acid, advantageously in the presence of a solvent, at temperatures between 100 and 200°C. Ethylene glycol, ethanol, butanol, pentanol, propylene glycol serve as solvents, for example, as bases concentrated aqueous or alcoholic alkali and alkaline earth hydroxides such as potassium hydroxide, sodium hydroxide, which acidify aqueous mineral acids such as hydrochloric acid, hydrobromic acid, especially in a polar solvent such as e.g. glacial acetic acid. The salts precipitated by the use of bases are transferred to their free acids by acidification, e.g. with hydrochloric acid.

It was further found that compounds with the general formula I where the residue B is a hydroxy group can advantageously and in good yield also be prepared by a butyronitrile of the general formula Va:

where

has the above meanings and

Q is a cyano or carboxamide group or a carboxy group which may optionally be esterified with an aliphatic or araliphatic alcohol or a phenol, saponified and decarboxylated.

The saponification and decarboxylation can also be carried out

in a. workflow. It must thereby be open whether the cyano group is first, possibly also partly, saponified or whether carbon dioxide is first split off and the intermediate products with the general formulas V, Vb and Vc

occurs.

In this case, concentrated aqueous or alcoholic alkali and alkaline earth hydroxides as well as aqueous mineral acids have proven useful for the saponification. When heating nitriles of the general formula Va with alkali hydroxides in ethanol, higher alcohols or ethylene glycol or with concentrated hydrohalic acids in a polar solvent such as e.g. glacial acetic acid, the compounds of the general formula I where B is a hydroxy group are obtained directly, or their alkali salts.

The compounds with the general formula I are also obtained by reduction and simultaneous saponification and decarboxylation of nitriles with the general formula Vd:

where

has the above meanings and

Q means a cyano or carboxamide group or one optionally with

an aliphatic or araliphatic alcohol or a phenol esterified carboxy group. This also results in compounds of the general formula I where B is a hydroxy group.

The reduction is carried out with hydroiodic acid in heat, possibly in a suitable polar solvent, such as e.g. in glacial acetic acid, at temperatures up to reflux for the solvent used. This is converted, without stating anything about the order of

the individual steps, the unsaturated bond in the side chain of a saturated bond, the group Q, provided this is not already a carboxy group, and the cyano group is saponified, as well as carbon dioxide is split off, whereby a compound of the general formula I is obtained directly and without isolation of intermediates .

6) For making connections with it. general formula I where B means a hydroxy group, carbinols are oxidized with the general formula VI:

where

R^ is as stated above.

Oxidation takes place with strong oxidising agents such as e.g. alkali permanganate, chromium VI oxide, alkali chromates or bichromates.

The oxidation with potassium permanganate is preferred in neutral or alkaline solution, with chromium VI oxide in aqueous or mineral acid, preferably sulfuric acid, solution at temperatures between -10 and +80°C.

7) For the preparation of compounds with the general formula I where B means a hydroxy group, a Grignard compound with the general formula is reacted. VII:

where

is as stated above and

Hal means a halogen atom, preferably a chlorine or bromine atom, with carbon dioxide in a solvent.

As a solvent for the Grignard compound with the general formula VII, an ether such as e.g. diethyl ether. The ethereal solution freed of magnesium residues is thereby preferably poured onto solid, divided carbon dioxide. After evaporation of excess carbon dioxide, a mineral acid is added, the ether phase is separated and from this the acid with the general formula I (B = a hydroxy group) is isolated.

8) Compounds with the general formula I where B is a hydroxy or alkoxy group are obtained by solvolysis of compounds with the general formula VIII:

where

R^ is as stated above and

Y is a divalent, saturated, 2- or 3-membered hydrocarbon residue, which may optionally be substituted with further alkyl groups.

If the solvent is an alcohol, compounds of the general formula I are obtained in the presence of concentrated mineral acids, for example concentrated sulfuric acid or anhydrous hydrogen chloride, at temperatures up to the boiling point of the solvent used, where the residue B is the corresponding alkoxy group. If, on the other hand, aqueous mineral acids, for example 3n hydrochloric acid, act on a compound of the general formula VIII, compounds of the general formula I are formed where the residue B is a hydroxy group.

9) Compounds with the general formula I where the residue B is a tertiary alkoxy group are obtained from halides with the general formula Ila by reaction with metallated acetic acid tert-alkyl esters with the general formula IX:

where

Me means a lithium or sodium atom and tert-alkyl an alkyl radical of 4 to 10 carbon atoms. The necessary enolates of acetic acid tert.alkyl esters, e.g. Acetic acid tert-butyl ester lithium menolate, produced in situ from acetic acid tert-alkyl esters and alkali metal amides, e.g. lithium dialkylamides, preferably lithium-N-isopropyl-cyclohexylamide in tetrahydrofuran at -78°C, or even better by the action of lithium amide in liquid ammonia. Particularly favorable results are obtained by using 2 mol of alkali amide and 2 mol of acetic acid tert.alkyl ester per moles of halide with the general formula Ila.

If compounds of the general formula I where B is a hydroxy group are prepared from the thus obtained compounds of the general formula I where B is a tertiary alkoxy group, these compounds are subjected, for example, to pyrolysis.

The pyrolysis is carried out at temperatures between 150 and 250°C, whereby an isoalkylene is released.

10) For the production of..compounds with the general formula I where B means a hydroxy group, ketene thioacetals with the general formula X are hydrolyzed:

where

is as stated above and

the residues Rg and Rg mean lower alkyl residues which may be equal to or

different or together with the group

can form one

5-, 6- or 7-membered ring, which may possibly be interrupted by a

additional sulfur atom.

Keten thioacetals of the general formula X allow

hydrolyze with acids. The hydrolysis of compounds with

the general formula X where the group

means the residue with a weaker acid, for example formic acid, a compound of the general formula XI can be isolated as an intermediate: which is advantageously further reacted with caustic soda to a salt of a carboxylic acid of the general formula I. However, a compound of the general formula is boiled X with concentrated acids, for example with concentrated hydrochloric acid in the presence of glacial acetic acid, a free acid with the general formula I (B = hydroxy group) is obtained directly. 11) Compounds of the general formula I where B means a hydroxy group or an alkoxy group can be obtained by desulfurization of compounds of the general formula XII:

where

is as stated above and

Rg means a hydrogen atom or an alkyl radical, preferably a methyl, ethyl or propyl radical.

For the desulfurization of compounds of the general formula

XII, the action of mercuric or silver salts, especially mercuric (II) chloride in alcohols at an elevated temperature, has proved beneficial. The desulphurisation is preferably carried out with finely divided nickel, for example Raney nickel, or with nickel boride, which is obtained by reducing nickel (II) salts with sodium borohydride. The desulphurisation is carried out in suitable solvents, preferably in lower alcohols such as e.g. ethanol, propanol and.at temperatures up to the boiling point of the solvent used.

12) For the preparation of compounds of the general formula I where B means a hydroxy group, an alkoxy or a primary amino group, a diazoketone of the general formula XIII is rearranged

where

is as stated above.

When rearrangement of a diazoketone with the general formula XIII is obtained, depending on whether it is carried out in the presence of water, alcohols or anhydrous ammonia, the corresponding carboxylic acids, their esters or amides with the general•formula I.

The rearrangement is catalyzed by silver(II) oxide, sodium thiosulphate, potassium hydroxide in methanol/water, tertiary amines in benzyl alcohol or simply by illumination. The most suitable homogeneous catalyst is silver benzoate in triethylamine, preferably in the presence of tertiary butanol.

13) For the preparation of compounds of the general formula I where the radical B means a hydroxy group, an alkoxy or aralkyl radical, a compound of the general formula IIa: is reacted.

where R^ has the meanings given above and

Hal is a halogen atom, preferably a chlorine, bromine or iodine atom first with an alkali salt of an acetoacetic acid ester of a compound of the general formula XIV:-

where the rest

R7- means an alkyl or aralkyl radical.

The alkali salts with the enol form of the acetoacetic acid esters are known compounds. To prepare them, an acetoacetic acid ester is allowed to react in a manner known per se with an alkali alcoholate solution. Preferably, the acetoacetic acid ester is used as a sodium derivative, which is a cheap commercial product.

The reaction of compounds of formula IIa is usually carried out in a carbinol as solvent, suitably in the carbinol with which the acetoacetic acid is esterified.

To increase the turnover rate, the mixture is heated.

In this way, the alkali halide is separated and can be removed by filtration after cooling. The filtrate contains the new 3-ketocarboxylic acid esters of formula XIV which can be distilled.

The 3-ketocarboxylic acid esters of formula XIV are then subjected to cleavage to the esters of general formula I.

This cleavage is carried out with strong alkalis. However, the alcoholysis method is preferred. This is preferably done in the presence of catalytic amounts of an alkoxide such as e.g. sodium ethylate in a

anhydrous carbinol, such as e.g. ethanol, whereby it is heated and the resulting mixture of acetic acid ethyl ester and carbinol is continuously distilled off as an azeotrope. This results in the esters with the general formula I.

The formation of ketones as by-products, which occur by cleavage of the esters of the general formula'XIV with alkaline lye,. is thereby practically avoided and the yield of esters of the general formula I is excellent.'

However, the 3-ketocarboxylic acid esters of the general formula XIV can also be cleaved by the action of acids, e.g. a mineral acid such as hydrochloric acid or dilute sulfuric acid on the compounds of the general formula I where B means a hydroxy group.

The 3-ketocarboxylic acid esters of formula XIV are new and are antiphlogistically active compounds. The esters with the general

formula I curry is transferred to the free acids of the general formula I by means of alkaline or acid saponification.

14) Compounds with the general formula I where B is a hydroxy, alkoxy or aralkyl group can be obtained advantageously and in good yield also by a compound of the general formula IIa:

where

is as stated above and

Hal is a halogen atom, preferably a chlorine or bromine atom, a compound of the general formula XV is reacted:

where

R^means an alkyl or aralkyl residue, -first to a compound of the general formula XVI:

where

and R^ have the meanings given above, after which this is transferred to a compound of the general formula I.

In the formulas XV and XVI, the alkyl groups preferably comprise the methyl, ethyl, propyl, isopropyl, butyl, isobutyl and pentyl groups, the aralkyl groups are benzyl, 2-phenylethyl, 4-biphenylyl-methyl and 2-(4 -biphenylyl.)-ethyl groups.

The reaction of a compound of the general formula IIa with a compound of the general formula XV to a compound of the general formula XVI takes place by heating in an inert anhydrous solvent, for example in ethyl acetate, tetrahydrofuran or toluene, suitably to temperatures between 60 and 120° C. Thereby, the double molar amount of the compound of formula XV calculated on the molar amount of the compound of formula IIa is advantageously used.

During the course of the reaction, carboxymethyl-triphenyl-phosphonium halide esters with the general formula XVII fall:

out, and it is then sucked off. The compound of general formula XVI remains in the filtrate. The filtrate is evaporated, heated with a strong base, preferably an alkali liquor, and then acidified. This results in a compound with the general formula I where B is a hydroxy group. If, however, the compound of the general formula XVI is heated with water instead of with a base, a compound of the general formula I is isolated, where B has the meaning of an alkoxy or aralkyl radical, depending on which of these meanings the radical R^ in the compound of the general formula XV had. 15) For the preparation of compounds with the general formula I where B is a hydroxy group, an aldehyde with the general formula XXXII is oxidized:

where.

■is as stated above. As oxidizing agents, for example, alkali permanganates, chromates(VI), chromium(III) and copper(II) salts are used, e.g. halides or sulphates, mercury(II)-, manganese(IV)-

or silver(I) oxide, as well as hydrogen peroxide: Potassium permanganate has proven beneficial, preferably in neutral or alkaline-aqueous solution, or chromium(VI) oxide, preferably in alkaline-aqueous solution, or chromium(VI).- oxide, preferably in sulfuric acid aqueous solution, at temperatures between -10 and +80°C. It is particularly advantageous to oxidize with silver(I) oxide in an aqueous-alkaline solution at temperatures between 40 and 100°C.

The compounds of the general formula I precipitate as racemates which can easily be separated into their two optically active single components by fractional crystallization of their salts with optically active bases, if they are not prepared from optically active intermediates. In particular, the racemate cleavage with quinine has thus proven beneficial.

If, according to the stated methods, compounds with the general formula I are obtained where B is an alkoxy group, these can then, if desired, be transferred to their acids (B hydroxy residue) resp. to their salts of the general formula I by saponification, for example with an alkali liquor. From the possibly thus obtained salts, the free acids can be released by acidification with a mineral acid. The saponification can also be acid catalyzed.

If, according to one of the methods indicated above, an acid with the general formula I is obtained (here B means a hydroxy group), these can, if desired, be transferred to the esters in a manner known per se.

The acids of the general formula I where B is a hydroxy group can, if desired, be transferred to salts, for example with inorganic or organic bases. As organic bases, in particular diethanolamine, morpholine, cyclohexylamine and piperazine have proven beneficial.

If compounds of the general formula I where B

if an amino group is desired, an ester of the general formula I where B is an alkoxy group is reacted with ammonia. The reaction is suitably carried out in an inert solvent, preferably in an alcohol or an aromatic hydrocarbon at elevated temperature and pressure. However, the acid amides of the general formula I can also be obtained by reacting a compound of the general formula I where B is a halogen atom, i.e. an acid halide, with ammonia.

Compounds of the general formula I where B is an NH2 group can also be obtained by partial acid or alkaline saponification. of nitriles with the general formula V. Heating with polyphosphoric acid has, for example, proven particularly beneficial.

The starting compounds of the general formula II where X is a hydroxy group can be easily obtained by reduction of ketones of the general formula XVIII:

with complex metal hydrides, especially sodium borohydride. Compounds of the general formula II where X is a halogen atom (formula IIa) or an acyloxy group can be easily prepared from the corresponding compounds of the general formula II where X is a hydroxy group, in a manner known per se by treatment e.g. with halogen hydrogen acids, a phosphorus halide or thionyl halide resp. by acylation.

The starting compounds with the general formula XVIII are prepared, for example, from 3'-halo-4<1->amino-acetophenones by diazotization and subsequent reaction with benzene in the presence of caustic soda or sodium acetate. In this way, for example, 4-acetyl-

2-Chloro-biphenyl with melting point 42-44°C and bp^ , „ 134-142°C.

J 3 r0.1 mm Hg

However, these starting compounds can also be prepared by reacting methylmagnesium halides with suitable 4-cyano-2-halo-biphenyls and subsequent hydrolysis of the resulting ketimine-magnesium halides. In this way, for example, 4-acetyl-2-fluoro-biphenyl with a melting point of 97-98°C was produced.

The starting compounds have the general formula III where A

or the CH2 groups are obtained, for example, by first reacting a ketone with the general formula XVIII with the zinc compound of a corresponding haloacetic acid ethyl ester to a compound with the general formula III where A means the group whereby these compounds form the starting compounds in method 3, and then water is split off from the compounds thus obtained. The reaction to a compound with the general formula III where A means a CH2~ group is carried out in an organic solvent, for example in an ether such as diethyl ether, dimethoxyethane, diethoxyethane, dioxane, tetrahydrofuran or in mixtures of these solvents or also in indifferent solvents such as .ex. benzene or toluene at temperatures from 15 to 120, preferably between 20 and 60°C. Removal of water from a compound of the general formula III where A is one

CI^ group is carried out in the presence of a water-

splitting agent, preferably in the presence of an inert solvent which is not miscible with water, advantageously with the inclusion of a water separator, at temperatures up to the boiling point of the solvent used. Acid-reactive salts, for example salts of pyridine or alkylpyridines with hydrohalic acids or potassium hydrogensulphate, but also metal salts such as e.g. zinc chloride, further acids such as e.g. p-toluene acid, phosphoric acid, or sulfuric acid or, if B is an alkoxy group, preferably inorganic acid halides such as e.g. phosphoroxy-halides, in consideration. For example, benzene, toluene or xylene serve as inert solvents. However, the reaction can be carried out without a solvent.

The new starting compounds with the general formula Va are obtained, for example, by reduction of nitriles with the general formula Vd. This reduction is effected by the action of amalgamated zinc on a strong, inorganic acid, for example hydrochloric or hydrobromic acid, advantageously in the presence of a solvent, for example an aliphatic or aromatic hydrocarbon such as, for example, benzene or toluene. However, the reduction can also take place catalytically with hydrogen. As catalysts, precious metal catalysts such as e.g. platinum oxide or palladium on charcoal suitable. Carbinol is preferably used as a solvent such as e.g. methanol, ethanol or hydrocarbons such as benzene or ethers such as dioxane or mixtures of these solvents. bet is worked at room temperature or temperatures up to 100°C and at pressure between 1-50 atm., preferably 1-5 atm.

The new starting compounds with the general formula Vd are obtained by a ketone with the general formula XVIII:

where

R^ as indicated above is reacted with cyanoacetic acid or one of its derivatives with the general formula XIX:

where

Q is a cyano group, a carboxy group or a carboxy group which is optionally restricted with an aliphatic or araliphatic alcohol or a phenyl, in the presence of an inert solvent, e.g. in a carbinol such as ethanol, isopropanol, butanol, however preferably in an aromatic hydrocarbon such as e.g. benzene and in the presence of ammonia resp. of ammonium salts or of amines, preferably tertiary amines such as e.g. triethylamine, piperidine or its salts, suitably in the presence of acetic acid, preferably with the inclusion of a water separator at temperatures up to the boiling point of the solvent.

The starting compounds with the general formula V are obtained, for example, by decarboxylation of compounds with the general formula Va where Q is a carboxyl group. Decarboxylation begins by heating these compounds above their melting points. The heating is continued for as long as no more carbon dioxide escapes.

The starting compounds with the general formula V allow

also prepared directly from such compounds having the general formula Va where the radical Q means an esterified carboxyl group. The decarbalkoxylation is carried out, for example, in the presence of aqueous dimethylsulfoxide in the absence of sodium chloride at temperatures from 130-190°C. The starting compounds of the general formula V can also be prepared from the halides of the general formula XX by reaction with an alkali cyanide in a solvent such as, for example, dimethylsulfoxide, dimethylformamide, ethanol and the like.

The starting compounds with the general formula VI are obtained starting from a 2-(4-biphenylyl)-1-propyl halide with the general formula XX

where

Hal is a halogen atom, preferably an iodine or bromine atom, by transfer to a Grignard compound and subsequent reaction with paraformaldehyde. The transaction is made in an ether such as e.g. diethyl.ter or dioxane at temperatures up to the boiling point of. the solvent used. The compounds of formula XX can, for example, be prepared as follows: By reacting a correspondingly substituted biphenyl with oxalic acid monoethyl ester chloride and anhydrous aluminum chloride, the corresponding 2-(4-biphenylyl)-glyoxylic acid ester is obtained, which with one mole of methylmagnesium bromide gives a 2r- ( 4-biphenylyl) -

2-hydroxy-propionic acid. By per se known methods, e.g. by means of hydroiodic acid in acetic acid, the corresponding 2-(4-biphenylyl)-propionic acid can be prepared from it. The reduction of this acid with lithium aluminum hydride in ether then leads to a 2-(4-biphenylyl)-propanol of the general formula XXI:

as by heating with a phosphorus trihalide, e.g. with phosphorus

tribromide can be transferred to the corresponding compound of the general formula XX.

The compounds of the general formula XXI can also be prepared from substituted hydratropaaldehydes of the general formula XXII: by reduction with sodium borohydride in a solvent, for example in an alcohol such as e.g. ethanol or methanol. The substituted hydratropaaldehydes of the general formula XXII are in turn prepared from 4-biphenyl-α,3-epoxy-3-methyl-hydrocinnamic acid esters of the general formula XXIII:

by heating in alcoholic solution to temperatures up to the boiling point of the solvent in the presence of an alkali liquor. The compounds with the general formula XXIII can in turn be prepared from ketones with the general formula XVIII by the action of a chloroacetic acid ester in the presence of sodium amide in benzene solution at temperatures between 0 and 100°C, preferably at 10 to 20°C.

The starting compounds with the general formula VIII are obtained by reacting compounds with the general formula II where X is a halogen atom with metallated heterocyclic compounds with the general formula XXIV:

where

Me is an alkali metal atom, preferably a lithium atom. The reaction is preferably carried out in ether or tetrahydrofuran as solvent at temperatures between -100°C and room temperature. Thereby, work is carried out under an oxygen- and carbon dioxide-free protective gas, preferably under the purest argon or nitrogen.

The metallated heterocyclic compounds of the general formula XXIV are in turn produced by the action of metallating agents, such as, for example, organometallic compounds of the general formula XXXIII:

or XXXIV: or of alkali metal dialkylamides of the general formula XXXV):

where

Me is an alkali metal atom and

1 and R^<1> are alkyl, cycloalkyl or aralkyl residues with 1 to 10 carbon atoms, preferably of n-butyl lithium, tert-butyl lithium, lithium diisopropylamide or lithium cyclohexylisopropylamide, on heterocyclic compounds of the general formula XXV

thus on optionally substituted 2-methyl-2-oxazolines resp. 2-methyl-5,6-dihydro-1,3-oxazines. The metal connections are further processed without insulation. The compounds with the general formula XXV are known from the literature (cf. P. Allen jr., J. Ginos,

J. org. Chem. 28, 2761 (1963) and A. I. Meyers et al., J. org. Chem. 38, 49 (1973)).

The starting compounds of the general formula X can be prepared as follows: Thioacetals of the general formula XXVII:

are readily available from suitable carbonyl compounds and mercaptans resp. sulfur hydrogen (cf. Weygand-Hilgetag, Org. chem. Experimentierkunst, pp. 698-701, Joh. Ambrosius Barth Verlag, Leipzig 1964 and D. Seebach, Synthesis 1, 19, 32 (1969)). 1,3-dithiane and 1,3,5-trithiane are commercial products. When lithium alkyls act on thioacetals, metallated thioacetals with the general formula XXVIII are obtained: n-butyl lithium in particular has proved to be beneficial here. Work is then carried out at temperatures between -80°C and room temperature, preferably at -40 to -20°C, as well as when using anhydrous, inert, usually ethereal solvents. Preferred solvent is tetrahydrofuran. Instead of thioacetals which are metallated with lithium, the corresponding halogen magnesium derivatives can also be used. These are obtained by adding anhydrous magnesium bromide or chloride to solutions of lithium dithioacetals with the general formula XXVIII.

The compounds of the general formula XXVIII are then reacted with aldehydes of the general formula XXII. This hydroxyalkylation proceeds rapidly even at -78°C. This results in compounds with the general formula XXIX:

which can be dehydrated to ketene dithioacetals of the general formula X by heating in the presence of an inert solvent and of catalytic amounts of a mineral acid such as concentrated sulfuric acid, phosphoric acid or sulphonic acids." As inert solvents come into consideration, for example: benzene, toluene, xylene and higher homologues, chlorobenzene, o-dichlorobenzene, tetrachloromethane and trichloroethylene. In particular, heating in benzene in the presence of p-toluenesulphonic acid with water separator proved beneficial.

The starting compounds with the general formula XII, which are new, are obtained by alkylation of 1,3-dithiane-2-carboxylates with the general formula XXX:

where

R_ means an alkyl radical, with halogen compounds of the general formula II (X = halogen) in the presence of metallating agents. Metal organyls and metal hydrides of the metals in the 1st and 2nd main groups and alkali-dialkylamides come into consideration as metallating agents. Dipolar, aprotic solvents such as e.g. dimethylformamide, dimethylacetamide, dimethylsulfoxide, hexamethylphosphoric triamide, possibly in a mixture with ethers or hydrocarbons such as e.g. pentane, benzene, . xylene. The reaction is carried out at temperatures between -50 and +100°C, preferably between room temperature and 100°C. In particular, the use of sodium hydride as a metallizing agent and working in a mixture of anhydrous dimethylformamide and benzene has proven beneficial.

The necessary 1,3-dithian-2-carboxylic acid esters of the general formula XXX are easily obtained according to the method of E. L. Eliel et al., J. org. Chem. 31_, 505 (1972) from 1,3-propanedithiol and a dihydroxyacetic acid ester.

The diazoketones with it. general formula XIII is prepared from carboxylic acid halides of general formula XXXI:

where

Hal is a chlorine, bromine or iodine atom, and diazomethane, preferably at low temperatures and in the presence of solvents such as diethyl ether, further preferably in the presence of a tertiary aliphatic or aromatic amine.

The carboxylic acid halides with the general formula XXXI are obtained from the similarly substituted 2-(4-biphenylyl)-propionic acids known from the literature, for example by reaction with a thionyl halide, a phosphorus halide such as phosphorus(III) bromide or phosphorus(V) chloride or with oxalyl chloride.

Aldehydes of the general formula XXXII:

obtained in per se known ways, e.g. by reduction of a nitrile of the general formula V. The aforementioned nitrile is reduced, for example, by the equivalent amount of a complex hydride such as e.g. lithium aluminum tri-tert.-butoxy-hydride in solvents such as e.g. tetrahydrofuran at temperatures between -70 and 20°C. The aldehyde is released by hydrolysis with water or dilute acids (cf. H. C. Brown et al., Tetrah. Letters, _3, 9 (1959)).

The starting compounds with the general formula XV are known from the literature or can be prepared analogously to methods known from the literature, cf. Isler et al., Heiv. chim. Acta 40, 1243. (1957).

The new compounds of the general formula I exhibit valuable pharmacological properties and in particular have a good anti-. phlogistic' effect.

The following substances were examined as examples with regard to their absolute antiphlogistic activity and their compatibility: 3-(2-fluoro-4-biphenylyl)-butyric acid = A 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester. = B

and

3-(2-Fluoro-4-biphenylyl)-butyramide = C

The substances were examined in comparison with phenylbutazone for their antiexudative effect against kaolinedema and carrageenedema in rat hind paws, as well as their ulcerogenicity and their absolute toxicity after oral administration to rats.

a) Kaolin edema in rat hind paw

The release of the edema took place according to the indications of

Hillebrecht (Arzneimittel-Forsch. 4, 607 (1954)) by subplantar injection of 0.05 ml of a 10% suspension of kaolin in 0.85%

NaCl solution. The measurement of the paw thickness was carried out using

by the technique set forth by Doepfner and Cerletti (Int. Arch. Allergy Immunol. 12, 89 (1958)).

Male FW 49 rats weighing 120-150 g received the test substances for 30 min. before triggering the edema via a pharyngeal tube,

. 5 hours after the induction of edema, the mean swelling values were

for the animals treated with the test substances compared to the control animals. From the percentage inhibition values obtained with the different doses, by graphical extrapolation the dose was calculated which led to a: 35% impairment. of the swelling (ED^^)•

b) Carrageenan edema in rat hind paw

For triggering the edema served according to Winter

et al. (Proe. Soc. exp. Biol. Med. 111, 544 (1962)) the subplantar injection of 0.05 ml of a 1% solution of carrageenan in 0.85% NaCl solution. The test substances were given for 60 min. before the edema provocation.

For assessment of the edema-inhibiting effect, measurement values taken 3 hours after the edema release were used. The other details corresponded to those given for kaolin oedema.

c) Ulcerogenic effect

The investigation of the ulcerogenic effect took place on FW

49 rats of both sexes (1:1) with a weight of between 130-150 g.

The animals received the substances to be tested for ulcerogenic effect once per day for 3 consecutive days as extraction in tylose via a pharyngeal tube. 4 hours after the last application, the animals were killed. The stomach and duodenal mucosa were examined for ulcers. From the percentage of animals which after the various doses showed at least one ulcer, ED^Q was calculated according to Litchfield and Wilcoxon (J. Pharmacol. exp. Therap. 96^, 99 (1949)).

d) Acute toxicity

LD,-0 was determined after oral administration to equal numbers of each

of male and female FW 49 rats with a mean weight of 135 g. The substances were given as extract in tylose.

The calculation of LD^q took place as far as possible according to Litchfield and Wilcoxon from the percentage of the animals that died within 14 days after the various doses.

e) The therapeutic indices as a measure of the therapeutic width were calculated by forming the quotient between the ED5Q for the ulcero-gethity resp. for oral LD5Q in rats and the calculated ED^^ in the antiexudative effect test (mean value of the kaolin edema and carrageenan edema tests) in rats.

The results obtained in these experiments are compiled in the following tables.

The mentioned compounds surpass the known phenylbutazone in their desired antiphlogistic effect.

The toxicity and ulcerogenicity of these substances are not enhanced to the same extent as was to be expected after the increase in the antiphlogistic effect. The resulting significantly more favorable therapeutic indices mean that for these compounds a clearly more favorable therapeutic range is to be expected than is known for phenylbutazone.

The following examples shall explain the invention in more detail:

Examples for the production of starting materials:

Example A

1-bromo-1-(2-fluoro-4-biphenylyl)-ethane

While maintaining a reaction temperature of from 8 to 12°C and with stirring, dry bromine hydrogen gas is introduced for two hours into a solution of 109 g (0.504 mol) 1-(2-fluoro-4-biphenylyl)-1-ethanol (melting point 84- 85°C (from cyclohexane)) in 500 ml of dry benzene, whereby the course of the reaction is checked by thin-layer chromatography. Thereby, water is separated, which is removed by stirring in 142 g (1.0 mol) of anhydrous sodium sulphate. After complete reaction of the carbinol, the mixture is filtered, the solvent is distilled off and 1-bromo-1-(2-fluoro-4-biphenylyl)-ethane with melting point 54-55°c: (from petroleum ether) is obtained in quantitative yield.

If hydrogen chloride is introduced into the carbinol, 1-chloro-1-(2-fluoro-4-biphenylyl)-ethane is also obtained in quantitative yield. Melting point: 46-47°C (from petroleum ether).

Example B

1-chloro-1-(2-chloro-4-biphenylyl)-ethane

At a reaction temperature of 30 to 40°C, dry hydrogen chloride is introduced into a solution of 121.1 g (0.522 mol) 1-(2-chloro-4-biphenylyl)-1-ethanol (melting point: 41-43° C (from petroleum ether)) in 130 ml of dry ethylene chloride to which was added 74.5 g (0.524 mol) of anhydrous sodium sulfate, whereby the course of the reaction was controlled by thin-layer chromatography. After complete reaction of the carbinol, the solvent is distilled off and 1-chloro-1-(2-chloro-4-biphenylyl)-ethane is obtained in quantitative yield, which partially solidifies on cooling.

When hydrogen bromide is used instead of hydrogen chloride, 1-bromo-1-(2-chloro-4-biphenylyl)-ethane is obtained correspondingly and in quantitative yield as well.

Examples of the production of the final products:

Example 1

3-(2-fluoro-4-biphenylyl)-butyric acid

a) [1-(2-fluoro-4-biphenylyl)-1-ethyl]-malonic acid

11.7 g (0.51 mol) of sodium are dissolved while stirring in 500 ml

absolutely, ethanol. To the 40°C hot solution, 88.0 g (0.54 mol) of malonic acid diethyl ester are added, the solution is stirred for 30 minutes, then 142.0 g (0.51 mol) of 1-bromo-1-(2-fluoro- 4-biphenylyl)-ethane

dissolved in 500 ml of absolute ethanol, heated for 2 hours under reflux, cooled and the resulting sodium bromide filtered off with suction. The filtrate containing [1-(2-fluoro-4-biphenylyl)-1-ethyl]-malonic acid is heated with 400 ml of 20% caustic soda for 15 minutes on a boiling water bath, whereby the disodium salt of [1-(2-fluoro-4 -biphenylyl)-1-ethyl]-malonic acid is excreted. By adding 3 1 of water, a solution is obtained which is shaken with 800 ml of ether. The ether solution is discarded. The alkaline, aqueous solution is acidified by adding dilute hydrochloric acid, the dicarboxylic acid is taken up in ethyl acetate, the solvent is evaporated and the residue is boiled off with benzene.

After recrystallization from cyclohexane/acetic acid ethyl ester

in the volume ratio 1:1. 135.0 g (88% of theory) of colorless [1-(2-fluoro-4-biphenylyl)-1-ethyl]-malonic acid with melting point 180°C (under decomposition) is obtained.

The above-mentioned [1-(2-fluoro-4-biphenylyl)-1-ethyl}-malonic acid diethyl ester can also be prepared and isolated in the following way: While stirring at room temperature, add to a solution 36 g (approx. 0.20 mol) of sodium methylate (30% in methanol) in 70 ml absolute ethanol 35.2 g (0.22 mol) malonic acid diethyl ester, stirring is continued, 15 minutes later 46.8 g. (0.20 mol) 1-chloro-l-(2 -fluoro-4-biphenylyl)-ethane and the reaction mixture is heated for 3 hours under reflux. After cooling, the separated sodium chloride is suctioned off and the filtrate is freed of solvent. The remaining residue is added to 500 ml of water, then taken up in ether and the ether solution is shaken out with water. The oil residue after evaporation of the solvent is distilled in vacuum.

50 g (70% of theory) of diester with mp Q ^ ^ Hg 166-167°C are obtained.

b) 3-(2-fluoro-4-biphenylyl)-butyric acid

135.0 g (0.447 mol) of [1-(2-fluoro-4-biphenylyl)-1-ethyl]-malonic acid is heated in a flask in an oil bath at 180-190 C to end the carbon dioxide evolution (approx. 15 minutes long) . A liquid reaction product is obtained which is cooled to approx. 90°C and stirred into cyclohexane, whereby a reddish colored product crystallizes out. This is filtered off and recrystallized from petroleum ether/cyclohexane in the volume ratio 1:1.

110.0 g. (95% of theory) of colorless crystals with melting point 96-97°C are obtained, which according to spectra and analysis

is the sought after 3-(2-fluoro-4-biphenylyl)-butyric acid.

Example 2

3-(2-chloro-4-biphenylyl)-butyric acid

a) [ 1- ( 2- chloro- 4- biphenylyl)- 1- ethyl 3- malonic acid

Prepared analogous example la from 1-chloro-1-(2-chloro-4-biphenylyl)-ethane.

Yield: 61% of theory, melting point: 170-171°C (dec.).

b) 3-(2-chloro-4-biphenylyl-butyric acid

Prepared analogous example 1b from [1-(2-chloro-4-biphenylyl)-1-ethyl]-malonic acid in a yield of 50% of theory.

Melting point: 117-118°C (cyclohexane).

Example 3

3-(2-fluoro-4-biphenylyl)-butyric acid

42.8 g: (0.20 mol) 4-acetyl-2-fluoro-biphenyl is added portionwise with stirring to a Reformatsky reagent of 57.5 g (0.88 mol) zinc and 73.5 g (0.44 mol) of bromoacetic acid ethyl ester in 500 ml of absolute ether/tetrahydrofuran (volume ratio 1:1) and the mixture is heated after the addition has been completed for a further hour under reflux. The reaction mixture is then introduced into water, acidified with dilute hydrochloric acid, the organic phase is separated, shaken out once more with water and dried over sodium sulphate. After evaporation of the solvent, the crude ester is saponified using alcoholic caustic soda under slight heating. The crude acid that precipitates when the alkaline solution is acidified with dilute hydrochloric acid is taken up in ethyl acetate, washed with water, dried and. is evaporated.

The crude 3-(2-fluoro-4-biphenylyl)-3-hydroxybutyric acid thus obtained is heated without further purification in 600 ml of toluene with 4 g of p-toluenesulfonic acid and with the inclusion of an ion separator for one hour under reflux. After cooling, 400 ml of ethyl acetate are added, the organic solution is washed with water and the solvent is evaporated. The residue, which consists of crude 3-(2-fluoro-4-biphenylyl)-2-butenoic acid, is added after dissolving in 2 1 methanol while stirring and heating to approx. 30°C in portions, a total of 48.6 g (2.0 mol) of magnesium shavings, whereby the temperature during vigorous hydrogen evolution rises to 40°C. The mixture is stirred further at this temperature until all the magnesium has dissolved, 8 1 of ice water is added and the mixture is acidified with dilute hydrochloric acid. It is then extracted several times with a total of 4 1 ether, the combined ether extracts are washed with water, dried over sodium sulphate and the solvent is distilled off. The remaining solid residue is recrystallized from petroleum ether/cyclohexane

in the volume ratio. 1:1.

It is obtained. 13.1 g (25% of theory) 3-(2-fluoro-4-biphenylyl)-butyric acid with melting point 96-97°C.

Example 4

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

90.6 g: (0.30 mol) crude 3-(2-fluoro-4-biphenylyl)-3-hydroxybutyric acid ethyl ester in 500 ml benzene is heated with 67 g. (0.44 mol) phosphorus oxychloride for 10 minutes under reflux , the solvent is then distilled off, the residue is added to water and the separated oil is taken up in ether. From the ether solution, which is washed neutral with water and a 5% sodium bicarbonate solution, dried and filtered over activated charcoal, the solvent is distilled off. The residue, crude 3-(2-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester, is dissolved in 700 ml of ethanol and hydrated with the addition of 10 g of Raney nickel as catalyst at room temperature and 5 atm. pressure until the calculated amount of hydrogen is taken up. The catalyst is then suctioned off and the solvent is distilled off.

54.9 g (64% of theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester with bp, are obtained. , „ 150-170°C, melting

u, x mm rig

point: 44-45 C (from petroleum ether).

Example. 5

: 3-(2-fluoro-4-biphenylyl)-butyric acid

28.43 g. (0.10 mol) of crude 3-(2-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester, prepared as in example 4, is dissolved in 220 ml of ethanol and hydrated under, addition of 1 g of platinum oxide as a catalyst at room temperature and 5 atm. pressure until absorption of the calculated amount of hydrogen. The catalyst is then suctioned off and the solvent is distilled off. 22.8 (80% of theory) of 3-(2-fluoro-4-

biphenylyl)-butyric acid ethyl ester with bp.. „ 153-168°C, melting point:

O/i mm rig

56-56.5 C (from petroleum ether) .'

By the usual method of saponification of the ester with alcoholic potash, 3r-(2-fluoro-4-biphenylyl)-butyric acid is obtained with m.p. 96-97°C (from cyclohexane/petroleum ether in volume ratio 1:1).

Example 6 3-(2-fluoro-4-biphenylyl)-butyric acid

38.4 g. (0.14 mol) of crude 3-(2-fluoro-4-biphenylyl)-3-hydroxybutyric acid, prepared according to example 3, is heated in 200 ml of glacial acetic acid with 100 ml of hydroiodic acid (d 2.00) for one hour with stirring in an oil bath (150°C). The reaction solution is then introduced into 500 ml of water

and decolorized with sodium hydrogen sulphite. Then extract with ether. The ether solution is washed once more with water, it is dried and the solvent is distilled off. The remaining acid is recrystallized from cyclohexane.

3-(2-fluoro-4-biphenylyl)-butyric acid melts at 96-97°C (petroleum ether/cyclohexane) and is obtained in a yield of 19.2 g (53% of theory).

Example 7

3-(2-fluoro-4-biphenylyl)-butyric acid

4.00 g (0.0156 mol) of crude 3-(2-fluoro-4-biphenylyl)-2-butenoic acid, prepared according to Example 3, is heated with 75 ml of hydroiodic acid (d 2.00) in 50 ml of glacial acetic acid in 2 hours under reflux, the reaction mixture is then stirred into 300 ml of water, decolorized with sodium hydrogen sulphite, the separated precipitate is filtered off with suction and dissolved in ether. The ether solution is dried over sodium sulfate and evaporated, the residue is recrystallized from cyclohexane/petroleum ether in the volume ratio 1:1 twice. The desired 3-(2-fluoro-4-biphenylyl)-butyric acid with melting point 96-97°C is obtained in a yield of 3.52 g (87% of theory).

Example 8.

3-(2-fluoro-4-biphenylyl)-butyric acid amide

15.0 g (0.0582 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid are heated with 30.0 g of thionyl chloride (0.252 mol) in 150 ml of absolute benzene for 60 min., under reflux. The crude acid chloride that remains after distillation of excess thionyl chloride is dissolved in 200 ml of anhydrous dioxane and saturated with ammonia gas while stirring and cooling. After completion of the introduction of ammonia, stirring is continued for a further 30 minutes, then the reaction mixture is introduced into 1500 ml of water and the separated precipitate is suctioned off.

13.0 g (87% of theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid amide with melting point 120-121°C (from ethanol) are obtained.

Example 9

3-(2-fluoro-4-biphenylyl)-butyric acid

27.43 g (0.10 mol) 3-(2-fluoro-4-biphenylyl)-3-hydroxy-. butyric acid, prepared according to example 3, is hydrated in 200 ml of glacial acetic acid with the addition of 2 ml of perchloric acid and 5 g of palladium on charcoal (10%) as catalyst at 45°C and 5 atm. Print. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the filtrate is introduced into water, the precipitate that has formed is suctioned off, washed with water and dissolved in ether. After drying the ether solution is distilled off

the solvent. The solid residue melts after recrystallization

cyclohexane/petroleum ether in the volume ratio 1:1 at 96-97°C. The yield amounts to 21.5 g (83% of theory).

Example 10

3-(2-chloro-4-biphenylyl)-butyric acid

While stirring at 0°C, a solution of 58.1 g (0.25 mol) 1-(2-chloro-4-biphenylyl)-1-ethanol (melting point: 41-43°C (from petroleum ether)) in 242 g (2.5 mol) of 1,1-dichloroethylene. After the addition is complete, stirring is continued for a further 2 hours at room temperature, then the reaction mixture is introduced into 2.5 kg of ice water and the separated oil is taken up in ether. The ether solution is extracted with 500 ml of 10% caustic soda. The alkaline, aqueous solution is acidified with 15% hydrochloric acid, the resulting precipitate is taken up in ether, the ether solution is dried with sodium sulphate and the solvent is distilled off.

34.3 g (50% of theory) of 3-(2-chloro-4-biphenylyl)-butyric acid with melting point 117-118°C (from cyclohexane) are obtained.

In the same way, we obtain:

3-(2-fluoro-4-biphenylyl)-butyric acid,

with melting point 96-97°C (from petroleum ether/cyclohexane in volume ratio 1:1) in a yield of 45% of theory from 1-(2-fluoro-4-biphenylyl)-1-ethanol (melting point: 84-85°C (from cyclohexane)).

Example 11

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester and

2- acetyl- 3-( 2- fluoro- 4- biphenylyl)- butyric acid ethyl ester

To a solution of 5.80 g (0.252 mol) of sodium in 150 ml of absolute ethanol, while stirring, 32.7 g (0.252 mol) of acetoacetic acid ethyl ester is added dropwise and the stirring is continued for a further 30 minutes, then the solution is added dropwise with 61.0 g (0.259 mol) 1-chloro-1-(2-fluoro-4-biphenylyl)-ethane in 150 ml of absolute ethanol and then heated for 12 hours under reflux. After cooling, the sodium chloride formed is filtered off and the solvent is distilled off in vacuo. The remaining residue is added to 500 ml of water and the reaction product is taken up in ether. The ether solution is washed with water, dried and freed from solvent, leaving behind a liquid residue which is distilled in a vacuum.

The yield of 60 g of non-uniform product obtained is separated into 2 components column chromatographically on 2 kg of silica gel using first petroleum ether, later a mixture of petroleum ether and methylene

chloride in the volume ratio 9:1 for elution.

According to the spectra and elemental analysis, the first component is 3-(2-fluoro-4-biphenylyl)-butyric acid with kpQ 1 ^ 155-165°C, melting point: 56-56.5°C (petroleum ether).

The yield amounts to 13.21 g (18% of theory).

The second component is a mixture of both possible diastereomers (H-NMR spectrum) of 2-acetyl-3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester in the approximate quantity ratio 1:1 with kpQ x ^ Hg 160 -180°C. The yield amounts to 15.0 g (18% of theory).

C20H2]F03 (328.38)

Calculated: C 73.15 H 6.45

found: C 73.40 H 6.46

Example 12

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

To a solution of 75 mg sodium in 4.00 g (0.087 mol) absolute ethanol, 11.80 g (0.036 mol) 2-acetyl-3-(2-fluoro-4-biphenylyl-butyric acid ethyl ester) is added and the reaction mixture is heated so that the resulting ethanol/ethyl acetate mixture is passed dropwise over a 10-cm Vigreux column. After about 2\ hours, 4.00 g of absolute ethanol is added again. The reaction is finished after 5 hours. After this time, excess ethanol is distilled off, the remaining residue is added to 150 ml of 5% hydrochloric acid and taken up in ether. The solvent is distilled off from the water-washed ether solution. The remaining residue is distilled under fine vacuum and 8.42 g (82% of theory) of 3-(2-fluoro-4- biphenylyl)-butyric acid ethyl ester [jhed bp^ , TT<1>50-170°C, melting point: 56-56.5°C (from petroleum ether).

^0.1 mm Hg

Example 13

3-(2-fluoro-4-biphenylyl)-butyric acid

9.0 g. (0.0314 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester is dissolved in 150 ml of methanol, 30% potassium hydroxide is added until a strong alkaline reaction occurs and the mixture is heated under reflux for 30 minutes. The solvent is then distilled off, the remaining solid residue is dissolved in water and acidified with dilute hydrochloric acid. The precipitated acid is filtered off, washed with water, dried and recrystallized from cyclohexane/petroleum ether in the volume ratio 1:1. 3-(2-Fluoro-4-biphenylyl)-butyric acid melts at 96-97°C. The yield amounts to 6.7 g (83% of theory).

Example 14.

3-(2-fluoro-4-biphenylyl)-butyric acid

While stirring, 42.6 g (0.28 mol) of acetoacetic acid ethyl ester sodium salt are dissolved in 200 ml of absolute ethanol, then 59.5 g (0.252 mol) of 1-chloro-1-(2-fluoro-4-biphenylyl) are added dropwise. -ethane and then heated for 30 minutes under reflux. After cooling, the formed sodium chloride is suctioned off and the solvent is distilled off in vacuum from the filtrate. The remaining residue is added to 300 ml of water, the reaction product is taken up in ether and the ether solution is washed with water, dried over sodium sulphate and freed from solvent, leaving a liquid residue which is distilled in vacuum.

The above-mentioned ester is obtained as a colorless liquid with

bp,_ , „ 155-167°C in a yield of 50.5 g (61% of theory).

0.1 mm Hg J ■

Example 15

3-(2-chloro-4-biphenylyl)-butyric acid

To a solution of 2.53 g (0.11 mol) of sodium in 70 ml of absolute ethanol, 14.3 g (0.11 mol) of acet- are added dropwise while stirring. acetic acid ethyl ester, stirring is continued for a further 30 minutes, then 25.1 g (0.10 mol) of 1-chloro-1-(2-chloro-4-biphenylyl)-ethane are added dropwise and then heated for 30 minutes under reflux. After cooling, the formed sodium chloride is suctioned off and the solvent is distilled off from the filtrate in vacuum. The remaining residue is added to 250 ml of water and then taken up in ether. The ether solution is then washed with water, dried and freed of solvent, leaving a liquid residue which is added to a solution of 280 mg (0.0122 mol) sodium in 16.0 g (0.348 mol) absolute ethanol, after which the reaction mixture is heated as follows that the ethanol/acetic ester mixture formed drop by drop passes over via a 10 cm Vigreux column. After approx. After 2 hours, 16.0 g of absolute ethanol is added once. The reaction is finished after 5 hours. Then 500 ml of methanol is added and 30% caustic soda is added to the solution until a strong alkaline reaction.' It is then heated for 30 minutes under reflux and the solvent is distilled off. The residue is added to 250 ml of water and shaken with ether. The ether solution is discarded. The aqueous alkaline solution is acidified with dilute hydrochloric acid and extracted with ether. The ether solution is washed with water, dried and freed from solvent. The remaining residue is dissolved in 400 ml of acetone/ethyl acetate (1:1) and cyclohexylamine is added for an alkaline reaction. The formed precipitate is filtered off and washed with ethyl acetate. From the thus treated cyclohexylamine salt, the desired 3-(2-chloro-4-biphenylyl)-butyric acid is released by treatment with 10% hydrochloric acid, which after recrystallization from

cyclohexane melts at 117-118°C.

Example 16

: 3-(2-fluoro-4-biphenylyl)-butyric acid

a) [ 1-( 2- fluoro- 4- biphenylyl)- 1- ethyl]-( triphenylphosphoranylidene)-acetic acid ethyl ester

69.7 g (0.20 mol) of tri±phenylphosphine-ethoxycarbonylmethylene (melting point: 124-125°C) is heated with 27.9 g (0.10 mol) of 1-bromo-1-(2-fluoro-4-biphenylyl )-ethane in 300 ml of absolute acetic acid ethyl ester for 54 hours under stirring and under reflux. It is then suctioned off

precipitated carbethoxymethyl-triphenyl-phosphonium bromide and discarded. From the filtrate, the solvent is distilled off in vacuo and [1-(2-fluoro-4-biphenylyl)-1-ethyl]-(triphenylphosphoranylidene)-acetic acid ethyl ester is obtained as a thick liquid, which is further processed as a crude product.

b) 3-(2-fluoro-4-biphenylyl)-butyric acid

The crude ester obtained according to 17a is dissolved in 500 ml of methanol,

150 ml of 20% cabbage lye is added and then heated for one hour under reflux. The methanol is then distilled off, the residue is added to 600 ml of water and the mixture is shaken twice with 200 ml of ether each time. The ether solution is discarded. The aqueous solution is then acidified with dilute hydrochloric acid and the precipitate is taken up in ether. The ether solution is washed with water, dried and freed from solvent.

13.1 g (51% of theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid with melting point 96-97°C (from petroleum ether/cyclohexane) in the volume ratio 1:1) are obtained.

Example 17

3-(2-chloro-4-biphenylyl)-butyric acid

a) [ 1-( 2- chloro- 4- biphenylyl)- 1- ethyl]-( triphenylphosphoranylidene)-acetic acid ethyl ester

7.55 g. (0.0256 mol) . 1-(2-chloro-4-biphenylyl)-1-bromoethane and 17.4 g (0.050 mol) of triphenylphosphine-ethoxy-carbonylmethylene are heated in 100 ml of absolute ethyl acetate for 84 hours under reflux, the procedure is as described in example 16a and the above-mentioned ester is obtained as a semi-solid product which is processed further without further purification.

b), 3-(2-chloro-4-biphenylyl)-butyric acid

The crude ester obtained from example 17a is used and that

work as described in example 16a, whereby the desired 3-(2-chloro-4-biphenylyl)-butyric acid is obtained, which after recrystallization from cyclo-

hexane melts at 117-118°C. The yield amounts to 2.96 g (43% of theory).

Example 18

3-(2-fluoro-4-biphenylyl)-butyric acid

While stirring and switching on a water separator, a mixture of 107 g (0.50 mol) 4-acetyl-2-fluoro-biphenyl, 42.5 g (0.50 mol) cyanoacetic acid, 7.5 g ammonium acetate and 12.5 ml of glacial acetic acid in 100 ml of benzene for 40 hours under reflux, then cool, the separated solid precipitate is suctioned off and it is washed well with water. The crude 2-cyano-3-(2-fluoro-4-biphenylyl)-2-butenoic acid obtained is heated in 560 ml of glacial acetic acid with 1100 ml of hydroiodic acid (density 2.0) for 3 hours in an oil bath with stirring and reflux. The reaction mixture is then introduced into water and the separated oil is taken up in ether. The ether solution is decoloured with sodium hydrogen sulphite solution, washed several times with water, dried and freed from solvent. After the remaining, crystalline solidified residue has been dissolved in ethyl acetate, cyclohexylamine is added, whereby the cyclohexylamine salt of 3-(2-fluoro-4-biphenylyl)-butyric acid is precipitated. The melting point for the free acid is after recrystallization from cyclohexane/petroleum ether (volume ratio 1:1) at 96-97°C. The yield amounts to 41.4 g (32% of theory).

Example 19

3-(2-fluoro-4-biphenylyl)-butyric acid

While stirring and switching on a water separator, a mixture of 107 g (0.50 mol) 4-acetyl-2-fluoro-biphenyl, 56.5 g (0.50 mol) cyanoacetic acid ester, 200 ml benzene, 7.7 is heated. g (0.10 mol) ammonium acetate and 24 g (0.4 mol) glacial acetic acid for 9 hours under reflux. The reaction mixture is then cooled, it is shaken twice with water, dried and the solvent is distilled off. The remaining residue is boiled in a mixture of 560 ml of glacial acetic acid and 1100 ml of hydroiodic acid (d 2.0) for 3 hours under reflux and further processed in the same way as described in example 18. The desired 3-(2-fluoro-4-biphenylyl )-butyric acid with m.p. 96-97°C (from cyclohexane/petroleum ether) is obtained in a yield of 41% of theory.

Example 20

3-(2-chloro-4-biphenylyl)-butyric acid

A mixture of 23.01 g (0.10 mol) 4-acetyl-2-chloro-biphenyl, 8.5 g (0.10 mol) cyanoacetic acid > 1.5 g ammonium acetate and 2.5 ml glacial acetic acid in 50 ml benzene is heated with stirring and switching on a water separator for 12 hours under reflux. Processing takes place as described in example 18.

The crude 2-cyano-3-(2-chloro-4-biphenylyl)-2-butenoic acid obtained is further processed as described in example 18.

The desired 3-(2-chloro-4-biphenylyl)-butyric acid is obtained in a yield of 10.4 g (38% of theory).

Melting point after recrystallization from cyclohexane: 117-118°C.

Example 21

3-(2-chloro-4-biphenylyl)-butyric acid

A mixture of 57.7 g (0.25 mol) 4-acetyl-2-chloro-biphenyl, 28.25 g (0.25 mol) cyanoacetic acid ester, 3.85 g ammonium acetate and 12 ml glacial acetic acid in 100 ml benzene is heated under stirring and switching on a water separator for 9 hours under reflux. The processing takes place as in example 20 and the obtained 2-cyano-3-(2-chloro-4-biphenylyl)-2-butenoic acid ethyl ester is reacted in the same way as in example 18 with glacial acetic acid and hydroiodic acid. After work-up, the cyclohexylamine salt of 3-(2-chloro-4-biphenylyl)-butyric acid is obtained in a yield of 58% of theory.

The free acid melts at 117-118°C (from cyclohexane).

Example 22

3-(2-fluoro-4-biphenylyl)-butyric acid

To 20 g of amalgamated zinc dust (Org. Synth. Coll. Vol. II,

p. 499) is added in order 70 ml toluene, 15 ml water, 35 ml conc. hydrochloric acid and 10 g (0.0356 mol) crude, according to example 18 obtained 2-cyano-3-(2-fluoro-4-biphenylyl)-2-butenoic acid and this mixture is heated in total for 3% hour while stirring under reflux, whereby after lh hours, a further 20 ml conc. is added. hydrochloric acid. The mixture is then cooled, decanted from zinc and extracted with ether. The solvent is evaporated from the ether solution, which is washed with water. The remaining 2-cyano-3-(2-fluoro-4-biphenylyl)-butyric acid is heated without further purification with 50 ml of glacial acetic acid and 50 ml of conc. hydrochloric acid for 8 hours under reflux, whereby after 2 and 4 hours 20 ml conc. hydrochloric acid every time. After cooling, shake off with ether, the ether solution is washed with water, dried and the solvent is distilled off, whereby 3-(2-fluoro-4-biphenylyl)-butyric acid remains. For purification, this acid is transferred into the cyclohexylamine salt, which is recrystallized from acetone. The acid quaternized from the salt melts after recrystallization from cyclohexane/petroleum ether (volume ratio 1:1)

at 96-97°C. The yield amounts to 4.15 g (45% of theory).

Example 2 3

3-(2-fluoro-4-biphenylyl)-butyric acid

2.50 g (0.0088 mol) of crude 2-cyano-3-(2-fluoro-4-biphenylyl)-butyric acid obtained according to example 22 is heated with 7 ml of hydroiodic acid (d, 2.00) in 10 ml of glacial acetic acid for 8 hours while stirring under reflux, After cooling, shake out with ether. The ether solution is washed with sodium hydrogen sulphite solution and then with water and dried. The crude 3-(2-fluoro-•4-biphenylyl)-butyric acid which remains after distilling off the solvent is transferred into the cyclohexylamine salt. The resulting acid melts at 96-97°C (petroleum ether/cyclohexane). The yield amounts to 1.48 g (65% of theory).

Example 2 4

3-(2-fluoro-4-biphenylyl)-butyric acid

To 20 g of amalgamated zinc dust, 70 ml of toluene, 15 ml of water, 35 ml of conc. hydrochloric acid and 10 g (0.0324 mol) crude, according to . example.. 19 obtained 2-cyano-3-(2-fluoro-4-biphenylyl)-butenoic acid ethyl ester and this mixture is heated for a total of 5 hours while stirring at reflux. The mixture is allowed to cool, decanted from zinc and extracted with ether. The ether solution is washed with water and evaporated. The remaining 2-cyano-3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester with bp_ 171-174°C is heated with 3.4 g (0.0612 mol) of potassium hydroxide in 50 ml of ethylene glycol for 8 hours at an external temperature of 160°C. After cooling, plenty of water is added and it is shaken with ether. The aqueous alkaline solution is then acidified with dilute hydrochloric acid and the precipitated product is taken up in ether. The solvent is distilled from the ether solution washed with water, dried and filtered over activated charcoal. The remaining residue is dissolved in ethyl acetate. By adding cyclohexylamine, the cyclohexylamine salt of 3-(2-fluoro-4-biphenylyl)-butyric acid is obtained.

The acid liberated therefrom melts at 96-97°C (from cyclohexane/petroleum ether in the volume ratio 1:1). The yield was 1.72 g (20% of theory).

Example 25

3-(2-fluoro-4-biphenylyl)-butyric acid

Under stirring and switching on a water separator, 21.42 g. (0.10 mol) 4-acetyl-2-fluoro-bipheyl, 6.60 g. (0.10 mol) malonic acid dinitrile and .1.5 g ammonium acetate are heated in 70 ml of benzene while adding 2.5 ml of glacial acetic acid for 5 hours under reflux. The warm

the solution is filtered over activated charcoal and then petroleum ether is added

(150 ml) whereby a precipitate falls out which is suctioned off. The 2-cyano-3-(2-fluoro-4-biphenylyl)-2-butenoic acid nitrile obtained is heated without further purification with 240 ml of hydroiodic acid (d 2.00) and 120 ml of glacial acetic acid for 5 hours under reflux. The preparation takes place in the same way as described in example 18. 3.73 g (10% of theory) of the cyclohexylamine salt of 3-(2-fluoro-4-biphenylyl)-butyric acid with m.p. 173-174°C (from acetone). The acid liberated therefrom melts after recrystallization from cyclohexane/petroleum ether (volume ratio 1:1) at 96-97°C.

Example 26

3-(2-fluoro-4-biphenylyl)-butyric acid

While stirring and switching on a water separator, 21.42 g (0.10 mol) 4-acetyl-2-fluoro-biphenyl, 8.40 g (0.10 mol) cyanoacetamide, 1.5 g ammonium acetate and 2.5 ml glacial acetic acid in 50 ml of benzene for 18 hours under reflux. After cooling, the separated precipitate is suctioned off and washed first with benzene and then with water. Without further purification, the 2-cyano-3-(2-fluoro-4-biphenylyl)-2-butenoic acid amide obtained is heated with 900 ml of hydroiodic acid (d 2.00) and 450 ml of glacial acetic acid for 3 hours under reflux. Processing takes place as described

in example 18. After purification over the cyclohexylamine salt, 4.03 g (16% of theory) are obtained of: 3-(2-fluoro-4-biphenylyl)-butyric acid with m.p. 96-97°C (after recrystallization from petroleum ether/cyclohexane).

Example 27

3-(2-fluoro-4-biphenylyl)-butyric acid

To 4 g of amalgamated zinc, 25 ml of toluene, 6.5 ml of water, 12 ml of conc. hydrochloric acid and 2.00 g (0.00707 mol) of 2-cyano-3-(2-fluoro-4-biphenylyl)-2-butenoic acid amide and this mixture is heated for a total of .3 hours with stirring and reflux. The mixture is then cooled, it is decanted from zinc and the mixture is extracted with ether. The solvent is evaporated from the ether phase, which is washed with water.

The remaining crude 2-cyano-3-(2-fluoro-4-biphenylyl)-butyric acid amide is stirred without further purification with 0.5 g (0.01 mol)

potassium hydroxide in 10 ml of ethylene glycol for 3 hours at an external temperature of 160°C. Processing takes place in the same way as described in example 24.

0.6.8 g is obtained; (27% of theory) of the cyclohexylamine salt of 3-(2-fluoro-4-biphenylyl)-butyric acid with melting point 173-174°C (from acetone). The released acid melts at 96-97°C (after

recrystallization from petroleum ether/cyclohexane).

Example 2 8

3-(2-fluoro-4-biphenylyl)-butyric acid

6.18 g (0.02 mol) of 2-cyano-3-(2-fluoro-4-biphenylyl)-2-butenoic acid ethyl ester are hydrated in 50 ml of benzene/methanol (1:1) with the addition of 0.5 g of platinum ( IV)oxide at room temperature and.2 atm. Print. After absorption of the calculated amount of hydrogen, the catalyst is filtered off and the solvent is distilled off in a vacuum. The remaining colorless liquid consisting of 2-cyano-3-(2-fluoro-4-biphenylyl)-butyric acid-

ethyl ester with bp_ _ ^<1>77-181°C is heated in 25 ml of ethanol with

0.3 mmHg

38 ml 2n caustic soda for a short time at 40°C, the mixture is then left to stand

4 hours at room temperature, water is added and acidified with diluted

hydrochloric acid. The precipitate is filtered off, dissolved in ether and, after drying, the solvent is distilled off. The obtained crude 2-cyano-3-(2-fluoro-4-biphenylyl)-butyric acid is heated above the melting point for so long that carbon dioxide is no longer evolved. The remaining residue, which partially crystallizes and consists of crude 3-(2-fluoro-4-biphenylyl)-butyronitrile, is heated in 30 ml of ethylene glycol with the addition of 2.24 g (0.040 mol) of potassium hydroxide for 3 hours at 160 °C with stirring. The reaction mixture is then diluted with water, extracted with ether and the ether solution discarded. The aqueous phase is acidified with dilute hydrochloric acid and the precipitate is taken up in ether. After filtering over charcoal, the solvent is distilled off.

1.45 g (28% of theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid are obtained, which is recrystallized from cyclohexane/petroleum ether and then melts at 96-97°C.

Example 29

3-(2-fluoro-4-biphenylyl)-butyric acid

a) 4, 4- dimethyl- 2-[ 2-( 2- fluoro- 4- biphenylyl)- 1- propyl]- 2- oxazoline

Into a 1 liter wooden-necked flask equipped with a stirrer, low-temperature thermometer and dropping funnel, introduce 150 ml of absolute ether. After filling the ■ apparatus with dry, oxygen- and carbon dioxide-free nitrogen, 2.29 g (0.33 mol) of lithium are cut up directly into the reaction flask while still introducing nitrogen. Then, while stirring, add approx. 30 drops of a solution of 41.0 g (0.299 mol) of n-butyl bromide in 80 ml of ether and the reaction mixture

cooled by means of a dry ice^methanol bath of -30 to -40 C to a temperature of -10°C. Once the reaction has started, the solution becomes

faintly cloudy and bright spots appear on the lithium. The remainder of the n-butyl bromide is then added in equal portions and while maintaining an internal temperature of -10°C over the course of 30 minutes. After the addition is finished, the mixture is allowed to heat up with stirring for 90 minutes to 0°C. While maintaining this temperature, a solution of 34.0 g (0.30 mol) 2,4,4-trimethyl-2-oxazoline in 50 ml of absolute tetrahydrofuran and finally a solution of 48.2 g. (0.173 mol) 1-bromo-1-(2-fluoro-4-biphenylyl)-ethane in 1100 ml of dry tetrahydrofuran. Finally, the solution is allowed to stand for 90 minutes with stirring at 0°C. The resulting mixture is filtered over glass wool, the filtrate is evaporated in vacuo, and the residue is chromatographed on 2 kg of silica gel using a with a few drops of conc. ammonia added mixture of 8 parts by volume benzene and 2 parts by volume ethyl acetate for elution. The progress of the column chromatographic purification is continuously monitored in thin-layer chromatograms. By evaporation of the eluate, 13.2 g (25% of theory) of a colourless, highly viscous oil are obtained.

C20H22FNO (311.40)

Calculated: C 77.14 H 7.12 N 4.50

Found: C 76.90 H 7.09 N 4.5 8

b) 3-(2-fluoro-4-biphenylyl)-butyric acid

2.00 g (0.00643 mol) of 4,4-dimethyl-2-[2-(2-fluoro-4-biphenylyl)-1-propyl]-2-oxazblin are dissolved in 20 ml of 3N hydrochloric acid and boiled under bake for 30 minutes. After cooling, dilute with 100 ml of water and extract thoroughly with ether. The ether extracts are washed with water, dried over sodium sulphate and evaporated in vacuo. The remaining oil is crystallized by trituration with petroleum ether and then recrystallized twice from petroleum ether/cyclohexane (volume ratio 1:1).

Melting point: 96-97°C. Yield: 1.15 g (69% of theory).

Example 30

3-(2-fluoro-4-biphenylyl)-butyric acid

To a suspension of lithium amide in 320 ml of liquid ammonia prepared by the action of a spatula tip of iron(III) nitrate nonahydrate on a solution of 1.11 g (0.16 mol) of lithium in ammonia, is added dropwise, maintaining a reaction temperature of - 40°C 18.6 g (0.16 mol) anhydrous acetic acid tert-butyl ester, after which the mixture is stirred for a further 45 minutes at the mentioned temperature. Then, still at an internal temperature of -40 C, a solution of -23.6 g (0.085 mol) 1-bromo-1-(2-fluoro-4-biphenylyl)-ethane 1 30 ml of anhydrous ether is added dropwise and the stirring is continued further for 2 hours at -40°C.

All these operations are conveniently carried out under an atmosphere of dry, pure nitrogen.

By portionwise addition of 10.7 g (0.2 mol) of ammonium chloride, the reaction mixture is split, it is diluted with 200 ml of ether and the ammonia is allowed to evaporate overnight. The mixture is then stirred into 300 ml of water, the phases are separated and the water layer is extracted exhaustively with ether. The combined ether phases are washed three times with each time 100 ml of water, dried over sodium sulphate and evaporated.

The thus obtained, crude, still highly contaminated 3-(2-fluoro-4-biphenylyl)-butyric acid tert-butyl ester is heated for 2 hours to 200°C. Thereafter, no ester can be detected by thin-layer chromatography in a sample that is taken. After cooling, the reaction product is taken up in 500 ml of ether, the solution is washed once with 200 ml of water, it is dried over sodium sulphate and evaporated. The remaining oil residue is dissolved in hot acetone and transferred to the corresponding salt by treatment with cyclohexylamine.

Melting point: 173-174°C (from acetone).

The free acid melts after recrystallization from cyclohexane/petroleum ether (volume ratio 1:1) at 96-97°C and according to mixed melting point and thin layer chromatogram is identical to a preparation prepared according to example 1.

The yield amounts to 5.5 g (25% of theory).

Example 31

3-(2-fluoro-4-biphenylyl)-butyric acid

a) 2-[ 2-( 2- fluoro- 4- biphenylyl)- 1- hydroxy- 1- propyl]- 1, 3- dithiane

A solution of n-butyl lithium-i is added under nitrogen

n-hexane (34.8 ml of a 3.13 molar solution, 0.109 mol) over 15 minutes to a -30°C cooled solution of 12.5 g (0.106 mol) of 1,3-dithiane in 105 ml absolute tetrahydrofuran. Then stir in

5 hours at -20 to -30°C. A solution of 2 3.8 g (0.104 mol) 2-(2-fluoro-4-biphenylyl)-propionaldehyde in 30 ml anhydrous tetrahydrofuran is then added to the mixture cooled to -78°C, the mixture is allowed to warm slowly to room temperature and stand at this temperature overnight. After dilution with the fivefold volume of water, extract completely with ether. The combined ether extracts are washed with 10% caustic soda and water, dried over sodium sulfate and evaporated. The crude product obtained in a yield of 32.5 g (90% of theory) with Rp = 0.274: ("Merck-DC-Fertigplatten, Kieselgel F-254", benzene as eluent) is further processed without further purification.

b) 2-[2-(2-fluoro-4-biphenylyl)-propylidene]-!,3-dithiane

32.0 g (0.092 mol) of 2-[2-(2-fluoro-4-biphenylyl)-1-hydroxyl-propyl]-1,3-dithiane is dissolved in 400 ml of benzene and boiled for 2 hours with a water separator after the addition of 3, 5 g of p-toluenesulfonic acid. After completion of the water separation, the mixture is allowed to cool, after which it is washed with water, saturated sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate and evaporated in vacuo. The red-brown oil obtained is purified by column chromatography using benzene for elution on 1 kg of silica gel, whereby a yellow, non-crystallizing oil is isolated in a yield of 6.9 g (23% of theory), which according to spectroscopic examination is not completely uniform, but which contains the sought-after title compound and is therefore processed further without further purification operations. c) 3-(2-fluoro-4-biphenylyl)-butyric acid A mixture of 6.7 g. (0.0197 mol) 2-[2-(2-fluoro-4-biphenylyl)-propylidene]-1, 3-dithiane, 105 ml glacial acetic acid and 35 ml conc. hydrochloric acid is boiled for 7 hours under reflux. The mixture is then evaporated in vacuo, stirred into 200 ml of water and the product is taken up in ether. The ether phase is washed several times with water, dried over sodium sulphate and evaporated. The residue is purified by transfer into the cyclohexylammonium salt. Melting point: 173-174°C (from acetone).- From this salt the desired 3-(2-fluoro-4-biphenylyl)-butyric acid is released, which after recrystallization from cyclohexair/petroleum ether (volume ratio 1:1 ) melts at 96-97°C. According to the thin-layer chromatogram own mixed melting point, the product is identical to a preparation synthesized according to example 1. Dividend: 2.15. g (42% of theory).

Example 32

3-(2-fluoro-4-biphenylyl)-butyric acid

a) 2-(2-fluoro-4-biphenylyl)-propionyl chloride

25.1 g. (0.103 mol) 2-(2-fluoro-4-biphenylyl)-propionic acid

110 ml (1.5 3 mol) of thionyl chloride are poured over and boiled under reflux and moisture connection until gas evolution has ended.

Excess thionyl chloride is then distilled off on a water bath, twice 10 ml of dry benzene are added to the residue and evaporated under vacuum. The crude product obtained in a yield of 24.9 g (92% of theory) can be further processed without further purification.

b) 1-diazo-3-(2-fluoro-4-biphenylyl)-2-butanone

To a solution dried over potassium hydroxide of 0.2 6 mol

diazdmethane (from N-methyl-N-nitroso-p-toluenesulfonamide) in 490 ml of ether is added dropwise to a solution of: 31.1 g (0.118 mol) 2-(2-fluoro-4-biphenylyl)-propionyl chloride in 100 ml of absolute benzene, whereby the temperature in the mixture is kept at -22 to -20°C by external cooling. It is then stirred for a further 30 minutes at this temperature, the cold bath is removed and the mixture is allowed to stand overnight until it reaches room temperature. The solvents are distilled off in a vacuum and 31.3 g are obtained

(99% of theory) crude 1-diazd-3-(2-fluoro-4-biphenylyl)-2-butanone which is processed further without further purification.

c) 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

Dissolve 31.0 g (0.115 mol) 1-diazo-3-(2-fluoro-4-biphenylyl)-2-butanone in hot ethanol, add while stirring a total of 5.0 g of freshly prepared silver(I) oxide in small portions during approx. 3 hours, whereby a temperature of 50 to 55°C is regulated. The mixture is kept for a further 3 hours at this temperature, it is filtered and the filtrate is evaporated. The residue is taken up in ether, filtered and evaporated to dryness. The product is distilled in vacuum: kp^ ^c TT<1>28-

^0.05 mm Hg 130 C.

Yield: 5.9 g (18% of theory). When pulling out with

petroleum ether, the substance can be brought to crystallize.

Melting point: 56-56.5°C (from petroleum ether).

d) 3-(2-fluoro-4-biphenylyl)-butyric acid

5.8 g (0.0202 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester are dissolved in 150 ml of methanol and heated on a water bath after adding 30 ml of 0.ln sodium hydroxide solution for 30 minutes. The methanol is distilled off to approx. four fifths in vacuum, the residue is diluted with 200 ml of water and brought to pH 3 first with concentrated and then with 5% hydrochloric acid. The separated carboxylic acid is taken up in ether, the ether solution is washed twice with water, dried over sodium sulphate and evaporated. The residue melts after two recrystallizations from petroleum ether/cyclohexane. (volume ratio 1:1) at 96-97°C, the yield amounts to 5.15 g (99% of theory).

Example 33

3-(2-fluoro-4-biphenylyl)-butyric acid

2.1 g (0.086 mol) of magnesium is reacted with a solution of 24.6 g (0.084 mol) of 1-bromo-2-(2-fluoro-4-biphenylyl)-propane (prepared from 2-(2-fluoro-4 -biphenylyl)-1-propanol with phosphorus tribromide) in 400 ml of dry ether at 30-35°C to Grignard reagent. The cooled solution is decanted from magnesium residues and it is poured while stirring in small portions of approx. 50 g solid, split carbon dioxide. After evaporation of excess carbon dioxide, hydrochloric acid is added, the ether phase is separated and the aqueous solution is exhausted. The dry residue obtained from the combined ether solutions is taken up in ethyl acetate and combined with cyclohexylamine. 13.7 g of the cyclohexylamine salt are obtained (corresponding to 46% of theory) with a melting point of 173-174°C (from acetone).

The free 3-(2-fluoro-4-biphenylyl)-butyric acid melts at 96-97°C (from cyclohexane/petroleum ether in volume ratio 1:1).

Example 34

3-(2-fluoro-4-biphenylyl)-butyric acid

To a suspension of 7.30 g (0.0299 mol) 3-(2-fluoro-4-biphenylyl)-1-butanol, 2.24 g (0.040 mol) potassium hydroxide and 150 ml water are added dropwise at approx. 10°C during one hour a solution of 7.9 g (0.05 mol) of potassium permanganate in 600 ml of water. It is then stirred for two hours at room temperature and 4 hours at 60°C. After cooling, the precipitate is filtered off and washed with warm water. The permanganate-free aqueous portion is extracted, the aqueous solution is acidified and, by extraction with ether and ethylene chloride, the crude carboxylic acid is obtained, which is purified by chromatography on silica gel. After recrystallization from cyclohexane/petroleum ether (volume ratio 1:1), the pure 3-(2-fluoro-4-biphenylyl)-butyric acid melts at 96-97°C. Yield: 0.66 g (9% of theory).

Example 35

3-(2-fluoro-4-biphenylyl)-butyric acid

A solution of 2.70 g (0.0111 mol) 3-(2-fluoro) -4-biphenylyl)-butyraldehyde (bpQ Q4<1>18-122°C) in 25 ml of ethanol. It is heated for 8 hours under reflux and filtered off from undissolved matter. The filtrate is acidified after cooling with 2N nitric acid. The precipitate is filtered off and washed with water. 2.58 g (90% of theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid with melting point 96-97°C are obtained (from cyclohexane/petroleum ether in the volume ratio 1:1).-

Example 36

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 5 from crude 3-(2-chloro-4-biphenylyl)-2-butenoic acid ethyl ester.

Yield: 77% of theory. Melting point: 117-118°C (cyclohexane).

Example 37

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 6 from crude 3-(2-chloro-4-biphenylyl)-3-hydroxybutyric acid.

Yield: 49% of theory. Melting point: H7>-118°C (cyclohexane).

Example. 38

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 7 from crude 3-(2-chloro-4-biphenylyl)-2-butenoic acid.

Yield: 71% of theory. Melting point: 116-118°C (cyclohexane).

Example 39

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 9 from 3-(2-chloro-4-biphenylyl)-3-hydroxybutyric acid.

Yield: 85% of theory. Melting point: 117-118°C (cyclohexane) -.

Example 40

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to example 22 from crude, according to example 20 obtained 2-cyano-3-(2-chloro-4-biphenylyl)-2-butenoic acid.

Yield: 37% of theory. Melting point: 117-118°C (cyclohexane)..

Example 41

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to example 24 from crude, according to example 21 obtained 2-cyano-3-(2-chloro-4-biphenylyl)-2-butenoic acid ethyl ester. Yield: 51% of theory. Melting point: 117-118°C (cyclohexane).

Example 42 ...

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 2 5 from 4-acetyl-2-chloro-biphenyl and malonic acid dinitrile.

Yield: 14% of theory. Melting point: 117-118°C (cyclohexane).

Example 43

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 26 from 4-acetyl-2-chloro-biphenyl and cyanoacetamide.

Yield: 12% of theory. Melting point: 117-118°C (cyclohexane).

Example 44

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to example 27 from 2-cyano-3-(2-chloro-4-biphenylyl)-2-butenoic acid amide, which in the preceding example acts as an intermediate, zinc and hydrochloric acid.

Yield: 22% of theory. Melting point: 117-118°C.

Example 45

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 28 from 2-cyano-3-(2-chloro-4-biphenylyl)-2-butenoic acid ethyl ester.

Yield: 31% of theory. Melting point: 117-118°C (cyclohexane).

Example 4 6

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 29 from 1-bromo-1-(2-chloro-4-biphenylyl)-ethane and 2,4,4-trimethyl-oxazoline.

Total yield: 18% of theory. Melting point: 117-118°C (cyclohexane).

Example 4 7.

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared from 1-bromo-1-(2-chloro-4-biphenylyl)-ethane and acetic acid-tert. butyl ester analogous to example 30.

Yield: 24% of theory. Melting point: 116-118°C.

Example 4 8

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 31 from 2-(2-chloro-4-biphenylyl)-propionaldehyde and 1,3-dithiane.

Total yield: 84% of theory. Melting point: 117-118°C (cyclohexane).

Example 49

3-(2-chloro-4-biphenylyl)-butyric acid ethyl ester

Prepared analogously to Example 32 from 2-(2-chloro-4-biphenylyl)-propionic acid.

Yield: 15% of theory. Kp0>004 ^ Rg<1>30-132°C.

Example 50

■ 3-(2-chloro-4-biphenylyl)-butyric acid.

Prepared analogous example 32d from 3-(2-chloro-4-biphenylyl)-

butyric acid ethyl ester.

Yield: 82% of theory. Melting point: 117-118°C (cyclohexane).

Example 51

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to Example 33 from 1-bromo-2-(2-chloro-4-biphenylyl)-propane.

Yield: 38% of theory. Melting point: 117-118°C (cyclohexane).

Example 52

3- ( 2- chloro- 4- biphenylyl)^ butyric acid

Prepared analogously to 34 from 3-(2-chloro-4-biphenylyl)-1-butanol by oxidation with aqueous alkaline potassium permanganate solution. Yield: 7% of theory. Melting point: 117-118°C (cyclohexane).

Example 53

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to example 35 from 3-(2-chloro-4-biphenylyl)-butyraldehyde by oxidation with silver oxide in aqueous-ethanolic solution.

Yield: 82% of theory. Melting point: 117-118°C (cyclohexane).

Example 54

3-(2-fluoro-4-biphenylyl)-butyric acid amide

A solution of 10.35 g (0.0375 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid chloride, obtained as in Example 8, in 40 ml of acetone is added dropwise at a temperature of 10°C with stirring to 75 ml 30% aqueous ammonia solution. After the addition is complete, stir for a further 15 minutes, the reaction solution is then introduced into 300 ml of water, the precipitate formed is suctioned off and washed well with water. The crude product is then dissolved in acetic acid ethyl ester/diethyl ether. (1:1), dried and the solvent distilled off. The remaining residue is recrystallized from ethanol. 7.5 g (78% of theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid amide with melting point 120-121°C are obtained.

Example 55

3-(2-fluoro-4-biphenylyl)-butyric acid amide

In a melt of 4.4. g (0.017 mol): 3-(2-fluoro-4-biphenyl)-butyric acid, a stream of ammonia is introduced. It is heated for 3 hours to 120-130°C, then 4 hours, at 180-190°C and the mixture is allowed to cool. Yield: 3.4 g (78% of theory). Melting point: 120-121°C (ethanol).

Example 56

3-(2-fluoro-4-biphenylyl)-butyric acid amide

12.9 g (0.05 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid are dissolved in 75 ml of absolute tetrahydrofuran and, with stirring, 5.05 g. (0.05 mol) of absolute triethylamine are added dropwise. 5.4 g (0.05 mol) ethyl chloroformate is added dropwise to the solution cooled to -20 to -30°C. It is stirred for a further 15 minutes at this temperature, dry ammonia gas is introduced until a clear ammoniacal reaction occurs, it is stirred for a further 4 hours at room temperature and the mixture is allowed to stand for 12 hours. The residue remaining after distilling off the solvent is taken up in ether and the ether solution is successively shaken with dilute hydrochloric acid, water, dilute ammonia and then again with water. The solvent is distilled off from the ether solution and the remaining solid residue is recrystallized from ethanol. The desired 3-(2-fluoro-4-biphenylyl)-butyric acid amide with melting point 120-121°C is obtained in a yield of 6.8 g (53% of theory).

Example 57

3-(2-fluoro-4-biphenylyl)-butyric acid amide

While stirring, 5.97 g (0.025 mol) of 3-(2-fluoro-4-biphenylyl)-butyronitrile (bp,. _ „ 159-165°C) are added to polyphosphoric acid

U/Dmm rig

which is heated to 100 C (prepared from 25 g of 85% phosphoric acid and 32 g of phosphorus pentoxide), the temperature is maintained for 150 minutes, the mixture is then cooled and 200 ml of ice water is added. The thus precipitated viscous oil is taken up in ethyl acetate, washed with water and freed from solvent. The residue is recrystallized from ethanol and 3-(2-fluoro-4-biphenylyl)-butyric acid amide with melting point 120-121°C is thus obtained in a yield of 4.2 g (65% of theory).

Example 58

3-(2-fluoro-4-biphenylyl)-butyric acid amide

A mixture of 6.5 g (0.023 mol) 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester, 100 ml of methanol and 100 ml of 30% aqueous ammonia is heated in an autoclave for 2 hours at 100°C, the mixture is evaporated then to dryness, add 50 ml of water and shake off with ethyl acetate. The acetic acid ethyl ester solution is evaporated and the remaining residue is recrystallized from ethanol. 4.72 g (80% of

the theory) of 3-(2-fluoro-4-biphenylyl)-butyric acid amide with melting point 120-121°C.

Example 59

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

25.83 g (0.1 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid and

100 ml of anhydrous ethanol is added to 1.96 g (0.02 mol) of concentrated sulfuric acid and boiled for 5 hours under reflux and moisture exclusion. The main amount of excess alcohol is then distilled off under reduced pressure and the distillation residue is added to five times the amount of ice water. The organic layer is separated and filtered three times. The combined organic layers are deacidified with concentrated aqueous soda solution, washed neutral with water, dried over sodium sulfate and distilled. Kp^ , TT 154-170°C. Melt-^ ^0.1 mm Hg

point: 44-45 C (from petroleum ether). Yield: 22.7 g (79% of theory).

Example 60

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

25.83 g (0.1 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid and .8.06 g. (0.175 mol) of ethanol, 0.5 g of p-toluenesulfonic acid and 100 ml of chloroform are heated with a water separator under reflux until no more water is secreted.

After the reaction is finished, the solution is allowed to cool, the catalyst acid is washed out with water, saturated sodium hydrogencarbonate solution and again with water, the release agent is distilled off, whereby at the same time the remains of the washing water are transferred, and the residue is distilled under high vacuum. Bp_ „ 149-168°C. Melting point: 44-45°C (from

0.1 mm Hg

petroleum ether). Yield: 21.5 g (75% of theory).

Example 61

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

25.83 g (0.1 mol) 3-(2-fluoro-4-biphenylyl)-butyric acid, 13.82 g ethanol (0.2 mol), 100 ml ethylene chloride and 5 ml concentrated sulfuric acid are heated for 10 hours under reflux and moisture exclusion. After cooling, the lower organic layer is separated, washed with water, saturated aqueous sodium bicarbonate solution and again with water,

the extractant is distilled off and the residue is distilled in vacuum.

Kp^ , „ 150-170°C. Melting point: 44-45°C (petroleum ether).

0.1 mm Hg

Yield: 23.0 g (80% of theory).

Example 62

3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester

0.5 g (0.011 mol) of ethanol in 3 ml of pyridine is added to 2.00 g (0.0072 mol) of 3-(2-fluoro-4-biphenylyl)-butyric acid chloride (prepared as in Example 8) carefully under ice-cooling. It is then heated for 10 minutes in a water bath. It is poured into ice water and carefully acidified with concentrated hydrochloric acid. The ester secreted as oil is taken up in

ether, washed with water, saturated sodium bicarbonate solution and again with water, dried, over sodium sulfate and evaporated. The residue is distilled in vacuum, kp ' mm Hg145-170°C, and recrystallized

(j, x mm rig

then from petroleum ether. 1.45 g (71% of theory) colorless crystals with melting point 44-45°C.

Example 63

3-(2-fluoro-4-biphenylyl)-butyric acid

To a suspension of 2.76 g (0.115 mol) sodium hydride (3.45 g of an 80% suspension in mineral oil) in 150 ml of anhydrous benzene is added dropwise over approx. 30 minutes while maintaining a reaction temperature of 5°C a solution of 20.0 g (0.112 mol) 1,3-dithiane-2-carboxylic acid methyl ester and 35.0 g (0.125 mol) 1-bromo-1-(2-fluoro -4-biphenylyl)-ethane in 90 ml of absolute dimethylformamide,

it is then kept under stirring for 1 hour at 10°C and 12 hours at room temperature, the benzene is distilled off extensively under reduced pressure and the mixture is heated for 1 hour at 30°C after adding a further 100 ml of anhydrous dimethylformamide. The mixture is stirred into 500 ml of ice water, acidified with dilute hydrochloric acid and the precipitated crystalline product is taken up in acetic acid ethyl ester. The combined acetate extracts are washed successively with water, saturated sodium bicarbonate solution and again with water, dried over sodium sulfate and evaporated. The remaining residue, crude 2-[1-(2-fluoro-4-biphenylyl)-1-ethyl]-1,3-dithiane-2-carboxylic acid methyl ester, is boiled without further purification with 8.9 g.(0, 16 mol) of potassium hydroxide and 200 ml of ethanol for 15 hours under reflux. About 2/3 of the ethanol is distilled off, the remaining mixture is stirred into 1 liter of water and the resulting solution is extracted several times with ether. The ether extracts are discarded. The aqueous-alkaline phase is brought to pH 3. by the addition of dilute hydrochloric acid and then extracted exhaustively with acetic acid ethyl ester. The combined acetic ester solutions are washed several times with water, dried over sodium sulfate and evaporated. The remaining yellowish oil crystallizes after extraction with petroleum ether. The crude 2-[1-(2-fluoro-4-biphenylyl)]-1,3-dithiane-2-carboxylic acid thus obtained is dissolved in 200 ml of ethanol and boiled after adding 144 g (approx. 2.46 mol) Raney nickel for 16 hours under reflux. The Raney nickel is filtered off, the filtrate is evaporated in vacuo, the residue, an ordinary oil, is taken up in 10% caustic soda and then extracted several times. The ether extracts are discarded. The aqueous-alkaline phase is acidified with dilute hydrochloric acid and

the precipitated product is taken up in ether. This ether solution is washed with water, dried over sodium sulphate and evaporated. The remaining residue is purified over the cyclohexyl ammonium salt (melting point 173-174°C after recrystallization from acetone). The free acid melts at 96-97°C (from petroleum ether/cyclohexane in the volume ratio 1:1). Yield: 10.7 g (37% of theory).

Example 64

3-(2-chloro-4-biphenylyl)-butyric acid

Prepared analogously to the preceding example from 1-bromo-1-(2-chloro-4-biphenylyl)-ethane and 1,3-dithiane-2-carboxylic acid methyl ester. Yield: ^ 32% of theory. Melting point: 117-118°C (cyclohexane).

The new compounds of the general formula I can be incorporated into the usual pharmaceutical preparation forms for pharmaceutical use, possibly in combination with other active substances of the general formula I. The single dose amounts to 50 to 400 mg, preferably 100 to 300 mg. The daily dose amounts to 100 to 1000 mg, preferably 150 to 600 mg.

Claims (3)

1. Analogy method for the production of pharmacological ac tive biphenyl derivatives of the general formula I where means a chlorine or fluorine atom, and B means a hydroxy group, an alkoxy or araloxy group or an amino group, and, if B represents a hydroxy group, salts thereof with inorganic or organic bases, characterized in that a) For the preparation of compounds with the general formula I where B means a hydroxy group, a compound is reacted with the general formula formula II where R^ is as indicated at the outset, and X is a hydroxy group, a halogen atom or an arbitrary acyloxy residue, with a 1,1-dihalogenethylene in sulfuric acid, and the intermediate product is hydrolyzed by the addition of water, or,b) A compound of the general formula III, where R and B are as above, and A means the group or is reduced, or c) For the preparation of a compound of the general formula I where B means a hydroxy or alkoxy group, a compound is reduced else with the general formula III where R 1 and B are as above, and A means the group or d) For the preparation of a compound with the general formula I where B means a hydroxy group, react a compound with the general formula IIa where R 1 has the meanings given above, and Hal means a halogen atom, with an alkali salt or an alkoxymagnesium salt of a malonic acid ester, and the malonic acid ester obtained with the general formula IV where R, have the meanings indicated at the beginning, and the residues Rc mean lower alkyl residues, saponified to the free acid and then decarboxylated to an acid with the general formula I during cleavage of etmoyl carbonoxide resp. a compound of the general formula IV where R^ is as indicated above and R,, means an alkyl residue is decarboxylated directly in dipolar aprotic solvents in the presence of salts at temperatures between 130° and 190°C to compounds of the general formula I where B represents an alkoxy group, or e) For the preparation of compounds of the general formula I where the radical B means a hydroxy group. saponified 3-(4-biphenylyl)-butyro-. nitriles of the general formula V where R has the meanings given above, in the presence of a base or acid at temperatures between 100° and 200°C, resp. for the preparation of the same compounds with the general formula I, butyronitriles with the general formula Va are saponified and decarboxylated where R^ is as above and Q means a cyano- or carboxamide group or a carboxy group, which may optionally be esterified with an aliphatic or araliphatic alcohol or a phenol, resp. nitriles of the general formula V d where R^ and Q are as indicated above, are reduced, saponified and decarboxylated, resp., for preparation with the general formula I where B means a free amino group, a nitrile with the general formula V is partially saponified, or f) For the preparation of compounds of the general formula I where B means a hydroxy group, carbinols are oxidized with it general formula VI where R-^ is as above.jangited, or' g) For the preparation of compound: with the general formula I where B means a hydroxy group, a Grignard compound is reacted with the general formula VII where R^ is as above and Hal means a halogen atom, with carbon dioxide in a solvent, or h) For the preparation of compounds with the general formula I where B means a hydroxy or alkoxy group, solvolytically split a connection with the general formula VIII where R^ is as indicated above and Y means a divalent, saturated, 2- or a 3-membered hydrocarbon residue, which may optionally be substituted with further alkyl groups, in an alcohol or in water in the presence of a mineral acid, whereby when an alcohol is used, a compound of the general formula I is formed where B means the corresponding alkoxy group, while when water is used, a compound of the general formula I is formed, where B means a hydroxy group, or | i) For the preparation of compounds with the general formula-.. I where the residue B is a tertiary alkoxy group, react with a halide ^ with the general formula II a where is as above and Hal means a halogen atom, with a. metal-bound acetic acid tert-alkyl ester of the general formula. IX where Me means a lithium or sodium atom, and tert.alkyl means a tertiary alkyl residue with 4 to 10 carbon atoms, and if it is desired to form a compound of the general formula I in which the residue B is a hydroxy group, the product thus obtained is subjected to pyrolysis by temperatures between 150° and 250°C, or j) For the preparation of compounds of the general formula I where B means a hydroxy group, ketene thioacetals are hydrolyzed with the general formula X where R., is as indicated above and the residues RQ and R_ mean lower alkyl residues which may be the same or different or together with the group can form a 5-, 6- or 7-membered ring, which may optionally be interrupted by an additional sulfur atom, or k) For the preparation of compounds with the general formula I where B means a hydroxy or alkoxy group, compounds with the general formula XII where is as stated above and R^ means a hydrogen atom or an alkyl residue, preferably a methyl, ethyl or propyl residue, or 1) For the preparation of compounds of the general formula I where the radical B means a hydroxy group, an alkoxy group or a primary amino group, a diazoketone of the general formula XIII is rearranged where R^ is as indicated above, in the presence of water to the corresponding carboxylic acid, in the presence of alcohols to the corresponding esters, or in the presence of ammonia to the corresponding amides of the general formula I, or . m) For the preparation of compounds of the general formula I where B means a hydroxy group,' an alkoxy or aralkoxy radical, is reacted a compound of the general formula IIa where R 2 has the meaning given above and Hal means a halogen atom, first with an alkali salt of an acetoacetic acid ester to a compound with the general formula XIV where the radical R_ means an alkyl or aralkyl radical, in a solvent part, and then the β-keto carboxylic acid ester of the general formula XIV is cleaved by means of strong alkalis, or n) For the preparation of compounds with the general formula I where B means a hydroxy, alkoxy or aralcatosy group, react a connection with the general formula IIa where R 2 is as above, and Hal means a halogen atom, with a compound of the general formula XV where the residue R 1 denotes an alkyl or aralkyl group, first to a compound of the general formula XVI where R- and R^ have the meanings given above, by heating in an anhydrous, inert solvent1, and then the formed compound of the general formula XVI is heated either with a strong base whereby, after acidification, a compound of the general ffo rm < &> Y~ <T> j-where the radical B means a hydroxy group, or is heated with water whereby a compound of the general formula I is formed where B means an alkoxy or aralkoxy radical, depending on which of these meanings the radical R? in connection with the general formula XV had, or o) For the preparation of compounds with the general formula I where B means a hydroxy group, an aldehyde is oxidized with the general formula XXXII where R^ is as stated above, and the racemates obtained are optionally split into both of their optically active individual components by fractional crystallization of the salts with optically active bases, and optionally saponified compounds obtained with the general formula I where B means an alkoxy group, into compounds with it. general formula I where B means a hydroxy group, and optionally, obtained compounds with the general formula I where B means a hydroxy group are transferred in a manner known per se to the esters or salts thereof with inorganic or organic bases, or optionally for the production of compounds with the general formula I where B means an amino residue, reacts a compound with the general formula I where B means an alkoxy group or a halogen atom, with ammonia at an elevated temperature. 2. Method as stated in claim 1 for the production of 3-(2-fluoro-4-biphenylyl)-butyric acid, characterized in that starting materials are used where means fluorine and B, when present, means hydroxyl or is converted thereto. 3. Process as stated in claim 1 for the production of 3-(2-fluoro-4-biphenylyl)-butyric acid ethyl ester, characterized in that starting materials are used where R^' means fluorine and B, when present, means ethoxy or is converted thereto .